Clinical trial NCT03371251
Conditions: Systemic Lupus Erythematosus
Keywords: Adults BOS161721 standard of care moderately to severely active Systemic Lupus Erythematosus
Sponsor: Boston Pharmaceuticals
Start date: 2018-01-10; Completion date: 2020-11-26
Enrollment: 143 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to assess the safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20 milligrams \[mg\], 60 mg, and 120 mg) administered subcutaneously in adult participants with moderately to severely active Systemic Lupus Erythematosus (SLE) on limited background standard of care treatment, in order to estimate the optimal dose.

BOS161721 at the chosen dose will be compared to placebo for response on the SLE Responder Index 4, with sustained reduction of oral corticosteroids, in the same participant population.

Detailed description:

Arms: arm 1: Participants will be randomized to receive a 20 milligram (mg), 60 mg, or 120 mg subcutaneous (SC) dose of BOS161721. Participants may receive a total of 7 SC monthly doses of BOS161721 on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270. arm 2: Participants will be randomized to receive a 20 mg, 60 mg, or 120 mg SC dose of placebo. Participants may receive a total of 7 SC monthly doses of placebo on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270. arm 3: Participants will be randomized to receive a 120 mg SC dose of BOS161721 (as determined from Phase 1b of the study). Participants may receive a total of 7 SC monthly doses of BOS161721 on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270. arm 4: Participants will be randomized to receive a 120 mg SC dose of placebo (as determined from Phase 1b of the study). Participants may receive a total of 7 SC monthly doses of placebo on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits on at Days 210, 240, and 270.
Interventions: intervention 1: BOS161721 intervention 2: Placebo
Intervention descriptions: intervention 1: SC administration intervention 2: SC administration

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
BOS161721-02: A Randomized Double-Blind Phase 1b/2 Combined Staggered 
Multiple Dose Escalation Study of BOS161721 In Systemic Lupus 
Erythematosus (SLE) Patients on a Background of Limited Standard of Care 
 
ClinicalTrials.gov Identifier: NCT03371251  
 
Final Protocol, Version 7.0 (Amendment 6), dated 30-April-2020 
Final Protocol, Version 6.0 (Amendment 5), dated 23-July-2019 
Final Protocol, Version 5.0 (Amendment 4), dated 23-January-2019 
Final Protocol, Version 4.0 (Amendment 3), dated 27-July-2018 
Final Protocol, Version 3.0 (Amendment 2), dated 21-March-2018 
Final Protocol, Version 2.0 (Amendment 1), dated 08-November-2017 
Final Protocol, Version 1.0, dated 06-October-2017 
 


BOS161721 
Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
Page 1 of 130 
 
A RANDOMIZED DOUBLE-BLIND PHASE 1B/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF 
BOS161721 IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 
PATIENTS ON A BACKGROUND OF 
LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc.  
55 Cambridge Parkway, Suite 400 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721 
PROTOCOL NUMBER: 
BOS161721-02 
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
06 October 2017 
VERSION NUMBER: 
V7.0 (Amendment 6) 
VERSION DATE: 
30 April 2020 
 


BOS161721 
Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
Page 2 of 130 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose 
Escalation Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background 
of Limited Standard of Care.  
Study Number: BOS161721-02 
Version 
Date 
Original Protocol 
06 October 2017 
Protocol Version 2.0 (Amendment 1) 
14 November 2017 
Protocol Version 3.0 (Amendment 2) 
21 March 2018 
Protocol Version 4.0 (Amendment 3) 
27 July 2018 
Protocol Version 5.0 (Amendment 4) 
23 January 2019 
Protocol Version 6.0 (Amendment 5) 
23 July 2019 
Protocol Version 7.0 (Amendment 6) 
30 April 2020 
This study protocol was subject to critical review and has been approved by the 
sponsor. The information contained in this protocol is consistent with: 
 The current risk-benefit evaluation of the investigational product 
 The moral, ethical and scientific principles governing clinical research as set out in 
the Declaration of Helsinki (Appendix 2), and principles of Good Clinical Practices 
(GCP) as described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 
312 and according to applicable local requirements 
The Investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product.  
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature and Date 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
 
, MD 
Vice President 
Clinical Development  
Boston Pharmaceuticals 
 
PPD
PPD
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
Page 3 of 130 
Name and Title 
Signature and Date 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
 
BOS161721-02 
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose 
Escalation Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients 
on a Background of Limited Standard of Care.  
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
Page 4 of 130 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to 
BOS161721 are the confidential and proprietary information of Boston Pharmaceuticals, 
Inc., and except as may be required by federal, state, or local laws or regulation, may 
not be disclosed to others without prior written permission of Boston Pharmaceuticals, 
Inc.  
I have read the protocol (Version 7.0, dated 30 April 2020), including all appendices, 
and I agree that it contains all of the necessary information for me and my staff to 
conduct this study as described. I will conduct this study as outlined herein, in 
accordance with the regulations stated in the Federal Code of Regulations for Good 
Clinical Practices and International Council for Harmonisation (ICH) guidelines, and will 
make a reasonable effort to complete the study within the time designated.  
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., 
or specified designees. I will discuss the material with them to ensure that they are fully 
informed about BOS161721 and the study.  
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
___________ 
___________ 
Date  
 
Site Number 


BOS161721 
Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
Page 5 of 130 
PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered 
Multiple Dose Escalation Study of BOS161721 in Systemic Lupus 
Erythematosus (SLE) Patients on a Background of Limited Standard 
of Care.  
Indication 
Adults with moderately to severely active SLE 
Background 
and 
Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course. There is 
evidence that B- and T-cells are critical to the development of the 
disease, and that T-cell-derived cytokines such as interleukin-21 
(IL-21) are involved in the SLE-associated inflammatory pathological 
response.  
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple 
mutation monoclonal antibody (mAb) intended to have an extended 
terminal elimination half-life (t½) that selectively binds to and 
neutralizes IL-21, which acts on multiple cell types that drive 
inflammation and autoimmunity. In vivo, BOS161721 inhibits T-cell 
dependent antigen responses of B-cells and is being developed as a 
potential treatment for adults with moderately to severely active SLE.  
Nonclinical studies have evaluated the toxicity, pharmacodynamics 
(PD), toxicokinetics (TK), pharmacokinetics (PK), and 
immunogenicity of BOS161721 administered intravenously (IV) and 
subcutaneously (SC). The no observed adverse effect level 
(NOAEL) in Cynomolgus monkeys was determined to be 100 mg/kg 
(SC and IV), the highest dose tested. There were no injection site 
reactions in animals dosed subcutaneously.  
In a phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects. 
This double-blind, placebo-controlled study evaluated 8 ascending 
dose levels (1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 
120 [SC], or 240 [SC] mg) for safety, tolerability, PK, PD and 
immunogenicity. Overall, there were no clinically significant safety or 
tolerability findings from this study.  
Results from the phase 1 SAD study informed the dose regimens 
used for the multiple ascending doses (MAD) phase 1b portion of 
this trial. The MAD portion will involve 3 cohorts. The phase 2 
portion will be a proof of concept (POC) part, where dose selection 
will be based on the data monitoring committee (DMC) and 
sponsor’s assessment of safety, tolerability, immunogenicity, and PK 
and PD data from the MAD portion of 30 patients treated with 
BOS161721/placebo. The purpose of the study is to establish a safe 
and effective dosage for adult patients with moderately to severely 
active SLE.  


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Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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Objectives 
and 
Endpoints: 
MAD Phase 1b 
OBJECTIVES 
ENDPOINTS 
Primary 
 To assess safety, 
tolerability, and 
immunogenicity of repeat 
doses of BOS161721 (20, 
60, and 120 mg) 
administered SC in adult 
patients with moderately 
to severely active SLE on 
limited background 
standard of care 
treatment, in order to 
estimate the optimal dose 
Safety Endpoints 
 Incidence and severity of 
adverse events (AEs) and 
serious adverse events (SAEs), 
related AEs, AEs leading to 
study drug discontinuation, AEs 
by severity and relatedness 
 Injection site reactions 
 Columbia Suicide Severity 
Rating Scale (C-SSRS) 
 12-lead electrocardiograms 
(ECGs) parameter results at 
each visit and change from 
baseline 
 Vital signs (blood pressure 
[BP], heart rate, and 
temperature) parameter results 
at each visit and change from 
baseline 
 Clinical laboratory results and 
change from baseline 
 Physical examinations changes 
from baseline 
 Anti-drug antibodies (ADAs) 
 Study drug 
exposure/compliance 
 


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Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
Confidential 
 
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Secondary 
 To characterize the PK of 
BOS161721 and select 
the optimal dose of 
BOS161721 based on 
safety, PK, and PD 
effects in patients with 
moderately to severely 
active SLE 
Pharmacokinetic Endpoints 
 BOS161721 concentration by 
visit and time point 
 Maximum observed 
concentration (Cmax), first time 
to maximum concentration 
(Tmax), area under the 
concentration-time curve 
(AUC), t½, systematic 
clearance (CL), volume of 
distribution (Vd) 
Pharmacodynamic Endpoints 
 Results and changes (or shifts) 
from baseline to each visit in 
phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3), C3 
and C4 levels, and leukocyte 
immunophenotype 
 Results and changes (or shifts) 
from baseline in anti-double-
stranded DNA (dsDNA), 
antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B 
(SSA, SSB), Smith (Sm), and 
antiphospholipid (APL) 
autoantibodies at each visit 
 Results and changes (or shifts) 
from baseline in abrogation of 
IL-21 gene signature at each 
indicated visit 
Exploratory 
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Protocol Date and Version: 30 April 2020; V7.0 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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POC Phase 2 
OBJECTIVES 
ENDPOINTS 
Primary 
 To demonstrate a 
superior effect of 
BOS161721 at the 
chosen dose compared 
with placebo for 
response on the SLE 
Responder Index 4 
(SRI-4) 
Primary Efficacy Endpoint 
 The proportion of patients with 
a SRI-4 response at Day 210 
(see Section 6.3.4.1) 
 
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Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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Secondary 
 To demonstrate a 
superior effect of 
BOS161721 at the 
chosen dose compared 
with placebo for 
response on clinical 
indicators of SLE activity, 
in adult patients with 
moderately to severely 
active SLE on limited 
background standard of 
care treatment 
Secondary Efficacy Endpoints 
 The proportion of patients with: 
- SRI-4 response at each 
visit 
- SRI-5 and SRI-6 response 
at each visit 
(Section 6.3.4.2) 
- a sustained reduction from 
baseline of oral 
corticosteroid (CS) 
( ≤ 7.5 mg/day and < Day 0 
dose) between Day 150 
and Day 210 
- new or recurrent BILAG 
flares ( ≥ 1 qualifying 
BILAG A or > 1 qualifying 
BILAG B) through Day 210 
- PGA worsening 
- a BICLA response 
- a CLASI response 
- medication failures 
 Changes and percent changes 
from baseline in: 
- CLASI 
- PGA 
- Total number of swollen 
joints, tender joints, and 
active joints (swelling and 
tenderness in the same 
joint) in the ACR-28 joint 
count 
- SLEDAI-2K 
- SLICC/ACR damage index 
 Time to medication failure 
 Group mean percent reduction 
in corticosteroid administration 
from baseline Day 0 dose 
through Day 210 in patients 
receiving ≥ 7.5 mg/day 
prednisone equivalent at Day 0 
 Duration of longest SRI-4 
response 


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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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 Time to first BILAG flare ( ≥ 1 
new or recurrent BILAG A 
or > 1 new or recurrent 
BILAG B) relative to baseline 
through Day 210 
Safety 
 To assess safety and 
tolerability of repeat 
doses of BOS161721 at 
the chosen dose 
administered SC in adult 
patients with moderately 
to severely active SLE on 
limited background 
standard of care 
treatment 
Safety Endpoints 
 Incidence and severity of 
adverse events (AEs) and 
serious adverse events 
(SAEs), related AEs, AEs 
leading to study drug 
discontinuation, AEs by 
severity and relatedness 
 Injection site reactions 
 C-SSRS 
 12-lead ECGs parameter 
results at each visit and 
change from baseline 
 Vital signs (blood pressure 
[BP], heart rate, and 
temperature) parameter results 
at each visit and change from 
baseline 
 Clinical laboratory results and 
change from baseline 
 Physical examinations changes 
from baseline 
 ADAs 
 Study drug 
exposure/compliance 
Exploratory 
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Boston Pharmaceuticals, Inc 
Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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Study 
Design: 
This is a phase 1b/2 combined, randomized, multicenter, 
double-blind, placebo-controlled trial to study the clinical efficacy, 
safety, and PK of multiple SC doses of BOS161721 in adult patients 
with moderately to severely active SLE. After successfully 
completing a screening phase, eligible patients will be randomized 
to a specified dose of BOS161721 or placebo. The dosing schedule 
will be monthly. The trial will consist of 2 double-blinded portions: 
MAD phase 1b and POC phase 2. Patients may receive a total of 
7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, 
and 180, followed by safety follow-up visits at Days 210, 240, and 
270.  
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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The MAD phase 1b portion of the study design will consist of 
3 cohorts, with Cohort 1 containing 6 patients, where 5 of these 
patients will receive BOS161721 (active), and 1 will receive placebo. 
Cohorts 2 and 3 will each contain 12 patients, including 9 active and 
3 placebo patients. Dose selection for each cohort is based on 90 
day safety, tolerability, PK, and PD data review from the phase 1 
SAD study (BOS161721-01) in healthy subjects. Each of the 
3 doses (20, 60, and 120 mg) selected for the MAD portion are 
projected not to exceed the mean exposure of that achieved in the 
SAD study following the single 240 mg SC dose. Each patient may 
receive a total of 7 SC monthly doses on Days 0, 30, 60, 90, 120, 
150, and 180.  
The MAD portion design is staggered, where after the 6 patients in 
Cohort 1 have received 2 doses and have completed 2 weeks of 
follow-up after the second dose, Cohort 2 begins dosing (after the 
DMC evaluates the safety and tolerability data from Cohort 1). 
Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow-up after the second 
dose, Cohort 3 begins dosing after the DMC evaluation of the safety 
and tolerability data from Cohort 2 and Cohort 1. Thirty days after 
the last patient in Cohort 3 receives the third dose, the DMC and 
Boston Pharmaceuticals will conduct a data review to determine 
which dose will be carried forward into the POC part of the study. 
This dose will not exceed doses tested during the MAD portion.  
For the POC portion, approximately 110 additional patients will be 
randomized to active or placebo groups in a 2:1 ratio. As in the MAD 
portion, each patient in the POC portion may receive a total of 7 SC 
monthly doses on Days 0, 30, 60, 90, 120, 150, and 180.  
A maximum stable (for at least 6 weeks prior to Day 0) daily dose of 
30 mg/day of oral CS will be acceptable for eligibility for the study. 
One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 120. Tapering of steroids 
during the course of the study will be highly encouraged and should 
be evaluated during the protocol-allowed tapering windows (Day 0 
through Day 150) with the target of achieving a CS daily dose 
of ≤ 7.5 mg and < Day 0 dose between Day 150 and Day 210. 
Between Day 150 and Day 210, oral CS doses must be held 
constant due to the Day 210 endpoint evaluations.  
DMC safety reviews will be conducted periodically throughout the 
study as described in the DMC charter.  
Main Criteria 
for Inclusion 
and 
Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive 


BOS161721 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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2. Patients must be mentally capable of giving consent and there 
must be evidence of a personally signed and dated informed 
consent document indicating that the patient has been informed 
of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the 
Systemic Lupus International Collaborating Clinics (SLICC) 
classification criteria for SLE (with at least 1 clinical and 
1 immunologic criterion OR Lupus nephritis as the sole clinical 
criterion in the presence of antinuclear antibodies [ANA] or 
anti-double-stranded deoxyribonucleic acid [dsDNA] 
antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the 
central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal 
level as determined by the central laboratory 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
Note: Points from lupus headache and organic brain syndrome will 
also be excluded from qualifying total and clinical SLEDAI-2K scores 
at screening and Day 0.  
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0. Clinical 
SLEDAI-2K score is defined as follows: 
a. Contains points from arthritis, rash, myositis, mucosal ulcers, 
pleurisy, pericarditis, or vasculitis 
b. Excludes parameters which require central laboratory results: 
hematuria, pyuria, urinary casts, proteinuria, positive anti-
dsDNA, decreased complement, thrombocytopenia, and 
leukopenia 
Note: Points from lupus headache and organic brain syndrome will 
also be excluded from qualifying total and clinical SLEDAI-2K scores 
at screening and Day 0.  
7. Patients must have at least 1 qualifying A or 2Bs from the 
following manifestations of SLE, as defined by the BILAG 
criteria as modified for use in this study, which must be 
confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system. If a 
BILAG B score is due to BILAG number 6, mild skin eruption, 
the CLASI activity score including erythema and 
scale/hypertrophy must be ≥ 3 excluding points from mucosal 
ulcers and alopecia 
b. BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis as defined in the protocol Section 4.4 


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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7.0 
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Note: Hips, shoulders, back, neck, and temporomandibular joints do 
not count towards the total number of joints with active synovitis.  
If only one “B” and no “A” score is present in the mucocutaneous 
body system or in the musculoskeletal body system due to arthritis, 
then at least 1 “B” must be present in at least 1 other body system 
for a total of 2 “B” BILAG body system scores.  
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose 
for at least 56 days (8 weeks prior to Day 0) of the following 
permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or 
mycophenolic acid, chloroquine, hydroxychloroquine, 
or methotrexate (MTX) 
b. If AZA, myocophenolate mofetil, mycophenolic acid, 
hydroxychloroquine, or MTX were discontinued prior to 
screening, the washout period must be ≥ 12 weeks 
c. Corticosteroids (prednisone or prednisone-equivalent) at a 
stable dose of up to 30 mg/day for at least 6 weeks prior to 
Day 0 (see Appendix 3) 
i. 
For patients whose only SLE treatment is CSs, the 
stable CS dose must be ≥ 10 mg/day for at least 
6 weeks prior to Day 0 and no more than 30 mg/day at 
the time of randomization 
ii. 
Topical steroids may be used, but the dose must be 
stable for at least 6 weeks prior to Day 0. PRN topical 
steroids are not permitted 
9. Women of childbearing potential (WOCBP; see Section 4.7 for 
full information regarding WOCBP, definition of menopause, 
and contraception): 
a. Must have a negative serum pregnancy test at screening. 
Urine pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug 
plus 52 weeks 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks 
11. Patients must demonstrate willingness and ability to comply with 
the scheduled study visits, treatment plans, laboratory tests, 
and other procedures 
Exclusion Criteria: 
Patients presenting with any of the following will not be included in 
this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 


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Clinical Study Protocol: BOS161721-02 
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2. Other systemic autoimmune disease (e.g., erosive arthritis, 
rheumatoid arthritis [RA], multiple sclerosis [MS], systemic 
sclerosis, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome 
are allowed 
3. Any major surgery within 6 weeks of study drug administration, 
(Day 0), or any elective surgery planned during the course of the 
study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active 
TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON®-TB Gold 
In-Tube (QFT-G) or other diagnostic test in the absence of 
clinical manifestations. Latent TB is not excluded if the patient 
has documented completion of adequate course of 
prophylactic treatment with regimen recommended by local 
health authority guideline, or the patient has started treatment 
with isoniazid, or other regimen recommended by local health 
authority guidelines for at least 1 month before Day 0 and 
continues to receive the prophylactic treatment during study 
until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, 
including but not limited to any condition defined by BILAG A 
criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed.  
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which 
requires or may require induction treatment with cytotoxic agents 
or high dose CS.  
7. Concomitant illness that, in the opinion of the Investigator or the 
sponsor or their designee, is likely to require additional systemic 
glucocorticosteroid therapy during the study, (e.g., asthma), is 
exclusionary.  
a. However, treatment for asthma with inhalational CS therapy 
is allowed 
8. Use or planned use of concomitant medication outside of 
standard of baseline treatment for SLE from Day -1 or for any 
time during the study.  
9. Active and clinically significant infection (bacterial, fungal, viral, 
or other) within 60 days prior to first dose of study drug. Clinically 
significant is defined as requiring systemic parenteral antibiotics 
or hospitalization.  
10. A history of opportunistic infection, or a history of recurrent or 
severe disseminated herpes zoster or disseminated herpes 
simplex within the last 3 years.  


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11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C 
(HCV) unless patient received curative treatment for HCV and 
has a documented negative viral load, known human 
immunodeficiency virus (HIV), or acquired immunodeficiency 
syndrome (AIDS)-related illness.  
12. Cryptosporidium in the stool sample at screening.  
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening.  
14. Absolute neutrophil count (ANC) < 500/mm3 at screening.  
15. CD4+ count < 150/µL at screening.  
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/mm3 
(35 × 109/L) if related to SLE, at screening.  
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE.  
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent 
level of proteinuria as assessed by protein/creatinine ratio 
(3 mg/mg or 339 mg/mmol).  
19. Serum creatinine > 2.0 mg/dL at screening or creatinine 
clearance (CrCL) < 40 mL/minute based on Cockcroft-Gault 
calculation.  
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the 
Investigator’s judgment.  
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related 
to lupus myositis.  
22. Total bilirubin > 1.5 × ULN at screening (unless related to 
Gilbert’s syndrome).  
23. Any other laboratory test results that, in the opinion of the 
Investigator or the sponsor or sponsor’s designee, might place a 
patient at unacceptable risk for participating in this study.  
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (e.g., IgG protein) or molecules made of 
components of mAbs.  
25. History substance and/or alcohol abuse, or dependence within 
the past 1 year, at the Investigator’s judgment.  
26. History of cancer within the last 5 years (except for cutaneous 
basal cell or squamous cell cancer, or cervical cancer in situ 
resolved by excision).  
27. Any other severe acute or chronic medical or psychiatric 
condition, including recent (within the past year) medical 
conditions (e.g., cardiovascular conditions, respiratory illnesses) 
that may increase the risk associated with study participation or 
investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the 
Investigator, sponsor or sponsor’s designee, would make the 
patient inappropriate for entry into this study.  


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28. Investigational site staff members directly involved in the conduct 
of the trial and their family members, site staff members 
otherwise supervised by the Investigator, or patients who are 
employees of the sponsor or directly involved in the conduct of 
the trial.  
29. Currently participating in, or who have participated in other 
interventional (drug or device) clinical study within 30 days or 
5 half-lives of baseline, whichever is longer.  
30. Recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 
on the C-SSRS.  
31. Current or pending incarceration.  
32. Current or pending compulsory detainment for treatment of either 
a psychiatric or physical (e.g., infectious disease) illness.  
33. Currently taking a total daily dose of > 30 mg morphine or 
morphine equivalent (see Appendix 7).  
34. Body mass index (BMI) ≥ 40.0.  
Statistical 
Consideratio
ns 
Below is a summary of the statistical methods. Further details can 
be found in Section 8.  
Two analyses are planned: 1) an interim analysis to select the POC 
dose based on the MAD data; and 2) a final analysis at study 
completion. Additionally, DMC safety analyses will be performed for 
each MAD cohort and throughout the POC to monitor patient safety 
as described in the DMC charter. An additional analysis may be 
performed for the MAD portion of the study when all MAD patients 
have completed the safety follow-up, or withdrawn from the study, 
and prior to the final analysis. Data from the POC part of the study 
will be excluded from this additional analysis.  
Unless stated otherwise, statistical testing will only be performed on 
the POC data and will be done using 2-sided overall alpha of 0.10. 
Data will be summarized descriptively by treatment and overall for 
each study phase. For the MAD portion, BOS161721 will be 
summarized overall and by each dose level and placebo patients 
from each cohort will be combined.  
The descriptive summaries for the categorical data will include 
number and percentage. The descriptive summaries for the 
continuous data will include number, mean, median, standard 
deviations (SD), 25th and 75th percentiles, minimum, median, and 
maximum. Counts, medians, 25th and 75th percentiles, and standard 
error will be presented for time-to-event data.  


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All safety analyses will be performed using the safety analysis set 
(SS), defined as all patients who receive at least 1 dose of study 
treatment. All efficacy analyses will be performed using the full 
analysis set (FAS), defined as all patients who receive at least 
1 dose of study treatment and have at least 1 evaluable post-
baseline efficacy evaluation. Select efficacy analyses may also be 
performed on the per protocol (PP) set.  
Binary efficacy endpoints, including the primary efficacy endpoint, 
will be assessed via Pearson’s chi-squared analysis.  
Continuous efficacy endpoints will be assessed via analysis of 
variance (ANOVA) or analysis of covariance (ANCOVA) when 
applicable, adjusting for the baseline value. Repeated measures 
mixed models may be performed to evaluate data collected at each 
visit and overall. Time-to-event endpoints will be assessed via 
Kaplan-Meier methodology and treatment will be compared using 
the log-rank test.  
Adverse event data will be coded to system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of patients experiencing 
any treatment-emergent AE, overall, and by system organ class and 
preferred term will be tabulated. Treatment-emergent AEs will also 
be summarized by severity and relationship.  
Concomitant medications will be summarized, based on coded 
terms, using frequency and percentage of patients. Observed values 
and changes from baseline in vital signs, ECG readings, and 
hematology and clinical chemistry parameters, will be summarized 
at each individual visit.  


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TABLE OF CONTENTS 
A RANDOMIZED DOUBLE-BLIND PHASE 1B/2 COMBINED STAGGERED 
MULTIPLE DOSE ESCALATION STUDY OF BOS161721 IN SYSTEMIC 
LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A BACKGROUND OF 
LIMITED STANDARD OF CARE ............................................................................. 1 
CLINICAL PROTOCOL APPROVAL FORM ................................................................... 2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ............................................. 4 
PROTOCOL SUMMARY ................................................................................................ 5 
TABLE OF CONTENTS ................................................................................................ 20 
LIST OF IN-TEXT TABLES ........................................................................................... 23 
LIST OF IN-TEXT FIGURES ......................................................................................... 24 
LIST OF ABBREVIATIONS ........................................................................................... 25 
1 
INTRODUCTION AND RATIONALE ...................................................................... 29 
1.1 
Indication ............................................................................................................ 29 
1.2 
Background and Rationale ................................................................................. 29 
1.2.1 
Overview of the Disease State ...................................................................... 29 
1.2.2 
BOS161721 Development............................................................................. 29 
1.2.2.1 
Interleukin-21 ........................................................................................... 30 
1.2.2.2 
Preclinical Studies ................................................................................... 31 
1.2.2.3 
Clinical Studies ........................................................................................ 33 
1.2.3 
Study Dose Selection .................................................................................... 33 
1.2.4 
Risk-Benefit Assessment .............................................................................. 35 
1.2.5 
Potential Risks .............................................................................................. 35 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions ............................................ 36 
1.2.5.2 
Injection Site Reactions ........................................................................... 36 
1.2.5.3 
Immune Complex Disease ....................................................................... 37 
1.2.5.4 
Infections ................................................................................................. 37 
1.2.5.5 
Malignancy ............................................................................................... 38 
1.2.5.6 
Hepatic Function Abnormality .................................................................. 38 
1.2.5.7 
Failure of Vaccination .............................................................................. 39 
1.2.5.8 
Potential for Drug-Drug Interactions ........................................................ 39 
1.2.5.9 
Potential Risk to Fetal Development ........................................................ 39 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 39 
2.1 
Phase 1b Multiple Ascending Dose .................................................................... 40 
2.2 
Phase 2 Proof of Concept .................................................................................. 41 
3 
STUDY PLAN ......................................................................................................... 43 
3.1 
Study Design ...................................................................................................... 43 
3.1.1 
Multiple Ascending Dose Phase 1b ............................................................... 43 
3.1.1.1 
Dose Escalation for the MAD Portion....................................................... 44 
3.1.1.2 
Dose Limiting Toxicity (DLT) .................................................................... 44 


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3.1.1.3 
DMC Recommendations .......................................................................... 45 
3.1.2 
POC Phase 2 ................................................................................................ 45 
3.1.2.1 
BOS161721 POC Dose Selection and Justification ................................. 45 
3.1.2.2 
POC Study Design ................................................................................... 46 
3.2 
Randomization and Blinding ............................................................................... 46 
3.3 
Study Schematic ................................................................................................. 48 
3.4 
Schedule of Assessments .................................................................................. 49 
3.5 
End of Study ....................................................................................................... 54 
4 
POPULATION ......................................................................................................... 54 
4.1 
Participant Recruitment ...................................................................................... 54 
4.2 
Number of Patients ............................................................................................. 54 
4.3 
Patient Screening ............................................................................................... 54 
4.4 
Inclusion Criteria ................................................................................................. 54 
4.5 
Exclusion Criteria ................................................................................................ 57 
4.6 
Concomitant Medications ................................................................................... 59 
4.6.1 
Corticosteroid ................................................................................................ 60 
4.6.2 
Other Prohibited and/or Restricted Treatments ............................................. 61 
4.7 
Women of Childbearing Potential ....................................................................... 61 
4.7.1 
Determination of Menopause ........................................................................ 62 
4.7.2 
Contraception ................................................................................................ 62 
4.8 
Deviation from Inclusion/Exclusion Criteria ........................................................ 63 
4.8.1 
Patient Withdrawal and Replacement ........................................................... 63 
5 
STUDY PROCEDURES ......................................................................................... 63 
5.1 
Screening ........................................................................................................... 63 
5.1.1 
Retesting During Screening Period ............................................................... 64 
5.2 
Enrollment/Randomization and Day 0 Treatment ............................................... 65 
5.3 
Treatment Period/Follow-Up Visits ..................................................................... 66 
5.4 
Safety Follow-Up Visits ....................................................................................... 67 
5.5 
Premature Discontinuation ................................................................................. 67 
5.6 
Contingency Plans During the COVID-19 Pandemic .......................................... 68 
6 
ASSESSMENTS ..................................................................................................... 69 
6.1 
Medical History, Demographic and Other Baseline Information ......................... 69 
6.2 
Safety Assessments ........................................................................................... 69 
6.2.1 
Laboratory Assessments ............................................................................... 69 
6.2.1.1 
Pregnancy testing .................................................................................... 71 
6.2.1.2 
Tuberculosis Screening ........................................................................... 71 
6.2.2 
Adverse Events ............................................................................................. 72 
6.2.2.1 
Definitions ................................................................................................ 72 
6.2.2.2 
Recording of Adverse Events .................................................................. 72 
6.2.2.3 
Severity of Adverse Events ...................................................................... 73 
6.2.2.4 
Causality of Adverse Events .................................................................... 73 


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6.2.2.5 
Seriousness of Adverse Events ............................................................... 74 
6.2.2.6 
Adverse Events of Special Interest .......................................................... 74 
6.2.2.7 
Reporting of Adverse Events ................................................................... 77 
6.2.2.8 
Follow Up of Adverse Events ................................................................... 79 
6.2.3 
Vital Signs ..................................................................................................... 80 
6.2.4 
12-Lead Electrocardiograms ......................................................................... 80 
6.2.5 
Physical Examinations .................................................................................. 80 
6.2.6 
C-SSRS......................................................................................................... 80 
6.2.7 
Injection Site Reactions ................................................................................. 81 
6.2.8 
Immunogenicity ............................................................................................. 81 
6.3 
Efficacy Assessments ......................................................................................... 81 
6.3.1 
SLEDAI-2K .................................................................................................... 81 
6.3.2 
BILAG 2004 ................................................................................................... 82 
6.3.3 
PGA of Disease Activity ................................................................................ 82 
6.3.4 
Composite Endpoints: SRI-4, SRI-5, SRI-6, and BICLA Response .............. 82 
6.3.4.1 
SRI-4 Response ...................................................................................... 82 
6.3.4.2 
SRI-5 and SRI-6 Response ..................................................................... 83 
6.3.4.3 
BICLA Response ..................................................................................... 83 
6.3.5 
CLASI Response ........................................................................................... 83 
6.3.6 
ACR-28 Joint Count ...................................................................................... 83 
6.4 
Other Variables ................................................................................................... 83 
6.4.1 
SLICC/ACR Damage Index ........................................................................... 83 
6.4.2 
PROs ............................................................................................................ 84 
6.5 
Pharmacokinetic Assessments ........................................................................... 84 
6.6 
Pharmacodynamic Assessments ........................................................................ 84 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................. 84 
6.8 
Protocol Deviations ............................................................................................. 85 
7 
STUDY DRUG MANAGEMENT ............................................................................. 85 
7.1 
Description.......................................................................................................... 85 
7.1.1 
Formulation ................................................................................................... 85 
7.1.2 
Storage.......................................................................................................... 85 
7.2 
Packaging and Shipment .................................................................................... 85 
7.3 
Dose and Administration .................................................................................... 85 
7.4 
Accountability ..................................................................................................... 86 
7.5 
Prohibited Concomitant Therapy ........................................................................ 86 
7.6 
Compliance......................................................................................................... 86 
8 
STATISTICS ........................................................................................................... 86 
8.1 
Sample Size ....................................................................................................... 87 
8.2 
Statistical Methods ............................................................................................. 88 
8.2.1 
Analysis Populations ..................................................................................... 88 
8.2.2 
Demographics and Baseline Characteristics ................................................. 88 


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8.2.3 
Primary Efficacy Endpoint(s) ......................................................................... 89 
8.2.4 
Secondary Efficacy Endpoint(s) .................................................................... 89 
8.2.5 
Analysis of Safety .......................................................................................... 89 
8.2.5.1 
Safety Analysis ........................................................................................ 89 
8.2.6 
Pharmacokinetic and Pharmacodynamic Data.............................................. 90 
8.2.6.1 
Analysis of Pharmacokinetic Data ........................................................... 90 
8.2.6.2 
Analysis of Pharmacodynamic Data ........................................................ 90 
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ....................... 90 
8.3 
Interim Analysis and Power ................................................................................ 90 
9 
ETHICS AND RESPONSIBILITIES ........................................................................ 91 
9.1 
Good Clinical Practice ........................................................................................ 91 
9.2 
DMC ................................................................................................................... 91 
9.3 
Institutional Review Board/Independent Ethics Committee ................................ 92 
9.4 
Informed Consent ............................................................................................... 92 
9.5 
Records Management ........................................................................................ 92 
9.6 
Source Documentation ....................................................................................... 93 
9.7 
Study Files and Record Retention ...................................................................... 93 
10 AUDITING AND MONITORING .............................................................................. 94 
11 AMENDMENTS ...................................................................................................... 94 
12 STUDY REPORT AND PUBLICATIONS ................................................................ 95 
13 STUDY DISCONTINUATION ................................................................................. 95 
14 CONFIDENTIALITY ................................................................................................ 95 
15 REFERENCES ....................................................................................................... 96 
16 APPENDICES ....................................................................................................... 100 
16.1 
Appendix 1: Names of Study Personnel ........................................................... 101 
16.2 
Appendix 2: Declaration of Helsinki .................................................................. 102 
16.3 
Appendix 3: Commonly Used Corticosteroid Equivalents ................................. 107 
16.4 
Appendix 4: Medication Washout Periods ........................................................ 108 
16.5 
Appendix 5: BILAG-2004 (Study-Specific Modified Criteria) ............................. 109 
16.6 
Appendix 6: Injection Site Reaction Grading Scale .......................................... 110 
16.7 
Appendix 7: Opioid Oral Morphine mg Equivalents of Commonly Used 
Opioids ........................................................................................................... 111 
16.8 
Appendix 8: Schedule of Assessments - Phase 1b Multiple Ascending 
Dose ............................................................................................................... 114 
16.9 
Appendix 9: Protocol Summary of Changes ..................................................... 120 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) ................ 49 
Table 2. 
Laboratory Tests ...................................................................................... 70 
Table 3. 
Causality Definitions ................................................................................ 73 


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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose ......... 114 
 
LIST OF IN-TEXT FIGURES 
Figure 1.  
Individual pSTAT3 Cmin Levels Versus Dose ........................................... 34 
Figure 2.  
Study Diagram for MAD Phase 1b and POC Phase 2 ............................. 48 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 


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ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
 
 
FAS 
full analysis set 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
IFNγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
interactive web response system 
CCI


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JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary of Regulatory Activities 
MS 
multiple sclerosis 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PP 
per protocol 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON®-TB Gold In-Tube  
RA 
rheumatoid arthritis 


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RR 
(interval) from the onset of the r-wave to the onset of the next 
consecutive r-wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS  
safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
CCI


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1 INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately 
to severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State 
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in 
multiple organ systems and follows a relapsing and remitting course. The disease 
process includes abnormal immune responses mediated by tissue-binding 
autoantibodies and immune complex deposition, giving rise to tissue damage often 
resulting in end organ disease and even mortality. Survival of SLE has improved due to 
earlier detection, improved overall medical care, and standardized SLE treatment with 
corticosteroids (CS), immunosuppressants, and cytotoxic agents.1 However, some of 
the morbidity in patients with SLE is related to its treatment. Comparison of early and 
late outcomes in patients with SLE demonstrate that death in early disease is most 
commonly due to infections and active SLE causing multi-system organ damage, while 
thromboses were the most common cause of death during later disease.2  
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 
100,000 people.3 More than 90% of cases of SLE occur in women, frequently starting at 
childbearing age. Women of color are disproportionately affected by SLE. This suggests 
multiple genetic and environmental factors are at play. Accordingly, a multifactorial view 
of the immunopathogenesis of SLE suggests more than 1 area of interest, including 
breach in central tolerance in the adaptive arm of the immune system, peripheral 
amplification of the autoimmune response by the innate immune system, and local 
processes in the target organ that facilitate end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE. 
BOS161721 is a humanized immunoglobulin G1 (IgG1) mAb with extended half-life 
directed against human IL-21.  
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse 
hybridoma technology.19E3 has subpicomolar (pM) affinity to human IL-21 and was 
selected for its potent neutralization of IL-21 bioactivity. BOS161721 was generated by 
the humanization of mAb 19E3 where its complementarity-determining regions were 
grafted onto a human IgG1 kappa backbone. The fragment crystallizable (Fc) portion of 
BOS161721 contains a YTE (M252Y/S254T/T256E triple mutation) in the constant 
domain of the IgG1 heavy chain that was introduced into the parental molecule, 19E3, 
intended to prolong the in vivo terminal elimination half-life (t½) of the mAb.5 Thus, 


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BOS161721 retains sub-pM binding to IL-21 and prevents IL-21 from binding to the 
IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.  
BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both. BOS161721 is specific for IL-21 as 
it does not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to 
specifically neutralize the IL-21 pathway. In in vitro studies, BOS161721 inhibited 
downstream IL-21-induced signaling, IL-21-induced plasma cell differentiation, and 
IL-21-induced natural killer (NK) cell activation. In in vivo studies, BOS161721 
significantly inhibited the T-cell dependent antibody response (TDAR) to immunization 
with a protein antigen as well as B-cell expansion following a second protein antigen 
immunization in Cynomolgus monkeys.  
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also 
includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex 
with the common cytokine receptor γc.6 Most cytokines in this family are critically 
important for both the maintenance and function of T-cell and B-cell responses. IL-21 
signals through a receptor complex consisting of its own private receptor, the IL-21R 
and γc.6,7 Engagement of the IL-21R/γc complex leads to the activation of several 
signaling pathways, including the Janus kinase/signal transducer and activator of 
transcription, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase 
pathways.8 IL-21 is produced mainly by T-cells and NK T-cells, but neutrophils have 
also been reported to produce IL-21.9,10 The IL-21R is expressed on a broad array of 
cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, as well 
as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, 
and intestinal epithelial cells.9,11 Activation of signal transducer and activator of 
transcription 3 (STAT3) via phosphorylation is critical in regulating human B-cell 
responses to IL-2112; phosphorylated STAT3 (pSTAT3) forms a homodimer, which 
translocates to the nucleus where it initiates transcription of the IL-21 gene, forming an 
autocrine loop for IL-21 production via STAT3 phosphorylation.13 In addition, IL-21 has 
been shown to upregulate expression of its own receptor14 and induces an autocrine 
feedback loop.15 
IL-21 modulates various aspects of immune function. It promotes cluster of 
differentiation 4 (CD4+) T-cell differentiation and promotes the generation of T-helper 
(Th)1716 and T-follicular helper (Tfh) cells.15,17 In mice, IL-21 has been shown to 
regulate the balance between Th17 and regulatory T-cell (Treg), in that it increases 
Th17, while inhibiting Treg differentiation.18 Less is understood with regards to human 
Tregs, although IL-21 has been reported to counteract Treg suppression of human 
effector T-cells19 and blockade of IL-21 promotes Treg generation in a murine model of 
graft versus host disease induced by human T-cells.20 IL-21 upregulates CD8+ T-cell 
and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22 
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells 
and B-cells resulting in inhibition of T-cell responses.23,24 IL-21 also has a variety of 


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effects on nonhematopoietic cells, such as stromal cells and induces inflammation 
through matrix metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, 
differentiation, or death during humoral immune responses.14 Furthermore, increased 
IL-21 production is characteristic of several autoimmune diseases and is likely to 
contribute to autoantibody production as well as pathologic features of autoimmune 
disease.26 The critical role of IL-21 in promoting humoral and other immune responses 
makes it an important focus of potential therapeutic interventions in conditions 
characterized by overproduction of pathogenic autoantibodies. IL-21 production by Tfh 
cells in humans is believed to play a major role in driving the autoantibody production 
through its role in plasma cell differentiation. Importantly, Tfh cell populations are 
expanded in patients with autoimmune diseases such as lupus, bullous pemphigoid, 
rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29 
Furthermore, loss of number and functionality of Tregs has been associated with 
autoimmune diseases such as SLE and giant cell arteritis, which IL-21 is expected to 
modulate.30,31 Thus, neutralization of IL-21 in settings of autoimmunity is expected to 
impact several cell populations believed to be involved in the pathogenesis of 
autoimmune disorders including SLE.  
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations 
believed to be involved in the pathogenesis of SLE. Importantly, patients with SLE have 
elevated IL-21 plasma levels that correlate with the severity of the disease. Recently, 
genome-wide association studies (GWAS) have provided convincing evidence that the 
chromosomal 4q 27 region harbors the IL-21 genes and is associated with chronic 
inflammatory disorders, including SLE.29  
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose 
intravenous (IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus 
monkeys or repeat, every 2 weeks IV administration (15 to 100 mg/kg) and 
subcutaneous (SC) administration (50 mg/kg) in male and female Cynomolgus 
monkeys. Systemic exposure was approximately dose-proportional within the tested 
dose range. SC bioavailability was determined to be 64.3%. 
 
.  
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in 
Cynomolgus monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics 
(TK), and immunogenicity of BOS161721. Following a single IV administration (slow 
bolus), there were no BOS161721-related adverse changes, resulting in a no-observed-
adverse-effect-level (NOAEL) value of 30 mg/kg, the highest dose tested among 
2 studies. 
 
 
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.  
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was 
administered every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total 
of 7 doses). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. The 
NOAEL was determined to be 100 mg/kg (SC and IV), the highest dose tested.  
An additional GLP, repeat-dose toxicity study was conducted in Cynomolgus monkeys 
(4 males and 4 females per dose group) following every 2 weeks (Q2W) administration 
by SC (10, 30, and 100 mg/kg) injection for a total of 14 doses. 
 
 
 
 
 
 
 There were 
no BOS161721-related effects on survival, clinical signs, male body weights, 
ophthalmologic parameters, electrocardiogram (ECG) findings, clinical pathology, 
macroscopic observations, organ weights, or microscopic observations. 
 
 
 
 
 
 
 
 The 100 mg/kg/dose was 
the NOAEL 
 
 
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1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, phase 1, single ascending dose (SAD) study to 
assess the safety, PK, and PD of BOS161721 in healthy subjects. The primary objective 
of the study was to characterize the safety and tolerability of IV and SC SADs of 
BOS161721 in an otherwise healthy subject population without concomitant illnesses, 
immune abnormalities, or concomitant medications. Secondary objectives included 
characterization of the PK and immunogenicity of BOS161721, and exploratory 
objectives included the evaluation of the effect of BOS161721 on TDAR to keyhole 
limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy subjects, 
the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in 
blood. This study consisted of 8 cohorts. Subjects were randomized in a 3:1 ratio 
(BOS161721: placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 
10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety 
follow-up. For the first cohort, after the first 2 subjects were dosed (1 active and 
1 placebo), there was a minimum gap of 48 hours before the remaining subjects from 
that cohort were dosed, to allow for an initial review of any emerging safety and 
tolerability data. For all cohorts, escalation to the next dose was not sooner than 8 days 
after all the subjects in the prior cohort had been dosed and were based on a review of 
at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).  
Blood samples were collected at every in-house study visit for BOS161721 
concentration determinations. Blood samples were also collected for determination of 
IL-21 plasma levels (free and total). Safety was assessed based on the occurrence of 
treatment-emergent AEs, hepatic function abnormality, and acute and delayed 
hypersensitivity reactions. Other safety variables included ECGs, vital signs (blood 
pressure [BP], heart rate, and temperature), safety laboratory assessments, blood 
sampling for ADAs, total IgG and immunoglobulin M (IgM) levels, CD4+ count, and full 
and targeted physical examinations. Overall, there were no clinically significant findings 
from this study. Adverse events reported as related to the study drug, particularly 
infections, were expected for the compound, and there were no clinically relevant 
changes in laboratory and ECG results or vital signs. There was 1 serious adverse 
event (SAE; death due to pulmonary embolism) that occurred 127 days after a single 
administration of 240 mg SC dose of BOS161721. The causality of this single SAE was 
not attributed to study drug and further information can be found in the Investigator’s 
Brochure. Final PK data from the SAD study demonstrates BOS161721 has a mean t½ 
ranging from 80 to 87 days for doses of ≥ 30 mg in healthy subjects.  
1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) phase 1b portion 
based on a 90 day safety, tolerability, PK, and PD data review from the phase 1 SAD 
study (BOS161721-01); the SDMT reviewed the blinded safety data from subjects for 
each dose cohort (8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 
120 [SC], or 240 [SC] mg), along with the accumulated safety and available PK/PD data 


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from all subjects in the previous dose cohorts, to make a decision on whether to 
proceed to the next higher dose level, repeat a dose level, or stop dose escalation. 
Overall, there were no clinically significant safety or tolerability findings from this study.  
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 
study, the recommended doses for evaluation in the MAD portion of this study are 20, 
60, and 120 mg SC monthly. This dose recommendation is supported by evidence of 
linear PK with BOS161721 resulting in a median first time to maximum concentration 
(Tmax) of 6 days and an apparent terminal half-life of 44 days. Furthermore, pSTAT3 
suppression, a marker of IL-21 target engagement, follows a similar time course of the 
mAb levels, with maximal and sustained suppression apparent with doses greater than 
30 mg SC (Figure 1).  
Figure 1.  Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; 
SC = subcutaneous 
All doses selected for the MAD portion are projected not to exceed the mean exposure 
of that achieved following the highest single dose of 240 mg SC administered in the 
phase 1 SAD study. Cohort 1 will include randomized treatment to the 20 mg dose. 
Based on the staggered study design, the data monitoring committee (DMC) will 
perform a scheduled review of safety data and sequentially consider dose escalation for 
Cohorts 2 and 3. In addition, the DMC and Boston Pharmaceuticals will conduct a data 


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review to determine which dose will be carried forward into the proof of concept (POC) 
phase 2 portion. This POC dose decision will be based on evaluation of the PK, safety 
(inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD portion (see Section 3.1.2.1 
for the chosen POC dose and justification).  
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study 
BOS161721-01, and existing clinical information on IL-21 inhibitors suggest that the 
present clinical study has an acceptable risk-benefit ratio. In this study, the risk-benefit 
assessment of BOS161721 in adult patients with moderately to severely active SLE will 
be ongoing, with step-wise evaluations during the staggered MAD portion. The DMC 
used in this study is charged with assessing such actions in light of an acceptable 
benefit-risk profile for BOS161721 as an anti-IL-21 mAb. Formal DMC monitoring 
meetings will occur as described in the DMC Charter. Two weeks after Cohort 1 has 
received a second dose of study drug, the DMC will evaluate the safety and tolerability 
data from Cohort 1 to determine the recommended dose for Cohort 2. Two weeks after 
8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation 
to Cohort 3 can proceed. Thirty days after the last patient in Cohort 3 receives the third 
dose, the DMC and Boston Pharmaceuticals will conduct a data review to determine 
which dose will be carried forward into the POC part of the study. This POC dose 
decision will be based on evaluation of the PK, safety (inclusive of dose-limiting toxicity 
[DLT]), and tolerability data (and available PD/biomarker data) from Cohorts 1, 2, and 3 
during the MAD part of study. Thereafter, DMC safety reviews will be conducted 
periodically throughout the study as described in the DMC charter. With the agreement 
of the DMC and sponsor, this schedule may be modified depending on the rate of 
patient accrual. Additional details can be found in the DMC Charter.  
The benefit of participation for all patients in this study is close monitoring of their 
medical condition and safety of their treatment. Those randomized to the active 
treatment arm may potentially experience improvement in their SLE disease. Those 
randomized to the placebo (in combination with standard of care) arm are not expected 
to obtain any additional benefit, beyond those of their background treatment, though 
close monitoring of their medical condition and safety may itself be associated with 
improving their SLE.  
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, 
risks associated with the administration of any foreign protein or biologic agent, 
including injection site reaction, anaphylaxis, serious allergic reaction, and development 
of ADAs. ADAs could result in immune complex disease (with manifestations such as 
arthralgias, serum-sickness, and vasculitis), or altered BOS161721 levels or activity. 
Further details can be found in the current Investigator’s Brochure (IB) for BOS161721, 
which contains comprehensive toxicology, preclinical and clinical information on 
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Two investigational drug products are considered to be in the same pharmacological 
class as BOS161721 based on interruption of signaling through the IL-21 signaling 
pathway. No potential risk generalizable across the class has been observed with these 
investigational products. Based on the clinical phase 1 SAD study (BOS161721-01), 
AEs reported as related to the study drug, particularly infections (flu-like symptoms, 
etc.), were expected for the compound, and there were no clinically relevant changes in 
laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase 
or receptor-mediated endocytosis. This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological 
target (e.g., a target receptor) serves as a significant contributor to the kinetics of 
antibody distribution and elimination. Renal elimination, which is a primary pathway of 
clearance of small-molecule drugs, is relatively unimportant for IgG, as its large size 
prevents efficient filtration through the glomerulus. Secretion into the bile is an important 
pathway of elimination of IgA antibodies, but this route is not a significant contributor to 
the elimination of IgG antibodies. Thus, risk to renal and hepatic systems due to 
metabolism of BOS161721 is low.33 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, 
and anaphylactoid reactions may follow infusion of mAbs and can be caused by various 
mechanisms. These acute hypersensitivity reactions may be severe and result in death.  
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are 
discussed in Section 6.2.2.6.1.  
Based on the phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic 
reactions in subjects who received BOS161721 was not observed.  
Patients with a known history of allergy or severe hypersensitivity reaction to any 
component of BOS161721 formulation or patients with a history of anaphylaxis to any 
other biological therapy such as mAbs will be excluded from studies with BOS161721. 
In addition, appropriate drugs and medical equipment to treat acute hypotensive, 
bronchoconstrictive, or anaphylactic reactions will be immediately available at the unit 
and study personnel will be trained to recognize and treat these reactions.  
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was 
administered every 2 weeks by IV or SC for 3 months (a total of 7 doses). There were 
no injection site reactions in animals dosed subcutaneously. Further, there were no 
reports of injection site reactions in the 26-week GLP toxicology study in Cynomolgus 
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Based on the phase 1 SAD study (BOS161721-01), incidence of injection site reactions 
in subjects who received BOS161721 was similar to placebo.  
Patients will be monitored for local injection site reactions in this study (see 
Section 6.2.7).  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on 
the known risks associated with mAbs. The administration of a mAb can result in the 
formation of ADAs. Administration of the mAb in the presence of ADA may result in the 
formation of circulating antibody-antigen complexes potentially resulting in altered 
BOS161721 levels or activity or deposition of the complexes in microvasculature. 
Complement is frequently involved in the latter setting, and the breakdown products of 
complement attract polymorphonuclear leukocytes to the site of deposition where they 
can provoke local tissue damage through specific or nonspecific release of enzymes. 
Two of the more common end-organ targets are the blood vessels (vasculitis) and 
kidney (nephritis). These clinical manifestations represent immune complex disease or 
Type III hypersensitivity. Although BOS161721 is a humanized mAb, ADAs may 
develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low. The findings of immune complex disease are typically reversible 
when mAb administration stops and the antibody-antigen complexes are cleared from 
the body.  
Based on the phase 1 SAD study (BOS161721-01), immune complex disease in 
subjects who received BOS161721 was not observed.  
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines. Like 
other medications modulating immune response, BOS161721 may increase the 
potential risk for infection, including serious infections. IL-21 produced by CD4+ T-cells 
is required to sustain the anti-viral function of CD8+ T-cells against chronic viral 
infections. Nonclinical evidence suggests that the risk of chronic viral infection 
recurrence or increased severity may occur with IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine 
laboratory and/or specialty testing and treated where indicated with appropriate local 
standard of care.  
Patients with a history of opportunistic infection, including recurrent or severe 
disseminated herpes zoster or disseminated herpes simplex within the last 3 years, or 
any other underlying pathology predisposing to serious infection, are excluded from 
studies with BOS161721 (for further details please refer to the current IB for 
BOS161721).  
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Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function 
gene mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37 
Since BOS161721 is expected to diminish the immunosurveillance activity of T-cell, 
B-cell, and NK-cell lines, a similar risk is biologically plausible with prolonged exposure 
to BOS161721.  
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the 
phase 1 SAD study (BOS161721-01). Patients with CD4+ count < 350 cells/mm3 and 
CD4+ count < 150 cells/mm3 will be excluded from the MAD and POC parts of the 
study, respectively. Patients exposed to investigational product who develop diarrhea 
during the course of the study should immediately undergo an assessment for 
opportunistic infection including stool for ova and parasites and stool examination for 
cryptosporidium. Positive cryptosporidium in stool sample at screening is an exclusion. 
Treatment by the Investigator where indicated should be guided by findings and be 
consistent with local standard of care.  
Based on the phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed.  
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may 
have anti-tumor activity. Nonclinical studies have demonstrated significant anti-tumor 
effects of IL-21 in a number of tumor models. IL-21 therapy of human metastatic 
melanoma and renal cell carcinoma has demonstrated POC with significant increases in 
levels of perforin, granzyme B, and interferon gamma (IFNγ) expression in CD8+ T-cells 
and NK T-cells. Clinical response has been limited in these generally unmanageable 
diseases.  
The impact of treatment with anti-IL-21 therapy on the development or growth of 
malignancies is not known; however, as with other immunomodulatory biologic agents, 
treatment with BOS161721 may result in an increase in the risk of malignancies. NK cell 
suppression by IL-21 neutralization may represent a biological mechanism for a 
potential risk for malignancy. Patients with a history or current diagnosis of cancer within 
the past 5 years, with the exception of non-melanoma skin cancer or cervical cancer in 
situ treated with apparent success with curative therapy, are excluded from the study.  
Based on the phase 1 SAD study (BOS161721-01), malignancy in subjects who 
received BOS161721 was not observed.  
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver 
function abnormality. However, as a precaution, patients with a history of abnormal 


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alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at 
screening (ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and 
judged by the Investigator to be clinically significant) were excluded from the phase 1 
SAD study (BOS161721-01), and will be excluded from this trial. Patients with a positive 
hepatitis B or C test or a history of alcohol dependence will also be excluded.  
Based on the phase 1 SAD study (BOS161721-01), hepatic function abnormality in 
subjects who received BOS161721 was not observed.  
1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma 
cells. Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer 
and activator of transcription (STAT3) pathway leads to defective humoral immune 
responses to both T-dependent and T-independent antigens and impairs the 
establishment of long-lasting B-cell memory. Abnormal signaling through the pathway 
has been related to decreased specific antibody responses following vaccination, and to 
increased susceptibility to encapsulated bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus 
monkey in which the animals received vaccination to T-cell dependent KLH antigen to 
stimulate a TDAR. These in vivo studies demonstrated that BOS161721 significantly 
inhibited B-cell proliferation and IgG antibody responses to the KLH protein antigen in a 
dose-dependent fashion; however, BOS161721 administration did not affect anti-
tetanus toxoid antibody data for IgM, IgG, IgG1, or immunoglobulin E (IgE) during the 
dosing phase in the same study.  
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the phase 1 SAD study (BOS161721-01), 
which included only healthy adult subjects. Use of prescription medications (with the 
exceptions of oral contraceptives), and over-the-counter (OTC) treatments including 
herbal supplements such as St John’s Wort (except multivitamins), in the 2 weeks prior 
to screening was prohibited in the SAD study.  
See Section 4.5 for other specific exclusion criteria which support lowered risk of 
interactions, and Section 4.6.1 for corticosteroid (CS) dosing. In addition, 
Section 1.2.5.6 describes considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.  
2 STUDY OBJECTIVES AND ENDPOINTS 
This trial has separate objectives and endpoints for the MAD phase 1b and POC 
phase 2 portions of the study. The primary, secondary, and exploratory objectives for 
each phase, as applicable, are described below with their corresponding endpoints.  


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2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients 
with moderately to severely active 
SLE on limited background standard 
of care treatment, in order to estimate 
the optimal dose 
Safety Endpoints 
 
Incidence and severity of AEs and SAEs, related 
AEs, AEs leading to study drug discontinuation, AEs 
by severity and relatedness 
 
Injection site reactions 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
12-lead ECGs parameter results at each visit and 
change from baseline 
 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and 
change from baseline 
 
Clinical laboratory results and change from baseline 
 
Physical examinations changes from baseline 
 
ADAs 
 
Study drug exposure/compliance 
Secondary 
 
To characterize the PK of 
BOS161721 and select the optimal 
dose of BOS161721 based on safety, 
PK, and PD effects in patients with 
moderately to severely active SLE 
Pharmacokinetic Endpoints 
 
BOS161721 concentration by visit and time point 
 
Maximum observed concentration (Cmax), Tmax, area 
under the concentration-time curve (AUC), terminal 
elimination half-life (t½), systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
 
Results and changes (or shifts) from baseline to each 
visit in phosphorylated signal transducer and 
activator of transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
 
Results and changes (or shifts) from baseline in 
anti-double-stranded DNA (dsDNA), antinuclear 
antibodies (ANA), anti-Sjögren syndrome A and B 
(SSA, SSB), Smith (Sm), and antiphospholipid (APL) 
autoantibodies at each visit 
 
Results and changes (or shifts) from baseline in 
abrogation of IL-21 gene signature at each indicated 
visit 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 
Phase 2 Proof of Concept 
OBJECTIVES 
ENDPOINTS 
Primary 
 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SRI-4  
Primary Efficacy Endpoint 
 
The proportion of patients with a SRI-4 response at 
Day 210 (see Section 6.3.4.1) 
Secondary 
 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on clinical indicators of SLE activity, in 
adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Secondary Efficacy Endpoints 
 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction from baseline of oral 
corticosteroid (CS) ( ≤ 7.5 mg/day and < Day 0 
dose) between Day 150 and Day 210 
- 
new or recurrent BILAG flares ( ≥ 1 qualifying 
BILAG A or > 1 qualifying BILAG B) through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
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- 
medication failures 
 
The changes and percent changes from baseline in: 
- 
CLASI 
- 
PGA 
- 
Total number of swollen joints, tender joints, and 
active joints (swelling and tenderness in the 
same joint) in the ACR-28 joint count 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
 
Time to medication failure 
 
Group mean percent reduction in CS administration 
from baseline Day 0 dose through Day 210 in patients 
receiving ≥ 7.5 mg/day prednisone equivalent at 
Day 0 
 
Duration of longest SRI-4 response 
 
Time to first BILAG flare ( ≥ 1 new or recurrent 
BILAG A or > 1 new or recurrent BILAG B) relative to 
baseline through Day 210 
Safety 
 
To assess safety and tolerability of 
repeat doses of BOS161721 at the 
chosen dose administered SC in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Safety Endpoints 
 
Incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs), related AEs, AEs 
leading to study drug discontinuation, AEs by severity 
and relatedness 
 
Injection site reactions 
 
C-SSRS 
 
12-lead ECGs parameter results at each visit and 
change from baseline 
 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and 
change from baseline 
 
Clinical laboratory results and change from baseline 
 
Physical examinations changes from baseline 
 
ADAs 
 
Study drug exposure/compliance 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 STUDY PLAN 
3.1 
Study Design 
This is a phase 1b/2 combined, randomized, multicenter, double-blind, placebo-
controlled trial to study the clinical efficacy, safety, and PK of SC doses of BOS161721 
in adult patients with moderately to severely active SLE. After successfully completing a 
screening phase, eligible patients will be randomized to a specified dose of BOS161721 
or placebo. The dosing schedule will be monthly.  
The trial will consist of 2 double-blinded portions: MAD phase 1b and POC phase 2. 
Patients may receive a total of 7 SC monthly doses of study drug on 
Days 0, 30, 60, 90, 120, 150, and 180, followed by safety follow-up visits at 
Days 210, 240, and 270.  
SLE disease activity assessment data will be centrally reviewed by medical monitor and 
sponsor to ensure the scores are clinically meaningful and compliant with specific 
definition. The scope of responsibility includes, but is not limited to, review and 
confirmation of “A” and “B” BILAG system organ disease, confirmation of clinical 
components of the SLEDAI-2K score at screening and during the study, and 
cross-validation of the instruments used in this study to assess the disease activity. 
Further details on the content and methods of data reports by the medical monitor and 
sponsor will be outlined in the Medical Data Review Plan along with the processes and 
procedures that will be followed.  
3.1.1 
Multiple Ascending Dose Phase 1b 
The MAD portion will consist of 3 cohorts:  
 Cohort 1 (20 mg SC) will include 6 patients 
o 
5 patients will receive BOS161721 (active group) and 1 patient will receive 
placebo (placebo group) 
 Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 
9 patients in the active group and 3 in the placebo group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Doses selected for each of the 3 cohorts is based on a 90 day safety, tolerability, PK 
and PD data review from the phase 1 SAD study (BOS161721-01) in healthy subjects. 
All doses selected for the MAD part of the study are projected not to exceed the mean 
exposure of that achieved at the highest dose in the SAD study.  
3.1.1.1 
Dose Escalation for the MAD Portion  
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 
have received 2 doses and have completed 2 weeks of follow-up after the second dose, 
Cohort 2 begins dosing (after the DMC evaluation of the safety and tolerability data from 
Cohort 1). Similarly, after 8 of the 12 patients in Cohort 2 have received 2 doses and 
have completed 2 weeks of follow-up after the second dose, Cohort 3 begins dosing 
after the DMC evaluation of the safety and tolerability data from Cohorts 1 and 2. Each 
cohort will continue at their assigned dose level through their respective 6-month 
treatment periods (see Study Schematic, Section 3.3). If patients discontinue the study 
in a cohort prior to adequate safety follow-up, he/she may be replaced.  
Criteria for dose escalation are further described in the DMC Charter. See 
Section 3.1.1.2 for additional details about DLTs.  
3.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. For the 
purpose of dose escalation, any of the following AEs occurring after study drug 
administration, which are attributable to the study drug, will be considered DLTs: 
Hematologic: 
 
Grade 4 neutropenia 
 
Grade 3 neutropenic infection 
 
Grade 3 thrombocytopenia with bleeding 
 
Grade 4 thrombocytopenia 
Non-Hematologic: 
 
Grade 3 or above toxicities, persisting after optimal treatment with standard medical 
therapy (e.g., anti-emetics, anti-diarrheals) 
 
Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 6.2.2.6.3 
Investigators should always manage their patients according to their medical judgment 
which may include interruption of study drug based on the particular clinical 
circumstances.  


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3.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or 
benefit-risk concern. During the MAD part of the study, the DMC may provide the 
following recommendations to the sponsor: 
 
Expanding a cohort at a specific dosing level, or repeating a lower dose in a 
subsequent cohort 
 
Continuing a dose level for a given cohort 
 
Escalating a dose level for a subsequent cohort 
 
Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed. For the POC portion, the DMC and Boston Pharmaceuticals will 
conduct a data review to determine which dose will be carried forward into the POC 
phase 2 part of the study. This POC dose decision will be based on evaluation of the 
PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2, and 3; this dose will not exceed doses tested 
during the MAD portion. The DMC will be reviewing all relevant data from Cohorts 1, 2, 
and 3 that is available 30 days after the last patient from Cohort 3 receives the third 
dose. Details are provided in the DMC Charter.  
3.1.2 
POC Phase 2  
3.1.2.1 
BOS161721 POC Dose Selection and Justification 
The dose for the POC portion of the study is 120 mg administered SC monthly (a total 
of 7 doses). The rationale for the BOS161721-02 phase 2 POC dose selection was 
based on cumulative safety, tolerability, immunogenicity, PK, and PD data available 
from an interim analysis (IA) performed during the MAD phase 1b portion of the trial.  
The data cut-off for this IA occurred on 
 and included all 6 patients 
and 7 doses from Cohort 1 (20 mg), 12 patients and 6 doses from Cohort 2 (60 mg), 
and 12 patients and 4 doses from Cohort 3 (120 mg).  
The safety analysis focused on incidence and severity of all AEs, SAEs, and pre-
determined adverse events of special interest (see Section 6.2.2.6). The DMC and 
designated unblinded Boston Pharmaceuticals team met on 
 and did 
not identify any untoward safety signals at any BOS161721 dose levels.  
Because there were no safety, tolerability, or immunogenicity trends observed at the 
time of the IA, the phase 2 POC dose selection was made based on available PK and 
PD data. pSTAT3 levels were assessed as the primary PD biomarker of IL-21R 
signaling levels. This is because IL-21R signaling, upon IL-21 binding, initially involves 
phosphorylation of JAK1/JAK3 which dissociate from the receptor complex, and 
phosphorylate STAT3 which translocates to the nucleus and drives IL-21-regulated 
gene expression. 
 
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.  
The 120 mg dose was communicated to site Investigators participating in the POC 
phase 2 portion, and to Institutional Review Boards (IRBs) and the Independent Ethics 
Committee (IEC).  
3.1.2.2 
POC Study Design 
For the POC part of the study, approximately 110 additional patients will be randomized 
to active or placebo groups in a 2:1 ratio.  
As in the MAD part of the study, each patient in the POC portion may receive a total of 
7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180. 
Assessments will be completed according to the Schedule of Assessments (Table 1 and 
Table 4).  
DMC safety reviews will be conducted periodically throughout the study as described in 
the DMC charter.  
3.2 
Randomization and Blinding 
This is a randomized, double-blind study.  
Patients meeting all inclusion and exclusion criteria will be centrally randomized to 
either placebo or BOS161721 using an IWRS according to a randomization list 
generated by an independent, non-study statistician. Randomization will be performed 
separately for each study portion and separately for each cohort in the phase 1b and 
2 portions as follows: 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set 
(FAS).  
Eligible patients will be assigned to the study portion which is active at time of 
enrollment. Similarly, patients in the phase 1b MAD will be assigned to the cohort which 
is active. Each patient will be assigned a unique randomization number which will not be 
reused.  
All patients, Investigators, and study team participants will be blinded to treatment 
assignment. An independent biostatistician not otherwise involved on the study will be 
unblinded and prepare materials for the IA, ad hoc analyses as needed, and the DMC 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
Approximately 110 
2:1 
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safety reviews. The DMC will review unblinded data during safety reviews and the IA. A 
limited team at Boston Pharmaceuticals will review unblinded results from the phase 1b 
MAD portion during the IA to determine the dose that will be used for the phase 2 POC 
portion of the study. Details regarding maintenance of the blinding and content of data 
reviews will be described in the DMC charter or related study documentation.  


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3.3 
Study Schematic 
Figure 2.  Study Diagram for MAD Phase 1b and POC Phase 2 
 
A = active drug (BOS161721); P = placebo 


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Page 49 of 130 
3.4 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up 
Safety Follow-Up 
Days 
-28 to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo 
dosing 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Screening assessments will be performed over more than 1 visit. 
b PK samples will only be collected at the investigational sites that participate in the PK portion of the study. On PK only days (i.e., Day 187 and 
Day 195 when no laboratory assessments are scheduled) samples will be collected at the investigational sites of the selected countries that 
participate in the PK portion of the study. Patients not participating in PK are not required to return for investigation site visits on Days 187 and 
195. 
c Concomitant use of oral corticosteroids: A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, 
the dose must be stable for at least 6 weeks prior to Day 0 (randomization day). See Section 4.6.1 for further details. 
d Randomization should occur after patient eligibility has been confirmed. The actual randomization procedure can be completed on Day -1 after 
eligibility confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
                                        


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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up 
Safety Follow-Up 
Days 
-28 to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Chest x-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessment 
 
Xg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
e If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during 
screening. The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 
3 months prior to screening or during the screening period must be documented in study records prior to randomization (Day 0) 
f ECGs will be performed after the patient has been supine for at least 5 minutes. On days of PK blood draws, the ECG will be collected before 
scheduled PK blood draws 
g Injection site reaction assessments to be performed at 2 hours postdose 
h Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes. Vital signs will be assessed on Day 0 at predose and at 1 
and 2 hours (± 15 minutes) postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at 
Days 187 and 195). When the timing of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of 
the blood collection 
                                        


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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up 
Safety Follow-Up 
Days 
-28 to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLEDAI-2K 
X 
Xi 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments (hematology 
and clinical chemistry)j 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
i SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary 
j Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting 
k When clinically indicated for hemolytic anemia 
                                        
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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up 
Safety Follow-Up 
Days 
-28 to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
ADAl 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbm 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test 
(women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)o 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test (QuantiFERON®-TB 
Gold In-Tube)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
l Blood samples for ADA analysis will be collected up to Day 90 from all patients. Subsequent ADA samples will be collected from all patients but 
only assayed (analyzed) if the patient had a positive ADA on Day 90 
m nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90 
n 
 will not be analyzed during safety follow-up visits 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits 
                                        
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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up 
Safety Follow-Up 
Days 
-28 to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labsb 
Predose 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations: ACR = American College of Rheumatology; ADA = anti-drug antibody; AE = adverse event; 
; 
BILAG = British Isles Lupus Assessment Group; BP = blood pressure; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and 
Severity Index; CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency 
virus; IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; nAb = neutralizing antibody; PGA = Physician’s Global 
Assessment; PK = pharmacokinetic; SAE = serious adverse event; 
; SLEDAI-2K = SLE Disease Activity Index 2000; 
SLICC = Systemic Lupus International Collaborating Clinics; 
 
 TB = tuberculosis.  
 
 
p Cryptosporidium test is required at screening. If a patient develops diarrhea during the study a stool sample must be provided to test for ova, 
parasites, and cryptosporidium 
                                        
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3.5 
End of Study 
End of Study (Individual Patient): A patient is considered at the end of study if he/she 
has withdrawn, prematurely discontinued, or completed all of the study procedures 
including the last visit.  
End of Study (End of trial): The end of the study is defined as the date of the last visit 
of the last patient in the study globally, or the date of which the last patient withdraws or 
discontinues if all prior enrolled patients have already completed/withdrawn.  
4 POPULATION 
4.1 
Participant Recruitment 
Advertisements approved by the IRB, and Investigator databases, may be used as 
recruitment procedures for adult men and women with moderately to severely active 
SLE.  
4.2 
Number of Patients 
Approximately 140 male and female patients are planned for enrollment, but may be 
adjusted upward according to the dropout (noncompliance) rate, which will be monitored 
in a blinded fashion in an ongoing basis. Approximately 30 patients will be randomized 
for the MAD phase 1b portion, and approximately 110 additional patients will be 
randomized in the POC phase 2 portion. Note that approximately 14 dropouts are 
assumed in the POC phase 2 portion.  
4.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled. The following 
eligibility criteria are designed to select patients for whom protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be 
taken into consideration when deciding whether this protocol is suitable for a particular 
individual. Patient eligibility will be reviewed and confirmed by the medical monitor or 
designee prior to randomization. Screening assessments (see the Schedule of 
Assessments [Table 1 and Table 4]) for this study must be performed between Day -28 
and Day -1.  
4.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this 
clinical study: 
1. Men and women, ages 18 to 70 years, inclusive.  


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2. Patients must be mentally capable of giving consent and there must be evidence of 
a personally signed and dated informed consent document indicating that the patient 
has been informed of all pertinent aspects of the study.  
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical 
and 1 immunologic criterion or Lupus nephritis as the sole clinical criterion in the 
presence of ANA or anti-dsDNA antibodies), either sequentially or simultaneously.  
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by 
the central laboratory 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including points from at least 1 
of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis 
Note: Points from lupus headache and organic brain syndrome will also be excluded 
from qualifying total and clinical SLEDAI-2K scores at screening and Day 0.  
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0. Clinical SLEDAI-2K score is 
defined as follows: 
a. Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, or vasculitis 
b. Excludes parameters which require central laboratory results: hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
Note: Points from lupus headache and organic brain syndrome will also be excluded 
from qualifying total and clinical SLEDAI-2K scores at screening and Day 0.  
7. Patients must have at least 1 qualifying A or 2Bs from the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, which must 
be confirmed by the central data reviewer:  
a. BILAG A or B score in the mucocutaneous body system. If a BILAG B score is 
due to BILAG number 6, mild skin eruption, the CLASI activity score including 
erythema and scale/hypertrophy must be ≥ 3 excluding points from mucosal 
ulcers and alopecia.  
b. BILAG A or B score in the musculoskeletal body system due to active 
polyarthritis defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis defined by BOTH swelling and tenderness in ≥ 6 joints with 
marked loss of functional range of movements and significant impairment of 
basic activities of daily living (ADLs) that has been present on several days 


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( > 4 days) cumulatively over the past 30 days, including at the time of the 
screening visit. See Appendix 5 for additional detailed specifications.  
 
Basic ADLs are defined as the following activities which require assistance 
or assistive devices, (at least 1 must be present and documented in 
source): 
o 
Ambulation, toileting, grooming- including bathing and dressing; 
feeding oneself 
ii. 
“BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis defined 
by BOTH swelling and tenderness in ≥ 3 joints, (observed or through patient 
history), with some loss of functional range of movements manifested by 
effects on instrumental ADLs such as: 
 
Cooking, driving, using the telephone or computer, shopping, cleaning, 
etc., and has been present on several days over the last 30 days, and is 
present at the time of the screening visit 
Note: Hips, shoulders, back, neck, and temporomandibular joints do not count towards 
the total number of joints with active synovitis.  
If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in at 
least 1 other body system for a total of 2 “B” BILAG body system scores.  
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to Day 0) of the following permitted steroid-sparing agents: 
i. Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. If AZA, myocophenolate mofetil, mycophenolic acid, hydroxychloroquine, or MTX 
were discontinued prior to screening, the washout period must be ≥ 12 weeks 
c. Corticosteroids (prednisone or prednisone-equivalent) at a stable dose of up to 
30 mg/day for at least 6 weeks prior to Day 0 (see Appendix 3) 
i. 
For patients whose only SLE treatment is CS, the stable CS dose must 
be ≥ 10 mg/day for at least 6 weeks prior to Day 0 and no more than 
30 mg/day at the time of randomization 
ii. 
Topical steroids may be used, but the dose must be stable for at least 
6 weeks prior to Day 0. PRN topical steroids are not permitted 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full information 
regarding WOCBP, definition of menopause, and contraception): 
a. Must have a negative serum pregnancy test at screening. Urine pregnancy test 
must be negative prior to first dose 
b. Must not be breastfeeding 


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c. Must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug plus 52 weeks.  
10. Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug plus 
52 weeks.  
11. Patients must demonstrate willingness and ability to comply with the scheduled 
study visits, treatment plans, laboratory tests, and other procedures.  
4.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE.  
2. Other systemic autoimmune disease (e.g., erosive arthritis, rheumatoid arthritis [RA], 
multiple sclerosis [MS], systemic sclerosis, or vasculitis not related to SLE).  
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any 
elective surgery planned during the course of the study.  
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations. Latent TB is not 
excluded if the patient has documented completion of adequate course of 
prophylactic treatment with regimen recommended by local health authority 
guideline, or the patient has started treatment with isoniazid, or other regimen 
recommended by local health authority guidelines for at least 1 month before 
Day 0 and continues to receive the prophylactic treatment during study until the 
treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to 
any condition defined by BILAG A criteria, with the exception of mononeuritis 
multiplex and polyneuropathy, which are allowed.  
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may 
require induction treatment with cytotoxic agents or high dose CS.  
7. Concomitant illness that, in the opinion of the Investigator or the sponsor or their 
designee, is likely to require additional systemic glucocorticosteroid therapy during 
the study, (e.g., asthma), is exclusionary.  
a. However, treatment for asthma with inhalational CS therapy is allowed.  


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8. Use or planned use of concomitant medication outside of standard of baseline 
treatment for SLE from Day -1 or for any time during the study. (See Section 4.6.2 
for prohibited concomitant medication).  
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 
60 days prior to first dose of study drug. Clinically significant is defined as requiring 
systemic parenteral antibiotics or hospitalization.  
10. A history of opportunistic infection, or a history of recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years.  
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) unless 
patient received curative treatment for HCV and has a documented negative viral 
load, known human immunodeficiency virus (HIV), or acquired immunodeficiency 
syndrome (AIDS)-related illness.  
12. Cryptosporidium in the stool sample at screening.  
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening.  
14. Absolute neutrophil count (ANC) < 500/mm3 at screening.  
15. CD4+ count < 150/µL at screening.  
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/mm3 (35 × 109/L) if related to SLE, 
at screening.  
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE.  
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria 
as assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol).  
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 
mL/minute based on Cockcroft-Gault calculation39: 
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW/(72 × Creatinine).  
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to 
lupus based on the Investigator’s judgment.  
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus 
myositis.  
22. Total bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome).  
23. Any other laboratory test results that, in the opinion of the Investigator or the sponsor 
or sponsor’s designee, might place a patient at unacceptable risk for participating in 
this study.  


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24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (e.g., IgG protein) or molecules made of components of 
monoclonal antibodies.  
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
Investigator’s judgment.  
26. History of cancer within the last 5 years (except for cutaneous basal cell or 
squamous cell cancer, or cervical cancer in situ resolved by excision).  
27. Any other severe acute or chronic medical or psychiatric condition, including recent 
(within the past year) medical conditions (e.g., cardiovascular conditions, respiratory 
illnesses) that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the Investigator, sponsor or sponsor’s designee, 
would make the patient inappropriate for entry into this study.  
28. Investigational site staff members directly involved in the conduct of the trial and 
their family members, site staff members otherwise supervised by the Investigator, 
or patients who are employees of the sponsor or directly involved in the conduct of 
the trial.  
29. Currently participating in, or who have participated in other interventional (drug or 
device) clinical study within 30 days or 5 half-lives of baseline, whichever is longer.  
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on 
patient responding “yes” to question 3, 4 or 5 on the C-SSRS.  
31. Current or pending incarceration.  
32. Current or pending compulsory detainment for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness.  
33. Currently taking a total daily dose of > 30 mg morphine or morphine equivalent (see 
Appendix 7).  
34. Body mass index (BMI) ≥ 40.0.  
4.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional 
remedies, is considered a concomitant medication. Patients should stay on stable 
regimen (not PRN) of other concomitant medications for the treatment of SLE (e.g., 
analgesics, nonsteroidal anti-inflammatory drugs [NSAIDs], statins, ACE 
inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments 
are clinically indicated. Patients should refrain from Tylenol, NSAIDs, and any pain 
medications including tramadol and other opiates for at least 12 hours before each visit, 
with the exception of the Screening Visit.  


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Use of any other drugs for non-SLE conditions, including over-the-counter medications 
and herbal preparations, should remain stable unless change or addition is clinically 
necessary. Discussion with the medical monitor prior to initiation of new medication is 
strongly recommended. Any concomitant therapies must be recorded on the eCRF. 
Prior and concomitant medication use will be recorded for the 30 days prior to screening 
until the last follow-up visit. In addition, historical treatment for SLE (including 
immunosuppressant, anti-malarial, corticosteroid, and/or biologic agent including 
investigational agents) will be recorded for the 48 weeks prior to screening in the eCRF.  
4.6.1 
Corticosteroid 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the Investigator’s clinical judgment and best standard of care. See 
Appendix 3 for examples of equivalents.  
 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for 
the study. For patients whose only SLE treatment is steroids, their stable steroid 
dose must be at least 10 mg/day and no more than 30 mg/day for a minimum of 
6 weeks at time of randomization on Day 0 
 
Topical steroids may be used, but the dose must be stable for at least 6 weeks prior 
to Day 0, and be maintained at a constant dose throughout the study duration until 
the rashes resolve. PRN topical steroids are not permitted 
 
Once the patient has received the first dose of study drug (Day 0), tapering of oral 
steroids will be highly encouraged and should be continually evaluated during the 
protocol-allowed tapering windows (Day 0 through Day 150) with the target of 
achieving a CS daily dose of < 7.5 mg and < Day 0 dose between Day 150 and 
Day 210 
 
Between Day 150 and Day 210 (i.e., within 60 days of primary endpoint 
assessments), oral CS doses must be held constant 
 
CS Burst for SLE-related Indications 
After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” equivalent 
to ≤ 40 mg/day prednisone for increased SLE disease activity will be allowed 
between Day 0 and Day 120, which must be tapered down to the baseline (Day 0) 
CS dose or lower within 14 days of initiation of the “burst”. Any “burst” continuing 
after Day 120 or occurring after Day 120 is considered a protocol deviation.  
o 
Alternatively, a single intramuscular (IM) dose of methylprednisolone 
( < 40 mg) is permitted during this period 
CS Burst for Non-SLE-related Indications.  
A single treatment of oral prednisone equivalent of ≤ 40 mg/day for 14 days is 
permitted for a non-SLE indication, though it must be completed prior to Day 120. 
No long acting steroid injections are permitted.  
Note: Treatment with inhaled CS are allowed for the treatment of non-SLE-related 
indications only (e.g., for asthma).  


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Any other increase from baseline of CS dose or systemic use of CS of any kind 
(including intra-articular and intravenous administration) are not permitted from Day 0 
through Day 210 and will result in the patient being considered a treatment failure. 
There is no restriction of CS usage after Day 210.  
4.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and 
during the study are described below, and washout requirements are provided in 
Appendix 4. All medications taken within 30 days prior to screening must be recorded 
on the eCRF.  
1. 
Prior exposure to BOS161721 
2. 
Patients who have received treatment with anti-CD20 monoclonal antibodies within 
24 weeks of screening 
3. 
Patients who have received treatment with cyclophosphamide within the 24 weeks 
prior to screening 
4. 
Patients who have received treatment with cyclosporine (with exception of 
ophthalmic use), any other calcineurin inhibitor or other immunosuppressive 
medication not specified in the inclusion criteria within 4 weeks for oral use or 8 
weeks for topical use of screening 
5. 
Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 24 weeks prior to 
screening 
6. 
Patients who have received any live vaccines within 30 days of screening. Note: 
Furthermore, live vaccines should not be used during the course of the study and 
within the 2 months following last dose. Other inactivated vaccines such as 
tetanus, etc., may be used according to local guidelines during treatment period 
7. 
Patients who are scheduled or anticipated to have elective surgery during the 
course of the study 
8. 
Initiation of new immunosuppressant or anti-malarial agent is not permitted. Note: 
Dose reduction or replacement may be allowed due to intolerability or shortage for 
patients on a stable dose prior to study initiation 
4.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not 
undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) and is not postmenopausal.  


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See Section 4.7.2 for detailed information regarding contraceptive requirements for 
WOCBP.  
4.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in 
the absence of other biological or physiological causes. Women under the age of 
55 years must have a documented serum FSH level > 40 mIU/mL at screening to 
confirm menopause.  
4.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study drug plus 52 weeks, due to the mean terminal ½ life of the study 
drug.  
Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug plus 52 weeks, 
due to the mean terminal ½ life of the study drug.  
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise WOCBP and men who are sexually active with 
WOCBP on the use of highly effective methods of contraception. Highly effective 
methods of contraception have a failure rate of < 1% when used consistently and 
correctly.  
 
Patients must agree to either complete abstinence, defined as a complete 
avoidance of heterosexual activity, or the use of 2 methods of effective 
contraception from the following: 
 
Male condoms with spermicide 
 
Diaphragm with spermicide 
 
Cervical cap with spermicide 
 
Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants, patches and intrauterine devices (IUDs) such as 
Mirena® by patients who are WOCBP or a male patient’s WOCBP partner. Women 
who are partner of men who are patients participating in the study may use 
hormone-based contraceptives as one of the acceptable methods of contraception 
since they will not be receiving study drug 
 
IUDs, such as ParaGard® 
 
Vasectomy 
 
Note: Women who are abstinent while participating in the study must continue to 
have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego 
complete abstinence 


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 
Azoospermic men and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements. However, WOCBP must still undergo 
pregnancy testing 
4.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed. If deviation of 
inclusion/exclusion criteria is discovered after randomization, the Investigator should 
contact the medical monitor for discussion. A decision will be made whether to allow a 
patient to continue or withdrawal from the study medication.  
See Section 6.8 for additional details.  
4.8.1 
Patient Withdrawal and Replacement 
See Section 5.5 for reasons for removal from the trial. Withdrawn patients may be 
replaced during the MAD part of the study after discussion between the Principal 
Investigator or designee and sponsor.  
5 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and 
documentation of study assessments/procedures.  
5.1 
Screening 
Screening will be the same for both the MAD and POC portions of the study.  
Screening will take place from Day -28 to Day -1, and assessments may be performed 
over more than 1 visit. Confirmation that the most current IRB/IEC approved informed 
consent form (ICF) has been signed must occur before any study-specific screening 
procedures are performed. Procedures that are part of standard of care are not 
considered study-specific procedures and may be performed prior to informed consent 
and used to determine eligibility.  
All screened patients will be assigned a unique screening number. The screening 
number will include a 3-digit site number and a 4-digit sequential number to identify 
patients from the time of screening. Only eligible patients who are confirmed by central 
review as meeting the inclusion/exclusion criteria, listed in Section 4.4 and Section 4.5 
respectively, will be enrolled in the study. Screened patients who drop out of the clinical 
study before randomization will be recorded as screen failures. If rescreening occurs, 
the site will assign a new screening number.  
Specific procedures at the screening visit will include: 
 Medical history documentation 
 Review of inclusion and exclusion criteria 


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o 
Patient medical records must contain documentation of SLE diagnosis 
o 
C-SSRS 
 Concomitant medication documentation 
 Demographics 
 Full physical examination 
 Vital signs 
 Chest x-ray (a prior x-ray can be used if taken within 12 weeks of screening date) 
 Laboratory evaluations (non-fasting): 
o 
Hematology and clinical chemistry 
o 
Serology (Hepatitis B and C; HIV-1/2 combination) 
o 
TB test 
o 
CRP 
o 
Direct Coomb’s test (if indicated for hemolytic anemia) 
o 
CD4+ count, total IgG and IgM levels, plasma 
, 
 
 
o 
Serum pregnancy test (WOCBP) 
o 
FSH (postmenopausal women under age 55 years) 
o 
Spot urine for protein/creatinine ratio 
o 
Urinalysis 
o 
Stool sample  
 12-lead ECG 
 SLE-related indices [BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity] 
 Screening procedures are listed in the Schedule of Assessments (Table 1 and 
Table 4), and details are provided in Section 6. 
5.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the 
screening period is permitted (in addition to any parameters that require a confirmatory 
value) only if: 
 medically indicated 
 there is evidence a laboratory sample was mislabeled, indeterminate, inadequately 
processed, and/or deteriorated in transit to the central laboratory 
Any new result will override the previous result (i.e., the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as 
it represents the patient’s most current clinical state. This will also apply to patients who 
are being rescreened.  
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5.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed 
by the central eligibility review. The central eligibility review team has the final decision 
on patient eligibility and can decide the patient is not eligible for the study based on their 
review of the eligibility packet.  
Prior to randomization, the study site should confirm that the patient still meets 
inclusion/exclusion criteria (especially SLE disease activity and treatment). The site will 
obtain a randomization number when registering the patient in interactive web response 
system (IWRS). All patients will receive BOS161721 or placebo according to the kit 
number assigned by the IWRS randomization scheme.  
After randomization, procedures include: 
 PROs: 
 
 C-SSRS 
 Laboratory evaluations (fasting): 
o 
Hematology and clinical chemistry 
o 
Direct Coomb’s test (if indicated for hemolytic anemia) 
o 
CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype (leukocyte 
immunophenotype for MAD patients only) 
o 
ADA 
o 
pSTAT3 (predose [trough] samples only in phase 1b)  
o 
 
o 
 
o 
 
o 
See Table 4 and Table 1 for details of PK sampling in the MAD and POC portions 
o 
Urine pregnancy test will be collected on WOCBP prior to study drug 
administration 
o 
Spot urine for protein/creatinine ratio 
o 
Urinalysis 
 Concomitant medication documentation 
 Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting 
requirements) 
 Full physical examination 
 Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours [± 15 minutes] 
postdose on Day 0) 
 12-lead ECG (prior to PK blood draw) 
 SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
PGA) 
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 SLICC/ACR damage index 
 Study drug administration: 
o 
Administration of BOS161721 or placebo will take place on-site, and is discussed 
in Section 7.3. 
 Injection site reaction assessment performed at 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Table 1 and Table 4), 
and details are provided in Section 6.  
All patients who are enrolled, randomized, and receive study drug, or undergo study-
specific procedures should reconsent with any updated versions of IRB/IEC approved 
informed consents during study participation as applicable and per institutional 
guidelines.  
5.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of 
Assessments (Table 1 and Table 4). See Schedule of Assessment tables for allowable 
windows for each visit.  
 Targeted physical examination 
 Vital signs (prior to PK blood draw) 
 Concomitant medication documentation 
 Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting 
requirements) 
 PROs: 
 
 Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
 Injection site reaction assessments will be performed predose  
 Direct Coomb’s test (if indicated for hemolytic anemia) 
 Spot urine for protein to creatinine ratio 
 Urinalysis 
 
 
 Plasma 
 
 PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
 SLICC/ACR Damage Index will be completed at Day 180 
 C-SSRS 
 ECGs prior to PK blood draw 
 See Table 4 and Table 1 for details of PK sampling in the MAD and POC studies, 
respectively 
 Fasting hematology and chemistry assessments 
 The CD4+ count and total IgG and IgM levels 
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 Plasma 
 and 
, ADA, and whole blood for leukocyte 
immunophenotype (leukocyte immunophenotype for MAD patients only) 
 pSTAT3 (predose [trough] samples only phase 1b) 
 nAb will be analyzed by central lab if patient is positive for ADA 
 CRP 
 
 
5.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270. These visits will 
include the following assessments as indicated in the Schedule of Assessments 
(Table 1 and Table 4): 
 PROs: 
 
 Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting 
requirements) 
 Injection site reactions 
 Targeted physical examination 
 Vital signs (prior to PK blood draw) 
 Spot urine for protein/creatinine ratio and urinalysis 
 Concomitant medication documentation 
 BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
 Fasting clinical laboratory assessments (hematology and clinical chemistry) 
 Direct Coomb’s test (if indicated for hemolytic anemia) 
 Plasma 
 
 
 
 12-lead ECG (prior to PK blood draw) 
 CRP 
 ADA 
 
 
 Urine pregnancy test 
 See Table 1 and Table 4 for details of PK sampling in the MAD and POC portions, 
respectively 
5.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw 
from the study at any time and for any reason. Every effort will be made to determine 
why any patient withdraws from the study prematurely. If the patient is unreachable by 
telephone, a registered letter, at the minimum, should be sent to the patient requesting 
him/her to contact the clinic.  
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All patients who withdraw from the study with an ongoing AE or SAE must be followed 
until the end of study or until the event is resolved or deemed stable, respectively.  
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should 
be performed (Day 180) and a last follow-up visit 90 days after dosing should be 
scheduled (Day 270). Safety follow-up visit procedures based on the Schedule of 
Assessments (see Section 5.4).  
Patient participation may be terminated prior to completing the study and the reason 
recorded as follows: 
 AE/SAE 
 Protocol deviation 
 Lost to follow-up 
 Patient withdraws consent at their own request 
 Investigator decision 
 Decision by the sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the Investigator or 
designee and sponsor.  
5.6 
Contingency Plans During the COVID-19 Pandemic 
 Safety oversight: In case a patient cannot return to the study site for the 
scheduled visit, the site staff will contact the patient remotely for safety follow up, 
for example, via telephone or video conferencing.   
 Central Laboratory: In the case there are courier issues that will prevent the 
protocol-required laboratory specimens to be sent to the study core laboratory, 
the site should have the safety laboratory speciments (Table 2: Hematology, 
Chemistry, and Urinalysis) sent to their local laboratory for analysis and review 
by the study physician. 
 Investigational Product Dosing: In cases when dosing cannot be performed 
during the protocol-designated windows, the Investigator should discuss each 
case with the Sponsor to determine whether it is a missed visit or whether the 
dosing can be performed outside protocol windows (as a protocol deviation). A 
minimum of 2 weeks must be maintained between consecutive doses. Patients 
who miss more than 2 doses of the study drug (whether consecutive or not) will 
be discontinued from the study and will undergo assessments as outlined in 
Section 5.5 (Premature Discontinuation).   
 


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6 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures 
are completed as described. However, it is anticipated that from time to time there may 
be circumstances, outside of the control of the Investigator, which may make it 
unfeasible to perform the test. In these cases, the Investigator will take all steps 
necessary to ensure the safety and wellbeing of the patient. When a protocol required 
test cannot be performed the Investigator will document the reason for this and any 
corrective and preventive actions which he/she has taken to ensure that normal 
processes are adhered to as soon as possible. All protocol violations are entered 
directly into the eCRFs.  
6.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
 General medical history 
 Documentation of SLE diagnosis 
 Historical medication therapy for SLE 
The following demographic information will be recorded:  
 Age 
 Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
 Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
 Height (without shoes, in cm) 
 Body weight, without shoes (kg) 
 BMI [kg/m2] 
Other baseline characteristics will be recorded as follows: 
 Concomitant medication documentation (see Section 4.6) 
 Status of child bearing potential and contraception 
6.2 
Safety Assessments 
6.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Table 1 and Table 4). Patient eligibility will be determined based on these tests at 
screening. Unscheduled clinical labs may be obtained at any time during the study to 
assess any perceived safety concerns.  
A central laboratory will be used (with the exception of urine pregnancy tests) to ensure 
accuracy and consistency in test results. Laboratory/analyte results that could unblind 
the study (i.e., biomarker results) will not be reported to investigative sites. Urinalysis 


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will be performed on midstream, clean catch specimens. Some biomarkers listed above 
will not be drawn at some sites due to geographical logistical challenges. See the 
laboratory manual for details.  
Endpoint analyses will be based on changes from baseline assessments at Days 120 
and 210.  
Table 2. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total 
CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte 
esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
Spot urine for protein/creatinine 
ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube 
test (QFT-G)d 
Serologyd (Hepatitis B and C; 
HIV-1/2 combination) 
Stool samplee 
Serum pregnancy test 
 
Additional Testsf  
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
Prothrombin 
time/international 
normalized ratio 
(repeat) 
Creatine kinase 
(repeat) 
 
ADA 
nAbg 
pSTAT3 (predose [trough] 
samples only in phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
& 
 
Whole blood for leukocyte 
immunophenotype (for MAD 
patients only) 
 
 
 
 
CRP  
Direct Coomb’s testh 
CCI
CCI
CCI
CCI
CCI
CCI


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Table 2. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Abbreviations: Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive 
protein; dsDNA = double-stranded deoxyribonucleic acid;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international 
normalized ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MAD = multiple 
ascending doses; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin 
concentration; MCV = Mean corpuscular volume; nAb = neutralizing antibody; 
pSTAT3 = phosphorylated signal transducer and activator of transcription 3; PT = prothrombin time; 
qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; SAE = serious adverse event; 
SC = subcutaneous; 
; TB = tuberculosis.  
a 
On all urine samples 
b 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 
55 years old 
c 
For WOCBP 
d 
Screening only 
e 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided 
to test for ova, parasites, and cryptosporidium 
f 
Additional testing for potential Hy's Law cases only (See Section 6.2.2.6.3) 
g 
If patient is positive for ADA 
h 
If clinically indicated for hemolytic anemia 
6.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening. Following a 
negative serum pregnancy result at screening, appropriate contraception must be 
commenced or continued and a further negative urine pregnancy test results will then 
be required at the baseline visit before the patient may receive the investigational 
product. Urine pregnancy tests will also be routinely repeated at study drug 
administration visits prior to study drug administration, at the last follow up visit day 
(Day 270) and additionally whenever 1 menstrual cycle is missed or when potential 
pregnancy is otherwise suspected. In the case of a positive pregnancy test or confirmed 
pregnancy, the patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose should be 
scheduled (Day 270). Safety follow-up visit procedures (see Section 5.4) are specified 
in the Schedule of Assessments (see Table 1 and Table 4).  
See Section 6.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during 
the study.  
6.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does 
not have evidence of active or latent or inadequately treated TB per the exclusion 
criteria (Section 4.5). The results of TB screening, which includes the 
QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 
CCI
CCI
CCI


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3 months prior to screening or during the screening period must be documented in 
study records prior to randomization (Day 0).  
6.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide 
cocktail simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in 
heparinized whole blood. Detection of INFγ performed by enzyme-linked 
immunosorbent assay (ELISA) is used to identify in vitro responses to these peptide 
antigens that are associated with Mycobacterium tuberculosis infection. QFT-G is an 
indirect test for M. tuberculosis infection (including disease) and is intended for use in 
conjunction with risk assessment, radiography and other medical and diagnostic 
evaluations.  
Test results will be reported as positive, negative, or indeterminate. A negative QFT-G 
test result is required to meet the inclusion criterion. In the case of an indeterminate 
result, repeat tests should be permitted for the purpose of determining eligibility of 
patients to enroll in this study. If a repeat test is indeterminate again, the patient is a 
screen failure. The procedure for using this test and interpreting the results will be 
described fully in the laboratory manual, which will be provided to Investigators.  
6.2.2 
Adverse Events 
6.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, 
whether or not considered drug related by the principal Investigator.  
AEs are unfavorable changes in a general condition, subjective or objective signs or 
symptoms, worsening of pre-existing concomitant disease, and clinically significant 
abnormality in laboratory parameters observed in a patient in the course of a clinical 
study.  
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease 
activity would not be recorded as AEs unless they meet the definition for SAEs 
(Section 6.2.2.5).  
6.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of 
study drug until the end of their participation in the study, including the safety follow up 
period.  
AEs may be volunteered spontaneously by the study patient, or discovered by the study 
staff during physical examinations or by asking an open, nonleading question such as 
‘How have you been feeling since you were last asked?’ All AEs and any required 
remedial action will be recorded on the Adverse Events eCRF and Safety Adverse 
Event Form. The details of the AE, date of AE onset, date of AE outcome, and action 


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taken for the AE will be documented together with the principal investigator’s 
assessment of the seriousness of the AE and causal relationship to the study drug 
and/or the study procedure.  
All AEs should be recorded individually, using diagnostic terms where possible. If the 
diagnosis is not established, individual symptoms may be reported. The AEs will 
subsequently be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  
6.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal Investigator according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 
criteria.41 When changes in the severity (grade) of an AE occur more frequently than 
once a day, the maximum severity for the event should be noted for that day. Any 
change in severity of signs and symptoms over a number of days will be captured by 
recording a new AE, with the amended severity grade and the date (and time, if known) 
of the change.  
6.2.2.4 
Causality of Adverse Events 
The principal Investigator will assess the causal relationship between BOS161721 or 
placebo and the AE. One of the following categories (Table 3) should be selected based 
on medical judgment, considering the definitions below and all contributing factors.  
Table 3. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time relationship 
to treatment administration and which concurrent disease or other drugs or chemicals cannot 
explain. The response to withdrawal of the treatment (dechallengea) should be clinically 
plausible. The event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallengeb procedure if necessary 
Unrelated 
A clinical event, including laboratory test abnormality, with little or no temporal relationship 
with treatment administration. May have negative dechallenge and rechallenge information. 
Typically explained by extraneous factors (e.g., concomitant disease, environmental factors, 
or other drugs or chemicals) 
 
a 
Dechallenge: Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE 
disappear partially or completely, within a reasonable time from drug discontinuation (positive 
dechallenge), or the symptoms continue despite withdrawal of the drug (negative dechallenge). Note that 
there are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug 
relatedness clearly exists (for example, as in bone marrow suppression, fixed drug eruptions, or tardive 
dyskinesia) 
b 
Rechallenge: Upon re-administration of a drug suspected of causing an AE in a specific patient in the 
past, the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative 
rechallenge) 
An unexpected adverse drug event is any adverse drug event for which the specificity or 
severity is not consistent with the current IP.  


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6.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death 
 Is life threatening; this means that the patient was at risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe 
 Requires hospitalization or prolongation in existing hospitalization 
 Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 Is a congenital anomaly or birth defect 
 Is other important medical event (see below) 
Important medical events that do not result in death, are not life threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
events are: 
 Intensive treatment in an emergency room or at home for allergic bronchospasm 
 Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
 Development of drug dependency or drug abuse 
Hospitalization for elective surgery or routine clinical procedures that are not the result 
of AE (e.g., elective surgery for a pre-existing condition that has not worsened) need not 
be considered SAEs. If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'nonserious' according to the 
usual criteria.  
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are 
associated with the use of the drug and are serious and unexpected.  
6.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Grades 2 to 5 injection site reaction, including erythema, pain, and induration 
(see Appendix 6) 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy (not including basal cell carcinoma or squamous cell carcinoma of skin) 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, 
disseminated herpes simplex, disseminated tuberculosis, Aspergillus sp., Candida 
albicans, Coccidioides immitis, Cryptococcus neoformans, Cytomegalovirus, 
Histoplasma capsulatum, Isospora belli, and Polyomavirus JC polyomavirus 


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6. Cryptosporidiasis 
6.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria. 42 In the event 
of anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient 
must discontinue IP and emergency resuscitation measures implemented. In case of 
other mild to moderate hypersensitivity reaction, depending on the severity, the 
Investigator may manage in accordance with the standard-of-care.  
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus, or flushing, swollen 
lips-tongue-uvula) and at least 1 of the following: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
 
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c. Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], 
syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
 
Reduced blood pressure after exposure to known allergen for that patient (minutes 
to several hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease 
from the patient’s baseline 
6.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs. These will include 
Grades 2 to 5 injection site erythema, pain, and induration (see Appendix 6), which are 
also captured as Adverse Events of Special Interest (see Section 6.2.2.6). The 
Investigator should provide a clear description of the observed or reported AE including 
location and severity. All concomitant treatments used to treat injection site reactions 
should be recorded and captured in the eCRF, together with the AE of injection site 
reactions.  


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6.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of DILI, and as potential Hy’s Law cases, and 
should always be considered important medical events. If symptoms compatible with 
DILI precede knowledge of serum chemical test abnormalities, liver enzyme 
measurements should be made immediately, regardless of when the next visit or 
monitoring interval is scheduled. In some cases, symptoms may be an early sign of 
injury and although typically less sensitive than serum enzyme elevations, they may 
indicate a need for prompt serum testing. An increase in liver enzymes should be 
confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event. Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline.  
All occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs (see Section 6.2.2.7.2 for reporting details).  
Potential DILI is defined as: 
1. 
ALT or AST elevation > 3 × ULN 
AND 
2. 
Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3. 
No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as 
possible, include laboratory tests, detailed history, and physical assessment. In addition 
to repeating measurements of AST and ALT, laboratory tests should include albumin, 
CK, total bilirubin, direct and indirect bilirubin, GGT, prothrombin time (PT)/International 
Normalized Ratio (INR), and alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, acetaminophen, recreational drug and 
supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of 
liver or allergic disease, and work exposure, should be collected. Further testing for 
acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) may be 
warranted. All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified 
at the time should be considered potential Hy’s Law cases irrespective of availability of 
all the results of the investigations performed to determine etiology of the abnormal 
LFTs. Such potential Hy’s Law cases should be reported as SAEs.  


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Study drug discontinuation is considered if there is marked serum AST or ALT elevation 
or evidence of functional impairment (as indicated by rising bilirubin or INR, which 
represent substantial liver injury) that is related to study drug. Discontinuation of 
treatment should be considered if: 
 ALT or AST > 8 × ULN 
 ALT or AST > 5 × ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
 ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia ( > 5%) 
6.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and 
communicated to the sponsor or designee. AEs should be reported as serious per the 
criteria in Section 6.2.2.5.  
After the first dose of study drug, when there is a decision to biopsy a potentially 
malignant tumor, lymph node, or other tissue (with the exception of suspected basal 
cell/squamous cell), the Investigator and/or consultant(s) should contact the sponsor 
clinicians or designee to discuss the issue and any decisions as soon as possible. Basal 
cell carcinoma or squamous cell carcinoma of skin is not considered an AE of special 
interest.  
6.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, disseminated herpes simplex, disseminated 
tuberculosis, Aspergillus sp., Candida albicans, Coccidioides immitis, Cryptococcus 
neoformans, Cytomegalovirus, Histoplasma capsulatum, Isospora belli, or Polyomavirus 
JC polyomavirus will be recorded as AEs of special interest.  
Cryptosporidiosis is also considered an AE of special interest. Patients will be evaluated 
for cryptosporidium in the stool at screening, and as clinically indicated (e.g., watery 
diarrhea) during the study. If a patient develops diarrhea during the study a stool sample 
must be provided to test for ova, parasites, and cryptosporidium.  
6.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.  
Each AE is to be assessed to determine if it meets the criteria for an SAE. If an SAE 
occurs, expedited reporting will follow local and international regulations, as appropriate, 
and is further outlined in Section 6.2.2.7.2.  


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6.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported 
within 24 hours to the sponsor via the Pregnancy Notification and Outcome Form, 
including pregnancy in female patients who received study drug and female partners of 
male study patients who received study drug. The pregnancy should be followed to term 
and/or outcome and this outcome should also be reported to the sponsor via the 
Pregnancy Notification and Outcome Form. Pregnancy itself is not regarded as an AE 
or SAE unless there is complication.  
In the case of a live birth, the structural integrity of the neonate can be assessed at the 
time of birth. In the event of a termination, the reason(s) for termination should be 
specified and, if clinically possible, the structural integrity of the terminated fetus should 
be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).  
If the outcome of the pregnancy meets the criteria for an AE or SAE (i.e., ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly [in a live born, a terminated fetus, an intrauterine fetal demise, or a 
neonatal death]), the Investigator should follow the procedures for reporting SAEs.  
Additional information about pregnancy outcomes that are reported as SAEs follows: 
 Spontaneous abortion includes miscarriage and missed abortion 
 Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as serious adverse events when the Investigator assesses the neonatal 
death as related or possibly related to exposure to investigational product. 
6.2.2.7.2 
Reporting of Serious Adverse Events 
The principal Investigator is responsible for providing notification to the sponsor of any 
SAE via the Safety Adverse Event Form, whether deemed study drug related or not, 
that a patient experiences during their participation in this study within 24 hours of 
becoming aware of the event.  
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information. This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy and 
exposure via breastfeeding cases. In the rare event that the Investigator does not 
become aware of the occurrence of an SAE immediately (e.g., if an outpatient study 
patient initially seeks treatment elsewhere), the Investigator is to report the event within 
24 hours after learning of it and document the time of his/her first awareness of the AE.  
The principal Investigator will review each SAE and evaluate the intensity and the 
causal relationship of the event to the study drug. All SAEs will be recorded from the 
time of first dose of study drug through the safety follow-up period (up to Day 270). 


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SAEs occurring after the final follow-up visit and coming to the attention of the principal 
Investigator must be reported only if there is (in the opinion of the principal Investigator) 
reasonable causal relationship with the study drug.  
As a minimum requirement, the initial notification should provide the following 
information: 
 Study number 
 Patient number 
 Details of the SAE (verbatim details are sufficient for immediate notification) 
 Criterion for classification as ‘serious’ 
 Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (e.g., hospital reports, consultant reports, 
autopsy reports, etc), with the study patient’s personal identifiers removed. All relevant 
information obtained by the principal Investigator through review of these documents 
will be recorded and submitted to the sponsor within 24 hours of receipt of the 
information. If a new Safety Adverse Event Form is submitted, then the principal 
Investigator must sign and date the form. The sponsor may also request additional 
information on the SAE, or clarification of omitted or discrepant information from the 
initial notification, which the principal Investigator or an authorized delegate should 
submit to the sponsor within 24 hours of the request as possible.  
6.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the 
site becoming aware of the event and recorded as such on the Adverse Events eCRF 
and Safety Adverse Event Form.  
Potential DILI will be reported based on specifications mentioned in Section 6.2.2.6.3.  
Each AE of special interest is to be assessed to determine if it meets the criteria for an 
SAE. If an SAE occurs, expedited reporting will follow local and international 
regulations, as appropriate, and is further outlined in Section 6.2.2.7.2.  
6.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits. All SAEs experienced by 
a patient, irrespective of the suspected causality, will be monitored until the event has 
resolved, until any abnormal laboratory values have returned to baseline or stabilized at 
a level acceptable to the principal Investigator and medical monitor, until there is a 
satisfactory explanation for the changes observed, or until the patient is lost to follow-
up.  


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See Section 6.2.2.7.1 for details related to follow-up of pregnancy. See 
Section 6.2.2.6.3 for details related to follow-up of potential DILI. See Section 6.2.2.6.4 
for details related to follow-up of malignancy.  
6.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as 
specified in the Schedule of Assessments (Table 1 and Table 4). Vital signs will be 
assessed on Day 0 at predose and at Day 0, 1 and 2 hours (± 15 minutes) postdose, as 
well as on each of the scheduled visit days during the study (excluding PK-only site 
visits). Supine BP and heart rate recordings will be made after the patient has been 
recumbent and at rest  5 minutes. When the timing of these measurements coincides 
with a blood collection, vital signs should be obtained prior to the time of the blood 
collection.  
6.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Table 1 and 
Table 4). ECG recording will initiate after the patient has been supine for at least 
5 minutes. On days of PK blood draws, the ECG will be collected before scheduled PK 
blood draws, though timing will be such that PK draws are collected on their scheduled 
times where possible.  
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of 
the tracing. The ECG will be recorded at a paper speed of 25 mm/second. The following 
ECG parameters will be collected: PR interval, QRS interval, RR interval, QT interval, 
and QT interval corrected for heart rate using Fridericia’s formula (QTcF).  
All ECGs must be evaluated by a qualified physician or qualified designee for the 
presence of abnormalities and will be captured electronically and retained for future 
evaluation if required, up to the time of the clinical study report (CSR) completion.  
6.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0. It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, 
throat, neck, thyroid, lymph nodes, and extremities, and dermatologic, respiratory, 
cardiovascular, gastrointestinal, musculoskeletal, neurologic, and psychiatric systems.  
The targeted (limited) physical examination will be completed at all other visits as 
indicated in the Schedule of Assessments (Table 1 and Table 4). It includes evaluation 
of patient complaints and SLE disease-related issues, and will exclude the genitourinary 
system.  
6.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior 
that was developed by Columbia University researchers for the National Institute of 


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Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity 
and track suicidal events through any treatment. It is a clinical interview providing a 
summary of both ideation and behavior that can be administered during any evaluation 
or risk assessment to identify the level and type of suicidality present. The C-SSRS can 
also be used during treatment to monitor for clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments 
(Table 1 andTable 4). Patients with recent (within the past 12 months) or active suicidal 
ideation or behavior based on patient responding “yes” to question 3, 4, or 5 is 
exclusionary at screening will be excluded from the study. Patients with recent or active 
suicidal ideation or behavior at subsequent study visits will have responses to the 
C-SSRS reviewed in detail to assess patient risk, and appropriate consultative mental 
health services will be provided.  
6.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule 
of Assessments (Table 1 and Table 4). Local injection site reactions will be assessed at 
2 hours postdose at baseline, and predose for each injection after baseline. Injection 
site reactions should be managed according to the standard of care. Injection site 
reactions, Grades 2 to 5, are to be reported as AEs of special interest (see 
Section 6.2.2.7.3).  
6.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in 
the Schedule of Assessments (Table 1 and Table 4). Blood samples (4 mL) to provide 
approximately 1.5 mL of plasma for anti BOS161721 antibody analysis will be collected 
into appropriately labeled tubes containing K2EDTA. The presence or absence of ADA 
will be determined in the serum samples using validated bioanalytical methods. Blood 
samples for ADA analysis will be collected up to Day 90 from all patients. Subsequent 
ADA samples will be collected from all patients but only analyzed by a central lab if the 
patient had a positive ADA on Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, a 
sample from this patient will be further analyzed in the neutralizing antibody (nAb) assay 
by a central lab.  
6.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of 
Assessments (Table 1 and Table 4).  
6.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients 
at the time of the visit and in the previous 30 days. It is a global index and includes 
24 clinical and laboratory variables that are weighted by the type of manifestation, but 


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not by severity. The total score falls between 0 and 105, with higher scores representing 
increased disease activity. The SLEDAI-2K has been shown to be a valid and reliable 
disease activity measure in multiple patient groups. A SLEDAI -2K of 6 or more 
generally represents moderately to severely active disease.44 
6.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the 
principle of the doctor’s intent to treat. Only clinical features attributable to SLE disease 
activity are to be recorded and based on the patient’s condition in the last 4 weeks 
compared with the previous 4 weeks. It will be scored as not present (0), improved (1), 
the same (2), worse (3), or new (4). Disease activity is graded separately for 9 body 
systems to 5 different grades (A to E) as follows: A (“Active”) is very active disease, B 
(“Beware”) is moderate activity, C (“Contentment”) is mild stable disease, D (“Discount”) 
is inactive now but previously active, and E (“Excluded”) indicates the organ was never 
involved.44 A shift from BILAG-2004 Grade A or B to a lower grade indicates a clinically 
relevant change in disease activity as the BILAG-2004 grades mirror the decision points 
for treatment interventions.  
Only Investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments. Preferably, the same Investigator should evaluate the 
patient at each BILAG-2004 assessment from screening to study completion. The 
Investigator must maintain documentation with descriptive details supporting the 
BILAG-2004 scoring (e.g., chart, worksheet, clinic notes, and labs) at each visit.  
See Appendix 5 for detailed specifications.  
6.3.3 
PGA of Disease Activity 
The PGA is used to assess Investigator’s general impression on the patient’s overall 
status of SLE disease activity via visual analogue scale (100 mm) with 0 being “very 
good, asymptomatic and no limitation of normal activities” with 100 mm being “most 
severe possible disease ever seen in all SLE patients”. PGA worsening is defined as an 
increase of > 30 mm from baseline.  
When scoring the PGA, the assessor should always look back at the score from the 
previous visit.  
6.3.4 
Composite Endpoints: SRI-4, SRI-5, SRI-6, and BICLA Response 
6.3.4.1 
SRI-4 Response 
The SRI-4 is a composite index of SLE disease improvement that consists of scores 
derived from the SLEDAI-2K and the BILAG 2004 Index. Response based on the SRI-4 
is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score; 2) no new severe disease activity 
(BILAG A organ score) or more than 1 new moderate organ score (BILAG B); and 3) no 


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deterioration from baseline in the PGA by ≥ 30 mm. The SRI-4 response in patients with 
moderate to severe SLE is associated with broad improvements in clinical and 
patient-reported outcomes.45  
6.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement 
that consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index. 
However, the SRI-5 and SRI-6 are computed with a minimal five-point or six-point 
improvement in SLEDAI-2K being required, respectively.46 
6.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it 
includes scores from the BILAG, SLEDAI-2K, and PGA. BICLA response is defined as: 
1) at least 1 gradation of improvement in baseline BILAG 2004 scores in all body 
systems with moderate disease activity at entry (e.g., all B [moderate disease] scores 
falling to C [mild], or D [no activity]); 2) no new BILAG A or more than 1 new BILAG B 
scores; 3) no worsening of total SLEDAI-2K score from baseline; 4) ≤ 10% deterioration 
in PGA score; and 5) no treatment failure.44 It is driven primarily by the BILAG, and has 
been used in phase 2 and 3 mAb studies.47 
For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined.  
6.3.5 
CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in 
cutaneous lupus, shown to be valid, reliable, and sensitive to changes in disease 
activity.48 Response is defined as 50% improvement from baseline in “A” or “B” scores. 
This assessment will be applied to all patients who have cutaneous disease activity.  
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on 
MAD and POC studies will be compared with baseline for 50% improvement.  
6.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the 
shoulder, elbow, wrist, hand, knee joints. Joints of the feet are excluded.  
6.4 
Other Variables 
6.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring 
system. This index records damage occurring in patients with SLE regardless of cause, 


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with demonstrated content, face, criterion, and discriminant validity.49 It will be 
performed on Days 0 and 180.  
6.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of 
the study visit prior to any clinical assessments. A member of the staff should be 
available if a patient requires further instruction and to review the PRO questionnaires 
for completeness prior to leaving the clinic. The PROs include the 
 and the 
 and will be assessed as specified in the Schedule of Assessments (Table 1 and 
Table 4).  
 
.50  
 
 
.  
6.5 
Pharmacokinetic Assessments 
During the MAD phase 1b (all sites) and POC phase 2 (select sites only) parts of the 
study, blood samples for PK analysis of BOS161721 or placebo concentration will be 
collected according to Table 4 and Table 1.  
Plasma concentrations of BOS161721 will be measured using a validated 
immunoassay. The PK parameters will be calculated from the plasma concentration 
actual time profiles.  
6.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the 
Schedule of Assessments (Table 1 and Table 4) for each of the following parameters: 
 pSTAT3 (predose [trough] samples only phase 1b) 
 Antibodies: 
 
 Plasma complement (
) 
 Plasma 
 and 
 
 Whole blood for leukocyte immunophenotype (for MAD patients only) 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers.  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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6.8 
Protocol Deviations 
Protocol deviations will be documented during the study.  
7 STUDY DRUG MANAGEMENT 
7.1 
Description 
7.1.1 
Formulation 
 
 
  
 
 
  
Additional information regarding dose preparation will be provided in a separate 
Pharmacy Manual.  
7.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the 
manufacturer’s instructions. BOS161721 or placebo will be stored in a securely locked 
area, accessible to authorized persons only, until needed for dosing.  
Information regarding storage and dose preparation will be provided in a separate 
Pharmacy Manual.  
7.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc. 
Investigational medicinal products will be packaged and labeled according to applicable 
local and regulatory requirements.  
7.3 
Dose and Administration 
Details of dosing are provided in Section 3.1.  
Each unit dose will be prepared by a qualified staff member. The vials of investigational 
product (IP) will appear identical and will have a "blinded" label on the vials that will 
state 
 mg or placebo. When the site goes into the IWRS to request the patient kit(s), 
the IWRS will assign the appropriate number of kits (regardless of assignment to 
placebo or active treatment) per the dose (i.e., 
 
). If a patient is randomized to the placebo arm, they will 
receive the matching number of kits.  
CCI
CCI
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CCI


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The designated staff member (or designee under the direction of the designated staff 
member) will dispense BOS161721 or placebo for each patient according to the 
protocol, randomization list, and Pharmacy Manual, if applicable.  
After receiving sponsor approval in writing, the investigational site is responsible for 
returning all unused or partially used BOS161721 or placebo to the sponsor or 
designated third party or for preparing BOS161721 or placebo for destruction via 
incineration.  
Further details are found in a separate Pharmacy Manual.  
7.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate 
accountability records of BOS161721 or placebo throughout the clinical study. The drug 
accountability log includes information such as, randomization number, amount 
dispensed, and amount returned to the pharmacy (if any). Used investigational product 
returned to the pharmacy may be maintained in an ambient condition. Unused product 
should follow the instructions in the Pharmacy Manual. The used product that is 
returned should be marked as ‘returned’ and kept separate from the products not yet 
dispensed.  
All dispensing and accountability records will be available for sponsor review after 
database lock procedures are completed. During safety monitoring, the drug 
accountability log will be reconciled with the products stored in the pharmacy.  
7.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 4.6 and Appendix 4 will be 
listed as protocol violations if taken when not permitted.  
7.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
Investigator. The date and time of dosing will be documented on each dosing day. 
Comments will be recorded if there are any deviations from the planned dosing 
procedures.  
8 STATISTICS 
The following analyses are planned: 
 
An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC part of the study.  
 
An additional analysis may be performed for the MAD portion of the study when all 
MAD patients have completed the safety follow-up or withdrawn from the study, and 


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prior to final analysis. Data from the POC part of the study will be excluded from this 
additional analysis.  
 
The final analysis will be performed when all patients have completed the POC 
safety follow-up or withdrawn from the study.  
 
Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data. The frequency and details 
of the content and format of the safety review meetings will be described in the SAP 
and/or DMC charter.  
All statistical analyses will be performed using Statistical Analysis Software (SAS®) 
Version 9 or higher.  
The following standards will be applied for the analysis unless otherwise specified. Data 
will be summarized descriptively by treatment and overall for each study portion. For the 
MAD part of the study, BOS161721 will be summarized overall and by each dose level, 
and placebo patients from each cohort will be combined. Select parameters may be 
summarized using patients from both study parts. Statistical testing will be performed on 
data from the phase 2 portion only. 
Continuous data will be summarized using number, mean, standard deviation (SD), 25th 
and 75th percentiles, minimum, median, and maximum. Categorical data will be 
summarized by treatment group using frequency tables (number and percentage). Time 
to event data will be summarized using counts, medians, 25th and 75th percentiles, and 
standard error. All data will be listed for all patients.  
Statistical inference will be based on a 2-tailed test with an overall 0.10 level of 
significance, unless stated otherwise.  
The effects of noncompliance, background therapy use, treatment discontinuations, 
premature withdrawal from study and covariates will be assessed to determine the 
impact on the general applicability of results from this study. Exploratory analyses of the 
data will be conducted as deemed appropriate. Any deviations from the planned 
analyses will be described and justified in the final integrated CSR.  
Protocol deviations and prohibited medications that define medication failures will be 
fully assigned and documented before database lock and unblinding.  
Further details of the analysis, including the handling of missing data, transformations 
and other data handling procedures will be provided in the SAP.  
8.1 
Sample Size 
Sample size in the phase 1b part of the study is based on operational consideration.  
The sample size in the phase 2 portion is based on the primary endpoint, SRI-4 
Response at Day 210. Based on efficacy data from a recently completed study with 
Ustekinumab51, where the primary endpoint was also SRI-4, the sample size in the 
phase 2 part of the BOS161721-02 study is set at 96 evaluable patients. In the 


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Ustekinumab study of 102 patients, a statistically significant difference in SRI-4 
response was shown in favor of Ustekinumab (62% of Ustekinumab treated patients 
achieved SRI-4 response vs. 33% in patients receiving placebo). The Ustekinumab 
phase 2 study is an appropriate comparator to BOS161721-02 because both studies 
share the same primary endpoint of SRI-4 response and BOS161721 and Ustekinumab 
have overlapping mechanisms of action (T follicular helper and Th17 cell biology).  
Approximately 110 additional patients will be randomized in a 2:1 ratio to BOS161721 
versus placebo to achieve approximately 96 evaluable patients in the FAS of the 
phase 2 portion. This assumes 14 patients will drop prior to having received treatment 
or having completed a post-baseline efficacy measure. Enrollment and randomization 
will be monitored in a blinded fashion and may be increased if needed to ensure at least 
96 evaluable patients are randomized into the FAS.  
A total of 96 evaluable patients randomized provides 80% power to detect a treatment 
difference of 29% in SRI-4 response rates at Day 210, based on a targeted 2-sided 
significance level of 10% and using a 2-sided Pearson’s chi-squared test. This assumes 
a response rate of 62% for BOS161721 and 33% for placebo.  
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all patients who 
receive at least 1 dose (partial or complete) of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation. FAS analyses will be conducted on the 
basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol violations 
from the efficacy analysis. The PP Population will include all patients from the FAS 
except those with major violations to the protocol deemed to impact the analysis of the 
primary endpoint. These violations will be identified based on blinded data prior to study 
unblinding. PP analyses will be conducted on the basis of the randomized treatment.  
Safety analyses will be based on the safety analysis set (SS), defined as all patients 
who receive at least 1 dose (partial or complete) of study treatment. Safety analyses will 
be conducted on the basis of actual treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, defined as the FAS 
with sufficient concentration data for the calculation of PK parameters.  
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all randomized patients.  


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8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will be assessed 
via Pearson’s chi-squared analysis. The primary efficacy endpoint will be analyzed 
using the FAS and if needed repeated in the PP analysis set. Missing values will be 
addressed by employing a last observation carried forward (LOCF) analysis. Other 
imputation methods may be employed as a sensitivity analysis and will be described in 
the SAP. Analyses based on observed values may also be performed.  
Exploratory subgroup analyses assessing impact of baseline factors such as baseline 
disease severity, background therapy, race, geography, baseline serologic activity and 
other characteristics may be performed. Additional exploratory analyses of disease 
activity endpoints may be performed based on emerging data.  
Patients that received prohibited medications or unallowable CS usage as described in 
Section 4.6 will be considered “medication failures” and will be treated as statistical 
non-responders at time points on or following the first date of prohibited medication or 
unallowable CS usage for the primary efficacy analysis. The determination of 
medication failures will be reviewed using blinded data and finalized prior to unblinding.  
The superiority of BOS161721 relative to placebo will be evaluated. If the proportion of 
SRI-4 responders for the selected POC dose in BOS161721 arm is higher than that of 
the placebo arm, then BOS161721 will be considered superior to placebo if the 2-sided 
p-value is < 0.10. Secondary and exploratory endpoints for this POC portion will be 
evaluated based on the same statistical hypothesis.  
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared analysis. 
Continuous efficacy endpoints will be assessed via analysis of variance (ANOVA) or 
analysis of covariance (ANCOVA) and treatment will be compared using the F-test. 
Repeated measures mixed models may be performed to evaluate data collected at 
each visit and overall. Time-to-event endpoints will be assessed via Kaplan-Meier 
methodology and treatment will be compared using the log-rank test. The secondary 
efficacy endpoints will be analyzed on the FAS and if needed repeated in the PP 
analysis set. Details including handling of missing data and “medication failures” will be 
available in the SAP.  
8.2.5 
Analysis of Safety 
8.2.5.1 
Safety Analysis 
Safety analyses will be performed on the SS. AE data will be coded to system organ 
class and preferred term using MedDRA. The number and percentage of patients 
experiencing any treatment-emergent AE, overall, and by system organ class and 
preferred term, will be tabulated. Treatment-emergent AEs will also be summarized by 
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Concomitant medications will be coded using the WHO Drug dictionary. Observed 
values and changes from baseline in vital signs, ECG readings, and hematology and 
clinical chemistry parameters will be summarized at each individual visit.  
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 
Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected during the MAD 
phase 1b portion of the study using non-compartmental analysis and include the 
following:  
 Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in tabular format.  
If data permit, the following analyses will be performed for plasma BOS161721 
concentration data: 
 A listing of all plasma BOS161721 concentrations by patient at actual times post 
dose; 
 A descriptive summary of plasma BOS161721 concentrations. Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, 
and maximum will be tabulated by study days with PK assessments. 
8.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format.  
Exploratory analyses examining the relationship between PD parameters and PK 
concentration and PK parameters will be performed.  
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each 
relevant PK parameter on X-axis will be examined for relationship. If relationships are 
revealed by these diagnostic plots, PK and PD data from this study may be analyzed 
using modeling approaches to describe the relationship and may also be pooled with 
data from other studies to investigate any association between BOS161721 exposure 
and biomarkers or significant safety endpoints.  
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the POC decision 
for dose selection.  
Since there is no IA during the POC part of the study, there is no impact on the type 1 
error.  


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9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the 
principal Investigator abide by the principles of the International Council for 
Harmonisation (ICH) guidelines on GCP and the Declaration of Helsinki (Version 2013). 
The clinical study also will be carried out in the keeping with national and local legal 
requirements (in accordance with US IND regulations [21 CFR 56]).  
9.2 
DMC 
This study will use an external DMC. The DMC is an independent committee 
established to provide oversight of safety considerations in study and to provide advice 
to the sponsor regarding actions the committee deems necessary for the continuing 
protection of enrolled patients and those yet to be recruited to the trial as well as for the 
continuing validity and scientific merit of the study results. The DMC is charged with 
assessing such actions in light of an acceptable benefit/risk profile for BOS161721. The 
recommendations made by the DMC (i.e., dose escalation, etc.) will be forwarded to the 
sponsor for final decision. The sponsor will forward such decisions, which may include 
summaries of safety data which are not endpoints, to regulatory authorities, as 
appropriate.  
The sponsor will appoint a DMC for the periodic review of available study data. The 
DMC is an independent group of experts that advises the sponsor and the study 
Investigators. The members of the DMC serve in an individual capacity and provide 
their expertise and recommendations. The primary responsibilities of the DMC are to 
(1) periodically review and evaluate the accumulated study data for participant safety, 
study conduct, and progress, (2) make recommendations to the sponsor concerning the 
continuation, modification, or termination of the study and (3) suggest dose for POC 
portion of the study as described in Section 3.1.1.3.  
The DMC considers study-specific data as well as relevant background knowledge 
about the disease, test agent, or patient population under study. The DMC is 
responsible for defining its deliberative processes, including event triggers that would 
call for an unscheduled review, stopping guidelines, unmasking (unblinding), and voting 
procedures prior to initiating any data review. The DMC is also responsible for 
maintaining the confidentiality of its internal discussions and activities as well as the 
contents of reports provided to it.  
The DMC will have access to unblinded treatment information during the clinical trial. 
Details regarding management and process of this committee are found in the DMC 
Charter.  
The DMC may recommend termination of BOS161721 treatment arm or the entire 
BOS161721 MAD/POC trial for any safety concern that is felt to outweigh potential 


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benefits. The recommendation must be supported by the sponsor as indicated in the 
DMC Charter.  
9.3 
Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees/IRB must meet the guidelines set out by the U. S. Food 
and Drug Administration (FDA) and conform to local laws and customs where 
appropriate. Written IRB/IEC approval for the protocol and the signed ICF must be 
obtained and transmitted to Boston Pharmaceuticals or representative before the study 
can be initiated. The IRB/IEC must be informed of and approve all protocol 
amendments. The Investigator will ensure that this study is conducted in full 
conformance with all applicable local and regional laws and regulations. The complete 
text of the World Medical Association Declaration of Helsinki is given in Appendix 2.  
9.4 
Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the 
written informed consent will be obtained according to the regulatory and legal 
requirements of the participating country. As part of this procedure, the principal 
Investigator must explain orally and in writing the nature, duration, and purpose of the 
study, and the action of the drug in such a manner that the study patient should be 
informed that he/she is free to withdraw from the study at any time. He/she will receive 
all information that is required by federal regulations and ICH guidelines. The principal 
Investigator or designee will provide the sponsor with a copy of the IRB-approved ICF 
prior to the start of the study.  
The informed consent document must be signed and dated; 1 copy will be handed to 
the patient and the principal Investigator will retain a copy as part of the clinical study 
records. The principal Investigator will not undertake any investigation specifically 
required for the clinical study until written consent has been obtained. The terms of the 
consent and when it was obtained must also be documented.  
If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC. Patients currently enrolled may need to sign this revision (based 
on IRB/IEC requirements) and all future patients enrolled in the clinical study will be 
required to sign this revised ICF.  
9.5 
Records Management 
The principal Investigator will ensure the accuracy, completeness, and timeliness of the 
data reported to the sponsor. Data collection processes and procedures will be 
reviewed and validated to ensure completeness, accuracy, reliability, and consistency. 
A complete audit trail will be maintained of all data changes. The principal Investigator 
or designee will cooperate with the sponsor’s representative(s) for the periodic review of 
study documents to ensure the accuracy and completeness of the data capture system 
at each scheduled monitoring visit.  


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Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study 
sites by means of electronic or manual queries.  
The principal Investigator or designee will prepare and maintain adequate and accurate 
study documents (medical records, ECGs, AE and concomitant medication reporting, 
raw data collection forms, etc.) designed to record all observations and other pertinent 
data for each patient receiving BOS161721 or placebo.  
The principal Investigator will allow sponsor representatives, contract designees, 
authorized regulatory authority inspectors, and the IRB to have direct access to all 
documents pertaining to the study.  
Electronic case report forms are required and should be completed for each randomized 
patient. It is the principal Investigator’s responsibility to ensure the accuracy, 
completeness, legibility, and timeliness of the data reported on the patients’ eCRF. 
Electronic case report forms should be completed in a timely fashion to support the 
study timelines. Source documentation supporting the eCRF data should indicate the 
patient’s participation in the study and should document the dates and details of study 
procedures, AEs, and patient status. The principal Investigator or designated 
representative should complete and the principal Investigator should verify the source 
documents as the information is collected. Any outstanding entries must be completed 
immediately after the final examination. An explanation should be given for all missing 
data.  
The principal Investigator will ensure the accuracy, completeness, and timeliness of the 
data reported to the Sponsor. Data collection processes and procedures will be 
reviewed and validated to ensure completeness, accuracy, reliability, and consistency. 
A complete audit trail will be maintained of all data changes.  
9.6 
Source Documentation 
The documents that will form the source data for the clinical study (e.g., patient charts, 
laboratory reports) must be defined and documented in the in-house study master file 
prior to the start of the study. Data on the eCRFs which will be checked against source 
data during monitoring visits must also be defined and documented in the in-house 
study master file including the percentage of each of the source data to be verified and 
the percentage of patients’ eCRFs to be monitored.  
9.7 
Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of 
BOS161721. However, these documents should be retained for a longer period if 
required by the applicable legal requirements.  


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10 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with 
the Investigator. This will include telephone calls and on-site visits. The study will be 
routinely monitored to ensure compliance with the study protocol and the overall quality 
of data collected. During the on-site visits, the eCRFs will be reviewed for completeness 
and adherence to the protocol. As part of the data audit, source documents will be 
made available for review by the study monitor. The study monitor may periodically 
request review of the Investigator study file to assure the completeness of 
documentation in all respects of clinical study conduct. The study monitor will verify that 
each patient has proper consent documentation from the patient and/or patient’s 
authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB. The study monitor will also 
verify that assent was obtained for patients not capable of providing informed consent or 
that documentation is provided by the Investigator explaining why the patient was 
unable to provide assent. The Investigator or appointed delegate will receive the study 
monitor during these on-site visits and will cooperate in providing the documents for 
inspection and respond to inquiries. In addition, the Investigator will permit inspection of 
the study files by authorized representatives of the regulatory agencies. On completion 
of the study, the study monitor will arrange for a final review of the study files after which 
the files should be secured for the appropriate time period.  
Throughout the course of the study, the medical monitor will determine eligibility of all 
screened patients, will address any medical issues that might arise, clarify medical 
questions, review patient safety data (e.g., AE/SAE, laboratory, and ECG), and partner 
with the study team in the overall study management. The study medical monitoring 
plan will document additional details of the study medical oversight and monitoring.  
11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study 
patients, may be made only by Boston Pharmaceuticals. A protocol change intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRB/IEC is notified within 5 days.  
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await 
approval before implementing the changes. Boston Pharmaceuticals will submit protocol 
amendments to the appropriate regulatory authorities for approval.  
If in the judgment of the IRB/IEC, the Investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the 
potential risk to the patient and/or has an impact on the patient's involvement as a study 
participant, the currently approved written ICF will require similar modification. In such 
cases, informed consent will be renewed for patients enrolled in the study before 
continued participation.  


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12 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate 
regulatory authorities with clinical study reports according to the applicable regulatory 
requirements.  
By signing the protocol, the principal Investigator agrees with the use of results of the 
clinical study for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals. If necessary, the competent 
authorities will be notified of the principal Investigator’s name, address, qualifications, 
and extent of involvement.  
The principal Investigator shall not publish any data (poster, abstract, paper, etc.) 
without having consulted and obtained approval from the sponsor in advance.  
13 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal Investigator reserve the right to 
terminate the study at the Investigator’s site at any time. Should this be necessary, 
Boston Pharmaceuticals or a specified designee will inform the appropriate regulatory 
authorities of the termination of the study and the reasons for its termination, and the 
principal Investigator will inform the IRB/IEC of the same. In terminating the study 
Boston Pharmaceuticals and the principal Investigator will assure that adequate 
consideration is given to the protection of the patients’ interests.  
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Boston Pharmaceuticals, except to the extent necessary to 
obtain informed consent from patients who wish to participate in the trial or to comply 
with regulatory requirements. However, authorized regulatory officials, IRB/IEC 
personnel, Boston Pharmaceuticals, and its authorized representatives are allowed full 
access to the records.  
Identification of patients and eCRFs shall be by initials, birthdate, or patient number. 
Documents that identify the patient (e.g., the signed informed consent document) must 
be maintained in confidence by the principal Investigator. If required, the patient's full 
name may be made known to an authorized regulatory agency or other authorized 
official.  


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25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al. Control of matrix 
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26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et 
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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al. Follicular helper T-cells (Tfh) and 
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29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al. Impact of interleukin-21 
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30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, 
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Arthritis Rheum. 2012a;64(6):2001-11.  
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al. Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic 
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33 Wang W, Wang EQ, Balthasar JP. Monoclonal Antibody Pharmacokinetics and 
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35 Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. 
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36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al. Loss-of-
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37 Hunter PR, Nichols G. Epidemiology and clinical features of Cryptosporidium 
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40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US: http://www. cdc. 
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41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, 
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42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, 
et al. Second symposium on the definition and management of anaphylaxis: 
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43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment 
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44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M. Indices to assess patients with 
systemic lupus erythematosus in clinical trials, long-term observational studies, 
and clinical care. Clin Exp Rheumatol 2014; 32(85):S85-95.  
45 Furie R, Wang L, Drappa J, Illei G. Systemic Lupus Erythematosus (SLE) Responder 
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(Cutaneous Lupus Erythematosus Disease Area and Severity Index): An 
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49 Stoll T, Seifert B, Isenberg DA. SLICC/ACR Damage Index is Valid, and Renal and 
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50 
 
  
51 Van Vollenhoven RF, Hahn BH, Tsokos GC, et al. Efficacy and safety of 
ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus 
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16 APPENDICES 


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16.1 Appendix 1: Names of Study Personnel 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 400 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
 
 
 
 
 
Clinical Research 
Organizations: 
 
 
  
 
 
 
 
 
 
Bioanalytical Laboratory: 
 
 
 
Central Laboratory: 
 
 
 
 
 
 
PPD
PPD
PPD
PPD


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16.2 Appendix 2: Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles For Medical Research Involving Human Subjects.  
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other participants 
in medical research involving human subjects. Medical research involving human 
subjects includes research on identifiable human material or identifiable data.  
It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty.  
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my subject will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the subject's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the subject".  
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects.  
In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society.  
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic, and therapeutic procedures and the understanding of the 
etiology and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility, and quality.  
In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens.  


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Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable 
and need special protection. The particular needs of the economically and medically 
disadvantaged must be recognized. Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and 
for those for whom the research is combined with care.  
Research Investigators should be aware of the ethical, legal, and regulatory 
requirements for research on human subjects in their own countries as well as 
applicable international requirements. No national ethical, legal, or regulatory 
requirement should be allowed to reduce or eliminate any of the protections for human 
subjects set forth in this Declaration.  
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject.  
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation.  
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected.  
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
Investigator, the sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any SAEs. The researcher should also submit to the committee, 
for review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects.  
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.  
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human subject must always rest with a subject of the research, 
even though the subject has given consent.  


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Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available.  
Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and 
can be satisfactorily managed. Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results.  
Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject. This is 
especially important when the human subjects are healthy volunteers.  
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research.  
The subjects must be volunteers and informed participants in the research project.  
The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the 
confidentiality of the subject’s information and to minimize the impact of the study on the 
subject's physical and mental integrity and on the personality of the subject.  
In any research on human beings, each potential subject must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed.  
When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship.  
For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the Investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons.  


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When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the Investigator must obtain that 
assent in addition to the consent of the legally authorized representative.  
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate.  
Both authors and publishers have ethical obligations. In publication of the results of 
research, the Investigators are obliged to preserve the accuracy of the results. Negative 
as well as positive results should be published or otherwise publicly available. Sources 
of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publication. Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication.  
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic, or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the subjects who are research subjects.  
The benefits, risks, burdens, and effectiveness of a new method should be tested 
against those of the best current prophylactic, diagnostic, and therapeutic methods. This 
does not exclude the use of placebo, or no treatment, in studies where no proven 
prophylactic, diagnostic, or therapeutic method exists.  
At the conclusion of the study, every subject entered into the study should be assured of 
access to the best-proven prophylactic, diagnostic, and therapeutic methods identified 
by the study.  
The physician should fully inform the subject which aspects of the care are related to 
the research. The refusal of a subject to participate in a study must never interfere with 
the subject-physician relationship.  
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent 
from the subject, must be free to use unproven or new prophylactic, diagnostic, and 
therapeutic measures, if in the physician’s judgment it offers hope of saving life, re-
establishing health, or alleviating suffering. Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy. In all cases, 


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new information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed.  


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16.3 Appendix 3: Commonly Used Corticosteroid Equivalents 
 
Medication  
Prednisone Dose Equivalence 
Prednisone 
1 mg 
Cortisone 
5 mg 
Hydrocortisone 
4 mg 
Prednisolone 
1 mg 
Methylprednisolone 
0.8 mg 
Triamcinolone 
0.8 mg 
Budesonide 
0.25 mg 
Dexamethasone 
0.16 mg 
Bethamethasone 
0.16 mg 


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16.4 Appendix 4: Medication Washout Periods 
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
24 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks for oral and 8 weeks for topical 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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16.5 Appendix 5: BILAG-2004 (Study-Specific Modified Criteria) 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
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16.6 Appendix 6: Injection Site Reaction Grading Scale 
Adverse event 
Injection site reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Definition: A disorder 
characterized by an 
intense adverse 
reaction (usually 
immunologic) 
developing at the site 
of an injection 
Tenderness 
with or without 
associated 
symptoms 
(e.g., warmth, 
erythema, 
itching) 
Pain; 
Lipodystrophy; 
Edema; 
phlebitis 
Ulceration or 
necrosis;  
Severe tissue 
damage; 
Operative 
intervention 
indicated 
Life-
threatening 
consequenc
es; 
urgent 
intervention 
indicated 
Death 
 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
 limiting self-
care ADL 
- 
- 
Rash 
maculopapular/Erythe
ma/Induration 
 
Definition: A disorder 
characterized by the 
presence of macules 
(flat) and papules 
(elevated). Also known 
as morbilliform rash, it 
is one of the most 
common cutaneous 
adverse events, 
frequently affecting the 
upper trunk, spreading 
centripetally, and 
associated with 
pruritus.  
Macules/papule
s 
covering < 10% 
BSA with or 
without 
symptoms 
(e.g., pruritus, 
burning, 
tightness) 
Erythema 
covering < 10% 
BSA with or 
without 
symptoms 
(e.g., pruritus, 
burning, 
tightness) 
Macules/papules 
covering 10% - 
30% BSA with or 
without 
symptoms (e.g., 
pruritus, burning, 
tightness); 
limiting 
instrumental 
ADL; 
Erythema 30% 
BSA with or 
without 
symptoms (e.g., 
pruritus, burning, 
tightness); 
limiting 
instrumental ADL 
Macules/pap
ules 
covering > 30
% BSA with 
or without 
associated 
symptoms; 
limiting 
self-care ADL 
 
Erythema 
covering > 30
% BSA with 
or without 
associated 
symptoms; 
limiting 
self-careADL 
- 
- 
ADL = active daily living 


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16.7 Appendix 7: Opioid Oral Morphine mg Equivalents of Commonly 
Used Opioids 
Note that this list is not comprehensive. If an opioid is being used which is not in this list, please see the 
appropriate conversion factor below.  
 
 
Opioid  
30 mg morphine equivalent 
butorphanol 
4.3 mg/day 
codeine 
200 mg/day 
dihydrocodeine 
120 mg/day 
fentanyl transdermal 
12.5 mg/day 
hydrocodone 
30 mg/day 
hydromorphone 
7.5 mg/day 
levorphanol tartrate 
2.7 mg/day 
meperidine HCl 
300 mg/day 
oxycodone 
20 mg/day 
oxymorphone 
10 mg/day 
pentazocine 
81.1 mg/day 
tapentadol 
75 mg/day 
tramadol 
300 mg/day 


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Opioid Oral Morphine Equivalent Conversion Factorsa,b 
CDC = Centers for Disease Control; CMS = Centers for Medicare and Medicaid Services; FDA = Food 
and Drug Administration; MAT = Medication Assisted Treatment; MME = morphine mg equivalent; 
OMS = Overutilization Monitoring System.  
a 
The MME conversion factor is intended only for analytic purposes where prescription data is used to 
calculate daily MME. It is to be used in the formula: Strength per Unit × (Number of Units/Days 
Supply) × MME conversion factor = MME/Day. This value does not constitute clinical guidance or 
recommendations for converting patients from one form of opioid analgesic to another. Please consult 
the manufacturer’s full prescribing information for such guidance. Use of this file for the purposes of 
any clinical decision-making warrants caution.  
Type of Opioid (strength in units) 
MME Conversion Factor 
Buprenorphine film/tablec (mg) 
30 
Buprenorphine patchd (mcg/hr) 
12.6 
Buprenorphine film (mcg) 
0.03 
Butorphanol (mg) 
7 
Codeine (mg) 
0.15 
Dihydrocodeine (mg) 
0.25 
Fentanyl buccal or SL tablets, or lozenge/trochee (mcg) 
0.13 
Fentanyl film or oral sprayf (mcg) 
0.18 
Fentanyl nasal sprayg (mcg) 
0.16 
Fentanyl patchh (mcg) 
7.2 
Hydrocodone (mg) 
1 
Hydromorphone (mg) 
4 
Levorphanol tartrate (mg) 
11 
Meperidine hydrochloride (mg) 
0.1 
Methadonei (mg) 
3 
> 0, ≤ 20 
4 
> 20, ≤ 40 
8 
> 40, ≤ 60 
10 
> 60 
12 
Morphine (mg) 
1 
Opium (mg) 
1 
Oxycodone (mg) 
1.5 
Oxymorphone (mg) 
3 
Pentazocine (mg) 
0.37 
Tapentadolj (mg) 
0.4 
Tramadol (mg) 
0.1 


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b 
National Center for Injury Prevention and Control. CDC compilation of benzodiazepines, muscle 
relaxants, stimulants, zolpidem, and opioid analgesics with oral morphine mg equivalent conversion 
factors, 2016 version. Atlanta, GA: Centers for Disease Control and Prevention; 2016. Available at 
https://www.cdc.gov/drugoverdose/media/. For more information, send an email to Mbohm@cdc.gov.  
c 
Buprenorphine formulations with a FDA approved indication for MAT are excluded from Medicare’s 
Overutilization Monitoring System’s opioid overutilization reporting.  
d 
The MME conversion factor for buprenorphine patches is based on the assumption that 1 mg of 
parenteral buprenorphine is equivalent to 75 mg of oral morphine and that one patch delivers the 
dispensed micrograms per hour over a 24 hour day. Example: 5 μg/hr buprenorphine patch × 
24 hrs = 120 μg/day buprenorphine = 0.12 mg/day = 9 mg/day oral MME. In other words, the 
conversion factor not accounting for days of use would be 9/5 or 1.8.  
However, since the buprenorphine patch remains in place for 7 days, we have multiplied the conversion 
factor by 7 (1.8 × 7 = 12.6). In this example, MME/day for 4 5 μg/hr buprenorphine patches dispensed for 
use over 28 days would work out as follows: Example: 5 μg/hr buprenorphine patch × (4 patches/28 days) 
× 12.6 = 9 MME/day. Please note that because this allowance has been made based on the typical 
dosage of 1 buprenorphine patch per 7 days, you should first change all Days Supply in your prescription 
data to follow this standard, i.e., Days Supply for buprenorphine patches = number of patches x 7.  
e 
The MME conversion factor for fentanyl buccal tablets, sublingual tablets, and lozenges/troche is 
0.13. This conversion factor should be multiplied by the number of micrograms in a given tablet or 
lozenge/troche.  
f 
The MME conversion factor for fentanyl film and oral spray is 0.18. This reflects a 40% greater 
bioavailability for films compared to lozenges/tablets and 38% greater bioavailability for oral sprays 
compared to lozenges/tablets.  
g 
The MME conversion factor for fentanyl nasal spray is 0.16, which reflects a 20% greater 
bioavailability for sprays compared to lozenges/tablets.  
h 
The MME conversion factor for fentanyl patches is based on the assumption that 1 mg of parenteral 
fentanyl is equivalent to 100 mg of oral morphine and that 1 patch delivers the dispensed micrograms 
per hour over a 24 hour day. Example: 25 μg/hr fentanyl patch × 24 hrs = 600 ug/day 
fentanyl = 60 mg/day oral morphine mg equivalent.  
In other words, the conversion factor not accounting for days of use would be 60/25 or 2.4.  
However, since the fentanyl patch remains in place for 3 days, we have multiplied the conversion factor 
by 3 (2.4 × 3 = 7.2). In this example, MME/day for 10 25 μg/hr fentanyl patches dispensed for use over 
30 days would work out as follows:  
Example: 25 μg/hr fentanyl patch × (10 patches/30 days) × 7.2 = 60 MME/day. Please note that because 
this allowance has been made based on the typical dosage of 1 fentanyl patch per 3 days, you should 
first change all Days Supply in your prescription data to follow this standard, i.e., Days Supply for fentanyl 
patches = number of patches × 3.  
i 
The CDC MME conversion factor to calculate morphine mg equivalents is 3. CMS uses this 
conversion factor when analyzing Medicare population opioid use. CMS uses the graduated 
methadone MME conversion factors to calculate MME within the OMS for identifying and reporting 
potential opioid overutilizers. https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-
a.pdf.  
j 
Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor. Oral MMEs are based on 
degree of mu-receptor agonist activity, but it is unknown if this drug is associated with overdose in the 
same dose-dependent manner as observed with medications that are solely mu receptor agonists.  


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16.8 Appendix 8: Schedule of Assessments - Phase 1b Multiple Ascending Dose 
Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Screening assessments will be performed over more than 1 visit. 
b Concomitant use of oral corticosteroids: A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, 
the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day). See Section 4.6.1 for 
further details. 
c Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
                                        


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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site 
reaction assessment 
 
Xf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
d If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during 
screening. The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 
3 months prior to screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e ECGs will be performed after the patient has been supine for at least 5 minutes. On days of PK blood draws, the ECG will be collected before 
scheduled PK blood draws. 
f Injection site reaction assessments to be performed at 2 hours postdose. 
g Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes. Vital signs will be assessed on Day 0 at predose and at 1 
and 2 hours (±15 minutes) postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 
7, 187, and 195). When the timing of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the 
blood collection 
                                        


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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
SLEDAI-2Kh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)i 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directj 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
h SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary 
i Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be non-fasting 
j When clinically indicated for hemolytic anemia 
                                        
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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAk 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbl 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3m 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
k Blood samples for ADA analysis will be collected up to Day 90 from all patients. Subsequent ADA samples will be collected from all patients, but 
only assayed (analyzed) if the patient had a positive ADA on Day 90 
l nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90 
m Predose (trough) samples only 
n Antibodies and autoantibodies (
) will not be analyzed during safety follow-up visits 
                                        
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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
FSH 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)o 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test 
(QuantiFERON®-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B 
and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labs 
Predose 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Predose PK Window 
 
60 m 
 
 
± 3 d 
 
± 
3 d 
± 
3 d 
± 
3 d 
± 
3 d 
± 3 d 
 
 
 
 
 
Postdose 
 
Xq 
X 
X 
Xq 
 
 
 
 
 
Xq 
X 
X 
X 
X 
X 
 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits 
p Cryptosporidium test is required at screening. If a patient develops diarrhea during the study a stool sample must be provided to test for ova, 
parasites, and cryptosporidium 
q Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180 
                                        


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Table 4. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up 
Safety Follow-Up 
Days 
-28 
to -1 
0 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
Postdose PK 
Window 
 
4 h ± 
30 m 
8 h ± 
45 m 
24 h ± 
60 m 
± 1d 
± 3 d 4 h ± 
30 m 
8 h ± 
45 m 
24 h ± 
60 m 
 
 
 
 
 
4 h ± 
30 m 
8 h ± 
45 m 
24h ± 
60 m 
± 3 d ± 3 d ± 3 d 
± 3 d ± 3 d 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; APL = antiphospholipid; 
BILAG = British Isles Lupus Assessment Group; BP = blood pressure; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and 
Severity Index; CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; nAb = neutralizing antibody; 
PGA = Physician’s Global Assessment; PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; 
SAE = serious adverse event; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus International 
Collaborating Clinics; 
 
; TB = tuberculosis.  
 
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Page 120 of 130 
16.9 Appendix 9: Protocol Summary of Changes 
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has necessitated social 
distancing and shelter-in-place type practices and limited transportation globally. A 
contingency plan was implemented in anticipation of disruptions to study visits and 
study assessments. This amendment summarizes the measures implemented during 
the COVID-19 pandemic to protect patient safety and data integrity.   
 Safety oversight: In case a patient cannot return to the study site for the scheduled 
visit, the site staff will contact the patient remotely for safety follow up, for example, 
via telephone or video conferencing.   
 Central Laboratory: In the case that there are courier issues that will prevent the 
protocol-required laboratory specimens to be sent to the study core laboratory, the 
site should have the safety laboratory specimens (Table 2: Hematology, Chemistry, 
and Urinalysis) sent to their local laboratory for analysis and review by the study 
physician. 
 Investigational Product Dosing: In cases when dosing cannot be performed during 
the protocol-designated windows, the Investigator should discuss each case with the 
Sponsor to determine whether it is a missed visit or whether the dosing can be 
performed outside protocol windows (as a protocol deviation). A minimum of 
2 weeks must be maintained between consecutive doses. Patients who miss more 
than 2 doses of the study drug (whether consecutive or not) will be discontinued 
from the study and will undergo assessments as outlined in Section 5.5 (Premature 
Discontinuation).   
Additional changes in this amendment include: 
1. Sample size recalculation based on data from the Ustekinumab Phase 2 study in 
SLE. 
2. Revisions to secondary and exploratory endpoints based on precedence in other 
successful clinical trials and to account for SLE disease heterogeneity. 
3. Additional options for acceptable contraception methods.  
Significant changes are described in the table below. Changed text is displayed for the 
first major occurrence only. Deleted text is presented in strikethrough format, and added 
text is presented in bold format.  
 
Section 
Description of Changes 
Rationale 
Global 
Replace: 
Protocol Date and Version: 23 July 2019; V6.0 
With: 
Protocol Date and Version: 30 April 2020; V7.0 
Administrative 
Global 
Change: 
Administrative 


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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 121 of 130 
Section 
Description of Changes 
Rationale 
Changed Version number from V6.0 (Amendment 5) 
to V7.0 (Amendment 6) and Version date from 
23 July 2019 to 30 April 2020.  
Global 
Made administrative and editorial (formatting, 
typographical, and grammatical) updates.  
Administrative 
CLINICAL 
PROTOCOL 
APPROVAL FORM 
Replace: 
Name and Title 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
With: 
Name and Title 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
New CMO.  
CLINICAL 
PROTOCOL 
APPROVAL FORM 
Replace: 
Name and Title 
, PhD 
Senior Vice President 
Clinical Development and 
Head of Clinical 
Operations 
Boston Pharmaceuticals 
With: 
Name and Title 
, MD 
Vice President 
Clinical Development  
Boston Pharmaceuticals 
New clinical lead for the 
program.  
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, 
Secondary 
Replace: 
Results and changes from baseline in: 
With: 
Changes and percent changes from baseline in: 
 
SLE is a very 
heterogeneous disease. 
As a result, baseline data 
could vary considerably 
from patient to patient. 
Percent change from 
baseline enables 
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BOS161721 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 122 of 130 
Section 
Description of Changes 
Rationale 
Endpoints, Bullet 2 
(sub-bullet 2) 
comparison between 
treatment arms despite 
baseline variability.  
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, 
Secondary 
Endpoints, Bullet 2 
(sub-bullet 2) 
Replace: 
The Results and changes from baseline in: 
CLASI 
With: 
The Changes and percent changes from baseline 
in: 
CLASI 
PGA 
PGA is added as an 
important disease activity 
score in SLE.  
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, 
Secondary 
Endpoints, Bullet 6 
Remove: 
Time to first SRI-4 response 
 
This endpoint is removed 
since the SRI-4 response 
is not always stable and 
could disappear from one 
visit to next.  
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, 
Exploratory 
Endpoints 
Insert: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
phase 2, 
Exploratory 
Endpoints, second 
row, second 
column, Bullet 2 
Replace: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
INTRODUCTION 
AND RATIONALE, 
Section 1.2.5, 
Potential Risks, 
Sub-section 
Replace: 
Since the risk of opportunistic cryptosporidium 
infection increases with low levels of CD4+ T-cells, 
patients with a CD4+ count < 500 cell/mm3 were 
The text is made 
consistent with the 
revised eligibility criteria 
for CD4+ count in POC.  
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 123 of 130 
Section 
Description of Changes 
Rationale 
1.2.5.4, Infections, 
Paragraph 7.  
excluded from the Phase 1 SAD study 
(BOS161721-01), and CD4+ < 350 cells/mm3 will be 
excluded from the MAD/POC parts of the study.  
With: 
Since the risk of opportunistic cryptosporidium 
infection increases with low levels of CD4+ T-cells, 
patients with a CD4+ count < 500 cell/mm3 were 
excluded from the phase 1 SAD study 
(BOS161721-01). Patients with CD4+ 
count < 350 cells/mm3 and CD4+ count < 150 
cells/mm3 will be excluded from the MAD and POC 
parts of the study, respectively.  
STUDY 
OBJECTIVES AND 
ENDPOINTS, 
Section 2.2, phase 
2 Proof of Concept, 
Secondary 
Endpoints, Bullet 2. 
Replace: 
Results and changes from baseline in: 
With: 
Changes and percent changes from baseline in: 
 
SLE is a very 
heterogeneous disease. 
As a result, baseline data 
could vary considerably 
from patient to patient. 
Percent change from 
baseline enables 
comparison between 
treatment arms despite 
baseline variability.  
STUDY 
OBJECTIVES AND 
ENDPOINTS, 
Section 2.2, phase 
2 Proof of Concept, 
Secondary 
Endpoints, Bullet 2.  
Replace: 
The Results and changes from baseline in: 
CLASI 
With: 
The Changes and percent changes from baseline 
in: 
CLASI 
PGA 
PGA is added as an 
important disease activity 
score in SLE.  
STUDY 
OBJECTIVES AND 
ENDPOINTS, 
Section 2.2, phase 
2 Proof of Concept, 
Secondary 
Endpoints, Bullet 6.  
Remove: 
Time to first SRI-4 response 
 
This endpoint is removed 
since the SRI-4 response 
is not always stable and 
could disappear from one 
visit to next.  


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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 124 of 130 
Section 
Description of Changes 
Rationale 
STUDY 
OBJECTIVES AND 
ENDPOINTS, 
Section 2.2, phase 
2 Proof of Concept, 
Exploratory 
Endpoints 
Insert: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
STUDY 
OBJECTIVES AND 
ENDPOINTS, 
Section 2.2, phase 
2 Proof of Concept, 
Exploratory 
Endpoints, second 
row, second 
column, Bullet 2 
Replace: 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PLAN, 
Section 3.1.1, 
Multiple Ascending 
Dose Phase 1b,  
Replace: 
All doses selected for the MAD part of the study are 
projected not to exceed the mean exposure of that 
achieved in the SAD study.  
With: 
All doses selected for the MAD part of the study are 
projected not to exceed the mean exposure of that 
achieved at the highest dose in the SAD study.  
Clarification is made as 
to the approach to dose 
selection.  
STUDY PLAN, 
Section 3.1.2.2, 
POC Study Design 
Replace: 
For the POC part of the study, approximately 
156 additional patients will be randomized to active 
or placebo groups in a 2:1 ratio.  
With: 
For the POC part of the study, approximately 
110 additional patients will be randomized to active 
or placebo groups in a 2:1 ratio.  
Efficacy data from a 
Phase 2 SLE study of 
SRI-4 response to 
Ustekinumab, which has 
a partially overlapping 
mechanism of action on 
T cells, became 
available51 and was 
therefore used to 
reassess power 
calculations in this study 
of BOS-161721 of SRI-4 
response in SLE. 
Ustekinumab produced a 
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BOS161721 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
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Page 125 of 130 
Section 
Description of Changes 
Rationale 
statistically significant 
difference in SRI-4 
response in favor of 
Ustekinumab (62% 
Ustekinumab vs. 33% 
placebo) with 102 
patients. Therefore, 
sample size was reduced 
in BOS161721-02 from 
156 to 96 evaluable 
patients.  
STUDY PLAN, 
Section 3.2, 
Randonization and 
Blinding 
Replace: 
Phase 2 
156* 
2:1 
With: 
Phase 2 
Approximately 110 
2:1 
 
Efficacy data from a 
Phase 2 SLE study of 
SRI-4 response to 
Ustekinumab, which has 
a partially overlapping 
mechanism of action on 
T cells, became 
available51 and was 
therefore used to 
reassess power 
calculations in this study 
of BOS-161721 of SRI-4 
response in SLE. 
Ustekinumab produced a 
statistically significant 
difference in SRI-4 
response in favor of 
Ustekinumab (62% 
Ustekinumab vs. 33% 
placebo) with 102 
patients. Therefore, 
sample size was reduced 
in BOS161721-02 from 
156 to 96 evaluable 
patients.  
STUDY PLAN, 
Section 3.4, 
Schedule of 
Assessments 
Replace: 
Vital signs will be assessed on Day 0 at predose 
and at 1 and 2 hours postdose, as well as on each 
of the scheduled outpatient days in the table above 
(excluding PK-only site visits at Days 187 and 195).  
With: 
Vital signs will be assessed on Day 0 at predose 
and at 1 and 2 hours (± 15 minutes) postdose, as 
well as on each of the scheduled outpatient days in 
the table above (excluding PK-only site visits at 
Days 187 and 195). 
Flexible language is 
introduced for the timing 
of the vital signs. 
STUDY PLAN, 
Section 4.2, 
Number of Patients 
Replace: 
Approximately 186 male and female patients are 
planned for enrollment, but may be adjusted upward 
according to the dropout (noncompliance) rate, 
Sample size 
re-calculation was 
performed based on 
recent data from the 


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Protocol Date and Version: 30 April 2020; V7. 0 
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Page 126 of 130 
Section 
Description of Changes 
Rationale 
which will be monitored in a blinded fashion in an 
ongoing basis. Approximately 30 patients will be 
randomized for the MAD Phase 1b portion, and 
approximately 156 additional patients will be 
randomized in the POC Phase 2 portion. Note that 
approximately 24 dropouts are assumed.  
With: 
Approximately 140 male and female patients are 
planned for enrollment, but may be adjusted upward 
according to the dropout (noncompliance) rate, 
which will be monitored in a blinded fashion in an 
ongoing basis. Approximately 30 patients will be 
randomized for the MAD phase 1b portion, and 
approximately 110 additional patients will be 
randomized in the POC phase 2 portion. Note that 
approximately 14 dropouts are assumed in the POC 
phase 2 portion.  
Ustekinumab phase 2 
study. Please see 
Section 8.1.  
STUDY PLAN, 
Section 4.7.2, 
Contraception 
Replace: 
Patients must agree to either complete abstinence, 
defined as a complete avoidance of heterosexual 
activity, or the use of 2 methods of highly effective 
contraception from the following: 
 
Male condoms with spermicide 
 
Hormonal methods of contraception 
including combined oral contraceptive pills, 
vaginal ring, injectables, implants, and 
intrauterine devices (IUDs) such as 
Mirena® by patients who are WOCBP or a 
male patient’s WOCBP partner. Women 
who are partner of men who are patients 
participating in the study may use hormone-
based contraceptives as one of the 
acceptable methods of contraception since 
they will not be receiving study drug 
 
IUDs, such as ParaGard® 
 
Vasectomy 
 
Note: Women who are abstinent while 
participating in the study must continue to 
have pregnancy tests. Acceptable alternate 
methods of highly effective contraception 
must be discussed in the event that the 
patient chooses to forego complete 
abstinence 
 
Azoospermic men and WOCBP who are 
continuously not heterosexually active are 
exempt from contraceptive requirements. 
However, WOCBP must still undergo 
pregnancy testing 
With:  
As many patients with 
SLE are unable to 
tolerate hormonal 
contraception, additional 
effective methods of 
contraception (diaphragm 
with spermicide, cervical 
cap with spermicide and 
hormonal patches) were 
introduced to provide 
more flexibility for study 
participants.   
 


BOS161721 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 127 of 130 
Section 
Description of Changes 
Rationale 
Patients must agree to either complete abstinence, 
defined as a complete avoidance of heterosexual 
activity, or the use of 2 methods of effective 
contraception from the following: 
 
Male condoms with spermicide 
 
Diaphragm with spermicide 
 
Cervical cap with spermicide 
 
Hormonal methods of contraception 
including combined oral contraceptive pills, 
vaginal ring, injectables, implants, patches, 
and intrauterine devices (IUDs) such as 
Mirena® by patients who are WOCBP or a 
male patient’s WOCBP partner. Women 
who are partner of men who are patients 
participating in the study may use hormone-
based contraceptives as one of the 
acceptable methods of contraception since 
they will not be receiving study drug 
 
IUDs, such as ParaGard® 
 
Vasectomy 
 
Note: Women who are abstinent while 
participating in the study must continue to 
have pregnancy tests. Acceptable alternate 
methods of highly effective contraception 
must be discussed in the event that the 
patient chooses to forego complete 
abstinence 
 
Azoospermic men and WOCBP who are 
continuously not heterosexually active are 
exempt from contraceptive requirements. 
However, WOCBP must still undergo 
pregnancy testing 
STUDY PLAN, 
Section 5.2, 
Enrollment/Random
ization and Day 0 
Treatment 
 
Replace: 
 
Vital signs (prior to PK blood draw, predose, 
and at 1 and 2 hours postdose on Day 0) 
With: 
 
Vital signs (prior to PK blood draw, predose, 
and at 1 and 2 hours [± 15 minutes] postdose 
on Day 0) 
Flexible language is 
introduced for the timing 
of the vital signs. 
STUDY PLAN, 
Section 5.6, 
Contingency Plans 
During the 
COVID-19 
Pandemic 
 
Inserted: 
 
Safety oversight: In case a patient cannot return 
to the study site for the scheduled visit, the site 
staff will contact the patient remotely for safety 
follow up, for example, via telephone or video 
conferencing.   
 
Central Laboratory: In the case there are courier 
issues that will prevent the protocol-required 
laboratory specimens to be sent to the study 
core laboratory, the site should have the safety 
During the COVID-19 
pandemic, due to social 
distancing and 
shelter-in-place type 
practices and limitations 
in transportation, 
measures were 
implemented to protect 
patient safety and data 
integrity.  


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Protocol Date and Version: 30 April 2020; V7. 0 
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Page 128 of 130 
Section 
Description of Changes 
Rationale 
laboratory speciments (Table 2: Hematology, 
Chemistry, and Urinalysis) sent to their local 
laboratory for analysis and review by the study 
physician. 
 
Investigational Product Dosing: In cases when 
dosing cannot be performed during the 
protocol-designated windows, the Investigator 
should discuss each case with the Sponsor to 
determine whether it is a missed visit or whether 
the dosing can be performed outside protocol 
windows (as a protocol deviation). A minimum of 
2 weeks must be maintained between 
consecutive doses. Patients who miss more 
than 2 doses of the study drug (whether 
consecutive or not) will be discontinued from the 
study and will undergo assessments as outlined 
in Section 5.5 (Premature Discontinuation).   
 
ASSESSMENTS, 
Section 6.2.3, 
Vital Signs 
 
Replace: 
Vital signs will be assessed on Day 0 at predose 
and at Day 0, 1 and 2 hours postdose, as well as on 
each of the scheduled visit days during the study 
(excluding PK-only site visits). 
With: 
Vital signs will be assessed on Day 0 at predose 
and at Day 0, 1 and 2 hours (± 15 minutes) 
postdose, as well as on each of the scheduled visit 
days during the study (excluding PK-only site visits). 
Flexible language is 
introduced for the timing 
of the vital signs. 
ASSESSMENTS, 
Section 6.3.5, 
CLASI Response, 
Paragraph 1.  
Replace: 
This assessment will be applied to all patients as all 
are required to have cutaneous disease activity.  
With: 
This assessment will be applied to all patients who 
have cutaneous disease activity.  
Inclusion criteria could be 
met without presence of 
mucocutaneous disease.  
STATISTICS, 
Section 8.1, 
Sample Size  
Replace: 
The sample size in the Phase 2 portion is based on 
the primary endpoint, SRI-4 Response at Day 210. 
Approximately 156 additional patients will be 
randomized in a 2:1 ratio to BOS161721 versus 
placebo to achieve 132 evaluable patients in the 
FAS. This assumes 24 patients will drop prior to 
having received treatment and an evaluable 
post-baseline efficacy measure. Enrollment and 
randomization will be monitored in a blinded fashion 
and increased if needed to ensure at least 132 
patients are randomized into the FAS.  
A total of 132 patients randomized provides more 
than 80% power to detect a treatment difference of 
25% in SRI-4 response rates at Day 210, based on 
a targeted 2-sided significance level of 10% and 
Efficacy data from a 
Phase 2 SLE study of 
SRI-4 response to 
Ustekinumab, which has 
a partially overlapping 
mechanism of action on 
T cells, became 
available51 and was 
therefore used to 
reassess power 
calculations in this study 
of BOS-161721 of SRI-4 
response in SLE. 
Ustekinumab produced a 
statistically significant 
difference in SRI-4 
response in favor of 


BOS161721 
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Clinical Study Protocol: BOS161721-02 
Protocol Date and Version: 30 April 2020; V7. 0 
Confidential 
 
Page 129 of 130 
Section 
Description of Changes 
Rationale 
using a 2-sided Pearson’s chi-squared test. This 
assumes of a response rate of 65% for BOS161721 
and 40% for placebo, where missing data at Day 
210 is carried forward from most recent non-missing 
result and patients are treated as a non-responder if 
a prohibited medication defined as a medication 
failure occurs.  
With: 
The sample size in the phase 2 portion is based on 
the primary endpoint, SRI-4 Response at Day 210. 
Based on efficacy data from a recently completed 
study with Ustekinumab, where the primary 
endpoint was also SRI-4, the sample size in the 
phase 2 part of the BOS161721-02 study is set at 
96 evaluable patients. In the Ustekinumab study of 
102 patients, a statistically significant difference in 
SRI-4 response was shown in favor of Ustekinumab 
(62% of Ustekinumab treated patients achieved 
SRI-4 response vs. 33% in patients receiving 
placebo). The Ustekinumab phase 2 study is an 
appropriate comparator to BOS161721-02 because 
both studies share the same primary endpoint of 
SRI-4 response and BOS161721 and Ustekinumab 
have overlapping mechanisms of action (T follicular 
helper and Th17 cell biology).  
Approximately 110 additional patients will be 
randomized in a 2:1 ratio to BOS161721 versus 
placebo to achieve approximately 96 evaluable 
patients in the FAS of the phase 2 portion. This 
assumes 14 patients will drop prior to having 
received treatment or having completed a 
post-baseline efficacy measure. Enrollment and 
randomization will be monitored in a blinded fashion 
and may be increased if needed to ensure at least 
96 evaluable patients are randomized into the FAS.  
A total of 96 evaluable patients randomized 
provides 80% power to detect a treatment difference 
of 29% in SRI-4 response rates at Day 210, based 
on a targeted 2-sided significance level of 10% and 
using a 2-sided Pearson’s chi-squared test. This 
assumes a response rate of 62% for BOS161721 
and 33% for placebo.  
Ustekinumab (62% 
Ustekinumab vs. 33% 
placebo) with 102 
patients. Therefore, 
sample size was reduced 
in BOS161721-02 from 
156 to 96 evaluable 
patients.  
 
STATISTICS, 
Section 8.2.1, 
Analysis 
Populations, 
Paragraph 1 and 3 
Inserted: 
(partial or complete) 
Words partial or 
complete are added for 
further clarity.  
STATISTICS, 
Section 8.2.3, 
Primary Efficacy 
Replace: 
The proportion of patients who achieve a SRI-4 
response at Day 210 will be assessed via Pearson’s 
chi-squared analysis. The primary efficacy endpoint 
Flexible language is 
introduced to perform 
additional analyses or 
apply additional 


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Protocol Date and Version: 30 April 2020; V7. 0 
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Page 130 of 130 
Section 
Description of Changes 
Rationale 
Endpoint(s), 
Paragraph 1 and 2.  
will be analyzed using the FAS and if needed 
repeated in the PP analysis set. Missing values will 
be addressed by employing a last observation 
carried forward (LOCF) analysis. Other imputation 
methods may be employed as a sensitivity analysis 
and will be described in the SAP. Additional 
analyses exploring impact of baseline factors such 
as baseline disease severity, race, and other 
characteristics may be performed.  
With: 
The proportion of patients who achieve a SRI-4 
response at Day 210 will be assessed via Pearson’s 
chi-squared analysis. The primary efficacy endpoint 
will be analyzed using the FAS and if needed 
repeated in the PP analysis set. Missing values will 
be addressed by employing a last observation 
carried forward (LOCF) analysis. Other imputation 
methods may be employed as a sensitivity analysis 
and will be described in the SAP. Analyses based 
on observed values may also be performed.  
Exploratory subgroup analyses assessing impact of 
baseline factors such as baseline disease severity, 
background therapy, race, geography, baseline 
serologic activity, and other characteristics may be 
performed. Additional exploratory analyses of 
disease activity endpoints may be performed based 
on emerging data.  
impuation methodology 
based on emerging data.  
APPENDICIES, 
Section 16.8, 
Appendix 8, 
Table 4 Schedule 
of Assessments - 
Phase 1b Multiple 
Assceding Dose 
Replace: 
Vital signs will be assessed on Day 0 at predose 
and at 1 and 2 hours postdose, as well as on each 
of the scheduled outpatient days in the table above 
(excluding PK-only site visits at Days 7, 187, and 
195). 
With: 
Vital signs will be assessed on Day 0 at predose 
and at 1 and 2 hours (±15 minutes) postdose, as 
well as on each of the scheduled outpatient days in 
the table above (excluding PK-only site visits at 
Days 7, 187, and 195). 
Flexible language is 
introduced for the timing 
of the vital signs. 
 


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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 1 of 139 
 
 
A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 400 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721 
PROTOCOL NUMBER: 
BOS161721-02 
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
06 October 2017 
VERSION NUMBER: 
V6.0 (Amendment 5) 
VERSION DATE: 
23 July 2019 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 2 of 139 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of 
BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care 
 
Study Number:  BOS161721-02 
Version 
Date 
Original Protocol 
06 October 2017 
Protocol Version 2.0 (Amendment 1) 
14 November 2017 
Protocol Version 3.0 (Amendment 2) 
21 March 2018 
Protocol Version 4.0 (Amendment 3) 
27 July 2018 
Protocol Version 5.0 (Amendment 4) 
23 January 2019 
Protocol Version 6.0 (Amendment 5) 
23 July 2019 
This study protocol was subject to critical review and has been approved by sponsor.  The 
information contained in this protocol is consistent with: 
 
The current risk-benefit evaluation of the investigational product. 
 
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to 
applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature and Date 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
, PhD 
Senior Vice President 
Clinical Development and Head of Clinical Operations 
Boston Pharmaceuticals 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 3 of 139 
BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol (Version 6.0, dated 23 July 2019), including all appendices, and I agree 
that it contains all of the necessary information for me and my staff to conduct this study as 
described.  I will conduct this study as outlined herein, in accordance with the regulations stated 
in the Federal Code of Regulations for Good Clinical Practices and International Council for 
Harmonisation (ICH) guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 4 of 139 
PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple 
Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus 
(SLE) Patients on a Background of Limited Standard of Care 
Indication 
Adults with moderately to severely active SLE 
Background 
and Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the disease, 
and that T-cell-derived cytokines such as interleukin-21 (IL-21) are involved 
in the SLE-associated inflammatory pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple mutation 
monoclonal antibody (mAb) intended to have an extended terminal 
elimination half-life (t½) that selectively binds to and neutralizes IL-21, 
which acts on multiple cell types that drive inflammation and autoimmunity.  
In vivo, BOS161721 inhibits T-cell dependent antigen responses of B-cells 
and is being developed as a potential treatment for adults with moderately to 
severely active SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics (PD), 
toxicokinetics (TK), pharmacokinetics (PK), and immunogenicity of 
BOS161721 administered intravenously (IV) and subcutaneously (SC).  The 
no observed adverse effect level (NOAEL) in Cynomolgus monkeys was 
determined to be 100 mg/kg (SC and IV), the highest dose tested.  There 
were no injection site reactions in animals dosed subcutaneously. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  This 
double-blind, placebo-controlled study evaluated 8 ascending dose levels 
(1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg) for safety, tolerability, PK, PD and immunogenicity.  Overall, 
there were no clinically significant safety or tolerability findings from this 
study.  
Results from the Phase 1 SAD study informed the dose regimens used for the 
multiple ascending doses (MAD) Phase 1b portion of this trial.  The MAD 
portion will involve 3 cohorts.  The Phase 2 portion will be a proof of 
concept (POC) part, where dose selection will be based on the data 
monitoring committee (DMC) and sponsor’s assessment of safety, 
tolerability, immunogenicity, and PK and PD data from the MAD portion of 
30 patients treated with BOS161721/placebo.  The purpose of the study is to 
establish a safe and effective dosage for adult patients with moderately to 
severely active SLE. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 5 of 139 
Objectives and 
Endpoints: 
MAD Phase 1b 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients 
with moderately to severely active 
SLE on limited background 
standard of care treatment, in order 
to estimate the optimal dose. 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale 
(C-SSRS) 
• 
12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
Anti-drug antibodies (ADAs) 
• 
Study drug exposure/compliance 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the optimal 
dose of BOS161721 based on 
safety, PK, and PD effects in 
patients with moderately to 
severely active SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time 
point 
• 
Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), t½, systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• 
Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• 
Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit  
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 6 of 139 
Exploratory 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
• 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 7 of 139 
POC Phase 2 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on the SLE Responder 
Index 4 (SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 
response at Day 210 (see Section 6.3.4.1) 
Secondary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on clinical indicators of 
SLE activity, in adult patients with 
moderately to severely active SLE 
on limited background standard of 
care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction from baseline of 
oral corticosteroid (CS) (≤ 7.5 mg/day 
and < Day 0 dose) between Day 150 
and Day 210 
- 
new or recurrent BILAG flares 
(≥ 1 qualifying BILAG A or 
> 1 qualifying BILAG B) through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
Total number of swollen joints, tender 
joints, and active joints (swelling and 
tenderness in the same joint) in the 
ACR-28 joint count 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Group mean percent reduction in 
corticosteroid administration from baseline 
Day 0 dose through Day 210 in patients 
receiving ≥ 7.5 mg/day prednisone 
equivalent at Day 0 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to first BILAG flare (≥ 1 new or 
recurrent BILAG A or > 1 new or recurrent 
BILAG B) relative to baseline through 
Day 210 
Safety 
• 
To assess safety and tolerability of 
repeat doses of BOS161721 at the 
chosen dose administered SC in 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 8 of 139 
adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each 
visit and change from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, 
placebo-controlled trial to study the clinical efficacy, safety, and PK of 
multiple SC doses of BOS161721 in adult patients with moderately to 
severely active SLE.  After successfully completing a screening phase, 
eligible patients will be randomized to a specified dose of BOS161721 or 
placebo.  The dosing schedule will be monthly.  The trial will consist of 
2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 
120, 150, and 180, followed by safety follow-up visits at Days 210, 240, and 
270.   
The MAD Phase 1b portion of the study design will consist of 3 cohorts, with 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 9 of 139 
Cohort 1 containing 6 patients, where 5 of these patients will receive 
BOS161721 (active), and 1 will receive placebo.  Cohorts 2 and 3 will each 
contain 12 patients, including 9 active and 3 placebo patients.  Dose selection 
for each cohort is based on 90-day safety, tolerability, PK, and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  
Each of the 3 doses (20, 60, and 120 mg) selected for the MAD portion are 
projected not to exceed the mean exposure of that achieved in the SAD study 
following the single 240 mg SC dose.  Each patient may receive a total of 
7 SC monthly doses on Days 0, 30, 60, 90, 120, 150, and 180.   
The MAD portion design is staggered, where after the 6 patients in Cohort 1 
have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 2 begins dosing (after the DMC evaluates the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in 
Cohort 2 have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing after the DMC evaluation of the 
safety and tolerability data from Cohort 2 and Cohort 1.  Thirty days after the 
last patient in Cohort 3 receives the third dose, the DMC and Boston 
Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This dose will not exceed 
doses tested during the MAD portion.   
For the POC portion, approximately 156 additional patients will be 
randomized to active or placebo groups in a 2:1 ratio.  As in the MAD 
portion, each patient in the POC portion may receive a total of 7 SC monthly 
doses on Days 0, 30, 60, 90, 120, 150, and 180.   
A maximum stable (for at least 6 weeks prior to Day 0) daily dose of 
30 mg/day of oral CS will be acceptable for eligibility for the study.  One oral 
CS “burst” for increased SLE disease activity may occur during the study 
between Day 0 and Day 120.  Tapering of steroids during the course of the 
study will be highly encouraged and should be evaluated during the 
protocol-allowed tapering windows (Day 0 through Day 150) with the target 
of achieving a CS daily dose of ≤ 7.5 mg and < Day 0 dose between Day 150 
and Day 210.  Between Day 150 and Day 210, oral CS doses must be held 
constant due to the Day 210 endpoint evaluations. 
DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 10 of 139 
Main Criteria 
for Inclusion 
and Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be 
evidence of a personally signed and dated informed consent document 
indicating that the patient has been informed of all pertinent aspects of the 
study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus 
International Collaborating Clinics (SLICC) classification criteria for SLE 
(with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis 
as the sole clinical criterion in the presence of antinuclear antibodies 
[ANA] or anti- double-stranded deoxyribonucleic acid [dsDNA] 
antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central 
laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as 
determined by the central laboratory 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including points 
from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis  
Note:  Points from lupus headache and organic brain syndrome will also 
be excluded from qualifying total and clinical SLEDAI-2K scores at 
screening and Day 0. 
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0.  Clinical 
SLEDAI-2K score is defined as follows: 
a. Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, or vasculitis 
b. Excludes parameters which require central laboratory results:  
hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 
decreased complement, thrombocytopenia, and leukopenia 
Note:  Points from lupus headache and organic brain syndrome will also 
be excluded from qualifying total and clinical SLEDAI-2K scores at 
screening and Day 0. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 11 of 139 
7. Patients must have at least 1 qualifying A or 2Bs from the following 
manifestations of SLE, as defined by the BILAG criteria as modified for 
use in this study, which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system.  If a 
BILAG B score is due to BILAG number 6, mild skin eruption, the 
CLASI activity score including erythema and scale/hypertrophy must 
be ≥ 3 excluding points from mucosal ulcers and alopecia. 
b. BILAG A or B score in the musculoskeletal body system due to active 
polyarthritis as defined in the protocol Section 4.4 
Note:  Hips, shoulders, back, neck, and temporomandibular joints do not 
count towards the total number of joints with active synovitis. 
If only one “B” and no “A” score is present in the mucocutaneous body 
system or in the musculoskeletal body system due to arthritis, then at least 
1 “B” must be present in at least 1 other body system for a total of 2 “B” 
BILAG body system scores. 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at 
least 56 days (8 weeks prior to Day 0) of the following permitted 
steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic 
acid, chloroquine, hydroxychloroquine, or methotrexate 
(MTX) 
b. If AZA, myocophenolate mofetil, mycophenolic acid, 
hydroxychloroquine, or MTX were discontinued prior to screening, 
the washout period must be ≥ 12 weeks. 
c. Corticosteroids (prednisone or prednisone-equivalent) at a stable dose 
of up to 30 mg/day for at least 6 weeks prior to Day 0 (see 
APPENDIX 3) 
i. 
For patients whose only SLE treatment is CSs, the stable CS 
dose must be ≥ 10 mg/day for at least 6 weeks prior to Day 0 
and no more than 30 mg/day at the time of randomization. 
ii. 
Topical steroids may be used, but the dose must be stable for at 
least 6 weeks prior to Day 0.  PRN topical steroids are not 
permitted. 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full 
information regarding WOCBP, definition of menopause, and 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 12 of 139 
contraception): 
a. Must have a negative serum pregnancy test at screening.  Urine 
pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug plus 52 weeks 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with study drug plus 52 weeks 
11. Patients must demonstrate willingness and ability to comply with the 
scheduled study visits, treatment plans, laboratory tests, and other 
procedures 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this 
study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid 
arthritis [RA], multiple sclerosis [MS], systemic sclerosis, or vasculitis not 
related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are 
allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), 
or any elective surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube 
(QFT-G) or other diagnostic test in the absence of clinical 
manifestations.  Latent TB is not excluded if the patient has 
documented completion of adequate course of prophylactic treatment 
with regimen recommended by local health authority guideline, or the 
patient has started treatment with isoniazid, or other regimen 
recommended by local health authority guidelines for at least 1 month 
before Day 0 and continues to receive the prophylactic treatment 
during study until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, including but 


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not limited to any condition defined by BILAG A criteria, with the 
exception of mononeuritis multiplex and polyneuropathy, which are 
allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires 
or may require induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator or the sponsor 
or their designee, is likely to require additional systemic 
glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is 
allowed 
8. Use or planned use of concomitant medication outside of standard of 
baseline treatment for SLE from Day -1 or for any time during the study 
9. Active and clinically significant infection (bacterial, fungal, viral, or 
other) within 60 days prior to first dose of study drug.  Clinically 
significant is defined as requiring systemic parenteral antibiotics or 
hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe 
disseminated herpes zoster or disseminated herpes simplex within the last 
3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) 
unless patient received curative treatment for HCV and has a documented 
negative viral load, known human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS)-related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 150/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if 
related to SLE, at screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of 
proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 
339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) 
< 40 ml/minute based on Cockcroft-Gault calculation 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the investigator’s 
judgment 


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21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related to lupus 
myositis  
22. Total bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s 
syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator or 
the sponsor or sponsor’s designee, might place a patient at unacceptable 
risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of components of 
mAbs 
25. History substance and/or alcohol abuse, or dependence within the past 1 
year, at the investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or 
squamous cell cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, 
including recent (within the past year) medical conditions (eg, 
cardiovascular conditions, respiratory illnesses) that may increase the risk 
associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, sponsor or sponsor’s designee, would 
make the patient inappropriate for entry into this study 
28. Investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by 
the investigator, or patients who are employees of the sponsor or directly 
involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional 
(drug or device) clinical study within 30 days or 5 half-lives of baseline, 
whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior 
based on patient responding “yes” to question 3, 4, or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a 
psychiatric or physical (eg, infectious disease) illness 
33. Currently taking a total daily dose of > 30 mg morphine or morphine 
equivalent (see APPENDIX 7) 
34. Body mass index (BMI) ≥ 40.0 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be found in 
Section 8. 
Two analyses are planned:  1) an interim analysis to select the POC dose 
based on the MAD data, and 2) a final analysis at study completion.  


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Additionally, DMC safety analyses will be performed for each MAD cohort 
and throughout the POC to monitor patient safety as described in the DMC 
charter.  An additional analysis may be performed for the MAD portion of the 
study when all MAD patients have completed the safety follow-up, or 
withdrawn from the study, and prior to the final analysis.  Data from the POC 
part of the study will be excluded from this additional analysis. 
Unless stated otherwise, statistical testing will only be performed on the POC 
data and will be done using 2-sided overall alpha of 0.10.  Data will be 
summarized descriptively by treatment and overall for each study phase.  For 
the MAD portion, BOS161721 will be summarized overall and by each dose 
level and placebo patients from each cohort will be combined.   
The descriptive summaries for the categorical data will include number and 
percentage.  The descriptive summaries for the continuous data will include 
number, mean, median, standard deviations (SD), 25th and 75th percentiles, 
minimum, median, and maximum.  Counts, medians, 25th and 75th percentiles, 
and standard error will be presented for time-to-event data. 
All safety analyses will be performed using the safety analysis set (SS), 
defined as all patients who receive at least 1 dose of study treatment.  All 
efficacy analyses will be performed using the full analysis set (FAS), defined 
as all patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  Select efficacy analyses may 
also be performed on the per protocol (PP) set. 
Binary efficacy endpoints, including the primary efficacy endpoint, will be 
assessed via Pearson’s chi-squared analysis.   
Continuous efficacy endpoints will be assessed via analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA) when applicable, adjusting 
for the baseline value.  Repeated measures mixed models may be performed 
to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be 
compared using the log-rank test.   
Adverse event data will be coded to system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class and preferred term will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and 
relationship.   
Concomitant medications will be summarized, based on coded terms, using 
frequency and percentage of patients.  Observed values and changes from 
baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters, will be summarized at each individual visit. 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................3 
PROTOCOL SUMMARY ...............................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF IN-TEXT TABLES ........................................................................................................19 
LIST OF IN-TEXT FIGURES.......................................................................................................20 
LIST OF ABBREVIATIONS ........................................................................................................21 
1. 
INTRODUCTION AND RATIONALE .................................................................................25 
1.1 
Indication ...........................................................................................................................25 
1.2 
Background and Rationale .................................................................................................25 
1.2.1 
Overview of the Disease State .....................................................................................25 
1.2.2 
BOS161721 Development ...........................................................................................25 
1.2.2.1 
Interleukin-21 .........................................................................................................26 
1.2.2.2 
Preclinical Studies ..................................................................................................27 
1.2.2.3 
Clinical Studies ......................................................................................................28 
1.2.3 
Study Dose Selection ...................................................................................................29 
1.2.4 
Risk-Benefit Assessment .............................................................................................30 
1.2.5 
Potential Risks .............................................................................................................31 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................32 
1.2.5.2 
Injection Site Reactions .........................................................................................32 
1.2.5.3 
Immune Complex Disease .....................................................................................32 
1.2.5.4 
Infections................................................................................................................33 
1.2.5.5 
Malignancy ............................................................................................................33 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................34 
1.2.5.7 
Failure of Vaccination............................................................................................34 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................34 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................35 
2 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................35 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................36 
2.2 
Phase 2 Proof of Concept ...................................................................................................38 
3 
STUDY PLAN ........................................................................................................................39 
3.1 
Study Design ......................................................................................................................39 
3.1.1 
Multiple Ascending Dose Phase 1b .............................................................................40 
3.1.1.1 
Dose Escalation for the MAD Portion ...................................................................40 
3.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................40 
3.1.1.3 
DMC Recommendations ........................................................................................41 
3.1.2 
POC Phase 2 ................................................................................................................41 
3.1.2.1 
BOS161721 POC Dose Selection and Justification...............................................41 


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3.1.2.2 
POC Study Design .................................................................................................42 
3.2 
Randomization and Blinding .............................................................................................42 
3.3 
Study Schematic.................................................................................................................44 
3.4 
Schedule of Assessments ...................................................................................................45 
3.5 
End of Study ......................................................................................................................49 
4 
POPULATION .......................................................................................................................49 
4.1 
Participant Recruitment .....................................................................................................49 
4.2 
Number of Patients ............................................................................................................49 
4.3 
Patient Screening ...............................................................................................................49 
4.4 
Inclusion Criteria ...............................................................................................................49 
4.5 
Exclusion Criteria ..............................................................................................................52 
4.6 
Concomitant Medications ..................................................................................................54 
4.6.1 
Corticosteroid ...............................................................................................................54 
4.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................55 
4.7 
Women of Childbearing Potential .....................................................................................56 
4.7.1 
Determination of Menopause .......................................................................................56 
4.7.2 
Contraception ...............................................................................................................56 
4.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................57 
4.8.1 
Patient Withdrawal and Replacement ..........................................................................57 
5 
STUDY PROCEDURES ........................................................................................................57 
5.1 
Screening............................................................................................................................57 
5.1.1 
Retesting During Screening Period ..............................................................................59 
5.2 
Enrollment/Randomization and Day 0 Treatment .............................................................59 
5.3 
Treatment Period/Follow-Up Visits ...................................................................................60 
5.4 
Safety Follow-Up Visits ....................................................................................................61 
5.5 
Premature Discontinuation .................................................................................................61 
6 
ASSESSMENTS .....................................................................................................................62 
6.1 
Medical History, Demographic and Other Baseline Information ......................................62 
6.2 
Safety Assessments ............................................................................................................63 
6.2.1 
Laboratory Assessments ..............................................................................................63 
6.2.1.1 
Pregnancy testing ...................................................................................................64 
6.2.1.2 
Tuberculosis Screening ..........................................................................................65 
6.2.2 
Adverse Events ............................................................................................................65 
6.2.2.1 
Definitions..............................................................................................................65 
6.2.2.2 
Recording of Adverse Events ................................................................................66 
6.2.2.3 
Severity of Adverse Events ....................................................................................66 
6.2.2.4 
Causality of Adverse Events ..................................................................................66 
6.2.2.5 
Seriousness of Adverse Events ..............................................................................67 
6.2.2.6 
Adverse Events of Special Interest ........................................................................68 
6.2.2.7 
Reporting of Adverse Events .................................................................................71 
6.2.2.8 
Follow Up of Adverse Events ................................................................................73 


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6.2.3 
Vital Signs ....................................................................................................................73 
6.2.4 
12-Lead Electrocardiograms ........................................................................................73 
6.2.5 
Physical Examinations .................................................................................................74 
6.2.6 
C-SSRS ........................................................................................................................74 
6.2.7 
Injection Site Reactions ...............................................................................................74 
6.2.8 
Immunogenicity ...........................................................................................................74 
6.3 
Efficacy Assessments .........................................................................................................75 
6.3.1 
SLEDAI-2K .................................................................................................................75 
6.3.2 
BILAG 2004 ................................................................................................................75 
6.3.3 
PGA of Disease Activity ..............................................................................................75 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................76 
6.3.4.1 
SRI-4 Response ......................................................................................................76 
6.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................76 
6.3.4.3 
BICLA Response ...................................................................................................76 
6.3.5 
CLASI Response ..........................................................................................................76 
6.3.6 
ACR-28 Joint Count ....................................................................................................77 
6.4 
Other Variables ..................................................................................................................77 
6.4.1 
SLICC/ACR Damage Index ........................................................................................77 
6.4.2 
PROs ............................................................................................................................77 
6.5 
Pharmacokinetic Assessments ...........................................................................................77 
6.6 
Pharmacodynamic Assessments ........................................................................................77 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................78 
6.8 
Protocol Deviations ............................................................................................................78 
7 
STUDY DRUG MANAGEMENT .........................................................................................78 
7.1 
Description .........................................................................................................................78 
7.1.1 
Formulation ..................................................................................................................78 
7.1.2 
Storage .........................................................................................................................78 
7.2 
Packaging and Shipment ....................................................................................................78 
7.3 
Dose and Administration ...................................................................................................78 
7.4 
Accountability ....................................................................................................................79 
7.5 
Prohibited Concomitant Therapy .......................................................................................79 
7.6 
Compliance ........................................................................................................................79 
8 
STATISTICS ..........................................................................................................................79 
8.1 
Sample Size ........................................................................................................................80 
8.2 
Statistical Methods .............................................................................................................81 
8.2.1 
Analysis Populations ....................................................................................................81 
8.2.2 
Demographics and Baseline Characteristics ................................................................81 
8.2.3 
Primary Efficacy Endpoint(s) ......................................................................................81 
8.2.4 
Secondary Efficacy Endpoint(s) ..................................................................................82 
8.2.5 
Analysis of Safety ........................................................................................................82 
8.2.5.1 
Safety Analysis ......................................................................................................82 


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8.2.6 
Pharmacokinetic and Pharmacodynamic Data .............................................................82 
8.2.6.1 
Analysis of Pharmacokinetic Data .........................................................................82 
8.2.6.2 
Analysis of Pharmacodynamic Data ......................................................................83 
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ..................................83 
8.3 
Interim Analysis and Power ...............................................................................................83 
9 
ETHICS AND RESPONSIBILITIES .....................................................................................83 
9.1 
Good Clinical Practice .......................................................................................................83 
9.2 
DMC ..................................................................................................................................83 
9.3 
Institutional Review Board/Independent Ethics Committee ..............................................84 
9.4 
Informed Consent...............................................................................................................84 
9.5 
Records Management .........................................................................................................85 
9.6 
Source Documentation .......................................................................................................86 
9.7 
Study Files and Record Retention......................................................................................86 
10 AUDITING AND MONITORING ........................................................................................86 
11 AMENDMENTS ....................................................................................................................86 
12 STUDY REPORT AND PUBLICATIONS ...........................................................................87 
13 STUDY DISCONTINUATION .............................................................................................87 
14 CONFIDENTIALITY ............................................................................................................87 
15 REFERENCES .......................................................................................................................89 
16 APPENDICES ........................................................................................................................93 
APPENDIX 1 
NAMES OF STUDY PERSONNEL ...............................................................93 
APPENDIX 2 
DECLARATION OF HELSINKI....................................................................94 
APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ......................98 
APPENDIX 4 
MEDICATION WASHOUT PERIODS..........................................................99 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) ......................100 
APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE ...................................101 
APPENDIX 7 
OPIOID ORAL MORPHINE MILLIGRAM EQUIVALENTS OF 
COMMONLY USED OPIOIDS ..........................................................................................102 
APPENDIX 8 
SCHEDULE OF ASSESSMENTS - PHASE 1B MULTIPLE 
ASCENDING DOSE ............................................................................................................105 
APPENDIX 9 
PROTOCOL SUMMARY OF CHANGES ...................................................110 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) ...............................45 
Table 2. 
Laboratory Tests ....................................................................................................63 
Table 3. 
Causality Definitions .............................................................................................67 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .......................105 
 


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LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................30 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 ...........................................44 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
 
 
CCI


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FAS 
full analysis set 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
IFNγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary of Regulatory Activities 
MS 
multiple sclerosis 


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MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
NSAID 
nonsteroidal anti-inflammatory drug 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PP 
per protocol 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-
wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS  
safety analysis set 
CCI


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SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1. INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids (CS), immunosuppressants, and cytotoxic 
agents.1  However, some of the morbidity in patients with SLE is related to its treatment.  
Comparison of early and late outcomes in patients with SLE demonstrate that death in early 
disease is most commonly due to infections and active SLE causing multi-system organ damage, 
while thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb with extended half-life directed against 
human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t½) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies. 
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses). 
 
 
 
 
 
 
 
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  The NOAEL was determined to be 100 mg/kg (SC and IV), the highest dose 
tested. 
An additional GLP, repeat-dose toxicity study was conducted in Cynomolgus monkeys (4 males 
and 4 females per dose group) following every 2 weeks (Q2W) administration by SC (10, 30, 
and 100 mg/kg) injection for a total of 14 doses.  
 
 
  
 
 
 
  There were no BOS161721-related effects on survival, clinical signs, male body 
weights, ophthalmologic parameters, electrocardiogram (ECG) findings, clinical pathology, 
macroscopic observations, organ weights, or microscopic observations.  
 
 
 
  
 
  
The 100 mg/kg/dose was the NOAEL
. 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: placebo) 
and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 
[SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first cohort, after the 
first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 48 hours before 
the remaining subjects from that cohort were dosed, to allow for an initial review of any 
emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not sooner 
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than 8 days after all the subjects in the prior cohort had been dosed and were based on a review 
of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team (SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included ECGs, vital signs (blood pressure [BP], heart rate, and temperature), safety 
laboratory assessments, blood sampling for ADAs, total IgG and immunoglobulin M (IgM) 
levels, CD4+ count, and full and targeted physical examinations.  Overall, there were no 
clinically significant findings from this study.  Adverse events reported as related to the study 
drug, particularly infections, were expected for the compound, and there were no clinically 
relevant changes in laboratory and ECG results or vital signs.  There was 1 serious adverse event 
(SAE; death due to pulmonary embolism) that occurred 127 days after a single administration of 
240 mg SC dose of BOS161721.  The causality of this single SAE was not attributed to study 
drug and further information can be found in the Investigator’s Brochure.  Final PK data from 
the SAD study demonstrates BOS161721 has a mean t½ ranging from 80 to 87 days for doses of 
≥ 30 mg in healthy subjects.  
1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1b portion based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose level, 
repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant safety or 
tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD portion of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median first time to maximum concentration (Tmax) of 6 days and an apparent 
terminal half-life of 44 days.  Furthermore, pSTAT3 suppression, a marker of IL-21 target 
engagement, follows a similar time course of the mAb levels, with maximal and sustained 
suppression apparent with doses greater than 30 mg SC (Figure 1).   


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Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 
All doses selected for the MAD portion are projected not to exceed the mean exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD study.  
Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered study 
design, the data monitoring committee (DMC) will perform a scheduled review of safety data 
and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC and Boston 
Pharmaceuticals will conduct a data review to determine which dose will be carried forward into 
the proof of concept (POC) Phase 2 portion.  This POC dose decision will be based on evaluation 
of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD portion (see Section 3.1.2.1 for the 
chosen POC dose and justification). 
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD portion.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  


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Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Thirty days after the last patient in Cohort 3 receives the third dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This POC dose decision will be based on 
evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 during the MAD part of study.  
Thereafter, DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter.  With the agreement of the DMC and sponsor, this schedule may 
be modified depending on the rate of patient accrual.  Additional details can be found in the 
DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), or altered BOS161721 levels or activity.  Further details can be found in the current 
Investigator’s Brochure (IB) for BOS161721, which contains comprehensive toxicology, 
preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational products.  
Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to the study 
drug, particularly infections (flu-like symptoms, etc.), were expected for the compound, and 
there were no clinically relevant changes in laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 
this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 


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1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 6.2.2.6.1. 
Based on the Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic reactions in 
subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC for 3 months (a total of 7 doses).  There were no injection site 
reactions in animals dosed subcutaneously.  Further, there were no reports of injection site 
reactions in the 26-week GLP toxicology study in Cynomolgus monkeys. 
Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 6.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 
ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 


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Based on the Phase 1 SAD study (BOS161721-01), immune complex disease in subjects who 
received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 
BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and CD4 + < 350 cells/mm3 will be excluded from the MAD/POC 
parts of the study.  Patients exposed to investigational product who develop diarrhea during the 
course of the study should immediately undergo an assessment for opportunistic infection 
including stool for ova and parasites and stool examination for cryptosporidium.  Positive 
cryptosporidium in stool sample at screening is an exclusion.  Treatment by the investigator 
where indicated should be guided by findings and be consistent with local standard of care. 
Based on the Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 


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and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from this trial.  Patients with a positive hepatitis B or C 
test or a history of alcohol dependence will also be excluded. 
Based on the Phase 1 SAD study (BOS161721-01), hepatic function abnormality in subjects who 
received BOS161721 was not observed. 
1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen in a dose-dependent fashion; however, 
BOS161721 administration did not affect anti-tetanus toxoid antibody data for IgM, IgG, IgG1, 
or immunoglobulin E (IgE) during the dosing phase in the same study. 
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 


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oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 4.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 4.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES AND ENDPOINTS 
This trial has separate objectives and endpoints for the MAD Phase 1b and POC Phase 2 portions 
of the study.  The primary, secondary, and exploratory objectives for each phase, as applicable, 
are described below with their corresponding endpoints. 
 
 


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2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment, in order to estimate the optimal 
dose. 
Safety Endpoints 
• 
Incidence and severity of AEs and SAEs, related AEs, AEs 
leading to study drug discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Secondary 
• 
To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with moderately to 
severely active SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time point 
• 
Maximum observed concentration (Cmax), Tmax, area under 
the concentration-time curve (AUC), terminal elimination 
half-life (t½), systematic clearance (CL), volume of 
distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from baseline to each visit in 
phosphorylated signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) from baseline in 
anti-double-stranded DNA (dsDNA), antinuclear antibodies 
(ANA), anti-Sjögren syndrome A and B (SSA, SSB), Smith 
(Sm), and antiphospholipid (APL) autoantibodies at each 
visit 
• 
Results and changes (or shifts) from baseline in abrogation 
of IL-21 gene signature at each indicated visit 


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Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
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• 
 
 
 
 
 
 
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2.2 
Phase 2 Proof of Concept 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on the SRI-4  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 response at 
Day 210 (see Section 6.3.4.1) 
Secondary 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction from baseline of oral 
corticosteroid (CS) (≤ 7.5 mg/day and < Day 0 dose) 
between Day 150 and Day 210 
- 
new or recurrent BILAG flares (≥ 1 qualifying 
BILAG A or > 1 qualifying BILAG B) through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
Total number of swollen joints, tender joints, and 
active joints (swelling and tenderness in the same joint) 
in the ACR-28 joint count 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Group mean percent reduction in CS administration from 
baseline Day 0 dose through Day 210 in patients receiving 
≥ 7.5 mg/day prednisone equivalent at Day 0 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time  to first BILAG flare (≥ 1 new or recurrent BILAG A 
or > 1 new or recurrent BILAG B) relative to baseline 
through Day 210 
Safety 
• 
To assess safety and tolerability of repeat 
doses of BOS161721 at the chosen dose 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), related AEs, AEs leading to study 
drug discontinuation, AEs by severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 


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3 STUDY PLAN 
3.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
moderately to severely active SLE.  After successfully completing a screening phase, eligible 
patients will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule 
will be monthly.   
The trial will consist of 2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visits at Days 210, 240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease activity.  Further details on the content and methods of data reports by the medical 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 
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monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
3.1.1 
Multiple Ascending Dose Phase 1b 
The MAD portion will consist of 3 cohorts:  
• 
Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• 
Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
the MAD part of the study are projected not to exceed the mean exposure of that achieved in the 
SAD study.   
3.1.1.1 
Dose Escalation for the MAD Portion  
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow-up after the second dose, Cohort 2 
begins dosing (after the DMC evaluation of the safety and tolerability data from Cohort 1).  
Similarly, after 8 of the 12 patients in Cohort 2 have received 2 doses and have completed 
2 weeks of follow-up after the second dose, Cohort 3 begins dosing after the DMC evaluation of 
the safety and tolerability data from Cohorts 1 and 2.  Each cohort will continue at their assigned 
dose level through their respective 6-month treatment periods (See Study Schematic, Section 3.1).  
If patients discontinue the study in a cohort prior to adequate safety follow-up, he/she may be 
replaced. 
Criteria for dose escalation are further described in the DMC Charter.  See Section 3.1.1.2 for 
additional details about DLTs.   
3.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia 
• Grade 3 neutropenic infection 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
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• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia 
Non-Hematologic: 
• 
Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals) 
• 
Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 6.2.2.6.3 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances. 
3.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD part of the study, the DMC may provide the following 
recommendations to the sponsor: 
• 
Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort 
• 
Continuing a dose level for a given cohort 
• 
Escalating a dose level for a subsequent cohort 
• 
Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC portion, the DMC and Boston Pharmaceuticals will conduct a 
data review to determine which dose will be carried forward into the POC Phase 2 part of the 
study.  This POC dose decision will be based on evaluation of the PK, safety (inclusive of 
dose-limiting toxicity [DLT]), and tolerability data (and available PD/biomarker data) from 
Cohorts 1, 2, and 3; this dose will not exceed doses tested during the MAD portion.  The DMC 
will be reviewing all relevant data from Cohorts 1, 2, and 3 that is available 30 days after the last 
patient from Cohort 3 receives the third dose.  Details are provided in the DMC Charter.  
3.1.2 
POC Phase 2  
3.1.2.1 
BOS161721 POC Dose Selection and Justification 
The dose for the POC portion of the study is 120 mg administered SC monthly (a total of 
7 doses).  The rationale for the BOS161721-02 Phase 2 POC dose selection was based on 
cumulative safety, tolerability, immunogenicity, PK, and PD data available from an interim 
analysis (IA) performed during the MAD Phase 1b portion of the trial. 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
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The data cut-off for this IA occurred on 
 and included all 6 patients and 
7 doses from Cohort 1 (20 mg), 12 patients and 6 doses from Cohort 2 (60 mg), and 12 patients 
and 4 doses from Cohort 3 (120 mg). 
The safety analysis focused on incidence and severity of all AEs, SAEs, and pre-determined 
adverse events of special interest (see Section 6.2.2.6).  The DMC and designated unblinded 
Boston Pharmaceuticals team met on 
 and did not identify any untoward 
safety signals at any BOS161721 dose levels. 
Because there were no safety, tolerability, or immunogenicity trends observed at the time of the 
IA, the Phase 2 POC dose selection was made based on available PK and PD data.  pSTAT3 
levels were assessed as the primary PD biomarker of IL-21R signaling levels.  This is because 
IL-21R signaling, upon IL-21 binding, initially involves phosphorylation of JAK1/JAK3 which 
dissociate from the receptor complex, and phosphorylate STAT3 which translocates to the 
nucleus and drives IL-21-regulated gene expression.  
 
. 
The 120 mg dose was communicated to site investigators participating in the POC Phase 2 
portion, and to Institutional Review Boards (IRBs) and the Independent Ethics Committee (IEC). 
3.1.2.2 
POC Study Design 
For the POC part of the study, approximately 156 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments (Table 1 and Table 4). 
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
3.2 
Randomization and Blinding 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
portion and separately for each cohort in the Phase 1b and 2 portions as follows: 
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Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1b MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the IA, ad hoc analyses as needed, and the DMC safety reviews.  The DMC will 
review unblinded data during safety reviews and the IA.  A limited team at Boston 
Pharmaceuticals will review unblinded results from the Phase 1b MAD portion during the IA to 
determine the dose that will be used for the Phase 2 POC portion of the study.  Details regarding 
maintenance of the blinding and content of data reviews will be described in the DMC charter or 
related study documentation.   
 


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3.3 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 
 
A = active drug (BOS161721); P = placebo 
Day 0
6 month treatment phase
Dose 1
Dose 120 mg N=104 
Placebo N=52
Low Dose (20 mg) N=6 (5A, 1P) 
Monthly visits 
Medium Dose (60 mg) N=12 (9A, 3P) 
Dose 3
2 month
6 patients complete dose 2:  dose escalate Cohort 2 if safe
Dose 1
Dose 2
1 month
High Dose (120 mg) N=12  (9A, 3P)
Dose 1
Dose 3 + 30 days: 
•
Phase 2 POC dose determined
•
Continue dosing Cohort 3 if safe
Follow up 
Dose 6
5 month
Dose 7
6 month
Dose 7
6 month
Dose 7
6 month
Screening
Week -4
8 patients complete dose 2:
•
Dose escalate Cohort 3 if safe
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Day 0
Day 0
Multiple Ascending Dose (MAD)
Phase 1b 
Proof of Concept (POC)
Phase 2 
Dose Evaluation
Phase
Follow up
90 days
90 days
Follow up 
90 days
Follow up 
90 days
Dose 1
Day 0
Dose 3
2 month
Dose 6
5 month
Dose 7
6 month
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Dose 3
2 month
Screening 
28 days
Screening 
28 days


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3.4 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo dosing 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction assessment 
 
Xg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
Xi 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory assessments 
(hematology and clinical 
chemistry)j 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
ADAl 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbm 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)o 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test (QuantiFERON-TB Gold 
In-Tube)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Spot urine for protein/creatinine 
ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labsb 
Predose 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb  = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity 
Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; 
TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
PK samples will only be collected at the investigational sites that participate in the PK portion of the study.  On PK only days (ie, Day 187 and Day 195 
when no laboratory assessments are scheduled) samples will be collected at the investigational sites of the selected countries that participate in the PK 
portion of the study.  Patients not participating in PK are not required to return for investigation site visits on Days 187 and 195. 
c 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the dose 
must be stable for at least 6 weeks prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
d 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after eligibility 
confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
e 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to screening 
or during the screening period must be documented in study records prior to randomization (Day 0). 
f 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled PK 
blood draws. 
g 
Injection site reaction assessments to be performed at 2 hours postdose. 
h 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 187 and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
i 
SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
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Table 1. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
j 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
k 
When clinically indicated for hemolytic anemia. 
l 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
m 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
n 
will not be analyzed during safety follow-up visits. 
o 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
p 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
 
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3.5 
End of Study  
End of Study (Individual Patient): A patient is considered at the end of study if he/she has 
withdrawn, prematurely discontinued, or completed all of the study procedures including the last 
visit. 
End of Study (End of trial): The end of the study is defined as the date of the last visit of the 
last patient in the study globally, or the date of which the last patient withdraws or discontinues if 
all prior enrolled patients have already completed/withdrawn. 
4 POPULATION 
4.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
4.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b portion, and approximately 156 additional patients will be randomized in the POC Phase 2 
portion.  Note that approximately 24 dropouts are assumed.   
4.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Table 1 and Table 4]) for this study 
must be performed between Day -28 and Day -1. 
4.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 


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immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including points from at least 1 of the 
following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
Note:  Points from lupus headache and organic brain syndrome will also be excluded from 
qualifying total and clinical SLEDAI-2K scores at screening and Day 0. 
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0.  Clinical SLEDAI-2K score is 
defined as follows: 
a. Contains points from arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, or 
vasculitis 
b. Excludes parameters which require central laboratory results:  hematuria, pyuria, urinary 
casts, proteinuria, positive anti-dsDNA, decreased complement, thrombocytopenia, and 
leukopenia 
Note:  Points from lupus headache and organic brain syndrome will also be excluded from 
qualifying total and clinical SLEDAI-2K scores at screening and Day 0. 
7. Patients must have at least 1 qualifying A or 2Bs from the following manifestations of SLE, 
as defined by the BILAG criteria as modified for use in this study, which must be confirmed 
by the central data reviewer:  
a. BILAG A or B score in the mucocutaneous body system.  If a BILAG B score is due to 
BILAG number 6, mild skin eruption, the CLASI activity score including erythema and 
scale/hypertrophy must be ≥ 3 excluding points from mucosal ulcers and alopecia. 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis defined by BOTH swelling and tenderness in ≥ 6 joints with marked 
loss of functional range of movements and significant impairment of basic activities 
of daily living (ADLs) that has been present on several days (> 4 days) cumulatively 
over the past 30 days, including at the time of the screening visit.  See APPENDIX 5 
for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require assistance or 
assistive devices, (at least 1 must be present and documented in source): 


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o Ambulation, toileting, grooming- including bathing and dressing; feeding 
oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis defined by 
BOTH swelling and tenderness in ≥ 3 joints, (observed or through patient history), 
with some loss of functional range of movements manifested by effects on 
instrumental ADLs such as: 
• Cooking, driving, using the telephone or computer, shopping, cleaning, etc., and 
has been present on several days over the last 30 days, and is present at the time 
of the screening visit 
Note:  Hips, shoulders, back, neck, and temporomandibular joints do not count towards 
the total number of joints with active synovitis. 
If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in at 
least 1 other body system for a total of 2 “B” BILAG body system scores. 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to Day 0) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. If AZA, myocophenolate mofetil, mycophenolic acid, hydroxychloroquine, or MTX were 
discontinued prior to screening, the washout period must be ≥ 12 weeks. 
c. Corticosteroids (prednisone or prednisone-equivalent) at a stable dose of up to 30 mg/day 
for at least 6 weeks prior to Day 0 (see APPENDIX 3)  
i. 
For patients whose only SLE treatment is CS, the stable CS dose must be 
≥ 10 mg/day for at least 6 weeks prior to Day 0 and no more than 30 mg/day at the 
time of randomization. 
ii. 
Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to 
Day 0.  PRN topical steroids are not permitted. 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose 
b. Must not be breastfeeding 


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c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 52 weeks 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
treatment plans, laboratory tests, and other procedures 
4.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic sclerosis, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any elective 
surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 0 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator or the sponsor or their designee, is 
likely to require additional systemic glucocorticosteroid therapy during the study, (eg, 
asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is allowed 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 4.6 for prohibited 
concomitant medication) 


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9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
parenteral antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) unless patient 
received curative treatment for HCV and has a documented negative viral load, known 
human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-
related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 150/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to lupus 
based on the investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Total bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator or the sponsor or 
sponsor’s designee, might place a patient at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision) 


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27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, sponsor or sponsor’s designee, would make the patient inappropriate for 
entry into this study 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
33. Currently taking a total daily dose of > 30 mg morphine or morphine equivalent (see 
APPENDIX 7) 
34. Body mass index (BMI) ≥ 40.0 
4.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen (not PRN) of 
other concomitant medications for the treatment of SLE (eg, analgesics, nonsteroidal anti-
inflammatory drugs [NSAIDs], statins, ACE inhibitors/ARBs and other antihypertensive drugs), 
unless changes in these treatments are clinically indicated.  Patients should refrain from Tylenol, 
NSAIDs, and any pain medications including tramadol and other opiates for at least 12 hours 
before each visit, with the exception of the Screening Visit. 
Use of any other drugs for non-SLE conditions, including over-the-counter medications and 
herbal preparations, should remain stable unless change or addition is clinically necessary.  
Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent including investigational agents) will be 
recorded for the 48 weeks prior to screening in the eCRF. 
4.6.1 
Corticosteroid 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 


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A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study.  
For patients whose only SLE treatment is steroids, their stable steroid dose must be at least 
10 mg/day and no more than 30 mg/day for a minimum of 6 weeks at time of randomization on 
Day 0. 
Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to Day 0, and 
be maintained at a constant dose throughout the study duration until the rashes resolve.  PRN 
topical steroids are not permitted. 
Once the patient has received the first dose of study drug (Day 0), tapering of oral steroids will 
be highly encouraged and should be continually evaluated during the protocol-allowed tapering 
windows (Day 0 through Day 150) with the target of achieving a CS daily dose of < 7.5 mg and 
< Day 0 dose between Day 150 and Day 210.   
Between Day 150 and Day 210 (ie, within 60 days of primary endpoint assessments), oral CS 
doses must be held constant. 
CS Burst for SLE-related Indications 
After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” equivalent to 
≤ 40 mg/day prednisone for increased SLE disease activity will be allowed between Day 0 
and Day 120, which must be tapered down to the baseline (Day 0) CS dose or lower within 
14 days of initiation of the “burst.”  Any “burst” continuing after Day 120 or occurring after 
Day 120 is considered a protocol deviation. 
o Alternatively, a single intramuscular (IM) dose of methylprednisolone (< 40 mg) is 
permitted during this period. 
CS Burst for Non-SLE-related Indications 
A single treatment of oral prednisone equivalent of ≤ 40 mg/day for 14 days is permitted for 
a non-SLE indication, though it must be completed prior to Day 120.  No long acting steroid 
injections are permitted. 
Note:  Treatment with inhaled CS are allowed for the treatment of non-SLE-related 
indications only (eg, for asthma). 
Any other increase from baseline of CS dose or systemic use of CS of any kind (including 
intra-articular and intravenous administration) are not permitted from Day 0 through Day 210 
and will result in the patient being considered a treatment failure.  There is no restriction of CS 
usage after Day 210. 
4.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and during the 
study are described below, and washout requirements are provided in APPENDIX 4.  All 
medications taken within 30 days prior to screening must be recorded on the eCRF. 


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1. Prior exposure to BOS161721 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
24 weeks of screening 
3. Patients who have received treatment with cyclophosphamide within the 24 weeks prior to 
screening 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria within 4 weeks for oral use or 8 weeks for topical use of screening 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 24 weeks prior to screening 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc., may be used 
according to local guidelines during treatment period 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation 
4.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 
See Section 4.7.2 for detailed information regarding contraceptive requirements for WOCBP. 
4.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   
4.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks, due to the mean terminal ½ life of the study drug. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 52 weeks, due to the mean 
terminal ½ life of the study drug. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  


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Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
Patients must agree to either complete abstinence, defined as a complete avoidance of 
heterosexual activity, or the use of 2 methods of highly effective contraception from the 
following: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, 
injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who are 
WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• 
IUDs, such as ParaGard® 
• 
Vasectomy 
Note:  Women who are abstinent while participating in the study must continue to have 
pregnancy tests.  Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the patient chooses to forego complete abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, WOCBP must still undergo pregnancy testing. 
4.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient to continue 
or withdrawal from the study medication.    
See Section 6.8 for additional details.  
4.8.1 
Patient Withdrawal and Replacement 
See Section 5.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD part of the study after discussion between the principal investigator or designee 
and sponsor. 
5 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
5.1 
Screening 
Screening will be the same for both the MAD and POC portions of the study. 


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Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria, listed in Section 4.4 and Section 4.5 respectively, will be enrolled in 
the study.  Screened patients who drop out of the clinical study before randomization will be 
recorded as screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• 
Medical history documentation 
• 
Review of inclusion and exclusion criteria 
o Patient medical records must contain documentation of SLE diagnosis 
o C-SSRS   
• 
Concomitant medication documentation 
• 
Demographics 
• 
Full physical examination 
• 
Vital signs 
• 
Chest x-ray (a prior x-ray can be used if taken within 12 weeks of screening date) 
• 
Laboratory evaluations (non-fasting): 
o Hematology and clinical chemistry 
o Serology (Hepatitis B and C; HIV-1/2 combination) 
o TB test 
o CRP 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, 
 
 
o Serum pregnancy test (WOCBP) 
o FSH (postmenopausal women under age 55 years) 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
o Stool sample  
• 
12-lead ECG 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity 
Screening procedures are listed in the Schedule of Assessments (Table 1 and Table 4), and 
details are provided in Section 6. 
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5.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• 
medically indicated 
• 
there is evidence a laboratory sample was mislabeled, indeterminate, inadequately processed, 
and/or deteriorated in transit to the central laboratory 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
5.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.  The central eligibility review team has the final decision on patient 
eligibility and can decide the patient is not eligible for the study based on their review of the 
eligibility packet. 
Prior to randomization, the study site should confirm that the patient still meets 
inclusion/exclusion criteria (especially SLE disease activity and treatment).  The site will obtain 
a randomization number when registering the patient in IWRS.  All patients will receive 
BOS161721 or placebo according to the kit number assigned by the IWRS randomization 
scheme.    
After randomization, procedures include: 
• 
PROs:  
 
• 
C-SSRS 
• 
Laboratory evaluations (fasting): 
o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype (leukocyte immunophenotype 
for MAD patients only) 
o ADA 
o pSTAT3 (predose [trough] samples only in Phase 1b)  
o 
 
o 
 
o 
 
o See Table 4 and Table 1for details of PK sampling in the MAD and POC portions 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration 
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o Spot urine for protein/creatinine ratio 
o Urinalysis 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Full physical examination 
• 
Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 0) 
• 
12-lead ECG (prior to PK blood draw) 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, PGA) 
• 
SLICC/ACR damage index 
• 
Study drug administration: 
o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 7.3 
• 
Injection site reaction assessment performed at 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Table 1 and Table 4), and details 
are provided in Section 6. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
5.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of Assessments 
(Table 1and Table 4).  See Schedule of Assessment tables for allowable windows for each visit.   
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
PROs:  
 
• 
Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
• 
Injection site reaction assessments will be performed predose  
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Spot urine for protein to creatinine ratio 
• 
Urinalysis 
• 
 
• 
Plasma 
 
• 
PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
• 
SLICC/ACR Damage Index will be completed at Day 180 
• 
C-SSRS 
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• 
ECGs prior to PK blood draw 
• 
See Table 4 and Table 1for details of PK sampling in the MAD and POC studies, 
respectively 
• 
Fasting hematology and chemistry assessments  
• 
The CD4+ count and total IgG and IgM levels  
• 
Plasma 
 and 
, ADA, and whole blood for leukocyte immunophenotype 
(leukocyte immunophenotype for MAD patients only) 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
nAb will be analyzed by central lab if patient is positive for ADA 
• 
CRP 
• 
 
5.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270.  These visits will include the 
following assessments as indicated in the Schedule of Assessments (Table 1 and Table 4):  
• 
PROs:  
 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Injection site reactions 
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Spot urine for protein/creatinine ratio and urinalysis 
• 
Concomitant medication documentation 
• 
BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
• 
Fasting clinical laboratory assessments (hematology and clinical chemistry) 
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Plasma 
 
• 
 
• 
12-lead ECG (prior to PK blood draw) 
• 
CRP 
• 
ADA 
• 
 
• 
Urine pregnancy test 
• 
See Table 4 and Table 1for details of PK sampling in the MAD and POC portions, 
respectively 
5.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
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withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Day 180) and a last follow-up visit 90 days after dosing should be scheduled 
(Day 270).  Safety follow-up visit procedures based on the Schedule of Assessments 
(see Section 5.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• 
AE/SAE 
• 
Protocol deviation 
• 
Lost to follow-up 
• 
Patient withdraws consent at their own request 
• 
Investigator decision 
• 
Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
6 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
6.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• 
General medical history 
• 
Documentation of SLE diagnosis 
• 
Historical medication therapy for SLE 
The following demographic information will be recorded:  
• 
Age 


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• 
Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• 
Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• 
Height (without shoes, in cm) 
• 
Body weight, without shoes (kg) 
• 
BMI [kg/m2] 
Other baseline characteristics will be recorded as follows: 
• 
Concomitant medication documentation (see Section 4.6) 
• 
Status of child bearing potential and contraception 
6.2 
Safety Assessments 
6.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments (Table 1 and 
Table 4).  Patient eligibility will be determined based on these tests at screening.  Unscheduled 
clinical labs may be obtained at any time during the study to assess any perceived safety 
concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests) to ensure accuracy 
and consistency in test results.  Laboratory/analyte results that could unblind the study (ie, 
biomarker results) will not be reported to investigative sites.  Urinalysis will be performed on 
midstream, clean catch specimens.  Some biomarkers listed above will not be drawn at some 
sites due to geographical logistical challenges.  See the laboratory manual for details. 
Endpoint analyses will be based on changes from baseline assessments at Days 120 and 210. 
Table 2. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test 
(QFT-G)d 
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
Serum pregnancy test 
 
 


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Table 2. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
Prothrombin 
time/international 
normalized ratio (repeat) 
Creatine kinase (repeat) 
 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only in Phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte 
immunophenotype (for MAD patients 
only) 
 
 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MAD = multiple ascending doses; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = Mean 
corpuscular volume; nAb = neutralizing antibody; pSTAT3 = phosphorylated signal transducer and activator of 
transcription 3; PT = prothrombin time; qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; 
SAE = serious adverse event; SC = subcutaneous; 
; TB 
= tuberculosis.  
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for 
ova, parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 6.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated for hemolytic anemia. 
6.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or 
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continued and a further negative urine pregnancy test results will then be required at the baseline 
visit before the patient may receive the investigational product.  Urine pregnancy tests will also 
be routinely repeated at study drug administration visits prior to study drug administration, at the 
last follow up visit day (Day 270) and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  In the case of a positive pregnancy test or 
confirmed pregnancy, the patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose should be scheduled 
(Day 270).  Safety follow-up visit procedures (see Section 5.4) are specified in the Schedule of 
Assessments (see Table 1 and Table 4). 
See Section 6.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
6.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 4.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 0). 
6.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 
study.  If a repeat test is indeterminate again, the patient is a screen failure.  The procedure for 
using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
6.2.2 
Adverse Events 
6.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   


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Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 6.2.2.5). 
6.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset, date of AE outcome, and action taken for the AE will be documented together 
with the principal investigator’s assessment of the seriousness of the AE and causal relationship 
to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
6.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 
and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 
6.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 3) should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 


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Table 3. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation (positive dechallenge), or the 
symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that there are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
6.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• 
Requires hospitalization or prolongation in existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly or birth defect 
• 
Is other important medical event (see below) 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• 
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Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
6.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Grades 2 to 5 injection site reaction, including erythema, pain, and induration 
(See APPENDIX 6) 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy (not including basal cell carcinoma or squamous cell carcinoma of skin) 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, disseminated 
herpes simplex, disseminated tuberculosis, Aspergillus sp., Candida albicans, Coccidioides 
immitis, Cryptococcus neoformans, Cytomegalovirus, Histoplasma capsulatum, Isospora 
belli, and Polyomavirus JC polyomavirus 
6. Cryptosporidiasis 
6.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 


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b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline 
6.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These will include Grades 2 to 5 
injection site erythema, pain, and induration (see APPENDIX 6), which are also captured as 
Adverse Events of Special Interest (See Section 6.2.2.6).  The investigator should provide a clear 
description of the observed or reported AE including location and severity.  All concomitant 
treatments used to treat injection site reactions should be recorded and captured in the eCRF, 
together with the AE of injection site reactions.   
6.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.2.2.7.2 for reporting details). 
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 


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3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 5× ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 
• 
ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
• 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
6.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 6.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue (with the exception of suspected basal cell/squamous cell), 
the investigator and/or consultant(s) should contact the sponsor clinicians or designee to discuss 
the issue and any decisions as soon as possible.  Basal cell carcinoma or squamous cell 
carcinoma of skin is not considered an AE of special interest. 


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6.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, disseminated herpes simplex, disseminated tuberculosis, 
Aspergillus sp., Candida albicans, Coccidioides immitis, Cryptococcus neoformans, 
Cytomegalovirus, Histoplasma capsulatum, Isospora belli, or Polyomavirus JC polyomavirus 
will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
6.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 6.2.2.7.2. 
6.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 


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adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 
6.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Day 270).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• 
Study number 
• 
Patient number 
• 
Details of the SAE (verbatim details are sufficient for immediate notification) 
• 
Criterion for classification as ‘serious’ 
• 
Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 
obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   


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6.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becoming aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 
Potential DILI will be reported based on specifications mentioned in Section 6.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as appropriate, 
and is further outlined in Section 6.2.2.7.2. 
6.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 6.2.2.7.1 for details related to follow-up of pregnancy.  See Section 6.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 6.2.2.6.4 for details related to 
follow-up of malignancy. 
6.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Table 1 and Table 4).  Vital signs will be assessed on Day 0 at predose 
and at Day 0, 1 and 2 hours postdose, as well as on each of the scheduled visit days during the 
study (excluding PK-only site visits).  Supine BP and heart rate recordings will be made after the 
patient has been recumbent and at rest ≥ 5 minutes.  When the timing of these measurements 
coincides with a blood collection, vital signs should be obtained prior to the time of the blood 
collection. 
6.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Table 1 and Table 4).  ECG 
recording will initiate after the patient has been supine for at least 5 minutes.  On days of PK 
blood draws, the ECG will be collected before scheduled PK blood draws, though timing will be 
such that PK draws are collected on their scheduled times where possible. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 


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All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 
6.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 
thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at all other visits as indicated in 
the Schedule of Assessments (Table 1 and Table 4).  It includes evaluation of patient complaints 
and SLE disease-related issues, and will exclude the genitourinary system. 
6.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments (Table 1 
and Table 4).  Patients with recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 is exclusionary at screening 
will be excluded from the study.  Patients with recent or active suicidal ideation or behavior at 
subsequent study visits will have responses to the C-SSRS reviewed in detail to assess patient 
risk, and appropriate consultative mental health services will be provided. 
6.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule of 
Assessments (Table 1 and Table 4).  Local injection site reactions will be assessed at 2 hours 
postdose at baseline, and predose for each injection after baseline.  Injection site reactions should 
be managed according to the standard of care.  Injection site reactions, Grades 2 to 5, are to be 
reported as AEs of special interest (see Section 6.2.2.7.3). 
6.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in the 
Schedule of Assessments (Table 1 and Table 4).  Blood samples (4 mL) to provide 
approximately 1.5 mL of plasma for anti BOS161721 antibody analysis will be collected into 
appropriately labeled tubes containing K2EDTA.  The presence or absence of ADA will be 
determined in the serum samples using validated bioanalytical methods.  Blood samples for 
ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be 


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collected from all patients but only analyzed by a central lab if the patient had a positive ADA on 
Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, a sample 
from this patient will be further analyzed in the neutralizing antibody (nAb) assay by a central 
lab. 
6.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of Assessments 
(Table 1 and Table 4). 
6.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
6.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 
4 weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, worksheet, 
clinic notes, and labs) at each visit. 
See APPENDIX 5 for detailed specifications. 
6.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 


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and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.  PGA worsening is defined as an increase of > 30 mm from baseline. 
When scoring the PGA, the assessor should always look back at the score from the previous visit. 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
6.3.4.1 
SRI-4 Response 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 30 mm.  The SRI-4 response in patients with moderate to severe SLE is 
associated with broad improvements in clinical and patient-reported outcomes.45  
6.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal five-point or six-point improvement in 
SLEDAI-2K being required, respectively.46 
6.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 
For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined. 
6.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 


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6.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 
6.4 
Other Variables 
6.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Days 0 
and 180. 
6.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
and will be assessed as 
specified in the Schedule of Assessments (Table 1 and Table 4). 
 
50     
 
.   
6.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) parts of the study, 
blood samples for PK analysis of BOS161721 or placebo concentration will be collected 
according to Table 4 and Table 1. 
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration actual time profiles.   
6.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the Schedule of 
Assessments (Table 1 and Table 4) for each of the following parameters: 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
Antibodies:  
  
• 
Plasma complement (
)  
CCI
CCI
CCI
CCI
CCI
CCI


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• 
Plasma 
 and 
  
• 
Whole blood for leukocyte immunophenotype (for MAD patients only) 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
6.8 
Protocol Deviations 
Protocol deviations will be documented during the study.   
7 STUDY DRUG MANAGEMENT 
7.1 
Description 
7.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
7.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
7.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
7.3 
Dose and Administration 
Details of dosing are provided in Section 3.1. 
CCI
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Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
7.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Used investigational product returned to the pharmacy may be 
maintained in an ambient condition.  Unused product should follow the instructions in the 
Pharmacy Manual.  The used product that is returned should be marked as ‘returned’ and kept 
separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
7.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 4.6 and APPENDIX 4 and will be 
listed as protocol violations if taken when not permitted. 
7.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal investigator.  
The date and time of dosing will be documented on each dosing day.  Comments will be 
recorded if there are any deviations from the planned dosing procedures. 
8 STATISTICS 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC part of the study.   
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• 
An additional analysis may be performed for the MAD portion of the study when all 
MAD patients have completed the safety follow-up or withdrawn from the study, and 
prior to final analysis.  Data from the POC part of the study will be excluded from this 
additional analysis. 
• The final analysis will be performed when all patients have completed the POC safety 
follow-up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
content and format of the safety review meetings will be described in the SAP and/or 
DMC charter. 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9 
or higher.   
The following standards will be applied for the analysis unless otherwise specified.  Data will be 
summarized descriptively by treatment and overall for each study portion.  For the MAD part of 
the study, BOS161721 will be summarized overall and by each dose level, and placebo patients 
from each cohort will be combined.  Select parameters may be summarized using patients from 
both study parts.  Statistical testing will be performed on data from the Phase 2 portion only. 
Continuous data will be summarized using number, mean, standard deviation (SD), 25th and 75th 
percentiles, minimum, median, and maximum.  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage).  Time to event data will be 
summarized using counts, medians, 25th and 75th percentiles, and standard error.  All data will be 
listed for all patients. 
Statistical inference will be based on a 2-tailed test with an overall 0.10 level of significance, 
unless stated otherwise.   
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data will be conducted as 
deemed appropriate.  Any deviations from the planned analyses will be described and justified in 
the final integrated CSR. 
Protocol deviations and prohibited medications that define medication failures will be fully 
assigned and documented before database lock and unblinding.  
Further details of the analysis, including the handling of missing data, transformations and other 
data handling procedures will be provided in the SAP.   
8.1 
Sample Size 
Sample size in the Phase 1b part of the study is based on operational consideration. 
The sample size in the Phase 2 portion is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable patients in the FAS.  This assumes 


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24 patients will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 patients are randomized into the FAS.    
A total of 132 patients randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes of a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 
from most recent non-missing result and patients are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all patients who receive at 
least 1 dose of study treatment and have at least 1 evaluable post-baseline efficacy evaluation.  
FAS analyses will be conducted on the basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol violations from the 
efficacy analysis.  The PP Population will include all patients from the FAS except those with 
major violations to the protocol deemed to impact the analysis of the primary endpoint.  These 
violations will be identified based on blinded data prior to study unblinding.  PP analyses will be 
conducted on the basis of the randomized treatment. 
Safety analyses will be based on the safety analysis set (SS), defined as all patients who receive 
at least 1 dose of study treatment.  Safety analyses will be conducted on the basis of actual 
treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, defined as the FAS with 
sufficient concentration data for the calculation of PK parameters.   
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all randomized patients.   
8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will be assessed via 
Pearson’s chi-squared analysis.  The primary efficacy endpoint will be analyzed using the FAS 
and if needed repeated in the PP analysis set.  Missing values will be addressed by employing a 
last observation carried forward (LOCF) analysis.  Other imputation methods may be employed 
as a sensitivity analysis and will be described in the SAP.  Additional analyses exploring impact 
of baseline factors such as baseline disease severity, race, and other characteristics may be 
performed.  
Patients that received prohibited medications or unallowable CS usage as described in 
Section 4.6 will be considered “medication failures” and will be treated as statistical 


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non-responders at time points on or following the first date of prohibited medication or 
unallowable CS usage for the primary efficacy analysis.  The determination of medication 
failures will be reviewed using blinded data and finalized prior to unblinding.   
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 0.10.  
Secondary and exploratory endpoints for this POC portion will be evaluated based on the same 
statistical hypothesis. 
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared analysis.  Continuous 
efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of covariance 
(ANCOVA) and treatment will be compared using the F-test.  Repeated measures mixed models 
may be performed to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be compared using the log-
rank test.  The secondary efficacy endpoints will be analyzed on the FAS and if needed repeated 
in the PP analysis set.  Details including handling of missing data and “medication failures” will 
be available in the SAP. 
8.2.5 
Analysis of Safety 
8.2.5.1 
Safety Analysis 
Safety analyses will be performed on the SS.  AE data will be coded to system organ class and 
preferred term using MedDRA.  The number and percentage of patients experiencing any 
treatment-emergent AE, overall, and by system organ class and preferred term, will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and relationship.   
Concomitant medications will be coded using the WHO Drug dictionary.  Observed values and 
changes from baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters will be summarized at each individual visit.   
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 
Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected during the MAD Phase 1b 
portion of the study using non-compartmental analysis and include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 


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• 
A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 
• 
A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 
8.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Exploratory analyses examining the relationship between PD parameters and PK concentration 
and PK parameters will be performed.   
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the POC decision for dose 
selection. 
Since there is no IA during the POC part of the study, there is no impact on the type 1 error.   
9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
9.2 
DMC 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC (ie, 
dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 


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forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in Section 3.1.1.3. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.3 
Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees/IRB must meet the guidelines set out by the U.S. Food and Drug 
Administration (FDA) and conform to local laws and customs where appropriate.  Written 
IRB/IEC approval for the protocol and the signed ICF must be obtained and transmitted to 
Boston Pharmaceuticals or representative before the study can be initiated.  The IRB/IEC must 
be informed of and approve all protocol amendments.  The investigator will ensure that this 
study is conducted in full conformance with all applicable local and regional laws and 
regulations.  The complete text of the World Medical Association Declaration of Helsinki is 
given in APPENDIX 2. 
9.4 
Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the written 
informed consent will be obtained according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the principal investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient should be informed that he/she is free to withdraw from the study 
at any time.  He/she will receive all information that is required by federal regulations and ICH 
guidelines.  The principal investigator or designee will provide the sponsor with a copy of the 
IRB-approved ICF prior to the start of the study.   


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The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 
study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   
If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future patients enrolled in the clinical study will be required to 
sign this revised ICF. 
9.5 
Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 


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9.6 
Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 
must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
9.7 
Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
10 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 
study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 


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immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
12 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 
The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
13 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 


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maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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17 Tangye SG, Ma CS, Brink R, Deenick EK.  The good, the bad and the ugly - TFH cells in 
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experimental colitis by modulating the balance between Treg and Th17 cells.  Eur J 
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19 Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al.  IL-21 
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20 Hippen KL, Bucher C, Schirm DK, Bearl AM, Brender T, Mink KA, et al.  Blocking IL-21 
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21 Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, et al.  An open- 
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22 Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, et al.  
IL-21 induces in vivo immune activation of NK cells and CD8(+) T-cells in patients with 
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23 Karrich JJ, Jachimowski LC, Nagasawa M, Kamp A, Balzarolo M, Wolkers MC, et al.  
IL-21- stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs 
their capacity to induce T-cell proliferation.  Blood. 2013;121(16):3103-11. 
24 Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TF, et al.  
Interleukin-21-induced granzyme B-expressing B-cells infiltrate tumors and regulate 
T-cells.  Cancer Res.  2013;73(8):2468-79. 
25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
metalloproteinase production in human intestinal fibroblasts by interleukin 21.  
Gut. 2006;55(12):1774-80. 
26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
contributes to the generation of plasma B-cells.  Clin Exp Rheumatol.  2013;31(2):172-9. 
 
 


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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 
28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
pathogenesis of primary Sjögren’s syndrome:  increased serum levels of interleukin-21 
and its expression in the labial salivary glands.  Arthritis Res Ther. 2011;13(5):R179. 
30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
Interleukin-21 modulates Th1 and Th17 responses in gianT-cell arteritis.  Arthritis 
Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
erythematosus.  J Rheumatol. 2012b;39(9):1819-28. 
32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
33 Wang W, Wang EQ, Balthasar JP.  Monoclonal Antibody Pharmacokinetics and 
Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
35 Elsaesser H, Sauer K, Brooks DG.  IL-21 is required to control chronic viral infection.  
Science.  2009;324(5934):1569-72 
36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.  
J Exp Med. 2013;210(3):433-43. 
37 Hunter PR, Nichols G.  Epidemiology and clinical features of Cryptosporidium infection in 
immunocompromised patients.  Clinical microbiology reviews.  2002;15(1):145-54. 
38 Desjardins M, Mazer BD.  B-cell memory and primary immune deficiencies:  interleukin-21 
related defects.  Curr Opin Allergy Clin Immunol. 2013;13(6):639-45. 
39 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
 
 


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40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US:  
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 
41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
doi:10.1136/lupus-2013-000005. 
47 Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M,et al.  Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
Cutaneous Lupus Erythematosus.  J Invest Derm. 2005;125(5):889-94. 
49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
Pulmonary Organ Scores are Predictors of Sever Outcome in Patients with Systemic 
Lupus Erythematosus.  Br J Rheumatol.  1996;35:248-54. 
50 
 
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CCI


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16 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 400 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my subject will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act only in the subject's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
quality. 
In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 


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Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 


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Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 


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review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Prednisone Dose Equivalence 
Prednisone 
1 mg 
Cortisone 
5 mg 
Hydrocortisone 
4 mg 
Prednisolone 
1 mg 
Methylprednisolone 
0.8 mg 
Triamcinolone 
0.8 mg 
Budesonide 
0.25 mg 
Dexamethasone 
0.16 mg 
Bethamethasone 
0.16 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS 
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
24 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks for oral and 8 weeks for topical 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with 
cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE 
Adverse event 
Injection site reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Definition:  A disorder 
characterized by an 
intense adverse reaction 
(usually immunologic) 
developing at the site of 
an injection 
Tenderness with 
or without 
associated 
symptoms (eg, 
warmth, 
erythema, 
itching) 
Pain; 
Lipodystrophy; 
Edema; 
phlebitis 
Ulceration or 
necrosis;  
Severe tissue 
damage; 
Operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
 limiting self-
care ADL 
- 
- 
Rash 
maculopapular/Erythema
/Induration 
 
Definition:  A disorder 
characterized by the 
presence of macules 
(flat) and papules 
(elevated).  Also known 
as morbilliform rash, it is 
one of the most common 
cutaneous adverse 
events, frequently 
affecting the upper trunk, 
spreading centripetally, 
and associated with 
pruritus. 
Macules/papules 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Erythema 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Macules/papules 
covering 10% - 
30% BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL; 
Erythema 30% 
BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL 
Macules/papul
es covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-care ADL 
 
Erythema 
covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-careADL 
- 
- 
ADL = active daily living 
 
 


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APPENDIX 7 
OPIOID ORAL MORPHINE MILLIGRAM 
EQUIVALENTS OF COMMONLY USED OPIOIDS 
Opioid  
30 mg morphine equivalent 
butorphanol 
4.3 mg/day 
codeine 
200 mg/day 
dihydrocodeine 
120 mg/day 
fentanyl transdermal 
12.5 mg/day 
hydrocodone 
30 mg/day 
hydromorphone 
7.5 mg/day 
levorphanol tartrate 
2.7 mg/day 
meperidine HCl 
300 mg/day 
oxycodone 
20 mg/day 
oxymorphone 
10 mg/day 
pentazocine 
81.1 mg/day 
tapentadol 
75 mg/day 
tramadol 
300 mg/day 
Note that this list is not comprehensive.  If an opioid is being used which is not in this list, please see the appropriate 
conversion factor below. 
 
 


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Opioid Oral Morphine Equivalent Conversion Factorsa,b 
Type of Opioid (strength in units) 
MME Conversion Factor 
Buprenorphine film/tablec (mg) 
30 
Buprenorphine patchd (mcg/hr) 
12.6 
Buprenorphine film (mcg) 
0.03 
Butorphanol (mg) 
7 
Codeine (mg) 
0.15 
Dihydrocodeine (mg) 
0.25 
Fentanyl buccal or SL tablets, or lozenge/trochee (mcg) 
0.13 
Fentanyl film or oral sprayf (mcg) 
0.18 
Fentanyl nasal sprayg (mcg) 
0.16 
Fentanyl patchh (mcg) 
7.2 
Hydrocodone (mg) 
1 
Hydromorphone (mg) 
4 
Levorphanol tartrate (mg) 
11 
Meperidine hydrochloride (mg) 
0.1 
Methadonei (mg) 
3 
> 0, ≤ 20 
4 
> 20, ≤ 40 
8 
> 40, ≤ 60 
10 
> 60 
12 
Morphine (mg) 
1 
Opium (mg) 
1 
Oxycodone (mg) 
1.5 
Oxymorphone (mg) 
3 
Pentazocine (mg) 
0.37 
Tapentadolj (mg) 
0.4 
Tramadol (mg) 
0.1 
CDC = Centers for Disease Control; CMS = Centers for Medicare and Medicaid Services; FDA = Food and Drug 
Administration; MAT = Medication Assisted Treatment; MME = morphine milligram equivalent; 
OMS = Overutilization Monitoring System. 
a. 
The MME conversion factor is intended only for analytic purposes where prescription data is used to calculate 
daily MME.  It is to be used in the formula:  Strength per Unit × (Number of Units/Days Supply) × MME 
conversion factor = MME/Day.  This value does not constitute clinical guidance or recommendations for 
converting patients from one form of opioid analgesic to another.  Please consult the manufacturer’s full 
prescribing information for such guidance.  Use of this file for the purposes of any clinical decision-making 
warrants caution. 
b. National Center for Injury Prevention and Control.  CDC compilation of benzodiazepines, muscle relaxants, 
stimulants, zolpidem, and opioid analgesics with oral morphine milligram equivalent conversion factors, 2016 
version.  Atlanta, GA: Centers for Disease Control and Prevention; 2016. Available at 
https://www.cdc.gov/drugoverdose/media/.  For more information, send an email to Mbohm@cdc.gov. 
c. 
Buprenorphine formulations with a FDA approved indication for MAT are excluded from Medicare’s 
Overutilization Monitoring System’s opioid overutilization reporting. 


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Page 104 of 139 
d. The MME conversion factor for buprenorphine patches is based on the assumption that 1 milligram of 
parenteral buprenorphine is equivalent to 75 milligrams of oral morphine and that one patch delivers the 
dispensed micrograms per hour over a 24 hour day.  Example:  5 μg/hr buprenorphine patch × 
24 hrs = 120 ug/day buprenorphine = 0.12 mg/day = 9 mg/day oral MME.  In other words, the conversion factor 
not accounting for days of use would be 9/5 or 1.8. 
However, since the buprenorphine patch remains in place for 7 days, we have multiplied the conversion factor 
by 7 (1.8 × 7 = 12.6).  In this example, MME/day for 4 5 μg/hr buprenorphine patches dispensed for use over 
28 days would work out as follows:  Example:  5 μg/hr buprenorphine patch × (4 patches/28 days) × 
12.6 = 9 MME/day.  Please note that because this allowance has been made based on the typical dosage of 
1 buprenorphine patch per 7 days, you should first change all Days Supply in your prescription data to follow 
this standard, i.e., Days Supply for buprenorphine patches = number of patches x 7. 
e. 
The MME conversion factor for fentanyl buccal tablets, sublingual tablets, and lozenges/troche is 0.13.  This 
conversion factor should be multiplied by the number of micrograms in a given tablet or lozenge/troche. 
f. 
The MME conversion factor for fentanyl film and oral spray is 0.18.  This reflects a 40% greater bioavailability 
for films compared to lozenges/tablets and 38% greater bioavailability for oral sprays compared to 
lozenges/tablets. 
g. The MME conversion factor for fentanyl nasal spray is 0.16, which reflects a 20% greater bioavailability for 
sprays compared to lozenges/tablets. 
h. The MME conversion factor for fentanyl patches is based on the assumption that 1 milligram of parenteral 
fentanyl is equivalent to 100 milligrams of oral morphine and that 1 patch delivers the dispensed micrograms 
per hour over a 24 hour day.  Example:  25 μg/hr fentanyl patch × 24 hrs = 600 ug/day fentanyl = 60 mg/day 
oral morphine milligram equivalent. 
In other words, the conversion factor not accounting for days of use would be 60/25 or 2.4. 
However, since the fentanyl patch remains in place for 3 days, we have multiplied the conversion factor by 
3 (2.4 × 3 = 7.2).  In this example, MME/day for 10 25 μg/hr fentanyl patches dispensed for use over 30 days 
would work out as follows:   
Example:  25 μg/hr fentanyl patch × (10 patches/30 days) × 7.2 = 60 MME/day.  Please note that because this 
allowance has been made based on the typical dosage of 1 fentanyl patch per 3 days, you should first change all 
Days Supply in your prescription data to follow this standard, i.e., Days Supply for fentanyl patches = number 
of patches × 3. 
i. 
The CDC MME conversion factor to calculate morphine milligram equivalents is 3.  CMS uses this conversion 
factor when analyzing Medicare population opioid use.  CMS uses the graduated methadone MME conversion 
factors to calculate MME within the OMS for identifying and reporting potential opioid overutilizers. 
https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf. 
j. 
Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor.  Oral MMEs are based on degree of 
mu-receptor agonist activity, but it is unknown if this drug is associated with overdose in the same 
dose-dependent manner as observed with medications that are solely mu receptor agonists. 


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Page 105 of 139 
APPENDIX 8 
SCHEDULE OF ASSESSMENTS - PHASE 1B MULTIPLE ASCENDING DOSE 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site 
reaction assessment 
 
Xf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


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Page 106 of 139 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2Kh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)i 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directj 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAk 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbl 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3m 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
CCI
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Page 107 of 139 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)o 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test 
(QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
(hepatitis B and C, 
HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CCI
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Page 108 of 139 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
PK Labs 
Predose 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Predose PK 
Window 
 
60 m 
 
 
± 3 d 
 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
 
 
 
 
 
Postdose 
 
Xq 
X 
X 
Xq 
 
 
 
 
 
Xq 
X 
X 
X 
X 
X 
Postdose PK 
Window 
 
4 h ± 
30 m 
8 h ± 
45 m 
24 h ± 
60 m 
± 1d 
± 3 d 
4 h ± 
30 m 
8 h ± 
45 m 
24 h ± 
60 m 
 
 
 
 
 
4 h ± 
30 m 
8 h ± 
45 m 
24h ± 
60 m 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
± 3 d 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; APL = antiphospholipid; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SAE = serious adverse event; 
SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 7, 187, and 195).  When the timing 
of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
CCI
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Page 109 of 139 
Table 4 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
h 
SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
i 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be non-fasting. 
j 
When clinically indicated for hemolytic anemia. 
k 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients, but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
l 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
m 
Predose (trough) samples only. 
n 
 Antibodies and autoantibodies (
) will not be analyzed during safety follow-up visits.  
o 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
p 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
q 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180. 
 
CCI


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Page 110 of 139 
 
APPENDIX 9 
PROTOCOL SUMMARY OF CHANGES 
The protocol summary of changes was moved to the end of the protocol for easier readability.   
Significant changes are described in the table below.  Changed text is displayed for the first 
major occurrence only.  Deleted text is presented in strikethrough format, and added text is 
presented in bold format.   
Section 
Description of Changes 
Rationale 
Global 
Replace: 
Protocol Date and Version:  23 January 2019; V5.0 
With: 
Protocol Date and Version:  23 July 2019; V6.0 
Administrative 
Global 
Change: 
Changed Version number from V5.0 (Amendment 4) to V6.0 
(Amendment 5) and Version date from 23 January 2019 to 
23 July 2019. 
Administrative 
Global 
Made administrative and editorial (formatting, typographical, and 
grammatical) updates. 
Administrative 
CLINICAL 
PROTOCOL 
APPROVAL FORM 
Replace: 
Name and Title 
, MD, FACR 
Vice President, Clinical Development 
Boston Pharmaceuticals 
With: 
Name and Title 
, PhD 
Senior Vice President 
Clinical Development and Head of 
Clinical Operations 
Boston Pharmaceuticals 
Administrative 
CLINICAL 
PROTOCOL 
APPROVAL FORM 
Delete: 
Name and Title 
Administrative 
PPD
PPD


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 111 of 139 
Section 
Description of Changes 
Rationale 
, MD, PhD 
Vice President, Clinical Development 
and Safety Officer 
Boston Pharmaceuticals 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Exploratory 
Endpoints, Bullet 1 
(sub-bullet 3) 
Section 2.1, Study 
Objectives and 
Endpoints, Phase 1b 
Multiple Ascending 
Dose, Exploratory 
Endpoints, Bullet 1 
(sub-bullet 3) 
Replace: 
• 
 
 
With: 
• 
 
 
Protocol 
clarification; 
 
 
 
 
 
 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Exploratory 
Endpoints, Bullet 1 
(sub-bullet 4) 
Section 2.1, Study 
Objectives and 
Endpoints, Phase 1b 
Multiple Ascending 
Dose, Exploratory 
Endpoints, Bullet 1 
(sub-bullet 4) 
Replace: 
• 
 
 
With: 
• 
 
 
 
 
 
 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Exploratory 
Endpoints, Bullet 2 
(sub-bullet 2) 
Section 2.1, Study 
Objectives and 
Endpoints, Phase 1b 
Multiple Ascending 
Dose, Exploratory 
Endpoints, Bullet 2 
Replace: 
• 
 
 
With: 
• 
 
 
 
 
 
Clarified to 
describe
 
. 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 112 of 139 
Section 
Description of Changes 
Rationale 
(sub-bullet 2) 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Exploratory 
Endpoints, Bullet 6 
Section 2.1, Study 
Objectives and 
Endpoints, Phase 1b 
Multiple Ascending 
Dose, Exploratory 
Endpoints, Bullet 6 
Replace: 
• 
 
 
With: 
• 
 
 
 
 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Endpoints, Bullet 1 
(sub-bullet 3) 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Secondary Endpoints, 
Bullet 1 (sub-bullet 3) 
Replace: 
• 
The proportion of patients with: 
o 
a sustained reduction of oral corticosteroid (CS) 
(≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and 
Day 210 
With: 
• 
The proportion of patients with: 
o 
a sustained reduction from baseline of oral 
corticosteroid (CS) (≤ 7.5 mg/day and < Day 0 dose) 
between Day 150 and Day 210 
Protocol 
clarification 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Endpoints, Bullet 1 
(sub-bullet 4) 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Secondary Endpoints, 
Bullet 1 (sub-bullet 4) 
Replace: 
• 
The proportion of patients with: 
o 
new BILAG A flare or > 1 BILAG B flares relative to 
baseline through Day 210 
With: 
• 
The proportion of patients with: 
o 
new or recurrent BILAG flares (≥ 1 qualifying 
BILAG A or > 1 qualifying BILAG B) through 
Day 210 
Clarified to be 
performed 
against previous 
visits, not only 
baseline. 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Endpoints, Bullet 2 
Replace: 
• 
Results and changes from baseline in: 
o 
Swollen and tender joints ACR-28 
With: 
Clarified to 
describe swollen 
joint changes 
from baseline. 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
Page 113 of 139 
Section 
Description of Changes 
Rationale 
(sub-bullet 2) 
Section 2.2, Study 
Objectives and 
Endpoints Phase 2 
Proof of Concept, 
Secondary Endpoints, 
Bullet 2 (sub-bullet 2) 
•
Results and changes from baseline in:
o
Total number of swollen joints, tender joints, and
active joints (swelling and tenderness in the same
joint) in the ACR-28 joint count
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Endpoints, Bullet 4 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Secondary Endpoints, 
Bullet 4 
Add: 
•
Group mean percent reduction in CS administration
from baseline Day 0 dose through Day 210 in patients
receiving ≥ 7.5 mg/day prednisone equivalent at Day 0
Add endpoint to 
measure overall 
CS reduction in 
patients 
receiving CS at 
baseline. 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Endpoints, Bullet 7 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Secondary Endpoints, 
Bullet 7 
Replace: 
•
Time to BILAG A flare or > 1 BILAG B flare compared to
baseline through Day 210
With: 
•
Time to first BILAG flare (≥ 1 new or recurrent
BILAG A or > 1 new or recurrent BILAG B) relative to
baseline through Day 210
Clarified this is 
for the time to 
first flare and 
allowed for new 
or recurrent 
BILAG flare to 
allow for 
improvement 
and subsequent 
worsening. 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Exploratory 
Endpoints 
(Pharmacodynamic) 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Exploratory Endpoints 
(Pharmacodynamic) 
Delete: 
•
 
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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 114 of 139 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, Study 
Design, Paragraph 5 
Replace: 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day).  One oral CS “burst” for increased SLE disease 
activity may occur during the study between Day 0 and Day 60.  
Tapering of steroids during the course of the study will be highly 
encouraged and should be evaluated at the protocol permitted visits 
(Day 0 through Day 60 and Day 120 through Day 150).  Between 
Day 60 and Day 120, and between Day 150 and Day 210, oral CS 
doses must be held constant due to the endpoint evaluations occurring 
at Day 120 and Day 210. 
With: 
A maximum stable (for at least 6 weeks prior to Day 0) daily dose of 
30 mg/day of oral CS will be acceptable for eligibility for the study.  
One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 120.  Tapering of steroids 
during the course of the study will be highly encouraged and should be 
evaluated during the protocol-allowed tapering windows (Day 0 
through Day 150) with the target of achieving a CS daily dose of 
≤ 7.5 mg and < Day 0 dose between Day 150 and Day 210.  Between 
Day 150 and Day 210, oral CS doses must be held constant due to the 
Day 210 endpoint evaluations. 
Protocol 
clarification. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 4, c 
Section 4.4, Inclusion 
Criteria, criteria 4, c 
Delete: 
c. 
 levels below normal as determined by the central lab 
Allowing 
patients to enroll 
on low 
compliment 
alone is not 
specific enough 
for SLE. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 5 
Replace: 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from 
at least 1 of the following clinical components: 
a. 
Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
i. 
Excluding parameters which require central laboratory 
results:  (hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. Points from lupus headache and organic brain syndrome 
will also be excluded 
With: 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 115 of 139 
Section 
Description of Changes 
Rationale 
points from at least 1 of the following clinical components: 
a. 
Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
Note:  Points from lupus headache and organic brain syndrome 
will also be excluded from qualifying total and clinical SLEDAI-2K 
scores at screening and Day 0. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 6 
Section 4.4, Inclusion 
Criteria, criteria 6 
Replace: 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at 
least 1 of the following clinical components: 
a. 
Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
i. 
Excluding parameters which require central laboratory 
results:  (hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. Points from lupus headache and organic brain syndrome 
will also be excluded 
With: 
6. A clinical SLEDAI-2K score of ≥ 6 at screening at Day 0.  
Clinical SLEDAI-2K score is defined as follows: 
a. 
Contains points from arthritis, rash, myositis, mucosal 
ulcers, pleurisy, pericarditis, or vasculitis 
b. Excludes parameters which require central laboratory 
results:  hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
Note:  Points from lupus headache and organic brain syndrome 
will also be excluded from qualifying total and clinical 
SLEDAI-2K scores at screening and Day 0. 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 7 
Replace: 
7. Patients must have at least 1A or 2Bs from the following 
manifestations of SLE, as defined by the BILAG criteria as 
modified for use in this study, which must be confirmed by the 
central data reviewer: 
a. 
BILAG A or B score in the mucocutaneous body system 
b. 
BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis defined in the protocol Section 4.4 
If only one “B” and no “A” score is present in the mucocutaneous 
body system or in the musculoskeletal body system due to 
arthritis, then at least 1 “B” must be present in the other body 
systems for a total of 2 “B” BILAG body system scores 
With: 
7. Patients must have at least 1 qualifying A or 2Bs from the 
following manifestations of SLE, as defined by the BILAG criteria 
as modified for use in this study, which must be confirmed by the 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 
Clarification of 
active joint 
term. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 116 of 139 
Section 
Description of Changes 
Rationale 
central data reviewer: 
a. 
BILAG A or B score in the mucocutaneous body system.  If a 
BILAG B score is due to BILAG number 6, mild skin 
eruption, the CLASI activity score including erythema 
and scale/hypertrophy must be ≥ 3 excluding points from 
mucosal ulcers and alopecia. 
b. 
BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis defined in the protocol Section 4.4 
Note:  Hips, shoulders, back, neck, and temporomandibular 
joints do not count towards the total number of joints with 
active synovitis. 
If only one “B” and no “A” score is present in the mucocutaneous 
body system or in the musculoskeletal body system due to 
arthritis, then at least 1 “B” must be present in at least 1 other 
body system for a total of 2 “B” BILAG body system scores. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 8 
Section 4.4, Inclusion 
Criteria, criteria 8 
Replace: 
8. Patients must be currently receiving at least 1 of the following: 
a. 
Administration for a minimum of 12 weeks, and a stable dose 
for at least 56 days (8 weeks prior to signing consent) of the 
following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or 
mycophenolic acid, chloroquine, hydroxychloroquine, or 
methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 
30 mg/day at screening for a patient to be eligible and must be 
stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 0 (randomization) 
 
With: 
8. Patients must be currently receiving at least 1 of the following: 
a. 
Administration for a minimum of 12 weeks, and a stable dose 
for at least 56 days (8 weeks prior to Day 0) of the following 
permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or 
mycophenolic acid, chloroquine, hydroxychloroquine, or 
methotrexate (MTX) 
b. If AZA, myocophenolate mofetil, mycophenolic acid, 
hydroxychloroquine, or MTX were discontinued prior to 
screening, the washout period must be ≥ 12 weeks. 
c. 
Corticosteroids (prednisone or prednisone-equivalent) at a 
stable dose of up to 30 mg/day for at least 6 weeks prior to 
Day 0 (see APPENDIX 3) 
i. 
For patients whose only SLE treatment is CSs, the 
stable CS dose must be ≥ 10 mg/day for at least 6 weeks 
prior to Day 0 and no more than 30 mg/day at the time 
of randomization. 
ii. Topical steroids may be used, but the dose must be 
stable for at least 6 weeks prior to Day 0.  PRN topical 
A stable dose is 
needed 8 weeks 
prior to Day 0; it 
is not necessary 
to be longer. 
Removed the 
tapering 
requirement 
prior to 
randomization, 
determined not 
to be required. 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 117 of 139 
Section 
Description of Changes 
Rationale 
steroids are not permitted. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Exclusion Criteria 
criterion 7, 23, and 27 
Section 4.5, Exclusion 
Criteria, criterion 7, 
23, and 27 
Add: 
7. Concomitant illness that, in the opinion of the investigator or the 
sponsor or their designee, is likely to require additional systemic 
glucocorticosteroid therapy during the study, (eg, asthma), is 
exclusionary 
23. Any other laboratory test results that, in the opinion of the 
Investigator or the sponsor or sponsor’s designee, might place a 
patient at unacceptable risk for participating in this study 
27. Any other severe acute or chronic medical or psychiatric condition, 
including recent (within the past year) medical conditions (eg, 
cardiovascular conditions, respiratory illnesses) that may increase 
the risk associated with study participation or investigational 
product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, sponsor or 
sponsor’s designee, would make the patient inappropriate for 
entry into this study 
To clarify that 
sponsor or 
designee can 
determine a 
patient is not 
eligible. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Exclusion Criteria 
criterion 15 
Section 4.5, Exclusion 
Criteria, criterion 15 
Replace: 
15. CD4+ count < 350/µL at screening 
With: 
15. CD4+ count < 150/µL at screening 
Reduced based 
on safety data 
from MAD 
portion of the 
study. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Exclusion Criteria 
criterion 22 
Section 4.5, Exclusion 
Criteria, criterion 22 
Replace: 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to 
Gilbert’s syndrome) 
With: 
22. Total bilirubin > 1.5 × ULN at screening (unless related to 
Gilbert’s syndrome) 
Total bilirubin is 
tested at 
screening, but 
direct bilirubin 
is only tested 
when there is 
potential liver 
injury. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Exclusion Criteria 
criterion 33 
Section 4.5, Exclusion 
Criteria, criterion 33 
Add: 
33. Currently taking a total daily dose of > 30 mg morphine or 
morphine equivalent (see Appendix 7) 
Opioid will 
mask SLE 
symptoms. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Add: 
34. Body mass index (BMI) ≥ 40.0 
Added 
restriction due 
to increased 
co-morbidities 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 118 of 139 
Section 
Description of Changes 
Rationale 
Exclusion Criteria 
criterion 34 
Section 4.5, Exclusion 
Criteria, criterion 34 
in patients with 
high BMI that 
will hinder SLE 
Assessments. 
LIST OF 
ABBREVIATIONS 
Add: 
ADL 
activities of daily living 
BMI 
body mass index 
NSAID nonsteroidal anti-inflammatory drug 
Terms added to 
protocol 
amendment. 
Section 3.1.2.1, 
BOS161721 POC 
Dose Selection and 
Justification, 
Paragraph 5 
Replace: 
The 120 mg dose will be communicated to site investigators 
participating in the POC Phase 2 portion, and to Institutional Review 
Boards (IRBs) and the Independent Ethics Committee (IEC). 
With: 
The 120 mg dose was communicated to site investigators participating 
in the POC Phase 2 portion, and to Institutional Review Boards (IRBs) 
and the Independent Ethics Committee (IEC). 
Protocol 
clarification. 
Section 3.1.2.2, POC 
Study Design, 
Paragraph 2 
Replace: 
As in the MAD part of the study, each patient in the POC portion may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 
90, 120, 150, and 180.  Assessments will be completed according to the 
Schedule of Assessments (Section 3.4). 
With: 
As in the MAD part of the study, each patient in the POC portion may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 
90, 120, 150, and 180.  Assessments will be completed according to the 
Schedule of Assessments (Table 1 and Table 4). 
Protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 1 
Delete: 
Since Phase 1b 
MAD has 
completed, the 
Schedule of 
Assessments for 
Phase 1b MAD 
was moved to 
the Appendix. 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 119 of 139 
Section 
Description of Changes 
Rationale 
 
 
 
 
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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
Page 120 of 139 
Section 
Description of Changes 
Rationale 
Replace: 
c 
Concomitant use of oral corticosteroids:  A maximum daily dose 
of 30 mg/day of oral CS will be acceptable for eligibility for the 
study, however, the daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0. 
With: 
c 
Concomitant use of oral corticosteroids:  A maximum daily dose 
of 30 mg/day of oral CS will be acceptable for eligibility for the 
study, however, the dose must be stable for at least 6 weeks 
prior to Day 0. 
Protocol 
clarification. 
Replace: 
n 
Only 
 collected during safety follow-up visits. 
With: 
n 
Antibodies and autoantibodies (
) will 
not be analyzed during safety follow-up visits. 
Correcting error 
in protocol. 
Delete: 
This data is no 
longer 
necessary; the 
MAD data 
collected has 
been sufficient. 
Section 3.4, Schedule 
of Assessments, 
Table 1 footnote “c” 
Section 3.4, Schedule 
of Assessments, 
Table 1 footnote “n” 
Section 3.4, Schedule 
of Assessments, 
Table 1, Whole blood 
leukocyte 
immunophenotype 
row 
Section 4.3, Patient 
Screening 
Replace: 
This study can fulfill its objectives only if appropriate patients are 
enrolled.  The following eligibility criteria are designed to select 
patients for whom protocol treatment is considered appropriate.  All 
relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a 
particular individual.  Patient eligibility will be reviewed and confirmed 
by the medical monitor or designee prior to randomization.  Screening 
assessments (see the Schedule of Assessments [Section 3.4]) for this 
Protocol 
clarification. 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
Confidential 
 
Page 121 of 139 
Section 
Description of Changes 
Rationale 
study must be performed between Day -28 and Day -1. 
With: 
This study can fulfill its objectives only if appropriate patients are 
enrolled.  The following eligibility criteria are designed to select 
patients for whom protocol treatment is considered appropriate.  All 
relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a 
particular individual.  Patient eligibility will be reviewed and confirmed 
by the medical monitor or designee prior to randomization.  Screening 
assessments (see the Schedule of Assessments [Table 1 and Table 4]) 
for this study must be performed between Day -28 and Day -1 
Section 4.4, Inclusion 
Criteria, criteria 5 
Replace: 
5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) 
must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. 
Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
i. 
Excluding parameters which require central laboratory 
results:  (hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. Points from lupus headache and organic brain syndrome 
will also be excluded 
With: 
5. At screening, the total SLEDAI-2K score must be ≥ 8, including 
points from at least 1 of the following clinical components: 
a. 
Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, 
and vasculitis 
Note:  Points from lupus headache and organic brain syndrome 
will also be excluded from qualifying total and clinical SLEDAI-2K 
scores at screening and Day 0. 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 
Section 4.4, Inclusion 
Criteria, criteria 7 
Replace: 
7. Patients must have at least 1A or 2Bs from the following 
manifestations of SLE, as defined by the BILAG criteria as 
modified for use in this study, which must be confirmed by the 
central data reviewer: 
a. 
BILAG A or B score in the mucocutaneous body system 
b. 
BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), 
manifested by observed active synovitis in ≥ 2 joints with 
marked loss of functional range of movements and 
significant impairment of basic activities of daily living that 
has been present on several days cumulatively over the past 
30 days, including at the time of the screening visit.  See 
To ensure 
patients with 
Moderate to 
Severe active 
disease are 
enrolled. 
Clarification of 
active joint 
term. 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 July 2019; V6.0 
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Page 122 of 139 
Section 
Description of Changes 
Rationale 
APPENDIX 5 for additional detailed specifications. 
• 
Basic ADLs are defined as the following activities 
which require assistance or assistive devices, (at least 1 
must be present and documented in source): 
o 
Ambulation, toileting, grooming- including 
bathing and dressing; feeding oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or 
Tenosynovitis, (BILAG item number 42), defined as 
tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of 
functional range of movements manifested by effects on 
instrumental ADLs such as: 
• 
Cooking, driving, using the telephone or computer, 
shopping, cleaning, etc., and has been present on 
several days over the last 30 days, and is present at the 
time of the screening visit 
If only one “B” and no “A” score is present in the mucocutaneous 
body system or in the musculoskeletal body system due to 
arthritis, then at least 1 “B” must be present in the other body 
systems for a total of 2 “B” BILAG body system scores 
With: 
7. Patients must have at least 1 qualifying A or 2Bs from the 
following manifestations of SLE, as defined by the BILAG criteria 
as modified for use in this study, which must be confirmed by the 
central data reviewer: 
a. 
BILAG A or B score in the mucocutaneous body system.  If a 
BILAG B score is due to BILAG number 6, mild skin 
eruption, the CLASI activity score must be ≥ 3 excluding 
points from mucosal ulcers and alopecia. 
b. 
BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), 
manifested by observed active synovitis defined by BOTH 
swelling and tenderness in ≥ 6 joints with marked loss of 
functional range of movements and significant impairment 
of basic activities of daily living (ADLs) that has been 
present on several days (> 4 days).cumulatively over the 
past 30 days, including at the time of the screening visit.  
See APPENDIX 5 for additional detailed specifications. 
• 
Basic ADLs are defined as the following activities 
which require assistance or assistive devices, (at least 1 
must be present and documented in source): 
o 
Ambulation, toileting, grooming- including 
bathing and dressing; feeding oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or 
Tenosynovitis, (BILAG item number 42), defined as 
tendonitis/tenosynovitis, or active synovitis defined by 
BOTH swelling and tenderness in ≥ 3 joints, (observed or 
through patient history), with some loss of functional range 


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of movements manifested by effects on instrumental ADLs 
such as: 
• 
Cooking, driving, using the telephone or computer, 
shopping, cleaning, etc., and has been present on 
several days over the last 30 days, and is present at 
the time of the screening visit 
Note:  Hips, shoulders, back, neck, and temporomandibular 
joints do not count towards the total number of joints with 
active synovitis. 
If only one “B” and no “A” score is present in the mucocutaneous 
body system or in the musculoskeletal body system due to 
arthritis, then at least 1 “B” must be present in at least 1 other 
body system for a total of 2 “B” BILAG body system scores. 
Section 4.6, 
Concomitant 
Medications 
Add: 
Any medicinal product, prescribed or OTC, including herbal and other 
nontraditional remedies, is considered a concomitant medication.  
Patients should stay on stable regimen (not PRN) of other concomitant 
medications for the treatment of SLE (eg, analgesics, nonsteroidal 
anti-inflammatory drugs [NSAIDs], statins, ACE inhibitors/ARBs 
and other antihypertensive drugs), unless changes in these treatments 
are clinically indicated.  Patients should refrain from Tylenol, 
NSAIDs, and any pain medications including tramadol and other 
opiates for at least 12 hours before each visit, with the exception of 
the Screening Visit. 
Use of any other drugs for non-SLE conditions, including over-the-
counter medications and herbal preparations, should remain stable 
unless change or addition is clinically necessary.  Discussion with the 
medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the 
eCRF.  Prior and concomitant medication use will be recorded for the 
30 days prior to screening until the last follow-up visit.  In addition, 
historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent including 
investigational agents) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
Protocol 
clarification. 
Protocol text 
further clarified 
to include 
investigational 
agents. 
Section 4.6.1, 
Corticosteroid 
Replace: 
4.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), 
may be used in accordance with the investigator’s clinical judgment 
and best standard of care.  See APPENDIX 3 for examples of 
equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, the daily dose must be tapered down 
to a maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day). 
Added further 
clarity to section 
regarding 
tapering and 
allowed burst 
Removed the 
restrictions of 
max burst dose 
and extended 
protocol allowed 
burst window to 
assist sites in 
managing their 
patients SLE. 
Text modified to 


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Tapering of steroids during the course of the study will be highly 
encouraged and should be evaluated at the protocol permitted visits 
(Day 0 through Day 60 and Day 120 through Day 150).  Between 
Day 60 and Day 120, and between Day 150 and Day 210, oral CS 
doses must be held constant due to the endpoint evaluations occurring 
at Day 120 and Day 210. 
• 
Once a patient has received the first dose of study drug (after 
Day 0), prednisone (or prednisone equivalent) dose is highly 
encouraged to continue tapering down as appropriate.  The 
investigator should evaluate the prednisone dose at each visit and 
make the decision, within the protocol allowed windows. 
o 
Exception:  Between Day 60 and Day 120, and between Day 
150 and Day 210 (ie, within 60 days of primary and secondary 
endpoint assessments), oral CS doses must be held constant. 
After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” 
for increased SLE disease activity will be allowed between Day 0 and 
Day 60, according to the following:   
• 
The oral CS dose is allowed to increase to ≤ 40 mg/day of 
prednisone or equivalent, which must be tapered down to 
≤ 10 mg/day within 2 weeks of initiation of the “burst” 
o 
Alternatively, a single intramuscular (IM) dose of 
methylprednisolone (40 mg or equivalent) is permitted 
o 
No increase of oral CS above baseline is permitted beyond 
Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any 
other route, but systemic administration, is allowed. 
Treatment with intra-articular or intravenous CS is prohibited during 
the course of the study. 
With: 
4.6.1 
Corticosteroid 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), 
may be used in accordance with the investigator’s clinical judgment 
and best standard of care.  See APPENDIX 3 for examples of 
equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study.  For patients whose only SLE treatment is 
steroids, their stable steroid dose must be at least 10 mg/day and no 
more than 30 mg/day for a minimum of 6 weeks at time of 
randomization on Day 0. 
Topical steroids may be used, but the dose must be stable for at 
ensure patients 
with Moderate 
to Severe active 
disease are 
enrolled. 
Further 
clarification of 
protocol 
intention. 


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least 6 weeks prior to Day 0, and be maintained at a constant dose 
throughout the study duration until the rashes resolve.  PRN 
topical steroids are not permitted. 
Once the patient has received the first dose of study drug (Day 0), 
tapering of oral steroids will be highly encouraged and should be 
continually evaluated during the protocol-allowed tapering 
windows (Day 0 through Day 150) with the target of achieving a CS 
daily dose of < 7.5 mg and < Day 0 dose between Day 150 and 
Day 210. 
Between Day 150 and Day 210 (ie, within 60 days of primary 
endpoint assessments), oral CS doses must be held constant. 
CS Burst for SLE-related Indications 
After Day 0 (first dose of study drug), a maximum of 1 oral CS 
“burst” equivalent to ≤ 40 mg/day prednisone for increased SLE 
disease activity will be allowed between Day 0 and Day 120, 
which must be tapered down to the baseline (Day 0) CS dose or 
lower within 14 days of initiation of the “burst.”  Any “burst” 
continuing after Day 120 or occurring after Day 120 is 
considered a protocol deviation. 
o 
Alternatively, a single intramuscular (IM) dose of 
methylprednisolone (<40 mg) is permitted during this 
period. 
CS Burst for Non-SLE-related Indications 
A single treatment of oral prednisone equivalent of 
≤ 40 mg/day for 14 days is permitted for a non-SLE indication, 
though it must be completed prior to Day 120.  No long acting 
steroid injections are permitted. 
Note:  Treatment with inhaled CS are allowed for the 
treatment of non-SLE-related indications only (eg, for 
asthma). 
Any other increase from baseline of CS dose or systemic use of CS 
of any kind (including intra-articular and intravenous 
administration) are not permitted from Day 0 through Day 210 and 
will result in the patient being considered a treatment failure.  
There is no restriction of CS usage after Day 210. 
Section 4.6.2, Other 
Prohibited and/or 
Restricted Treatments, 
Paragraph 1 
Replace: 
Prohibited and/or restricted medications taken prior to study drug 
administration and during the study are described below, and washout 
requirements are provided in APPENDIX 4.  Medications taken within 
30 days prior to screening must be recorded on the eCRF. 
Protocol 
clarification. 


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With: 
Prohibited and/or restricted medications taken prior to study drug 
administration and during the study are described below, and washout 
requirements are provided in APPENDIX 4.  All medications taken 
within 30 days prior to screening must be recorded on the eCRF. 
Section 4.6.2, Other 
Prohibited and/or 
Restricted Treatments, 
Item 2 
Delete: 
2. Patients who have received treatment with anti-CD20 monoclonal 
antibodies within 24 weeks of screening; recovery of B cells 
(CD19+) must be documented (record absolute number of CD19+ 
B cells) 
Protocol text 
removed as it 
was no longer 
necessary. 
Section 4.7.2, 
Contraception, 
Paragraph 4 
Replace: 
At a minimum, patients must agree to the use of 1 method of highly 
effective contraception from the following: 
With: 
Patients must agree to either complete abstinence, defined as a 
complete avoidance of heterosexual activity, or the use of 2 methods 
of highly effective contraception from the following: 
To ensure 
patients have 
appropriate 
contraception 
during the study. 
Section 4.7.2, 
Contraception, 
Paragraph 4, Bullet 4 
and 5 
Replace: 
• 
Vasectomy 
• 
Complete abstinence, defined as complete avoidance of 
heterosexual intercourse, is an acceptable form of contraception.  
Women who are abstinent while participating in the study must 
continue to have pregnancy tests.  Acceptable alternate methods of 
highly effective contraception must be discussed in the event that 
the patient chooses to forego complete abstinence. 
With: 
• 
Vasectomy 
Note:  Women who are abstinent while participating in the study must 
continue to have pregnancy tests.  Acceptable alternate methods of 
highly effective contraception must be discussed in the event that the 
patient chooses to forego complete abstinence. 
Protocol 
clarification. 
Section 5.1, 
Screening, 
Paragraph 5 
Replace: 
Screening procedures are listed in the Schedule of Assessments 
(Section 3.4), and details are provided in Section 6. 
With: 
Screening procedures are listed in the Schedule of Assessments 
Protocol 
clarification. 


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(Table 1 and Table 4), and details are provided in Section 6. 
Section 5.2, 
Enrollment/ 
Randomization and 
Day 0 Treatment, 
Paragraph 1 
Add: 
Randomization should occur after patient eligibility for enrollment has 
been confirmed by the central eligibility review.  The central 
eligibility review team has the final decision on patient eligibility 
and can decide the patient is not eligible for the study based on 
their review of the eligibility packet. 
To provide 
further 
clarification that 
the central 
eligibility 
review team can 
deem a patient 
in-eligible for 
randomization 
even if all 
entrance criteria 
are met.   
Section 5.2, 
Enrollment/ 
Randomization and 
Day 0 Treatment, 
bullet 3, sub-bullet 3 
Add: 
• 
Laboratory evaluations (fasting): 
o 
CD4+ count, total IgG and IgM levels, plasma 
, 
plasma 
 and 
, whole blood for leukocyte 
immunophenotype (leukocyte immunophenotype for MAD 
patients only) 
No longer 
necessary in 
POC portion of 
the study.  MAD 
data collected 
has been 
sufficient. 
Section 5.2, 
Enrollment/ 
Randomization and 
Day 0 Treatment, 
bullet 3, sub-bullet 9 
Replace: 
• 
Laboratory evaluations (non-fasting): 
o 
See Table 1 and Table 2 for details of PK sampling in the 
MAD and POC portions 
With: 
• 
Laboratory evaluations (non-fasting) : 
o 
See Table 4 and Table 1 for details of PK sampling in the 
MAD and POC portions 
Protocol 
clarification. 
Section 5.2, 
Enrollment/ 
Randomization and 
Day 0 Treatment, 
Paragraph 4 
Replace: 
Procedures on Day 0 are listed in the Schedule of Assessments 
(Section 3.4), and details are provided in Section 6. 
With: 
Procedures on Day 0 are listed in the Schedule of Assessments 
(Table 1 and Table 4), and details are provided in Section 6. 
Protocol 
clarification. 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits, Pararaph 1 and 
bullet 17 
Replace: 
The following procedures will be performed as indicated in the 
Schedule of Assessments (Table 1 and Table 2).  See Schedule of 
Assessment tables for allowable windows for each visit. 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD 
Protocol 
clarification. 
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and POC studies, respectively 
With: 
The following procedures will be performed as indicated in the 
Schedule of Assessments (Table 1 and Table 4).  See Schedule of 
Assessment tables for allowable windows for each visit. 
• 
See Table 4 and Table 1 for details of PK sampling in the MAD 
and POC studies, respectively 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits, bullet 20 
Replace: 
• 
Plasma 
 & 
, ADA, and whole blood for 
leukocyte immunophenotype 
With: 
• 
Plasma 
 and 
, ADA, and whole blood for 
leukocyte immunophenotype (leukocyte immunophenotype for 
MAD patients only) 
No longer 
necessary for 
POC portion of 
study.  MAD 
data collected 
has been 
sufficient. 
Section 5.4, Safety 
Follow-Up Visits, 
Paragraph 1 and 
bullet 18 
Replace: 
Safety follow-up visits will take place at Days 210, 240, and 270.  
These visits will include the following assessments as indicated in the 
Schedule of Assessments (Table 1 and Table 2): 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD 
and POC portions, respectively 
Replace: 
Safety follow-up visits will take place at Days 210, 240, and 270.  
These visits will include the following assessments as indicated in the 
Schedule of Assessments (Table 1 and Table 4): 
• 
See Table 4 and Table 1 for details of PK sampling in the MAD 
and POC portions, respectively 
Protocol 
clarification. 
Section 6.2.1, 
Laboratory 
Assessments, 
Paragraph 1 
Replace: 
Laboratory tests will be performed at times defined in the Schedule of 
Assessments (Section 3.4).  Patient eligibility will be determined based 
on these tests at screening.  Unscheduled clinical labs may be obtained 
at any time during the study to assess any perceived safety concerns. 
With: 
Laboratory tests will be performed at times defined in the Schedule of 
Assessments (Table 1 and Table 4).  Patient eligibility will be 
determined based on these tests at screening.  Unscheduled clinical labs 
may be obtained at any time during the study to assess any perceived 
Protocol 
clarification. 
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safety concerns. 
Section 6.2.1, 
Laboratory 
Assessments, Table 2, 
Immunogenicity, PD 
and other Biomarker 
Tests column 
Add: 
Immunogenicity, PD, and other 
Biomarker Tests 
ADA 
nAbg 
pSTAT3 (predose [trough] samples only in Phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte immunophenotype (for MAD patients 
only) 
 
 
 
CRP  
Direct Coomb’s testh 
No longer 
necessary for 
POC patients.  
MAD data 
collected has 
been sufficient. 
Section 6.2.1.1, 
Pregnancy testing 
Replace: 
For WOCBP, a serum pregnancy test will be performed at screening.  
Following a negative serum pregnancy result at screening, appropriate 
contraception must be commenced or continued and a further negative 
urine pregnancy test results will then be required at the baseline visit 
before the patient may receive the investigational product.  Urine 
pregnancy tests will also be routinely repeated at study drug 
administration visits prior to study drug administration, at the last 
follow up visit day (Day 270) and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  In 
the case of a positive pregnancy test or confirmed pregnancy, the 
patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose 
should be scheduled (Day 270).  Safety follow-up visit procedures (see 
Section 5.4) are specified in the Schedule of Assessments (see 
Section 3.4). 
With: 
For WOCBP, a serum pregnancy test will be performed at screening.  
Following a negative serum pregnancy result at screening, appropriate 
contraception must be commenced or continued and a further negative 
urine pregnancy test results will then be required at the baseline visit 
before the patient may receive the investigational product.  Urine 
pregnancy tests will also be routinely repeated at study drug 
administration visits prior to study drug administration, at the last 
follow up visit day (Day 270) and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  In 
the case of a positive pregnancy test or confirmed pregnancy, the 
patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose 
should be scheduled (Day 270).  Safety follow-up visit procedures (see 
Protocol 
clarification. 
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Section 
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Section 5.4) are specified in the Schedule of Assessments (see Table 1 
and Table 4). 
Section 6.2.2.4, 
Causality of Adverse 
Events, Paragraph 1 
Replace: 
The principal investigator will assess the causal relationship between 
BOS161721 or placebo and the AE.  One of the following categories 
(Table 4) should be selected based on medical judgment, considering 
the definitions below and all contributing factors. 
With: 
The principal investigator will assess the causal relationship between 
BOS161721 or placebo and the AE.  One of the following categories 
(Table 3) should be selected based on medical judgment, considering 
the definitions below and all contributing factors. 
Protocol 
clarification. 
Section 6.2.3, Vital 
Signs 
Replace: 
Vital signs (blood pressure, heart rate, and body temperature) will be 
assessed as specified in the Schedule of Assessments (Section 3.4).  
Vital signs will be assessed on Day 0 at predose and at Day 0, 1 and 2 
hours postdose, as well as on each of the scheduled visit days during 
the study (excluding PK-only site visits).  Supine BP and heart rate 
recordings will be made after the patient has been recumbent and at rest 
≥ 5 minutes.  When the timing of these measurements coincides with a 
blood collection, vital signs should be obtained prior to the time of the 
blood collection. 
With: 
Vital signs (blood pressure, heart rate, and body temperature) will be 
assessed as specified in the Schedule of Assessments (Table 1 and 
Table 4).  Vital signs will be assessed on Day 0 at predose and at Day 
0, 1 and 2 hours postdose, as well as on each of the scheduled visit days 
during the study (excluding PK-only site visits).  Supine BP and heart 
rate recordings will be made after the patient has been recumbent and at 
rest ≥ 5 minutes.  When the timing of these measurements coincides 
with a blood collection, vital signs should be obtained prior to the time 
of the blood collection. 
Protocol 
clarification 
Section 6.2.4, 12-Lead 
Electrocardiogram, 
Paragraph 1 
Replace: 
ECG will be assessed as specified in the Schedule of Assessments 
(Section 3.4).  ECG recording will initiate after the patient has been 
supine for at least 5 minutes.  On days of PK blood draws, the ECG 
will be collected before scheduled PK blood draws, though timing will 
be such that PK draws are collected on their scheduled times where 
possible. 
With: 
ECG will be assessed as specified in the Schedule of Assessments 
Protocol 
clarification. 


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(Table 1 and Table 4).  ECG recording will initiate after the patient 
has been supine for at least 5 minutes.  On days of PK blood draws, the 
ECG will be collected before scheduled PK blood draws, though timing 
will be such that PK draws are collected on their scheduled times where 
possible. 
Section 6.2.5, 
Physical Examination, 
Paragraph 2 
Replace: 
The targeted (limited) physical examination will be completed at all 
other visits as indicated in the Schedule of Assessments (Section 3.4).  
It includes evaluation of patient complaints and SLE disease-related 
issues, and will exclude the genitourinary system. 
With: 
The targeted (limited) physical examination will be completed at all 
other visits as indicated in the Schedule of Assessments (Table 1 and 
Table 4).  It includes evaluation of patient complaints and SLE disease-
related issues, and will exclude the genitourinary system. 
Protocol 
clarification. 
Section 6.2.6, 
C-SSRS, Paragraph 2 
Replace: 
The C-SSRS evaluation will be performed as specified in the Schedule 
of Assessments (Section 3.4).  Patients with recent (within the past 
12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4, or 5 is exclusionary at screening will 
be excluded from the study.  Patients with recent or active suicidal 
ideation or behavior at subsequent study visits will have responses to 
the C-SSRS reviewed in detail to assess patient risk, and appropriate 
consultative mental health services will be provided. 
With: 
The C-SSRS evaluation will be performed as specified in the Schedule 
of Assessments (Table 1 and Table 4).  Patients with recent (within 
the past 12 months) or active suicidal ideation or behavior based on 
patient responding “yes” to question 3, 4, or 5 is exclusionary at 
screening will be excluded from the study.  Patients with recent or 
active suicidal ideation or behavior at subsequent study visits will have 
responses to the C-SSRS reviewed in detail to assess patient risk, and 
appropriate consultative mental health services will be provided. 
Protocol 
clarification. 
Section 6.2.7, 
Injection Site 
Reactions 
Replace: 
Patients will be monitored for local injection site reactions as specified 
in the Schedule of Assessments (Section 3.4).  Local injection site 
reactions will be assessed at 2 hours postdose at baseline, and predose 
for each injection after baseline.  Injection site reactions should be 
managed according to the standard of care.  Injection site reactions, 
Grades 2 to 5, are to be reported as AEs of special interest (see 
Section 6.2.2.7.3). 
Protocol 
clarification. 


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Section 
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With: 
Patients will be monitored for local injection site reactions as specified 
in the Schedule of Assessments (Table 1 and Table 4).  Local 
injection site reactions will be assessed at 2 hours postdose at baseline, 
and predose for each injection after baseline.  Injection site reactions 
should be managed according to the standard of care.  Injection site 
reactions, Grades 2 to 5, are to be reported as AEs of special interest 
(see Section 6.2.2.7.3). 
Section 6.2.8, 
Immunogenicity, 
Paragraph 1 
Replace: 
The serum samples to measure the presence of ADA will be collected 
as specified in the Schedule of Assessments (Section 3.4).  Blood 
samples (4 mL) to provide approximately 1.5 mL of plasma for anti 
BOS161721 antibody analysis will be collected into appropriately 
labeled tubes containing K2EDTA.  The presence or absence of ADA 
will be determined in the serum samples using validated bioanalytical 
methods.  Blood samples for ADA analysis will be collected up to Day 
90 from all patients.  Subsequent ADA samples will be collected from 
all patients but only analyzed by a central lab if the patient had a 
positive ADA on Day 90. 
With: 
The serum samples to measure the presence of ADA will be collected 
as specified in the Schedule of Assessments (Table 1 and Table 4).  
Blood samples (4 mL) to provide approximately 1.5 mL of plasma for 
anti BOS161721 antibody analysis will be collected into appropriately 
labeled tubes containing K2EDTA.  The presence or absence of ADA 
will be determined in the serum samples using validated bioanalytical 
methods.  Blood samples for ADA analysis will be collected up to Day 
90 from all patients.  Subsequent ADA samples will be collected from 
all patients but only analyzed by a central lab if the patient had a 
positive ADA on Day 90. 
Protocol 
clarification. 
Section 6.3, Efficacy 
Assessments 
Replace: 
All efficacy assessments will be performed at times defined in the 
Schedule of Assessments (Section 3.4). 
With: 
All efficacy assessments will be performed at times defined in the 
Schedule of Assessments (Table 1 and Table 4). 
Protocol 
clarification. 
Section 6.4.2, PROs, 
Paragraph 1 
Replace: 
Patients should be encouraged to complete the PROs at the clinic at the 
beginning of the study visit prior to any clinical assessments.  A 
member of the staff should be available if a patient requires further 
instruction and to review the PRO questionnaires for completeness 
prior to leaving the clinic.  The PROs include the 
 and the 
Protocol 
clarification. 
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Section 
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Rationale 
 and will be assessed as specified in the Schedule of Assessments 
(Section 3.4). 
With: 
Patients should be encouraged to complete the PROs at the clinic at the 
beginning of the study visit prior to any clinical assessments.  A 
member of the staff should be available if a patient requires further 
instruction and to review the PRO questionnaires for completeness 
prior to leaving the clinic.  The PROs include the 
 and the 
 and will be assessed as specified in the Schedule of Assessments 
(Table 1 and Table 4). 
Section 6.5, 
Pharmacokinetic 
Assessments, 
Paragraph 1 
Replace: 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites 
only) parts of the study, blood samples for PK analysis of BOS161721 
or placebo concentration will be collected according to Table 1 and 
Table 2. 
With: 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites 
only) parts of the study, blood samples for PK analysis of BOS161721 
or placebo concentration will be collected according to Table 4 and 
Table 1. 
Protocol 
clarification. 
Section 6.6, 
Pharmacodynamic 
Assessments, 
Paragraph 1 
Replace: 
Blood samples for PD parameters (plasma) will be collected at times 
indicated in the Schedule of Assessments (Section 3.4) for each of the 
following parameters: 
With: 
Blood samples for PD parameters (plasma) will be collected at times 
indicated in the Schedule of Assessments (Table 1 and Table 4) for 
each of the following parameters: 
Protocol 
clarification. 
Section 6.6, 
Pharmacodynamic 
Assessments, Bullet 5 
Add: 
• 
Whole blood for leukocyte immunophenotype (for MAD patients 
only) 
No longer 
necessary for 
POC patients.  
MAD data 
collected has 
been sufficient. 
Section 7.4, 
Accountability, 
Paragraph 1 
Replace: 
The Principal Investigator or designee is responsible for maintaining 
accurate accountability records of BOS161721 or placebo throughout 
the clinical study.  The drug accountability log includes information 
such as, randomization number, amount dispensed and amount 
returned to the pharmacy (if any).  Products returned to the pharmacy 
will be stored under the same conditions as products not yet dispensed.  
Clarification 
regarding 
handling of 
returned 
product. 
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The returned products should be marked as ‘returned’ and kept 
separate from the products not yet dispensed. 
With: 
The Principal Investigator or designee is responsible for maintaining 
accurate accountability records of BOS161721 or placebo throughout 
the clinical study.  The drug accountability log includes information 
such as, randomization number, amount dispensed and amount 
returned to the pharmacy (if any).  Used investigational product 
returned to the pharmacy may be maintained in an ambient 
condition.  Unused product should follow the instructions in the 
Pharmacy Manual.  The used product that is returned should be 
marked as ‘returned’ and kept separate from the products not yet 
dispensed. 
Section 8.2.1, 
Analysis Populations, 
Paragraph 1 
Replace: 
The primary efficacy analysis will be based on the FAS, defined as all 
patients who receive at least 1 dose of study treatment and at have least 
1 evaluable post-baseline efficacy evaluation.  FAS analyses will be 
conducted on the basis of the randomized treatment. 
With: 
The primary efficacy analysis will be based on the FAS, defined as all 
patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  FAS analyses will be 
conducted on the basis of the randomized treatment. 
Correction of 
typo. 
Section 8.2.3, Primary 
Efficacy Endpoint(s), 
Paragraph 2 
Add: 
Patients that received prohibited medications or unallowable CS usage 
as described in Section 4.6 will be considered “medication failures” 
and will be treated as statistical non-responders at the time points on 
or following the first date of prohibited medication or unallowable 
CS usage for the primary efficacy analysis.  The determination of 
medication failures will be reviewed using blinded data and finalized 
prior to unblinding. 
Text added to 
address usage 
relative to 
analysis time 
points (ie 
patients are 
deemed non-
responders after 
usage but may 
still be 
responders prior 
to usage of 
prohibitive meds 
or CS). 
Appendix 5 
Replace: 
 
 
 
 
 
 
 
 
 
Clarification of 
active joint 
term. 
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Section 
Description of Changes 
Rationale 
i. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section 
Description of Changes 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Appendix 7 
Add: 
 
Added for 
opioid dosing in 
SLE patients. 
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Section 
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Rationale 
 


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Section 
Description of Changes 
Rationale 
 
Appendix 8, Table 4 
Add: 
 
Since Phase 1b 
MAD has 
completed, the 
Schedule of 
Assessments for 
Phase 1b MAD 
was moved to 
the Appendix. 


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Section 
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Rationale 
 
 
 
 
 
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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
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A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 400 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721 
PROTOCOL NUMBER: 
BOS161721-02 
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
06 October 2017 
VERSION NUMBER: 
V5.0 (Amendment 4) 
VERSION DATE: 
23 January 2019 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol: BOS 161721-02 
Protocol Date and Version: 23 January 2019; V5.0 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: A Randomized Double-Blind Phase lb/2 Combined Staggered Multiple Dose Escalation Study of 
B0S161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care 
Study Number: B0Sl6172l-02 
Version 
Date 
Original Protocol 
06 October 2017 
Protocol Version 2.0 (Amendment 1) 
14 November 2017 
Protocol Version 3.0 (Amendment 2) 
21 March 2018 
Protocol Version 4.0 (Amendment 3) 
27July 2018 
Protocol Version 5.0 (Amendment 4) 
23 January 2019 
This study protocol was subject to critical review and has been approved by sponsor. The 
information contained in this protocol is consistent with: 
• 
The current risk-benefit evaluation of the investigational product. 
• 
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to · 
applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
, MD, PhD 
Chief Medical Officer 
Boston Phannaceuticals 
, MD, FACR 
Vice President, Clinical Development 
Boston Phannaceuticals 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
, MD, PhD 
Vice President, Clinical Development and Safety Officer 
Boston Phannaceuticals 
Confidential 
Signature and Date 
Page 2 of 116 
PPD
PPD
PPD
PPD
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BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol (Version 5.0, dated 23 January 2019), including all appendices, and I 
agree that it contains all of the necessary information for me and my staff to conduct this study as 
described.  I will conduct this study as outlined herein, in accordance with the regulations stated 
in the Federal Code of Regulations for Good Clinical Practices and International Council for 
Harmonisation (ICH) guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
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PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple 
Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus 
(SLE) Patients on a Background of Limited Standard of Care 
Indication 
Adults with moderately to severely active SLE 
Background 
and Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the disease, 
and that T-cell-derived cytokines such as interleukin-21 (IL-21) are involved 
in the SLE-associated inflammatory pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple mutation 
monoclonal antibody (mAb) intended to have an extended terminal 
elimination half-life (t½) that selectively binds to and neutralizes IL-21, 
which acts on multiple cell types that drive inflammation and autoimmunity.  
In vivo, BOS161721 inhibits T-cell dependent antigen responses of B-cells 
and is being developed as a potential treatment for adults with moderately to 
severely active SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics (PD), 
toxicokinetics (TK), pharmacokinetics (PK), and immunogenicity of 
BOS161721 administered intravenously (IV) and subcutaneously (SC).  The 
no observed adverse effect level (NOAEL) in Cynomolgus monkeys was 
determined to be 100 mg/kg (SC and IV), the highest dose tested.  There 
were no injection site reactions in animals dosed subcutaneously. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  This 
double-blind, placebo-controlled study evaluated 8 ascending dose levels 
(1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg) for safety, tolerability, PK, PD and immunogenicity.  Overall, 
there were no clinically significant safety or tolerability findings from this 
study.  
Results from the Phase 1 SAD study informed the dose regimens used for the 
multiple ascending doses (MAD) Phase 1b portion of this trial.  The MAD 
portion will involve 3 cohorts.  The Phase 2 portion will be a proof of 
concept (POC) part, where dose selection will be based on the data 
monitoring committee (DMC) and sponsor’s assessment of safety, 
tolerability, immunogenicity, and PK and PD data from the MAD portion of 
30 patients treated with BOS161721/placebo.  The purpose of the study is to 
establish a safe and effective dosage for adult patients with moderately to 
severely active SLE. 


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Objectives and 
Endpoints: 
MAD Phase 1b 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients 
with moderately to severely active 
SLE on limited background 
standard of care treatment, in order 
to estimate the optimal dose. 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale 
(C-SSRS) 
• 
12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
Anti-drug antibodies (ADAs) 
• 
Study drug exposure/compliance 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the optimal 
dose of BOS161721 based on 
safety, PK, and PD effects in 
patients with moderately to 
severely active SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time 
point 
• 
Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), t½, systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• 
Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• 
Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit  
 
 
 


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Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
• 
 
 
 
 
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POC Phase 2 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on the SLE Responder 
Index 4 (SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 
response at Day 210 (see Section 6.3.4.1) 
Secondary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on clinical indicators of 
SLE activity, in adult patients with 
moderately to severely active SLE 
on limited background standard of 
care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B 
flares relative to baseline through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B 
flare compared to baseline through Day 210 
Safety 
• 
To assess safety and tolerability of 
repeat doses of BOS161721 at the 
chosen dose administered SC in 
adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each 
visit and change from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 


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baseline 
• 
Physical examinations changes from 
baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, 
placebo-controlled trial to study the clinical efficacy, safety, and PK of 
multiple SC doses of BOS161721 in adult patients with moderately to 
severely active SLE.  After successfully completing a screening phase, 
eligible patients will be randomized to a specified dose of BOS161721 or 
placebo.  The dosing schedule will be monthly.  The trial will consist of 
2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 
120, 150, and 180, followed by safety follow-up visits at Days 210, 240, and 
270.   
The MAD Phase 1b portion of the study design will consist of 3 cohorts, with 
Cohort 1 containing 6 patients, where 5 of these patients will receive 
BOS161721 (active), and 1 will receive placebo.  Cohorts 2 and 3 will each 
contain 12 patients, including 9 active and 3 placebo patients.  Dose selection 
for each cohort is based on 90-day safety, tolerability, PK, and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  
Each of the 3 doses (20, 60, and 120 mg) selected for the MAD portion are 
projected not to exceed the mean exposure of that achieved in the SAD study 
following the single 240 mg SC dose.  Each patient may receive a total of 
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7 SC monthly doses on Days 0, 30, 60, 90, 120, 150, and 180.   
The MAD portion design is staggered, where after the 6 patients in Cohort 1 
have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 2 begins dosing (after the DMC evaluates the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in 
Cohort 2 have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing after the DMC evaluation of the 
safety and tolerability data from Cohort 2 and Cohort 1.  Thirty days after the 
last patient in Cohort 3 receives the third dose, the DMC and Boston 
Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This dose will not exceed 
doses tested during the MAD portion.   
For the POC portion, approximately 156 additional patients will be 
randomized to active or placebo groups in a 2:1 ratio.  As in the MAD 
portion, each patient in the POC portion may receive a total of 7 SC monthly 
doses on Days 0, 30, 60, 90, 120, 150, and 180.   
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization 
day).  One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 60.  Tapering of steroids during the 
course of the study will be highly encouraged and should be evaluated at the 
protocol permitted visits (Day 0 through Day 60 and Day 120 through 
Day 150).  Between Day 60 and Day 120, and between Day 150 and Day 210, 
oral CS doses must be held constant due to the endpoint evaluations occurring 
at Day 120 and Day 210. 
DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter. 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
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Main Criteria 
for Inclusion 
and Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be 
evidence of a personally signed and dated informed consent document 
indicating that the patient has been informed of all pertinent aspects of the 
study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus 
International Collaborating Clinics (SLICC) classification criteria for SLE 
(with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis 
as the sole clinical criterion in the presence of antinuclear antibodies 
[ANA] or anti- double-stranded deoxyribonucleic acid [dsDNA] 
antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central 
laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as 
determined by the central laboratory 
c. C3 or C4 levels below normal as determined by the central lab 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis  
i. 
Excluding parameters which require central laboratory results:  
(hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 
decreased complement, thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome will also 
be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis 
i. 
Excluding parameters which require central laboratory results:  
hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 


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Clinical Study Protocol:  BOS161721-02 
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decreased complement, thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also 
be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, 
which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active 
polyarthritis as defined in the protocol Section 4.4 
If only one “B” and no “A” score is present in the mucocutaneous body 
system or in the musculoskeletal body system due to arthritis, then at least 
1 “B” must be present in the other body systems for a total of 2 “B” 
BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at 
least 56 days (8 weeks prior to signing consent) of the following 
permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic 
acid, chloroquine, hydroxychloroquine, or methotrexate 
(MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at 
screening for a patient to be eligible and must be stable at a maximum 
of 10 mg/day for at least 5 days prior to Day 0 (randomization) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full 
information regarding WOCBP, definition of menopause, and 
contraception): 
a. Must have a negative serum pregnancy test at screening.  Urine 
pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug plus 52 weeks 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 


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with study drug plus 52 weeks 
11. Patients must demonstrate willingness and ability to comply with the 
scheduled study visits, treatment plans, laboratory tests, and other 
procedures 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this 
study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid 
arthritis [RA], multiple sclerosis [MS], systemic sclerosis, or vasculitis not 
related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are 
allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), 
or any elective surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube 
(QFT-G) or other diagnostic test in the absence of clinical 
manifestations.  Latent TB is not excluded if the patient has 
documented completion of adequate course of prophylactic treatment 
with regimen recommended by local health authority guideline, or the 
patient has started treatment with isoniazid, or other regimen 
recommended by local health authority guidelines for at least 1 month 
before Day 0 and continues to receive the prophylactic treatment 
during study until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, including but 
not limited to any condition defined by BILAG A criteria, with the 
exception of mononeuritis multiplex and polyneuropathy, which are 
allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires 
or may require induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to 
require additional systemic glucocorticosteroid therapy during the study, 
(eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is 
allowed 


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8. Use or planned use of concomitant medication outside of standard of 
baseline treatment for SLE from Day -1 or for any time during the study 
9. Active and clinically significant infection (bacterial, fungal, viral, or 
other) within 60 days prior to first dose of study drug.  Clinically 
significant is defined as requiring systemic parenteral antibiotics or 
hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe 
disseminated herpes zoster or disseminated herpes simplex within the last 
3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) 
unless patient received curative treatment for HCV and has a documented 
negative viral load, known human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS)-related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 350/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if 
related to SLE, at screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of 
proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 
339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) 
< 40 ml/minute based on Cockcroft-Gault calculation 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the investigator’s 
judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related to lupus 
myositis  
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s 
syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, 
might place a patient at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of components of 
mAbs 
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year, at the investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or 
squamous cell cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, 
including recent (within the past year) medical conditions (eg, 
cardiovascular conditions, respiratory illnesses) that may increase the risk 
associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate 
for entry into this study 
28. Investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by 
the investigator, or patients who are employees of the sponsor or directly 
involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional 
(drug or device) clinical study within 30 days or 5 half-lives of baseline, 
whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior 
based on patient responding “yes” to question 3, 4, or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a 
psychiatric or physical (eg, infectious disease) illness 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be found in 
Section 8. 
Two analyses are planned:  1) an interim analysis to select the POC dose 
based on the MAD data, and 2) a final analysis at study completion.  
Additionally, DMC safety analyses will be performed for each MAD cohort 
and throughout the POC to monitor patient safety as described in the DMC 
charter.  An additional analysis may be performed for the MAD portion of the 
study when all MAD patients have completed the safety follow-up, or 
withdrawn from the study, and prior to the final analysis.  Data from the POC 
part of the study will be excluded from this additional analysis. 
Unless stated otherwise, statistical testing will only be performed on the POC 
data and will be done using 2-sided overall alpha of 0.10.  Data will be 
summarized descriptively by treatment and overall for each study phase.  For 
the MAD portion, BOS161721 will be summarized overall and by each dose 
level and placebo patients from each cohort will be combined.   
The descriptive summaries for the categorical data will include number and 
percentage.  The descriptive summaries for the continuous data will include 
number, mean, median, standard deviations (SD), 25th and 75th percentiles, 


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minimum, median, and maximum.  Counts, medians, 25th and 75th percentiles, 
and standard error will be presented for time-to-event data. 
All safety analyses will be performed using the safety analysis set (SS), 
defined as all patients who receive at least 1 dose of study treatment.  All 
efficacy analyses will be performed using the full analysis set (FAS), defined 
as all patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  Select efficacy analyses may 
also be performed on the per protocol (PP) set. 
Binary efficacy endpoints, including the primary efficacy endpoint, will be 
assessed via Pearson’s chi-squared analysis.   
Continuous efficacy endpoints will be assessed via analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA) when applicable, adjusting 
for the baseline value.  Repeated measures mixed models may be performed 
to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be 
compared using the log-rank test.   
Adverse event data will be coded to system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class and preferred term will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and 
relationship.   
Concomitant medications will be summarized, based on coded terms, using 
frequency and percentage of patients.  Observed values and changes from 
baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters, will be summarized at each individual visit. 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................3 
PROTOCOL SUMMARY ...............................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF IN-TEXT TABLES ........................................................................................................19 
LIST OF IN-TEXT FIGURES.......................................................................................................19 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION AND RATIONALE .................................................................................24 
1.1 
Indication ...........................................................................................................................24 
1.2 
Background and Rationale .................................................................................................24 
1.2.1 
Overview of the Disease State .....................................................................................24 
1.2.2 
BOS161721 Development ...........................................................................................24 
1.2.2.1 
Interleukin-21 .........................................................................................................25 
1.2.2.2 
Preclinical Studies ..................................................................................................26 
1.2.2.3 
Clinical Studies ......................................................................................................27 
1.2.3 
Study Dose Selection ...................................................................................................28 
1.2.4 
Risk-Benefit Assessment .............................................................................................29 
1.2.5 
Potential Risks .............................................................................................................30 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................31 
1.2.5.2 
Injection Site Reactions .........................................................................................31 
1.2.5.3 
Immune Complex Disease .....................................................................................31 
1.2.5.4 
Infections................................................................................................................32 
1.2.5.5 
Malignancy ............................................................................................................33 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................33 
1.2.5.7 
Failure of Vaccination............................................................................................33 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................34 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................34 
2 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................34 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................34 
2.2 
Phase 2 Proof of Concept ...................................................................................................36 
3 
STUDY PLAN ........................................................................................................................37 
3.1 
Study Design ......................................................................................................................37 
3.1.1 
Multiple Ascending Dose Phase 1b .............................................................................37 
3.1.1.1 
Dose Escalation for the MAD Portion ...................................................................38 
3.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................38 
3.1.1.3 
DMC Recommendations ........................................................................................39 
3.1.2 
POC Phase 2 ................................................................................................................39 
3.1.2.1 
BOS161721 POC Dose Selection and Justification...............................................39 


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3.1.2.2 
POC Study Design .................................................................................................40 
3.2 
Randomization and Blinding .............................................................................................40 
3.3 
Study Schematic.................................................................................................................42 
3.4 
Schedule of Assessments ...................................................................................................43 
3.5 
End of Study ......................................................................................................................52 
4 
POPULATION .......................................................................................................................52 
4.1 
Participant Recruitment .....................................................................................................52 
4.2 
Number of Patients ............................................................................................................52 
4.3 
Patient Screening ...............................................................................................................52 
4.4 
Inclusion Criteria ...............................................................................................................52 
4.5 
Exclusion Criteria ..............................................................................................................54 
4.6 
Concomitant Medications ..................................................................................................57 
4.6.1 
Corticosteroid ...............................................................................................................57 
4.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................58 
4.7 
Women of Childbearing Potential .....................................................................................58 
4.7.1 
Determination of Menopause .......................................................................................59 
4.7.2 
Contraception ...............................................................................................................59 
4.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................59 
4.8.1 
Patient Withdrawal and Replacement ..........................................................................60 
5 
STUDY PROCEDURES ........................................................................................................60 
5.1 
Screening............................................................................................................................60 
5.1.1 
Retesting During Screening Period ..............................................................................61 
5.2 
Enrollment/Randomization and Day 0 Treatment .............................................................61 
5.3 
Treatment Period/Follow-Up Visits ...................................................................................62 
5.4 
Safety Follow-Up Visits ....................................................................................................63 
5.5 
Premature Discontinuation .................................................................................................64 
6 
ASSESSMENTS .....................................................................................................................64 
6.1 
Medical History, Demographic and Other Baseline Information ......................................65 
6.2 
Safety Assessments ............................................................................................................65 
6.2.1 
Laboratory Assessments ..............................................................................................65 
6.2.1.1 
Pregnancy testing ...................................................................................................67 
6.2.1.2 
Tuberculosis Screening ..........................................................................................67 
6.2.2 
Adverse Events ............................................................................................................68 
6.2.2.1 
Definitions..............................................................................................................68 
6.2.2.2 
Recording of Adverse Events ................................................................................68 
6.2.2.3 
Severity of Adverse Events ....................................................................................68 
6.2.2.4 
Causality of Adverse Events ..................................................................................68 
6.2.2.5 
Seriousness of Adverse Events ..............................................................................69 
6.2.2.6 
Adverse Events of Special Interest ........................................................................70 
6.2.2.7 
Reporting of Adverse Events .................................................................................73 
6.2.2.8 
Follow Up of Adverse Events ................................................................................75 


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6.2.3 
Vital Signs ....................................................................................................................75 
6.2.4 
12-Lead Electrocardiograms ........................................................................................75 
6.2.5 
Physical Examinations .................................................................................................76 
6.2.6 
C-SSRS ........................................................................................................................76 
6.2.7 
Injection Site Reactions ...............................................................................................76 
6.2.8 
Immunogenicity ...........................................................................................................76 
6.3 
Efficacy Assessments .........................................................................................................77 
6.3.1 
SLEDAI-2K .................................................................................................................77 
6.3.2 
BILAG 2004 ................................................................................................................77 
6.3.3 
PGA of Disease Activity ..............................................................................................77 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................78 
6.3.4.1 
SRI-4 Response ......................................................................................................78 
6.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................78 
6.3.4.3 
BICLA Response ...................................................................................................78 
6.3.5 
CLASI Response ..........................................................................................................78 
6.3.6 
ACR-28 Joint Count ....................................................................................................79 
6.4 
Other Variables ..................................................................................................................79 
6.4.1 
SLICC/ACR Damage Index ........................................................................................79 
6.4.2 
PROs ............................................................................................................................79 
6.5 
Pharmacokinetic Assessments ...........................................................................................79 
6.6 
Pharmacodynamic Assessments ........................................................................................79 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................80 
6.8 
Protocol Deviations ............................................................................................................80 
7 
STUDY DRUG MANAGEMENT .........................................................................................80 
7.1 
Description .........................................................................................................................80 
7.1.1 
Formulation ..................................................................................................................80 
7.1.2 
Storage .........................................................................................................................80 
7.2 
Packaging and Shipment ....................................................................................................80 
7.3 
Dose and Administration ...................................................................................................80 
7.4 
Accountability ....................................................................................................................81 
7.5 
Prohibited Concomitant Therapy .......................................................................................81 
7.6 
Compliance ........................................................................................................................81 
8 
STATISTICS ..........................................................................................................................81 
8.1 
Sample Size ........................................................................................................................82 
8.2 
Statistical Methods .............................................................................................................83 
8.2.1 
Analysis Populations ....................................................................................................83 
8.2.2 
Demographics and Baseline Characteristics ................................................................83 
8.2.3 
Primary Efficacy Endpoint(s) ......................................................................................83 
8.2.4 
Secondary Efficacy Endpoint(s) ..................................................................................84 
8.2.5 
Analysis of Safety ........................................................................................................84 
8.2.5.1 
Safety Analysis ......................................................................................................84 


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8.2.6 
Pharmacokinetic and Pharmacodynamic Data .............................................................84 
8.2.6.1 
Analysis of Pharmacokinetic Data .........................................................................84 
8.2.6.2 
Analysis of Pharmacodynamic Data ......................................................................85 
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ..................................85 
8.3 
Interim Analysis and Power ...............................................................................................85 
9 
ETHICS AND RESPONSIBILITIES .....................................................................................85 
9.1 
Good Clinical Practice .......................................................................................................85 
9.2 
DMC ..................................................................................................................................85 
9.3 
Institutional Review Board/Independent Ethics Committee ..............................................86 
9.4 
Informed Consent...............................................................................................................86 
9.5 
Records Management .........................................................................................................87 
9.6 
Source Documentation .......................................................................................................88 
9.7 
Study Files and Record Retention......................................................................................88 
10 AUDITING AND MONITORING ........................................................................................88 
11 AMENDMENTS ....................................................................................................................88 
12 STUDY REPORT AND PUBLICATIONS ...........................................................................89 
13 STUDY DISCONTINUATION .............................................................................................89 
14 CONFIDENTIALITY ............................................................................................................89 
15 REFERENCES .......................................................................................................................91 
16 APPENDICES ........................................................................................................................95 
APPENDIX 1 
NAMES OF STUDY PERSONNEL ...............................................................95 
APPENDIX 2 
DECLARATION OF HELSINKI....................................................................96 
APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ....................100 
APPENDIX 4 
MEDICATION WASHOUT PERIODS........................................................101 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) ......................102 
APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE ...................................103 
APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES ...................................................104 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .........................43 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) ...............................48 
Table 3. 
Laboratory Tests ....................................................................................................65 
Table 4. 
Causality Definitions .............................................................................................69 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................29 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 ...........................................42 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
 
 
FAS 
full analysis set 
Fc 
fragment crystallizable 
CCI


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FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
IFNγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary of Regulatory Activities 
MS 
multiple sclerosis 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 


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NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PP 
per protocol 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-
wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS  
safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
STAT3 
signal transducer and activator of transcription 3 
CCI


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SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1. INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids (CS), immunosuppressants, and cytotoxic 
agents.1  However, some of the morbidity in patients with SLE is related to its treatment.  
Comparison of early and late outcomes in patients with SLE demonstrate that death in early 
disease is most commonly due to infections and active SLE causing multi-system organ damage, 
while thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb with extended half-life directed against 
human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t½) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies. 
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses). 
 
 
 
 
 
 
 
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  The NOAEL was determined to be 100 mg/kg (SC and IV), the highest dose 
tested. 
An additional GLP, repeat-dose toxicity study was conducted in Cynomolgus monkeys (4 males 
and 4 females per dose group) following every 2 weeks (Q2W) administration by SC (10, 30, 
and 100 mg/kg) injection for a total of 14 doses.  
 
 
 
 
 
  There were no BOS161721-related effects on survival, clinical signs, male body 
weights, ophthalmologic parameters, electrocardiogram (ECG) findings, clinical pathology, 
macroscopic observations, organ weights, or microscopic observations.  
 
 
 
 
 The 100 mg/kg/dose was the NOAEL
 
 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: 
placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 
30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first 
cohort, after the first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 
48 hours before the remaining subjects from that cohort were dosed, to allow for an initial review 
of any emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not 
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sooner than 8 days after all the subjects in the prior cohort had been dosed and were based on a 
review of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included ECGs, vital signs (blood pressure [BP], heart rate, and temperature), safety 
laboratory assessments, blood sampling for ADAs, total IgG and immunoglobulin M (IgM) 
levels, CD4+ count, and full and targeted physical examinations.  Overall, there were no 
clinically significant findings from this study.  Adverse events reported as related to the study 
drug, particularly infections, were expected for the compound, and there were no clinically 
relevant changes in laboratory and ECG results or vital signs.  There was 1 serious adverse event 
(SAE; death due to pulmonary embolism) that occurred 127 days after a single administration of 
240 mg SC dose of BOS161721.  The causality of this single SAE was not attributed to study 
drug and further information can be found in the Investigator’s Brochure.  Final PK data from 
the SAD study demonstrates BOS161721 has a mean t½ ranging from 80 to 87 days for doses of 
≥ 30 mg in healthy subjects.  
1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1b portion based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose 
level, repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant 
safety or tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD portion of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median first time to maximum concentration (Tmax) of 6 days and an apparent 
terminal half-life of 44 days.  Furthermore, pSTAT3 suppression, a marker of IL-21 target 
engagement, follows a similar time course of the mAb levels, with maximal and sustained 
suppression apparent with doses greater than 30 mg SC (Figure 1).   


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Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 
All doses selected for the MAD portion are projected not to exceed the mean exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD 
study.  Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered 
study design, the data monitoring committee (DMC) will perform a scheduled review of safety 
data and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC and 
Boston Pharmaceuticals will conduct a data review to determine which dose will be carried 
forward into the proof of concept (POC) Phase 2 portion.  This POC dose decision will be based 
on evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD portion (see 
Section 3.1.2.1 for the chosen POC dose and justification). 
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD portion.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  


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Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Thirty days after the last patient in Cohort 3 receives the third dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This POC dose decision will be based on 
evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 during the MAD part of study.  
Thereafter, DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter.  With the agreement of the DMC and sponsor, this schedule may 
be modified depending on the rate of patient accrual.  Additional details can be found in the 
DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), or altered BOS161721 levels or activity.  Further details can be found in the current 
Investigator’s Brochure (IB) for BOS161721, which contains comprehensive toxicology, 
preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational 
products.  Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to 
the study drug, particularly infections (flu-like symptoms, etc.), were expected for the 
compound, and there were no clinically relevant changes in laboratory and ECG results or vital 
signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 


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this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 6.2.2.6.1. 
Based on the Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic reactions in 
subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC for 3 months (a total of 7 doses).  There were no injection site 
reactions in animals dosed subcutaneously.  Further, there were no reports of injection site 
reactions in the 26-week GLP toxicology study in Cynomolgus monkeys. 
Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 6.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 


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ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 
Based on the Phase 1 SAD study (BOS161721-01), immune complex disease in subjects who 
received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 
BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and CD4 + < 350 cells/mm3 will be excluded from the MAD/POC 
parts of the study.  Patients exposed to investigational product who develop diarrhea during the 
course of the study should immediately undergo an assessment for opportunistic infection 
including stool for ova and parasites and stool examination for cryptosporidium.  Positive 
cryptosporidium in stool sample at screening is an exclusion.  Treatment by the investigator 
where indicated should be guided by findings and be consistent with local standard of care. 
Based on the Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 


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1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 
and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from this trial.  Patients with a positive hepatitis B or C 
test or a history of alcohol dependence will also be excluded. 
Based on the Phase 1 SAD study (BOS161721-01), hepatic function abnormality in subjects who 
received BOS161721 was not observed. 
1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen in a dose-dependent fashion; however, 


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BOS161721 administration did not affect anti-tetanus toxoid antibody data for IgM, IgG, IgG1, 
or immunoglobulin E (IgE) during the dosing phase in the same study. 
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 
oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 4.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 4.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES AND ENDPOINTS 
This trial has separate objectives and endpoints for the MAD Phase 1b and POC Phase 2 portions 
of the study.  The primary, secondary, and exploratory objectives for each phase, as applicable, 
are described below with their corresponding endpoints. 
2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment, in order to estimate the optimal 
dose. 
Safety Endpoints 
• 
Incidence and severity of AEs and SAEs, related AEs, AEs 
leading to study drug discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Secondary 
• 
To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with moderately to 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time point 
• 
Maximum observed concentration (Cmax), Tmax, area under 
the concentration-time curve (AUC), terminal elimination 


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severely active SLE. 
half-life (t½), systematic clearance (CL), volume of 
distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from baseline to each visit in 
phosphorylated signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) from baseline in 
anti-double-stranded DNA (dsDNA), antinuclear antibodies 
(ANA), anti-Sjögren syndrome A and B (SSA, SSB), Smith 
(Sm), and antiphospholipid (APL) autoantibodies at each 
visit 
• 
Results and changes (or shifts) from baseline in abrogation 
of IL-21 gene signature at each indicated visit 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
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2.2 
Phase 2 Proof of Concept 
 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on the SRI-4  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 response at 
Day 210 (see Section 6.3.4.1) 
Secondary 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction of oral corticosteroid (CS) 
(≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B flares relative to 
baseline through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B flare compared to 
baseline through Day 210 
Safety 
• 
To assess safety and tolerability of repeat 
doses of BOS161721 at the chosen dose 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), related AEs, AEs leading to study 
drug discontinuation, AEs by severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 


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3 STUDY PLAN 
3.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
moderately to severely active SLE.  After successfully completing a screening phase, eligible 
patients will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule 
will be monthly.   
The trial will consist of 2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visits at Days 210, 240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease activity.  Further details on the content and methods of data reports by the medical 
monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
3.1.1 
Multiple Ascending Dose Phase 1b 
The MAD portion will consist of 3 cohorts:  
• 
Cohort 1 (20 mg SC) will include 6 patients 
• 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
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o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• 
Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
the MAD part of the study are projected not to exceed the mean exposure of that achieved in the 
SAD study.   
3.1.1.1 
Dose Escalation for the MAD Portion  
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow-up after the second dose, Cohort 2 
begins dosing (after the DMC evaluation of the safety and tolerability data from Cohort 1).  
Similarly, after 8 of the 12 patients in Cohort 2 have received 2 doses and have completed 
2 weeks of follow-up after the second dose, Cohort 3 begins dosing after the DMC evaluation of 
the safety and tolerability data from Cohorts 1 and 2.  Each cohort will continue at their assigned 
dose level through their respective 6-month treatment periods (See Study Schematic, 
Section 3.1).  If patients discontinue the study in a cohort prior to adequate safety follow-up, 
he/she may be replaced. 
Criteria for dose escalation are further described in the DMC Charter.  See Section 3.1.1.2 for 
additional details about DLTs.   
3.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia 
• Grade 3 neutropenic infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia 
Non-Hematologic: 
• 
Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals) 


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• 
Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 6.2.2.6.3 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances. 
3.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD part of the study, the DMC may provide the following 
recommendations to the sponsor: 
• 
Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort 
• 
Continuing a dose level for a given cohort 
• 
Escalating a dose level for a subsequent cohort 
• 
Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC portion, the DMC and Boston Pharmaceuticals will conduct a 
data review to determine which dose will be carried forward into the POC Phase 2 part of the 
study.  This POC dose decision will be based on evaluation of the PK, safety (inclusive of 
dose-limiting toxicity [DLT]), and tolerability data (and available PD/biomarker data) from 
Cohorts 1, 2, and 3; this dose will not exceed doses tested during the MAD portion.  The DMC 
will be reviewing all relevant data from Cohorts 1, 2, and 3 that is available 30 days after the last 
patient from Cohort 3 receives the third dose.  Details are provided in the DMC Charter.  
3.1.2 
POC Phase 2  
3.1.2.1 
BOS161721 POC Dose Selection and Justification 
The dose for the POC portion of the study is 120 mg administered SC monthly (a total of 
7 doses).  The rationale for the BOS161721-02 Phase 2 POC dose selection was based on 
cumulative safety, tolerability, immunogenicity, PK, and PD data available from an interim 
analysis (IA) performed during the MAD Phase 1b portion of the trial. 
The data cut-off for this IA occurred on 
 and included all 6 patients and 
7 doses from Cohort 1 (20 mg), 12 patients and 6 doses from Cohort 2 (60 mg), and 12 patients 
and 4 doses from Cohort 3 (120 mg). 
The safety analysis focused on incidence and severity of all AEs, SAEs, and pre-determined 
adverse events of special interest (see Section 6.2.2.6).  The DMC and designated unblinded 
Boston Pharmaceuticals team met on 
 and did not identify any untoward 
safety signals at any BOS161721 dose levels. 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
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Because there were no safety, tolerability, or immunogenicity trends observed at the time of the 
IA, the Phase 2 POC dose selection was made based on available PK and PD data.  pSTAT3 
levels were assessed as the primary PD biomarker of IL-21R signaling levels.  This is because 
IL-21R signaling, upon IL-21 binding, initially involves phosphorylation of JAK1/JAK3 which 
dissociate from the receptor complex, and phosphorylate STAT3 which translocates to the 
nucleus and drives IL-21-regulated gene expression.  
 
 
The 120 mg dose will be communicated to site investigators participating in the POC Phase 2 
portion, and to Institutional Review Boards (IRBs) and the Independent Ethics Committee (IEC). 
3.1.2.2 
POC Study Design 
For the POC part of the study, approximately 156 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments (Section 3.4). 
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
3.2 
Randomization and Blinding 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
portion and separately for each cohort in the Phase 1b and 2 portions as follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1b MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the IA, ad hoc analyses as needed, and the DMC safety reviews.  The DMC will 
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Clinical Study Protocol:  BOS161721-02 
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review unblinded data during safety reviews and the IA.  A limited team at Boston 
Pharmaceuticals will review unblinded results from the Phase 1b MAD portion during the IA to 
determine the dose that will be used for the Phase 2 POC portion of the study.  Details regarding 
maintenance of the blinding and content of data reviews will be described in the DMC charter or 
related study documentation.   
 


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Protocol Date and Version:  23 January 2019; V5.0 
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Page 42 of 116 
3.3 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 
 
A = active drug (BOS161721); P = placebo 
Day 0
6 month treatment phase
Dose 1
Dose 120 mg N=104 
Placebo N=52
Low Dose (20 mg) N=6 (5A, 1P) 
Monthly visits 
Medium Dose (60 mg) N=12 (9A, 3P) 
Dose 3
2 month
6 patients complete dose 2:  dose escalate Cohort 2 if safe
Dose 1
Dose 2
1 month
High Dose (120 mg) N=12  (9A, 3P)
Dose 1
Dose 3 + 30 days: 
•
Phase 2 POC dose determined
•
Continue dosing Cohort 3 if safe
Follow up 
Dose 6
5 month
Dose 7
6 month
Dose 7
6 month
Dose 7
6 month
Screening
Week -4
8 patients complete dose 2:
•
Dose escalate Cohort 3 if safe
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Day 0
Day 0
Multiple Ascending Dose (MAD)
Phase 1b 
Proof of Concept (POC)
Phase 2 
Dose Evaluation
Phase
Follow up
90 days
90 days
Follow up 
90 days
Follow up 
90 days
Dose 1
Day 0
Dose 3
2 month
Dose 6
5 month
Dose 7
6 month
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Dose 3
2 month
Screening 
28 days
Screening 
28 days


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3.4 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site 
reaction assessment 
 
Xf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
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Page 44 of 116 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
SLEDAI-2Kh 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)i 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directj 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAk 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbl 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3m 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)o 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test 
(QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis 
B and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
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Page 46 of 116 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
PK Labs 
Predose 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Predose PK 
Window 
 
60m 
 
 
± 3d 
 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
 
 
 
 
 
Postdose 
 
Xq 
X 
X 
Xq 
 
 
 
 
 
Xq 
X 
X 
X 
X 
X 
Postdose PK 
Window 
 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
± 1d 
± 3d 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
 
 
 
 
 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SAE = serious adverse event; 
SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 7, 187, and 195).  When the timing 
of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
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Protocol Date and Version:  23 January 2019; V5.0 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose 
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
h 
SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
i 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
j 
When clinically indicated for hemolytic anemia. 
k 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
l 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
m 
Predose (trough) samples only. 
n 
Only 
 collected during safety follow-up visits.  
o 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
p 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
q 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180. 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo dosing 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessment 
 
Xg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
Xi 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory assessments 
(hematology and clinical 
chemistry)j 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directk 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Whole blood for leukocyte 
immunophenotype 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
ADAl 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbm 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)o 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test (QuantiFERON-TB Gold 
In-Tube)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Stool samplep 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for protein/creatinine 
ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labsb 
Predose 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb  = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity 
Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; 
TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
PK samples will only be collected at the investigational sites that participate in the PK portion of the study.  On PK only days (ie, Day 187 and Day 195 
when no laboratory assessments are scheduled) samples will be collected at the investigational sites of the selected countries that participate in the PK 
portion of the study.  Patients not participating in PK are not required to return for investigation site visits on Days 187 and 195. 
c 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the 
daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
d 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after eligibility 
confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
e 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
f 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
g 
Injection site reaction assessments to be performed at 2 hours postdose. 
h 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 187 and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187b 
(± 3) 
195b 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
i 
SLEDAI-2K should be done before randomization and dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
j 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
k 
When clinically indicated for hemolytic anemia. 
l 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
m 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
n 
Only 
 collected during safety follow-up visits. 
o 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
p 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, 
and cryptosporidium. 
 
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3.5 
End of Study  
End of Study (Individual Patient): A patient is considered at the end of study if he/she has 
withdrawn, prematurely discontinued, or completed all of the study procedures including the last 
visit. 
End of Study (End of trial): The end of the study is defined as the date of the last visit of the 
last patient in the study globally, or the date of which the last patient withdraws or discontinues if 
all prior enrolled patients have already completed/withdrawn. 
4 POPULATION 
4.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
4.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b portion, and approximately 156 additional patients will be randomized in the POC Phase 2 
portion.  Note that approximately 24 dropouts are assumed.   
4.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Section 3.4]) for this study must be 
performed between Day -28 and Day -1. 
4.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 


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immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory 
c. C3 or C4 levels below normal as determined by central lab 
5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) must be ≥ 6, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis 
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of SLE, as defined 
by the BILAG criteria as modified for use in this study, which must be confirmed by the 
central data reviewer:  
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis in ≥ 2 joints with marked loss of functional range of movements and 
significant impairment of basic activities of daily living that has been present on 
several days cumulatively over the past 30 days, including at the time of the 
screening visit.  See APPENDIX 5 for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require assistance or 
assistive devices, (at least 1 must be present and documented in source): 


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o Ambulation, toileting, grooming- including bathing and dressing; feeding 
oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional range of movements 
manifested by effects on instrumental ADLs such as: 
• Cooking, driving, using the telephone or computer, shopping, cleaning, etc., and 
has been present on several days over the last 30 days, and is present at the time 
of the screening visit 
If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to signing consent) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at screening for a patient 
to be eligible and must be stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 0 (randomization) (see APPENDIX 3) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 52 weeks 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
treatment plans, laboratory tests, and other procedures 
4.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 


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2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic sclerosis, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any elective 
surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 0 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to require additional 
systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is allowed 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 4.6 for prohibited 
concomitant medication) 
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
parenteral antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) unless patient 
received curative treatment for HCV and has a documented negative viral load, known 
human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-
related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 


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15. CD4+ count < 350/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to lupus 
based on the investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, might place a patient 
at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the C-SSRS 
31. Current or pending incarceration 


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32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
4.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen of other 
concomitant medications for the treatment of SLE (eg, analgesics, NSAIDs, statins, ACE 
inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments are 
clinically indicated.  Use of any other drugs for non-SLE conditions, including over-the-counter 
medications and herbal preparations, should remain stable unless change or addition is clinically 
necessary.  Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
4.6.1 
Corticosteroid 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, 
however, the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days 
prior to Day 0 (randomization day). 
Tapering of steroids during the course of the study will be highly encouraged and should be 
evaluated at the protocol permitted visits (Day 0 through Day 60 and Day 120 through Day 150).  
Between Day 60 and Day 120, and between Day 150 and Day 210, oral CS doses must be held 
constant due to the endpoint evaluations occurring at Day 120 and Day 210. 
• 
Once a patient has received the first dose of study drug (after Day 0), prednisone (or 
prednisone equivalent) dose is highly encouraged to continue tapering down as appropriate.  
The investigator should evaluate the prednisone dose at each visit and make the decision, 
within the protocol allowed windows. 
o Exception:  Between Day 60 and Day 120, and between Day 150 and Day 210 (ie, within 
60 days of primary and secondary endpoint assessments), oral CS doses must be held 
constant. 
After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” for increased SLE 
disease activity will be allowed between Day 0 and Day 60, according to the following:   
• 
The oral CS dose is allowed to increase to ≤ 40 mg/day of prednisone or equivalent, which 
must be tapered down to ≤ 10 mg/day within 2 weeks of initiation of the “burst” 


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o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o No increase of oral CS above baseline is permitted beyond Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any other route, but systemic 
administration, is allowed. 
Treatment with intra-articular or intravenous CS is prohibited during the course of the study. 
4.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and during the 
study are described below, and washout requirements are provided in APPENDIX 4.  
Medications taken within 30 days prior to screening must be recorded on the eCRF. 
1. Prior exposure to BOS161721 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
24 weeks of screening; recovery of B cells (CD19+) must be documented (record absolute 
number of CD19+ B cells) 
3. Patients who have received treatment with cyclophosphamide within the 24 weeks prior to 
screening 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria within 4 weeks for oral use or 8 weeks for topical use of screening 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 24 weeks prior to screening 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc., may be used 
according to local guidelines during treatment period 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation 
4.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 
See Section 4.7.2 for detailed information regarding contraceptive requirements for WOCBP. 


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4.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   
4.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks, due to the mean terminal ½ life of the study drug. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 52 weeks, due to the mean 
terminal ½ life of the study drug. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
At a minimum, patients must agree to the use of 1 method of highly effective contraception from 
the following: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who 
are WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• 
IUDs, such as ParaGard® 
• 
Vasectomy 
• 
Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception.  Women who are abstinent while participating in the study 
must continue to have pregnancy tests.  Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego complete 
abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, WOCBP must still undergo pregnancy testing. 
4.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient to continue 
or withdrawal from the study medication.    


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See Section 6.8 for additional details.  
4.8.1 
Patient Withdrawal and Replacement 
See Section 5.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD part of the study after discussion between the principal investigator or designee 
and sponsor. 
5 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
5.1 
Screening 
Screening will be the same for both the MAD and POC portions of the study. 
Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria, listed in Section 4.4 and Section 4.5 respectively, will be enrolled in 
the study.  Screened patients who drop out of the clinical study before randomization will be 
recorded as screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• 
Medical history documentation 
• 
Review of inclusion and exclusion criteria 
o Patient medical records must contain documentation of SLE diagnosis 
o C-SSRS   
• 
Concomitant medication documentation 
• 
Demographics 
• 
Full physical examination 
• 
Vital signs 
• 
Chest x-ray (a prior x-ray can be used if taken within 12 weeks of screening date) 
• 
Laboratory evaluations (non-fasting): 
o Hematology and clinical chemistry 
o Serology (Hepatitis B and C; HIV-1/2 combination) 
o TB test 


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o CRP 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, 
 
 
o Serum pregnancy test (WOCBP) 
o FSH (postmenopausal women under age 55 years) 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
o Stool sample  
• 
12-lead ECG 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity 
Screening procedures are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
5.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• 
medically indicated 
• 
there is evidence a laboratory sample was mislabeled, indeterminate, inadequately processed, 
and/or deteriorated in transit to the central laboratory 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
5.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.   
Prior to randomization, the study site should confirm that the patient still meets 
inclusion/exclusion criteria (especially SLE disease activity and treatment).  The site will obtain 
a randomization number when registering the patient in IWRS.  All patients will receive 
BOS161721 or placebo according to the kit number assigned by the IWRS randomization 
scheme.    
After randomization, procedures include: 
• 
PROs:  
 
• 
C-SSRS 
• 
Laboratory evaluations (fasting): 
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o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
 whole blood for leukocyte immunophenotype 
o ADA 
o pSTAT3 (predose [trough] samples only in Phase 1b)  
o 
 
o 
 
o 
 
o See Table 1 and Table 2 for details of PK sampling in the MAD and POC portions 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Full physical examination 
• 
Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 0) 
• 
12-lead ECG (prior to PK blood draw) 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, PGA) 
• 
SLICC/ACR damage index 
• 
Study drug administration: 
o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 7.3 
• 
Injection site reaction assessment performed at 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
5.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of Assessments 
(Table 1 and Table 2).  See Schedule of Assessment tables for allowable windows for each visit.   
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
PROs:  
 
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• 
Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
• 
Injection site reaction assessments will be performed predose  
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Spot urine for protein to creatinine ratio 
• 
Urinalysis 
• 
 
• 
Plasma 
 
• 
PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
• 
SLICC/ACR Damage Index will be completed at Day 180 
• 
C-SSRS 
• 
ECGs prior to PK blood draw 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
• 
Fasting hematology and chemistry assessments  
• 
The CD4+ count and total IgG and IgM levels  
• 
Plasma 
 & 
, ADA, and whole blood for leukocyte immunophenotype 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
nAb will be analyzed by central lab if patient is positive for ADA 
• 
CRP 
• 
 
5.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270.  These visits will include the 
following assessments as indicated in the Schedule of Assessments (Table 1 and Table 2):  
• 
PROs:  
 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Injection site reactions 
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Spot urine for protein/creatinine ratio and urinalysis 
• 
Concomitant medication documentation 
• 
BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
• 
Fasting clinical laboratory assessments (hematology and clinical chemistry) 
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Plasma 
 
• 
 
• 
12-lead ECG (prior to PK blood draw) 
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• 
CRP 
• 
ADA 
• 
 
• 
Urine pregnancy test 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC portions, 
respectively 
5.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Day 180) and a last follow-up visit 90 days after dosing should be scheduled 
(Day 270).  Safety follow-up visit procedures based on the Schedule of Assessments 
(see Section 5.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• 
AE/SAE 
• 
Protocol deviation 
• 
Lost to follow-up 
• 
Patient withdraws consent at their own request 
• 
Investigator decision 
• 
Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
6 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
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6.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• 
General medical history 
• 
Documentation of SLE diagnosis 
• 
Historical medication therapy for SLE 
The following demographic information will be recorded:  
• 
Age 
• 
Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• 
Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• 
Height (without shoes, in cm) 
• 
Body weight, without shoes (kg) 
• 
Body mass index (BMI [kg/m2]) 
Other baseline characteristics will be recorded as follows: 
• 
Concomitant medication documentation (see Section 4.6) 
• 
Status of child bearing potential and contraception 
6.2 
Safety Assessments 
6.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Section 3.4).  Patient eligibility will be determined based on these tests at screening.  
Unscheduled clinical labs may be obtained at any time during the study to assess any perceived 
safety concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests) to ensure accuracy 
and consistency in test results.  Laboratory/analyte results that could unblind the study (ie, 
biomarker results) will not be reported to investigative sites.  Urinalysis will be performed on 
midstream, clean catch specimens.  Some biomarkers listed above will not be drawn at some 
sites due to geographical logistical challenges.  See the laboratory manual for details. 
Endpoint analyses will be based on changes from baseline assessments at Days 120 and 210. 
Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
(QFT-G)d 
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
Serum pregnancy test 
 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
Prothrombin 
time/international 
normalized ratio (repeat) 
Creatine kinase (repeat) 
 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only in Phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte 
immunophenotype  
 
 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
dsDNA = double-stranded deoxyribonucleic acid;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; 
nAb = neutralizing antibody; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; 
PT = prothrombin time; qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; SAE = serious 
adverse event; SC = subcutaneous; 
; TB = tuberculosis.  
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for 
ova, parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 6.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated for hemolytic anemia. 
 
6.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or continued 
and a further negative urine pregnancy test results will then be required at the baseline visit 
before the patient may receive the investigational product.  Urine pregnancy tests will also be 
routinely repeated at study drug administration visits prior to study drug administration, at the 
last follow up visit day (Day 270) and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  In the case of a positive pregnancy test or 
confirmed pregnancy, the patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose should be scheduled 
(Day 270).  Safety follow-up visit procedures (see Section 5.4) are specified in the Schedule of 
Assessments (see Section 3.4). 
See Section 6.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
6.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 4.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 0). 
6.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 
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using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
6.2.2 
Adverse Events 
6.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 6.2.2.5). 
6.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset, date of AE outcome, and action taken for the AE will be documented together 
with the principal investigator’s assessment of the seriousness of the AE and causal relationship 
to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
6.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 
and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 
6.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 4) should be selected based on medical 
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Table 4. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation (positive dechallenge), or the 
symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that there are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
6.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• 
Requires hospitalization or prolongation in existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly or birth defect 
• 
Is other important medical event (see below) 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• 
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Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
6.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Grades 2 to 5 injection site reaction, including erythema, pain, and induration 
(See APPENDIX 6) 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy (not including basal cell carcinoma or squamous cell carcinoma of skin) 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, disseminated 
herpes simplex, disseminated tuberculosis, Aspergillus sp., Candida albicans, Coccidioides 
immitis, Cryptococcus neoformans, Cytomegalovirus, Histoplasma capsulatum, Isospora 
belli, and Polyomavirus JC polyomavirus 
6. Cryptosporidiasis 
6.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
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b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline 
6.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These will include Grades 2 to 5 
injection site erythema, pain, and induration (see APPENDIX 6), which are also captured as 
Adverse Events of Special Interest (See Section 6.2.2.6).  The investigator should provide a clear 
description of the observed or reported AE including location and severity.  All concomitant 
treatments used to treat injection site reactions should be recorded and captured in the eCRF, 
together with the AE of injection site reactions.   
6.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.2.2.7.2 for reporting details). 
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
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3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 5× ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 
• 
ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
• 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
6.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 6.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue (with the exception of suspected basal cell/squamous cell), 
the investigator and/or consultant(s) should contact the sponsor clinicians or designee to discuss 
the issue and any decisions as soon as possible.  Basal cell carcinoma or squamous cell 
carcinoma of skin is not considered an AE of special interest. 


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6.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, disseminated herpes simplex, disseminated tuberculosis, 
Aspergillus sp., Candida albicans, Coccidioides immitis, Cryptococcus neoformans, 
Cytomegalovirus, Histoplasma capsulatum, Isospora belli, or Polyomavirus JC polyomavirus 
will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
6.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 6.2.2.7.2. 
6.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 


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adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 
6.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Day 270).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• 
Study number 
• 
Patient number 
• 
Details of the SAE (verbatim details are sufficient for immediate notification) 
• 
Criterion for classification as ‘serious’ 
• 
Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 
obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   


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6.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becoming aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 
Potential DILI will be reported based on specifications mentioned in Section 6.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate, and is further outlined in Section 6.2.2.7.2. 
6.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 6.2.2.7.1 for details related to follow-up of pregnancy.  See Section 6.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 6.2.2.6.4 for details related to 
follow-up of malignancy. 
6.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Section 3.4).  Vital signs will be assessed on Day 0 at predose and at 
Day 0, 1 and 2 hours postdose, as well as on each of the scheduled visit days during the study 
(excluding PK-only site visits).  Supine BP and heart rate recordings will be made after the 
patient has been recumbent and at rest ≥ 5 minutes.  When the timing of these measurements 
coincides with a blood collection, vital signs should be obtained prior to the time of the blood 
collection. 
6.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Section 3.4).  ECG recording 
will initiate after the patient has been supine for at least 5 minutes.  On days of PK blood draws, 
the ECG will be collected before scheduled PK blood draws, though timing will be such that PK 
draws are collected on their scheduled times where possible. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 


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All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 
6.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 
thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at all other visits as indicated in 
the Schedule of Assessments (Section 3.4).  It includes evaluation of patient complaints and SLE 
disease-related issues, and will exclude the genitourinary system. 
6.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments 
(Section 3.4).  Patients with recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 is exclusionary at screening 
will be excluded from the study.  Patients with recent or active suicidal ideation or behavior at 
subsequent study visits will have responses to the C-SSRS reviewed in detail to assess patient 
risk, and appropriate consultative mental health services will be provided. 
6.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule of 
Assessments (Section 3.4).  Local injection site reactions will be assessed at 2 hours postdose at 
baseline, and predose for each injection after baseline.  Injection site reactions should be 
managed according to the standard of care.  Injection site reactions, Grades 2 to 5, are to be 
reported as AEs of special interest (see Section 6.2.2.7.3). 
6.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in the 
Schedule of Assessments (Section 3.4).  Blood samples (4 mL) to provide approximately 1.5 mL 
of plasma for anti BOS161721 antibody analysis will be collected into appropriately labeled 
tubes containing K2EDTA.  The presence or absence of ADA will be determined in the serum 
samples using validated bioanalytical methods.  Blood samples for ADA analysis will be 


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collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all 
patients but only analyzed by a central lab if the patient had a positive ADA on Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, a sample 
from this patient will be further analyzed in the neutralizing antibody (nAb) assay by a central 
lab. 
6.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of Assessments 
(Section 3.4). 
6.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
6.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 
4 weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, 
worksheet, clinic notes, and labs) at each visit. 
See APPENDIX 5 for detailed specifications. 
6.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 


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and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.  PGA worsening is defined as an increase of > 30 mm from baseline. 
When scoring the PGA, the assessor should always look back at the score from the previous 
visit. 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
6.3.4.1 
SRI-4 Response 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 30 mm.  The SRI-4 response in patients with moderate to severe SLE is 
associated with broad improvements in clinical and patient-reported outcomes.45  
6.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal five-point or six-point improvement in 
SLEDAI-2K being required, respectively.46 
6.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 
For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined. 
6.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 


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6.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 
6.4 
Other Variables 
6.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Days 0 
and 180. 
6.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
 and will be assessed as 
specified in the Schedule of Assessments (Section 3.4). 
 
50     
 
.   
6.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) parts of the study, 
blood samples for PK analysis of BOS161721 or placebo concentration will be collected 
according to Table 1 and Table 2. 
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration actual time profiles.   
6.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the Schedule of 
Assessments (Section 3.4) for each of the following parameters: 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
Antibodies:  
  
• 
Plasma complement (
)  
CCI
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CCI
CCI
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• 
Plasma 
 and 
  
• 
Whole blood for leukocyte immunophenotype  
6.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
6.8 
Protocol Deviations 
Protocol deviations will be documented during the study.   
7 STUDY DRUG MANAGEMENT 
7.1 
Description 
7.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
7.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
7.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
7.3 
Dose and Administration 
Details of dosing are provided in Section 3.1. 
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Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
7.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Products returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed.  The returned products should be marked as ‘returned’ 
and kept separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
7.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 4.6 and APPENDIX 4 and will be 
listed as protocol violations if taken when not permitted. 
7.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
investigator.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. 
8 STATISTICS 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC part of the study.   
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• 
An additional analysis may be performed for the MAD portion of the study when all 
MAD patients have completed the safety follow-up or withdrawn from the study, and 
prior to final analysis.  Data from the POC part of the study will be excluded from this 
additional analysis. 
• The final analysis will be performed when all patients have completed the POC safety 
follow-up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
content and format of the safety review meetings will be described in the SAP and/or 
DMC charter. 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9 
or higher.   
The following standards will be applied for the analysis unless otherwise specified.  Data will be 
summarized descriptively by treatment and overall for each study portion.  For the MAD part of 
the study, BOS161721 will be summarized overall and by each dose level, and placebo patients 
from each cohort will be combined.  Select parameters may be summarized using patients from 
both study parts.  Statistical testing will be performed on data from the Phase 2 portion only. 
Continuous data will be summarized using number, mean, standard deviation (SD), 25th and 75th 
percentiles, minimum, median, and maximum.  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage).  Time to event data will be 
summarized using counts, medians, 25th and 75th percentiles, and standard error.  All data will be 
listed for all patients. 
Statistical inference will be based on a 2-tailed test with an overall 0.10 level of significance, 
unless stated otherwise.   
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data will be conducted as 
deemed appropriate.  Any deviations from the planned analyses will be described and justified in 
the final integrated CSR. 
Protocol deviations and prohibited medications that define medication failures will be fully 
assigned and documented before database lock and unblinding.  
Further details of the analysis, including the handling of missing data, transformations and other 
data handling procedures will be provided in the SAP.   
8.1 
Sample Size 
Sample size in the Phase 1b part of the study is based on operational consideration. 
The sample size in the Phase 2 portion is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable patients in the FAS.  This assumes 


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24 patients will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 patients are randomized into the FAS.    
A total of 132 patients randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes of a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 
from most recent non-missing result and patients are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all patients who receive at 
least 1 dose of study treatment and at have least 1 evaluable post-baseline efficacy evaluation.  
FAS analyses will be conducted on the basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol violations from the 
efficacy analysis.  The PP Population will include all patients from the FAS except those with 
major violations to the protocol deemed to impact the analysis of the primary endpoint.  These 
violations will be identified based on blinded data prior to study unblinding.  PP analyses will be 
conducted on the basis of the randomized treatment. 
Safety analyses will be based on the safety analysis set (SS), defined as all patients who receive 
at least 1 dose of study treatment.  Safety analyses will be conducted on the basis of actual 
treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, defined as the FAS with 
sufficient concentration data for the calculation of PK parameters.   
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all randomized patients.   
8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will be assessed via 
Pearson’s chi-squared analysis.  The primary efficacy endpoint will be analyzed using the FAS 
and if needed repeated in the PP analysis set.  Missing values will be addressed by employing a 
last observation carried forward (LOCF) analysis.  Other imputation methods may be employed 
as a sensitivity analysis and will be described in the SAP.  Additional analyses exploring impact 
of baseline factors such as baseline disease severity, race, and other characteristics may be 
performed.  
Patients that received prohibited medications or unallowable CS usage as described in 
Section 4.6 will be considered “medication failures” and will be treated as non-responders for the 


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primary efficacy analysis.  The determination of medication failures will be reviewed using 
blinded data and finalized prior to unblinding.   
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 0.10.  
Secondary and exploratory endpoints for this POC portion will be evaluated based on the same 
statistical hypothesis. 
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared analysis.  Continuous 
efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of covariance 
(ANCOVA) and treatment will be compared using the F-test.  Repeated measures mixed models 
may be performed to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be compared using the log-
rank test.  The secondary efficacy endpoints will be analyzed on the FAS and if needed repeated 
in the PP analysis set.  Details including handling of missing data and “medication failures” will 
be available in the SAP. 
8.2.5 
Analysis of Safety 
8.2.5.1 
Safety Analysis 
Safety analyses will be performed on the SS.  AE data will be coded to system organ class and 
preferred term using MedDRA.  The number and percentage of patients experiencing any 
treatment-emergent AE, overall, and by system organ class and preferred term, will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and relationship.   
Concomitant medications will be coded using the WHO Drug dictionary.  Observed values and 
changes from baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters will be summarized at each individual visit.   
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 
Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected during the MAD Phase 1b 
portion of the study using non-compartmental analysis and include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 
• 
A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 


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• 
A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 
8.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Exploratory analyses examining the relationship between PD parameters and PK concentration 
and PK parameters will be performed.   
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the POC decision for dose 
selection. 
Since there is no IA during the POC part of the study, there is no impact on the type 1 error.   
9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
9.2 
DMC 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC (ie, 
dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 


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The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in Section 3.1.1.3. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.3 
Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees/IRB must meet the guidelines set out by the U.S. Food and Drug 
Administration (FDA) and conform to local laws and customs where appropriate.  Written 
IRB/IEC approval for the protocol and the signed ICF must be obtained and transmitted to 
Boston Pharmaceuticals or representative before the study can be initiated.  The IRB/IEC must 
be informed of and approve all protocol amendments.  The investigator will ensure that this 
study is conducted in full conformance with all applicable local and regional laws and 
regulations.  The complete text of the World Medical Association Declaration of Helsinki is 
given in APPENDIX 2. 
9.4 
Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the written 
informed consent will be obtained according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the principal investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient should be informed that he/she is free to withdraw from the study 
at any time.  He/she will receive all information that is required by federal regulations and ICH 
guidelines.  The principal investigator or designee will provide the sponsor with a copy of the 
IRB-approved ICF prior to the start of the study.   
The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 


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study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   
If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future patients enrolled in the clinical study will be required to 
sign this revised ICF. 
9.5 
Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 


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9.6 
Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 
must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
9.7 
Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
10 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 
study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 


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immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
12 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 
The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
13 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 


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maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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23 Karrich JJ, Jachimowski LC, Nagasawa M, Kamp A, Balzarolo M, Wolkers MC, et al.  
IL-21- stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs 
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24 Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TF, et al.  
Interleukin-21-induced granzyme B-expressing B-cells infiltrate tumors and regulate 
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25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
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26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 
28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
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30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
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Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
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32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
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Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
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36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
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40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
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http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 
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https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
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of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
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49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
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50 
 
 
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16 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 400 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
quality. 


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Page 97 of 116 
In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 


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subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 


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informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Prednisone Dose Equivalence 
Prednisone 
1 mg 
Cortisone 
5 mg 
Hydrocortisone 
4 mg 
Prednisolone 
1 mg 
Methylprednisolone 
0.8 mg 
Triamcinolone 
0.8 mg 
Budesonide 
0.25 mg 
Dexamethasone 
0.16 mg 
Bethamethasone 
0.16 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS 
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
24 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks for oral and 8 weeks for topical 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with 
cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE 
Adverse event 
Injection site reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Definition:  A disorder 
characterized by an 
intense adverse reaction 
(usually immunologic) 
developing at the site of 
an injection 
Tenderness with 
or without 
associated 
symptoms (eg, 
warmth, 
erythema, 
itching) 
Pain; 
Lipodystrophy; 
Edema; 
phlebitis 
Ulceration or 
necrosis;  
Severe tissue 
damage; 
Operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
 limiting self-
care ADL 
- 
- 
Rash 
maculopapular/Erythema
/Induration 
 
Definition:  A disorder 
characterized by the 
presence of macules 
(flat) and papules 
(elevated).  Also known 
as morbillform rash, it is 
one of the most common 
cutaneous adverse 
events, frequently 
affecting the upper trunk, 
spreading centripetally, 
and associated with 
pruritus. 
Macules/papules 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Erythema 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Macules/papules 
covering 10% - 
30% BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL; 
Erythema 30% 
BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL 
Macules/papul
es covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-care ADL 
 
Erythema 
covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-careADL 
- 
- 
ADL = active daily living 
 
 


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APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES 
The protocol summary of changes was moved to the end of the protocol for easier readability.   
Significant changes are described in the table below.  Changed text is displayed for the first 
major occurrence only.  Deleted text is presented in strikethrough format, and added text is 
presented in bold format.   
Section 
Description of Changes 
Rationale 
Global 
Replace: 
Protocol Date and Version:  27 July 2018; V4.0 
With: 
Protocol Date and Version:  23 January 2019; V5.0 
Administrative 
Global 
Change: 
Changed Version number from V4.0 (Amendment 3) to V5.0 
(Amendment 4) and Version date from 27 July 2018 to 
23 January 2019. 
Administrative 
Global 
Made administrative and editorial (formatting, typographical, and 
grammatical) updates. 
Administrative 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Secondary 
Objectives 
Section 2.1, Study 
Objectives and 
Endpoints, Phase 1b 
Multiple Ascending 
Dose, Secondary 
Objectives 
Replace: 
• 
To characterize the PK of BOS161721 and select the optimal dose 
of BOS161721 based on safety, PK, and PD effects in patients 
with mild to moderate SLE. 
With: 
• 
To characterize the PK of BOS161721 and select the optimal dose 
of BOS161721 based on safety, PK, and PD effects in patients 
with moderately to severely active SLE. 
Error in the 
previous 
protocol; text 
updated to 
“moderately to 
severely active.” 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Safety 
Objectives 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Replace: 
• 
To assess safety and tolerability of repeat doses of BOS161721 
(20, 60, and 120 mg) administered SC in adult patients with 
moderately to severely active SLE on limited background standard 
of care treatment 
With: 
• 
To assess safety and tolerability of repeat doses of BOS161721 at 
the chosen dose administered SC in adult patients with 
moderately to severely active SLE on limited background standard 
Error in the 
previous 
protocol; text 
updated to 
reflect the POC 
study and not 
the 3 doses used 
in the MAD 
Phase 1b study. 


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Protocol Date and Version:  23 January 2019; V5.0 
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Page 105 of 116 
Section 
Description of Changes 
Rationale 
Safety Objectives 
of care treatment 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Exploratory 
Objectives 
Section 2.2, Study 
Objectives and 
Endpoints, Phase 2 
Proof of Concept, 
Exploratory 
Objectives 
Replace: 
• 
 
With: 
• 
 
 
 
 
 
 
 
PROTOCOL 
SUMMARY, Study 
Design, Paragraph 5 
Replace: 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day).  One oral CS “burst” for increased SLE disease 
activity may occur during the study between Day 0 and Day 60.  
Tapering of steroids during the course of the study will be encouraged 
and should be evaluated at all visits.  Tapering may occur after 
randomization except within 60 days of the primary (Day 210) and 
secondary (Day 120) endpoint assessments.  Between Day 60 and Day 
120, and between Day 150 and Day 210, oral CS doses must be held 
constant. 
With: 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day).  One oral CS “burst” for increased SLE disease 
activity may occur during the study between Day 0 and Day 60.  
Tapering of steroids during the course of the study will be highly 
encouraged and should be evaluated at the protocol permitted 
visits (Day 0 through Day 60 and Day 120 through Day 150).  
Between Day 60 and Day 120, and between Day 150 and Day 210, 
oral CS doses must be held constant due to the endpoint 
evaluations occurring at Day 120 and Day 210. 
Protocol 
clarification; 
text was 
reworded to 
better explain 
the importance 
of tapering 
when allowed 
and to reiterate 
when it is not. 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Inclusion Criteria, 
criteria 9, c and 10 
Section 4.4, Inclusion 
Criteria, criteria 9, c 
Replace: 
9. Women of childbearing potential (WOCBP; see Section 4.7 for 
full information regarding WOCBP, definition of menopause, and 
contraception): 
c. 
Must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 
5 half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion 
Protocol 
clarification. 
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Section 
Description of Changes 
Rationale 
and 10 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of BOS161721 plus 90 
days (duration of sperm turnover) for a total of 44 weeks after 
treatment completion 
With: 
9. Women of childbearing potential (WOCBP; see Section 4.7 for 
full information regarding WOCBP, definition of menopause, and 
contraception): 
c. 
Must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 
52 weeks 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with study drug plus 52 weeks 
PROTOCOL 
SUMMARY, Main 
Criteria for Inclusion 
and Exclusion, 
Exclusion Criteria 
criterion 2 
Section 4.5, Exclusion 
Criteria, criterion 2 
Replace: 
2. Other systemic autoimmune disease (eg, erosive arthritis, 
rheumatoid arthritis [RA], multiple sclerosis [MS], systemic 
scleroderma, or vasculitis not related to SLE) 
With: 
2. Other systemic autoimmune disease (eg, erosive arthritis, 
rheumatoid arthritis [RA], multiple sclerosis [MS], systemic 
sclerosis, or vasculitis not related to SLE) 
Protocol 
clarification. 
PROTOCOL 
SUMMARY, 
Statistical 
Considerations, 
Paragraph 2 
Add: 
Two analyses are planned:  1) an interim analysis to select the POC 
dose based on the MAD data, and 2) a final analysis at study 
completion.  Additionally, DMC safety analyses will be performed for 
each MAD cohort and throughout the POC to monitor patient safety as 
described in the DMC charter.  An additional analysis may be 
performed for the MAD portion of the study when all MAD 
patients have completed the safety follow-up, or withdrawn from 
the study, and prior to the final analysis.  Data from the POC part 
of the study will be excluded from this additional analysis.  
Protocol 
clarification; 
text added to 
clarify that 
additional 
analysis would 
allow for 
flexibility if 
sponsor wanted 
to add an IA to 
review MAD 
only data. 
Section 1.2.2.3, 
Clinical Studies, 
Paragraph 2 
Replace: 
PK data from the SAD study demonstrates BOS161721 has an 
extended t½ (provisional single dose data indicates this to be 
approximately 42-46 days) which supports evaluation of monthly 
dosing. 
With: 
Final PK data from the SAD study demonstrates BOS161721 has a 
mean t½ ranging from 80 to 87 days for doses of ≥ 30 mg in healthy 
subjects. 
Updated to 
reflect that 
terminal 
elimination 
half-life (t½) is 
due to a full 
Healthy 
Volunteer 
Single 
Ascending Dose 
dataset. 


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Section 
Description of Changes 
Rationale 
Section 1.2.3, Study 
Dose Selection, 
Paragraph 3 
Replace: 
This POC dose decision will be based on evaluation of the PK, safety 
(inclusive of dose-limiting toxicity [DLT]), and tolerability data (and 
available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD 
portion (see Section 3.1.1.1). 
With: 
This POC dose decision will be based on evaluation of the PK, safety 
(inclusive of dose-limiting toxicity [DLT]), and tolerability data (and 
available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD 
portion (see Section 3.1.2.1 for the chosen POC dose and 
justification). 
Respective 
added section to 
be referenced. 
Section 1.2.5.1, 
Anaphylaxis and 
Serious Allergic 
Reactions, 
Paragraph 3 
Delete: 
Based on the limited Phase 1 SAD study (BOS161721-01), anaphylaxis 
and serious allergic reactions in subjects who received BOS161721 was 
not observed. 
Updated to 
reflect that all of 
the data is now 
acquired and 
‘limited’ no 
longer applies; 
there were no 
changes to the 
safety results. 
Section 1.2.5.3, 
Immune Complex 
Disease, Paragraph 2 
Delete: 
Based on the limited Phase 1 SAD study (BOS161721-01), immune 
complex disease in subjects who received BOS161721 was not 
observed. 
Updated to 
reflect that all of 
the data is now 
acquired and 
‘limited’ no 
longer applies; 
there were no 
changes to the 
safety results. 
Section 1.2.5.4, 
Infections, 
Paragraph 7 
Delete: 
Based on the limited Phase 1 SAD study (BOS161721-01), infections 
in subjects who received BOS161721 was not observed. 
Updated to 
reflect that all of 
the data is now 
acquired and 
‘limited’ no 
longer applies; 
there were no 
changes to the 
safety results. 


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Section 
Description of Changes 
Rationale 
Section 1.2.5.5, 
Malignancy 
Delete: 
Based on the limited Phase 1 SAD study (BOS161721-01), malignancy 
in subjects who received BOS161721 was not observed. 
Updated to 
reflect that all of 
the data is now 
acquired and 
‘limited’ no 
longer applies; 
there were no 
changes to the 
safety results. 
Section 1.2.5.6, 
Hepatic Function 
Abnormality, 
Paragraph 2 
Delete: 
Based on the limited Phase 1 SAD study (BOS161721-01), hepatic 
function abnormality in subjects who received BOS161721 was not 
observed. 
Updated to 
reflect that all of 
the data is now 
acquired and 
‘limited’ no 
longer applies; 
there were no 
changes to the 
safety results. 
Section 1.2.5.7, 
Failure of 
Vaccination, 
Paragraph 2 
Replace: 
The effect of BOS161721 was evaluated in in vivo single dose studies 
in Cynomolgus monkey in which the animals received vaccination to 
T-cell dependent KLH antigen to stimulate a TDAR.  These in vivo 
studies demonstrated that BOS161721 significantly inhibited B-cell 
proliferation and IgG antibody responses to the KLH protein antigen; 
however, it is worth noting that BOS161721 administration did not 
produce any remarkable changes in anti-KLH antibody data for IgM, 
IgG1, IgG3, and IgG4 or anti-tetanus toxoid (TT) antibody data for 
IgM, IgG, IgG1, or IgE during the dosing phase in the same study. 
With: 
The effect of BOS161721 was evaluated in in vivo single dose studies 
in Cynomolgus monkey in which the animals received vaccination to 
T-cell dependent KLH antigen to stimulate a TDAR.  These in vivo 
studies demonstrated that BOS161721 significantly inhibited B-cell 
proliferation and IgG antibody responses to the KLH protein 
antigen in a dose-dependent fashion; however, BOS161721 
administration did not affect anti-tetanus toxoid antibody data for 
IgM, IgG, IgG1, or immunoglobulin E (IgE) during the dosing 
phase in the same study. 
Protocol 
clarification; 
text added for 
specificity. 
Section 3.1.2.1, 
BOS161721 POC 
Dose Selection and 
Justification 
Replace: 
3.1.2.1 BOS161721 Dose 
The optimal dose is chosen based on MAD Phase 1b safety, 
tolerability, immunogenicity, and PK and PD data.  The dose will be 
Added text for 
POC dose and 
justification. 


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Section 
Description of Changes 
Rationale 
communicated by a letter to site investigators participating in the POC 
Phase 2 portion, and to the IRB/IEC. 
With: 
3.1.2.1 BOS161721 POC Dose Selection and Justification 
The dose for the POC portion of the study is 120 mg administered 
SC monthly (a total of 7 doses).  The rationale for the 
BOS161721-02 Phase 2 POC dose selection was based on 
cumulative safety, tolerability, immunogenicity, PK, and PD data 
available from an interim analysis (IA) performed during the MAD 
Phase 1b portion of the trial. 
The data cut-off for this IA occurred on 
 and 
included all 6 patients and 7 doses from Cohort 1 (20 mg), 
12 patients and 6 doses from Cohort 2 (60 mg), and 12 patients and 
4 doses from Cohort 3 (120 mg). 
The safety analysis focused on incidence and severity of all AEs, 
SAEs, and pre-determined adverse events of special interest (see 
Section 6.2.2.6).  The DMC and designated unblinded Boston 
Pharmaceuticals team met on 
 and did not 
identify any untoward safety signals at any BOS161721 dose levels. 
Because there were no safety, tolerability, or immunogenicity 
trends observed at the time of the IA, the Phase 2 POC dose 
selection was made based on available PK and PD data.  pSTAT3 
levels were assessed as the primary PD biomarker of IL-21R 
signaling levels.  This is because IL-21R signaling, upon IL-21 
binding, initially involves phosphorylation of JAK1/JAK3 which 
dissociate from the receptor complex, and phosphorylate STAT3 
which translocates to the nucleus and drives IL-21-regulated gene 
expression. 
 
 
 
The 120 mg dose will be communicated to site investigators 
participating in the POC Phase 2 portion, and to Institutional 
Review Boards (IRBs) and the Independent Ethics Committee 
(IEC). 
Section 3.1.2.2, POC 
Study Design, 
Paragraph 2 
Delete: 
As in the MAD part of the study, each patient in the POC portion may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 
90, 120, 150, and 180.  Assessments will be completed according to the 
Schedule of Assessments (Section 3.4).  Dose selection will be based 
on the DMC and sponsor’s assessment of safety, tolerability, 
immunogenicity, and PK and PD data from the MAD portion of 30 
Remove text to 
reduce 
redundancy with 
Section 3.1.2.1 
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Section 
Description of Changes 
Rationale 
patients treated with BOS161721/placebo. 
Section 3.2, 
Randomization and 
blinding, Paragraph 4 
Replace: 
An independent biostatistician not otherwise involved on the study will 
be unblinded and prepare materials for the interim analysis (IA) and the 
DMC safety reviews. 
With: 
An independent biostatistician not otherwise involved on the study will 
be unblinded and prepare materials for the IA, ad hoc analyses as 
needed, and the DMC safety reviews. 
Added in order 
to allow for 
ongoing analysis 
of the data in the 
IAs. 
Section 3.3, Study 
Schematic 
Replace: 
 
With: 
 
Protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 1, Footnote 
Add: 
h 
SLEDAI-2K should be done before randomization and 
Footnote added 
for protocol 
clarification.  
All subsequent 
footnotes after 
‘h’ were re-
lettered 
accordingly. 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 111 of 116 
Section 
Description of Changes 
Rationale 
dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
Section 3.4, Schedule 
of Assessments, 
Table 2, Footnote 
Add: 
 
Footnote added 
for protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 2, Footnote 
Replace: 
o 
PK samples will only be collected at the investigational sites 
that will be participating in the PK portion of the study. 
With: 
b 
PK samples will only be collected at the investigational sites 
that participate in the PK portion of the study.  On PK only days (ie, 
Day 187 and Day 195 when no laboratory assessments are 
scheduled) samples will be collected at the investigational sites of 
the selected countries that participate in the PK portion of the 
study.  Patients not participating in PK are not required to return 
for investigation site visits on Days 187 and 195. 
Footnote added 
for protocol 
clarification.  
All subsequent 
footnotes after 
‘b’ were re-
lettered 
accordingly. 
Section 3.4, Schedule 
of Assessments, 
Table 2, Footnote 
Add: 
i 
SLEDAI-2K should be done before randomization and 
dosing on Day 0 as SLEDAI-2K < 6 is exclusionary. 
Footnote added 
for protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 2, Predose and 
Postdose PK Window 
rows 
Delete: 
Removed 
Predose and 
Postdose PK 
Window rows to 
reduce 
redundancy as 
these are the 
same as visit 
window rows. 
Section 4.4, Inclusion 
Criteria, criterion 7, b, 
item ii 
Delete: 
ii. 
“BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, 
(BILAG item number 42), defined as tendonitis/tenosynovitis, or 
active synovitis in ≥ 1 joint, (observed or throughout history), 
with some loss of functional range of movements which lead to 
some loss of functional range of motion as manifested by effects 
on instrumental ADLs such as: 
Repetitive text 
removed. 
Section 4.6.1, 
Replace: 
Revised to 
reduce 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 112 of 116 
Section 
Description of Changes 
Rationale 
Corticosteroid 
4.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), 
may be used in accordance with the investigator’s clinical judgment 
and best standard of care.  See APPENDIX 3 for examples of 
equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, the daily dose must be tapered down 
to a maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day). 
After Day 0 (after initiation of study therapy), no up-titration above 
10 mg/day is allowed except for up to 1 CS burst for increased disease 
activity.  
Tapering of steroids during the course of the study will be encouraged 
and should be evaluated at all visits.  
• 
Once a patient has received the first dose of study drug, prednisone 
(or prednisone equivalent) may be tapered down at the discretion 
of the investigator. 
o 
Tapering is allowed after randomization except within 60 days 
of the primary (Day 210) and secondary (Day 120) endpoint 
assessments.  Between Day 60 and Day 120, and between Day 
150 and Day 210, oral CS doses must be held constant. 
A maximum of 1 oral CS “burst” for increased SLE disease activity 
will be allowed during the study between Day 0 and Day 60, according 
to the following:   
• 
An oral CS “burst” between Day 0 and Day 60; (an increase of 
≤ 40 mg/day of prednisone or equivalent), which must be tapered 
down to a maximum of 10 mg/day within 2 weeks of initiation of 
the “burst” 
o 
Alternatively, a single intramuscular (IM) dose of 
methylprednisolone (40 mg or equivalent) is permitted 
o 
The course of the oral CS “burst” is not permitted to extend 
beyond Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any 
other route, is allowed.  Other concomitant medications for SLE need 
to be taken at stable doses as per the inclusion criteria (Section 4.4). 
With: 
4.6.1 
Corticosteroid 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), 
may be used in accordance with the investigator’s clinical judgment 
redundancy and 
improve clarity.  
Text revised to 
clarify the 
meaning of “any 
other route” and 
added to address 
the use of CS 
for non-SLE 
conditions. Text 
regarding other 
medications not 
applicable to CS 
were removed. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 113 of 116 
Section 
Description of Changes 
Rationale 
and best standard of care.  See APPENDIX 3 for examples of 
equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, the daily dose must be tapered down 
to a maximum of 10 mg/day for at least 5 days prior to Day 0 
(randomization day). 
Tapering of steroids during the course of the study will be highly 
encouraged and should be evaluated at the protocol permitted 
visits (Day 0 through Day 60 and Day 120 through Day 150).  
Between Day 60 and Day 120, and between Day 150 and Day 210, 
oral CS doses must be held constant due to the endpoint 
evaluations occurring at Day 120 and Day 210. 
• 
Once a patient has received the first dose of study drug (after 
Day 0), prednisone (or prednisone equivalent) dose is highly 
encouraged to continue tapering down as appropriate.  The 
investigator should evaluate the prednisone dose at each visit 
and make the decision, within the protocol allowed windows. 
o 
Exception:  Between Day 60 and Day 120, and between Day 
150 and Day 210 (ie, within 60 days of primary and 
secondary endpoint assessments), oral CS doses must be 
held constant. 
After Day 0 (first dose of study drug), a maximum of 1 oral CS 
“burst” for increased SLE disease activity will be allowed between Day 
0 and Day 60, according to the following:   
• 
The oral CS dose is allowed to increase to ≤ 40 mg/day of 
prednisone or equivalent, which must be tapered down to 
≤ 10 mg/day within 2 weeks of initiation of the “burst” 
o 
Alternatively, a single intramuscular (IM) dose of 
methylprednisolone (40 mg or equivalent) is permitted 
o 
No increase of oral CS above baseline is permitted beyond 
Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any 
other route, but systemic administration, is allowed. 
Treatment with intra-articular or intravenous CS is prohibited 
during the course of the study. 
Section 4.7.2, 
Contraception, 
Paragraphs 1, 2, and 5 
Replace: 
WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 5 
half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion. 
Protocol 
clarification. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 114 of 116 
Section 
Description of Changes 
Rationale 
Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with study drug plus 5 half-lives of study drug BOS161721 plus 90 
days (duration of sperm turnover) for a total of 44 weeks after 
treatment completion. 
Azoospermic men and WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements.  
However, they must still undergo pregnancy testing. 
With: 
WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 
52 weeks, due to the mean terminal ½ life of the study drug. 
Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with study drug plus 52 weeks, due to the mean terminal ½ life of the 
study drug. 
Azoospermic men and WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements.  
However, WOCBP must still undergo pregnancy testing. 
Section 5.1, Screening 
Add: 
• 
Laboratory evaluations (non-fasting): 
o 
FSH (postmenopausal women under age 55 years) 
Protocol 
clarification. 
Section 6.2.2.5, 
Seriousness of 
Adverse Events 
Delete: 
• 
Is another important medical event (see below) 
Revised for 
clarity. 
Section 6.2.2.6, 
Adverse Events of 
Special Interest 
Replace: 
4. Malignancy 
5. Opportunistic infections such as disseminated histoplasmosis, 
cryptococcosis, and disseminated tuberculosis 
With: 
4. Malignancy (not including basal cell carcinoma or squamous 
cell carcinoma of skin) 
5. Opportunistic infections such as disseminated histoplasmosis, 
cryptococcosis, disseminated herpes simplex, disseminated 
tuberculosis, Aspergillus sp., Candida albicans, Coccidioides 
immitis, Cryptococcus neoformans, Cytomegalovirus, 
Histoplasma capsulatum, Isospora belli, and Polyomavirus JC 
polyomavirus 
Text added 1) to 
clarify that basal 
cell carcinoma 
is not a 
neoplasia 
associated with 
immune 
suppression, but 
rather secondary 
to sun exposure 
and 2) to clarify 
specific 
opportunistic 
infections of 
special interest 
in this study. 
Section 6.2.2.6.4, 
Malignancy, 
Add: 
Revised to align 
with text for 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 115 of 116 
Section 
Description of Changes 
Rationale 
Paragraph 2 
After the first dose of study drug, when there is a decision to biopsy a 
potentially malignant tumor, lymph node, or other tissue (with the 
exception of suspected basal cell/squamous cell), the investigator 
and/or consultant(s) should contact the sponsor clinicians or designee 
to discuss the issue and any decisions as soon as possible.  Basal cell 
carcinoma or squamous cell carcinoma of skin is not considered an 
AE of special interest. 
AEs of special 
interest. 
Section 6.2.2.6.5, 
Special Infections 
Replace: 
Any diagnosis or suggested diagnosis of opportunistic infections such 
as disseminated histoplasmosis, cryptococcosis, shingles, disseminated 
herpes simplex, or disseminated tuberculosis will be recorded as AEs 
of special interest. 
With: 
Any diagnosis or suggested diagnosis of opportunistic infections such 
as disseminated histoplasmosis, cryptococcosis, disseminated herpes 
simplex, disseminated tuberculosis, Aspergillus sp., Candida albicans, 
Coccidioides immitis, Cryptococcus neoformans, Cytomegalovirus, 
Histoplasma capsulatum, Isospora belli, or Polyomavirus JC 
polyomavirus will be recorded as AEs of special interest. 
Revised to align 
with text for 
AEs of special 
interest. 
Section 8, Statistics 
Add: 
• 
An additional analysis may be performed for the MAD portion 
of the study when all MAD patients have completed the safety 
follow-up or withdrawn from the study, and prior to final 
analysis.  Data from the POC part of the study will be excluded 
from this additional analysis. 
Analysis added 
to allow the 
sponsor to 
perform another 
interim 
evaluation of the 
MAD only data 
after all subjects 
complete or 
discontinue if 
wanted. 
Section 8.2.3, Primary 
Efficacy Endpoint(s) 
Delete: 
Patients that received prohibited medications or unallowable CS usage 
as described in Section 4.6 will be considered “medication failures” 
and will be treated as non-responders for the primary efficacy analysis.  
Patients that received an allowable CS burst but having missing data at 
Day 210 will considered a medication failure and will be treated as 
non-responders for the primary efficacy analysis.  The determination of 
medication failures will be reviewed using blinded data and finalized 
prior to unblinding. 
Correction of 
error in previous 
version; text is 
not applicable to 
the primary 
efficacy 
analysis. 
Appendix 1, Names of 
Study Personnel, 
Central Laboratory 
Add: 
 
 
 
Protocol 
clarification. 
PPD
PPD


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  23 January 2019; V5.0 
Confidential 
 
Page 116 of 116 
Section 
Description of Changes 
Rationale 
Industriepark Zwijnaarde 3b B-9052 Gent, Belgium 
Appendix 3 
Replace: 
Medication  
Dose Equivalence 
Prednisone 
20 mg 
Cortisone 
100 mg 
Hydrocortisone 
80 mg 
Prednisolone 
20 mg 
Methylprednisolone 
16 mg 
Triamcinolone 
16 mg 
Budesonide 
4 mg 
Dexamethasone 
3 mg 
Bethamethasone 
2.4 mg 
With: 
Medication 
Prednisone Dose Equivalence 
Prednisone 
1 mg 
Cortisone 
5 mg 
Hydrocortisone 
4 mg 
Prednisolone 
1 mg 
Methylprednisolone 
0.8 mg 
Triamcinolone 
0.8 mg 
Budesonide 
0.25 mg 
Dexamethasone 
0.16 mg 
Bethamethasone 
0.16 mg 
 
Revised to 
clarify 1:1 
equivalence to 
prednisone. 
Appendix 5, 
Paragraph 1 
Replace: 
 
 
With: 
 
Protocol 
clarification. 
Appendix 5, bullet b, 
item ii 
Delete: 
ii. 
 
 
 
 
 
Protocol 
clarification. 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 1 of 118 
  
 
A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 400 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721  
PROTOCOL NUMBER: 
BOS161721-02  
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
06 October 2017 
VERSION NUMBER: 
V4.0 (Amendment 3) 
VERSION DATE: 
27 July 2018 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 2 of 118 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of 
BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care 
 
Study Number:  BOS161721-02 
Version 
Date 
Original Protocol 
06 October 2017 
Protocol Version 2.0 (Amendment 1) 
14 November 2017 
Protocol Version 3.0 (Amendment 2) 
21 March 2018 
Protocol Version 4.0 (Amendment 3) 
27 July 2018 
This study protocol was subject to critical review and has been approved by sponsor.  The 
information contained in this protocol is consistent with: 
• 
The current risk-benefit evaluation of the investigational product. 
• 
The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to 
applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature and Date 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
 
, MD, FACR 
Vice President, Clinical Development 
Boston Pharmaceuticals 
 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
 
, MD, PhD 
Vice President, Clinical Development and Safety Officer 
Boston Pharmaceuticals 
 
 
PPD
PPD
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 3 of 118 
BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol (Version 4.0, dated 27 July 2018), including all appendices, and I agree 
that it contains all of the necessary information for me and my staff to conduct this study as 
described.  I will conduct this study as outlined herein, in accordance with the regulations stated 
in the Federal Code of Regulations for Good Clinical Practices and International Council for 
Harmonisation (ICH) guidelines, and will make a reasonable effort to complete the study within 
the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 4 of 118 
PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple 
Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus 
(SLE) Patients on a Background of Limited Standard of Care 
Indication 
Adults with moderately to severely active SLE 
Background 
and Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the disease, 
and that T-cell-derived cytokines such as interleukin-21 (IL-21) are involved 
in the SLE-associated inflammatory pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple mutation 
monoclonal antibody (mAb) intended to have an extended terminal 
elimination half-life (t1/2) that selectively binds to and neutralizes IL-21, 
which acts on multiple cell types that drive inflammation and autoimmunity.  
In vivo, BOS161721 inhibits T-cell dependent antigen responses of B-cells 
and is being developed as a potential treatment for adults with moderately to 
severely active SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics (PD), 
toxicokinetics (TK), pharmacokinetics (PK), and immunogenicity of 
BOS161721 administered intravenously (IV) and subcutaneously (SC).  The 
no observed adverse effect level (NOAEL) in Cynomolgus monkeys was 
determined to be 100 mg/kg (SC and IV), the highest dose tested.  There 
were no injection site reactions in animals dosed subcutaneously. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  This 
double-blind, placebo-controlled study evaluated 8 ascending dose levels 
(1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg) for safety, tolerability, PK, PD and immunogenicity.  Overall, 
there were no clinically significant safety or tolerability findings from this 
study.  
Results from the Phase 1 SAD study informed the dose regimens used for the 
multiple ascending doses (MAD) Phase 1b portion of this trial.  The MAD 
portion will involve 3 cohorts.  The Phase 2 portion will be a proof of 
concept (POC) part, where dose selection will be based on the data 
monitoring committee (DMC) and sponsor’s assessment of safety, 
tolerability, immunogenicity, and PK and PD data from the MAD portion of 
30 patients treated with BOS161721/placebo.  The purpose of the study is to 
establish a safe and effective dosage for adult patients with moderately to 
severely active SLE. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 5 of 118 
Objectives and 
Endpoints: 
MAD Phase 1b 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients 
with moderately to severely active 
SLE on limited background 
standard of care treatment, in order 
to estimate the optimal dose. 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale 
(C-SSRS) 
• 
12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
Anti-drug antibodies (ADAs) 
• 
Study drug exposure/compliance 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the optimal 
dose of BOS161721 based on 
safety, PK, and PD effects in 
patients with mild to moderate 
SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time 
point 
• 
Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), t½, systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• 
Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• 
Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit  
 
 
Exploratory 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 6 of 118 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
• 
 
 
 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 7 of 118 
POC Phase 2 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on the SLE Responder 
Index 4 (SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 
response at Day 210 (see Section 6.3.4.1) 
Secondary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on clinical indicators of 
SLE activity, in adult patients with 
moderately to severely active SLE 
on limited background standard of 
care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B 
flares relative to baseline through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B 
flare compared to baseline through Day 210 
Safety 
• 
To assess safety and tolerability of 
repeat doses of BOS161721 (20, 
60, and 120 mg) administered SC 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each 
visit and change from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 8 of 118 
baseline 
• 
Physical examinations changes from 
baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, 
placebo-controlled trial to study the clinical efficacy, safety, and PK of 
multiple SC doses of BOS161721 in adult patients with moderately to 
severely active SLE.  After successfully completing a screening phase, 
eligible patients will be randomized to a specified dose of BOS161721 or 
placebo.  The dosing schedule will be monthly.  The trial will consist of 
2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 
120, 150, and 180, followed by safety follow-up visits at Days 210, 240, and 
270.   
The MAD Phase 1b portion of the study design will consist of 3 cohorts, with 
Cohort 1 containing 6 patients, where 5 of these patients will receive 
BOS161721 (active), and 1 will receive placebo.  Cohorts 2 and 3 will each 
contain 12 patients, including 9 active and 3 placebo patients.  Dose selection 
for each cohort is based on 90-day safety, tolerability, PK, and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  
Each of the 3 doses (20, 60, and 120 mg) selected for the MAD portion are 
projected not to exceed the mean exposure of that achieved in the SAD study 
following the single 240 mg SC dose.  Each patient may receive a total of 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 9 of 118 
7 SC monthly doses on Days 0, 30, 60, 90, 120, 150, and 180.   
The MAD portion design is staggered, where after the 6 patients in Cohort 1 
have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 2 begins dosing (after the DMC evaluates the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in 
Cohort 2 have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing after the DMC evaluation of the 
safety and tolerability data from Cohort 2 and Cohort 1.  Thirty days after the 
last patient in Cohort 3 receives the third dose, the DMC and Boston 
Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This dose will not exceed 
doses tested during the MAD portion.   
For the POC portion, approximately 156 additional patients will be 
randomized to active or placebo groups in a 2:1 ratio.  As in the MAD 
portion, each patient in the POC portion may receive a total of 7 SC monthly 
doses on Days 0, 30, 60, 90, 120, 150, and 180.   
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization 
day).  One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 60.  Tapering of steroids during the 
course of the study will be encouraged and should be evaluated at all visits.  
Tapering may occur after randomization except within 60 days of the primary 
(Day 210) and secondary (Day 120) endpoint assessments.  Between Day 60 
and Day 120, and between Day 150 and Day 210, oral CS doses must be held 
constant. 
DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter. 


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Main Criteria 
for Inclusion 
and Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be 
evidence of a personally signed and dated informed consent document 
indicating that the patient has been informed of all pertinent aspects of the 
study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus 
International Collaborating Clinics (SLICC) classification criteria for SLE 
(with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis 
as the sole clinical criterion in the presence of antinuclear antibodies 
[ANA] or anti- double-stranded deoxyribonucleic acid [dsDNA] 
antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central 
laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as 
determined by the central laboratory 
c. C3 or C4 levels below normal as determined by the central lab 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis  
i. 
Excluding parameters which require central laboratory results:  
(hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 
decreased complement, thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome will also 
be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis 
i. 
Excluding parameters which require central laboratory results:  
hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 


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decreased complement, thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also 
be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, 
which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active 
polyarthritis as defined in the protocol Section 4.4 
If only one “B” and no “A” score is present in the mucocutaneous body 
system or in the musculoskeletal body system due to arthritis, then at least 
1 “B” must be present in the other body systems for a total of 2 “B” 
BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at 
least 56 days (8 weeks prior to signing consent) of the following 
permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic 
acid, chloroquine, hydroxychloroquine, or methotrexate 
(MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at 
screening for a patient to be eligible and must be stable at a maximum 
of 10 mg/day for at least 5 days prior to Day 0 (randomization) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full 
information regarding WOCBP, definition of menopause, and 
contraception): 
a. Must have a negative serum pregnancy test at screening.  Urine 
pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug plus 5 half-lives of study 
drug BOS161721 plus 30 days (duration of ovulatory cycle) for a total 
of 36 weeks after treatment completion 
10. Men who are sexually active with WOCBP must agree to follow 


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instructions for method(s) of contraception for the duration of treatment 
with study drug plus 5 half-lives of BOS161721 plus 90 days (duration of 
sperm turnover) for a total of 44 weeks after treatment completion 
11. Patients must demonstrate willingness and ability to comply with the 
scheduled study visits, treatment plans, laboratory tests, and other 
procedures 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this 
study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid 
arthritis [RA], multiple sclerosis [MS], systemic scleroderma, or vasculitis 
not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are 
allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), 
or any elective surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube 
(QFT-G) or other diagnostic test in the absence of clinical 
manifestations.  Latent TB is not excluded if the patient has 
documented completion of adequate course of prophylactic treatment 
with regimen recommended by local health authority guideline, or the 
patient has started treatment with isoniazid, or other regimen 
recommended by local health authority guidelines for at least 1 month 
before Day 0 and continues to receive the prophylactic treatment 
during study until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, including but 
not limited to any condition defined by BILAG A criteria, with the 
exception of mononeuritis multiplex and polyneuropathy, which are 
allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires 
or may require induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to 
require additional systemic glucocorticosteroid therapy during the study, 
(eg, asthma), is exclusionary 


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a. However, treatment for asthma with inhalational CS therapy is 
allowed 
8. Use or planned use of concomitant medication outside of standard of 
baseline treatment for SLE from Day -1 or for any time during the study 
9. Active and clinically significant infection (bacterial, fungal, viral, or 
other) within 60 days prior to first dose of study drug.  Clinically 
significant is defined as requiring systemic parenteral antibiotics or 
hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe 
disseminated herpes zoster or disseminated herpes simplex within the last 
3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) 
unless patient received curative treatment for HCV and has a documented 
negative viral load, known human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS)-related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 350/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if 
related to SLE, at screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of 
proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 
339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) 
< 40 ml/minute based on Cockcroft-Gault calculation 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the investigator’s 
judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related to lupus 
myositis  
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s 
syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, 
might place a patient at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of components of 


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mAbs 
25. History substance and/or alcohol abuse, or dependence within the past 1 
year, at the investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or 
squamous cell cancer, or cervical cancer in situ resolved by excision 
27. Any other severe acute or chronic medical or psychiatric condition, 
including recent (within the past year) medical conditions (eg, 
cardiovascular conditions, respiratory illnesses) that may increase the risk 
associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate 
for entry into this study 
28. Investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by 
the investigator, or patients who are employees of the sponsor or directly 
involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional 
(drug or device) clinical study within 30 days or 5 half-lives of baseline, 
whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior 
based on patient responding “yes” to question 3, 4, or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a 
psychiatric or physical (eg, infectious disease) illness 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be found in 
Section 8. 
Two analyses are planned:  1) an interim analysis to select the POC dose 
based on the MAD data, and 2) a final analysis at study completion.  
Additionally, DMC safety analyses will be performed for each MAD cohort 
and throughout the POC to monitor patient safety as described in the DMC 
charter.   
Unless stated otherwise, statistical testing will only be performed on the POC 
data and will be done using 2-sided overall alpha of 0.10.  Data will be 
summarized descriptively by treatment and overall for each study phase.  For 
the MAD portion, BOS161721 will be summarized overall and by each dose 
level and placebo patients from each cohort will be combined.   
The descriptive summaries for the categorical data will include number and 
percentage.  The descriptive summaries for the continuous data will include 
number, mean, median, standard deviations (SD), 25th and 75th percentiles, 
minimum, median, and maximum.  Counts, medians, 25th and 75th percentiles, 


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and standard error will be presented for time-to-event data. 
All safety analyses will be performed using the safety analysis set (SS), 
defined as all patients who receive at least 1 dose of study treatment.  All 
efficacy analyses will be performed using the full analysis set (FAS), defined 
as all patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  Select efficacy analyses may 
also be performed on the per protocol (PP) set. 
Binary efficacy endpoints, including the primary efficacy endpoint, will be 
assessed via Pearson’s chi-squared analysis.   
Continuous efficacy endpoints will be assessed via analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA) when applicable, adjusting 
for the baseline value.  Repeated measures mixed models may be performed 
to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be 
compared using the log-rank test.   
Adverse event data will be coded to system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class and preferred term will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and 
relationship.   
Concomitant medications will be summarized, based on coded terms, using 
frequency and percentage of patients.  Observed values and changes from 
baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters, will be summarized at each individual visit. 
 


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TABLE OF CONTENTS 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................3 
PROTOCOL SUMMARY ...............................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF IN-TEXT TABLES ........................................................................................................19 
LIST OF IN-TEXT FIGURES.......................................................................................................19 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION AND RATIONALE .................................................................................24 
1.1 
Indication ...........................................................................................................................24 
1.2 
Background and Rationale .................................................................................................24 
1.2.1 
Overview of the Disease State .....................................................................................24 
1.2.2 
BOS161721 Development ...........................................................................................24 
1.2.2.1 
Interleukin-21 .........................................................................................................25 
1.2.2.2 
Preclinical Studies ..................................................................................................26 
1.2.2.3 
Clinical Studies ......................................................................................................27 
1.2.3 
Study Dose Selection ...................................................................................................28 
1.2.4 
Risk-Benefit Assessment .............................................................................................29 
1.2.5 
Potential Risks .............................................................................................................30 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................31 
1.2.5.2 
Injection Site Reactions .........................................................................................31 
1.2.5.3 
Immune Complex Disease .....................................................................................31 
1.2.5.4 
Infections................................................................................................................32 
1.2.5.5 
Malignancy ............................................................................................................32 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................33 
1.2.5.7 
Failure of Vaccination............................................................................................33 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................34 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................34 
2 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................34 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................34 
2.2 
Phase 2 Proof of Concept ...................................................................................................36 
3 
STUDY PLAN ........................................................................................................................37 
3.1 
Study Design ......................................................................................................................37 
3.1.1 
Multiple Ascending Dose Phase 1b .............................................................................37 
3.1.1.1 
Dose Escalation for the MAD Portion ...................................................................38 
3.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................38 
3.1.1.3 
DMC Recommendations ........................................................................................39 
3.1.2 
POC Phase 2 ................................................................................................................39 
3.1.2.1 
BOS161721 Dose...................................................................................................39 


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3.1.2.2 
POC Study Design .................................................................................................39 
3.2 
Randomization and Blinding .............................................................................................40 
3.3 
Study Schematic.................................................................................................................41 
3.4 
Schedule of Assessments ...................................................................................................42 
3.5 
End of Study ......................................................................................................................51 
4 
POPULATION .......................................................................................................................51 
4.1 
Participant Recruitment .....................................................................................................51 
4.2 
Number of Patients ............................................................................................................51 
4.3 
Patient Screening ...............................................................................................................51 
4.4 
Inclusion Criteria ...............................................................................................................51 
4.5 
Exclusion Criteria ..............................................................................................................54 
4.6 
Concomitant Medications ..................................................................................................56 
4.6.1 
Oral Corticosteroid Dose .............................................................................................56 
4.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................57 
4.7 
Women of Childbearing Potential .....................................................................................57 
4.7.1 
Determination of Menopause .......................................................................................58 
4.7.2 
Contraception ...............................................................................................................58 
4.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................59 
4.8.1 
Patient Withdrawal and Replacement ..........................................................................59 
5 
STUDY PROCEDURES ........................................................................................................59 
5.1 
Screening............................................................................................................................59 
5.1.1 
Retesting During Screening Period ..............................................................................60 
5.2 
Enrollment/Randomization and Day 0 Treatment .............................................................60 
5.3 
Treatment Period/Follow-Up Visits ...................................................................................62 
5.4 
Safety Follow-Up Visits ....................................................................................................62 
5.5 
Premature Discontinuation .................................................................................................63 
6 
ASSESSMENTS .....................................................................................................................64 
6.1 
Medical History, Demographic and Other Baseline Information ......................................64 
6.2 
Safety Assessments ............................................................................................................64 
6.2.1 
Laboratory Assessments ..............................................................................................64 
6.2.1.1 
Pregnancy testing ...................................................................................................66 
6.2.1.2 
Tuberculosis Screening ..........................................................................................66 
6.2.2 
Adverse Events ............................................................................................................67 
6.2.2.1 
Definitions..............................................................................................................67 
6.2.2.2 
Recording of Adverse Events ................................................................................67 
6.2.2.3 
Severity of Adverse Events ....................................................................................67 
6.2.2.4 
Causality of Adverse Events ..................................................................................68 
6.2.2.5 
Seriousness of Adverse Events ..............................................................................68 
6.2.2.6 
Adverse Events of Special Interest ........................................................................69 
6.2.2.7 
Reporting of Adverse Events .................................................................................72 
6.2.2.8 
Follow Up of Adverse Events ................................................................................74 


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6.2.3 
Vital Signs ....................................................................................................................74 
6.2.4 
12-Lead Electrocardiograms ........................................................................................74 
6.2.5 
Physical Examinations .................................................................................................74 
6.2.6 
C-SSRS ........................................................................................................................75 
6.2.7 
Injection Site Reactions ...............................................................................................75 
6.2.8 
Immunogenicity ...........................................................................................................75 
6.3 
Efficacy Assessments .........................................................................................................76 
6.3.1 
SLEDAI-2K .................................................................................................................76 
6.3.2 
BILAG 2004 ................................................................................................................76 
6.3.3 
PGA of Disease Activity ..............................................................................................76 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................77 
6.3.4.1 
SRI-4 Response ......................................................................................................77 
6.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................77 
6.3.4.3 
BICLA Response ...................................................................................................77 
6.3.5 
CLASI Response ..........................................................................................................77 
6.3.6 
ACR-28 Joint Count ....................................................................................................77 
6.4 
Other Variables ..................................................................................................................78 
6.4.1 
SLICC/ACR Damage Index ........................................................................................78 
6.4.2 
PROs ............................................................................................................................78 
6.5 
Pharmacokinetic Assessments ...........................................................................................78 
6.6 
Pharmacodynamic Assessments ........................................................................................78 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................79 
6.8 
Protocol Deviations ............................................................................................................79 
7 
STUDY DRUG MANAGEMENT .........................................................................................79 
7.1 
Description .........................................................................................................................79 
7.1.1 
Formulation ..................................................................................................................79 
7.1.2 
Storage .........................................................................................................................79 
7.2 
Packaging and Shipment ....................................................................................................79 
7.3 
Dose and Administration ...................................................................................................79 
7.4 
Accountability ....................................................................................................................80 
7.5 
Prohibited Concomitant Therapy .......................................................................................80 
7.6 
Compliance ........................................................................................................................80 
8 
STATISTICS ..........................................................................................................................80 
8.1 
Sample Size ........................................................................................................................81 
8.2 
Statistical Methods .............................................................................................................82 
8.2.1 
Analysis Populations ....................................................................................................82 
8.2.2 
Demographics and Baseline Characteristics ................................................................82 
8.2.3 
Primary Efficacy Endpoint(s) ......................................................................................82 
8.2.4 
Secondary Efficacy Endpoint(s) ..................................................................................83 
8.2.5 
Analysis of Safety ........................................................................................................83 
8.2.5.1 
Safety Analysis ......................................................................................................83 


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8.2.6 
Pharmacokinetic and Pharmacodynamic Data .............................................................83 
8.2.6.1 
Analysis of Pharmacokinetic Data .........................................................................83 
8.2.6.2 
Analysis of Pharmacodynamic Data ......................................................................84 
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ..................................84 
8.3 
Interim Analysis and Power ...............................................................................................84 
9 
ETHICS AND RESPONSIBILITIES .....................................................................................84 
9.1 
Good Clinical Practice .......................................................................................................84 
9.2 
DMC ..................................................................................................................................84 
9.3 
Institutional Review Board/Independent Ethics Committee ..............................................85 
9.4 
Informed Consent...............................................................................................................85 
9.5 
Records Management .........................................................................................................86 
9.6 
Source Documentation .......................................................................................................86 
9.7 
Study Files and Record Retention......................................................................................87 
10 AUDITING AND MONITORING ........................................................................................87 
11 AMENDMENTS ....................................................................................................................87 
12 STUDY REPORT AND PUBLICATIONS ...........................................................................88 
13 STUDY DISCONTINUATION .............................................................................................88 
14 CONFIDENTIALITY ............................................................................................................88 
15 REFERENCES .......................................................................................................................89 
16 APPENDICES ........................................................................................................................93 
APPENDIX 1 
NAMES OF STUDY PERSONNEL ...............................................................93 
APPENDIX 2 
DECLARATION OF HELSINKI....................................................................94 
APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ......................98 
APPENDIX 4 
MEDICATION WASHOUT PERIODS..........................................................99 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) ......................100 
APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE ...................................101 
APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES ...................................................102 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .........................42 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) ...............................47 
Table 3. 
Laboratory Tests ....................................................................................................65 
Table 4. 
Causality Definitions .............................................................................................68 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................29 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 ...........................................41 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
CS 
corticosteroids 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
 
 
FAS 
full analysis set 
CCI


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Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
INFγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary of Regulatory Activities 
MS 
multiple sclerosis 
MTX 
methotrexate 


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NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PP 
per protocol 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-
wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS  
safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
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STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
TT 
tetanus toxoid 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1. INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids (CS), immunosuppressants, and cytotoxic 
agents.1  However, some of the morbidity in patients with SLE is related to its treatment.  
Comparison of early and late outcomes in patients with SLE demonstrate that death in early 
disease is most commonly due to infections and active SLE causing multi-system organ damage, 
while thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb with extended half-life directed against 
human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t1/2) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies. 
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses). 
 
 
 
 
 
 
 
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  The NOAEL was determined to be 100 mg/kg (SC and IV), the highest dose 
tested. 
An additional GLP, repeat-dose toxicity study was conducted in Cynomolgus monkeys (4 males 
and 4 females per dose group) following every 2 weeks (Q2W) administration by SC (10, 30, 
and 100 mg/kg) injection for a total of 14 doses.  
 
 
 
 
 
  There were no BOS161721-related effects on survival, clinical signs, male body 
weights, ophthalmologic parameters, electrocardiogram (ECG) findings, clinical pathology, 
macroscopic observations, organ weights, or microscopic observations.  
 
 
 
 
 The 100 mg/kg/dose was the NOAEL
 
 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: 
placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 
30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first 
cohort, after the first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 
48 hours before the remaining subjects from that cohort were dosed, to allow for an initial review 
of any emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not 
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sooner than 8 days after all the subjects in the prior cohort had been dosed and were based on a 
review of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included ECGs, vital signs (blood pressure [BP], heart rate, and temperature), safety 
laboratory assessments, blood sampling for ADAs, total IgG and immunoglobulin M (IgM) 
levels, CD4+ count, and full and targeted physical examinations.  Overall, there were no 
clinically significant findings from this study.  Adverse events reported as related to the study 
drug, particularly infections, were expected for the compound, and there were no clinically 
relevant changes in laboratory and ECG results or vital signs.  There was 1 serious adverse event 
(SAE; death due to pulmonary embolism) that occurred 127 days after a single administration of 
240 mg SC dose of BOS161721.  The causality of this single SAE was not attributed to study 
drug and further information can be found in the Investigator’s Brochure.  PK data from the SAD 
study demonstrates BOS161721 has an extended t1/2 (provisional single dose data indicates this 
to be approximately 42-46 days) which supports evaluation of monthly dosing.  
1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1b portion based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose 
level, repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant 
safety or tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD portion of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median first time to maximum concentration (Tmax) of 6 days and an apparent 
terminal half-life of 44 days.  Furthermore, pSTAT3 suppression, a marker of IL-21 target 
engagement, follows a similar time course of the mAb levels, with maximal and sustained 
suppression apparent with doses greater than 30 mg SC (Figure 1).   


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Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 
All doses selected for the MAD portion are projected not to exceed the mean exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD 
study.  Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered 
study design, the data monitoring committee (DMC) will perform a scheduled review of safety 
data and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC and 
Boston Pharmaceuticals will conduct a data review to determine which dose will be carried 
forward into the proof of concept (POC) Phase 2 portion.  This POC dose decision will be based 
on evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD portion (see 
Section 3.1.1.1).     
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD portion.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  


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Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Thirty days after the last patient in Cohort 3 receives the third dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to determine which dose will be 
carried forward into the POC part of the study.  This POC dose decision will be based on 
evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 during the MAD part of study.  
Thereafter, DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter.  With the agreement of the DMC and sponsor, this schedule may 
be modified depending on the rate of patient accrual.  Additional details can be found in the 
DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), or altered BOS161721 levels or activity.  Further details can be found in the current 
Investigator’s Brochure (IB) for BOS161721, which contains comprehensive toxicology, 
preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational 
products.  Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to 
the study drug, particularly infections (flu-like symptoms, etc), were expected for the compound, 
and there were no clinically relevant changes in laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 
this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 


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1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 6.2.2.6.1. 
Based on the limited Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic 
reactions in subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC for 3 months (a total of 7 doses).  There were no injection site 
reactions in animals dosed subcutaneously.  Further, there were no reports of injection site 
reactions in the 26-week GLP toxicology study in Cynomolgus monkeys. 
Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 6.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 
ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 


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Based on the limited Phase 1 SAD study (BOS161721-01), immune complex disease in subjects 
who received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 
BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and CD4 + < 350 cells/mm3 will be excluded from the MAD/POC 
parts of the study.  Patients exposed to investigational product who develop diarrhea during the 
course of the study should immediately undergo an assessment for opportunistic infection 
including stool for ova and parasites and stool examination for cryptosporidium.  Positive 
cryptosporidium in stool sample at screening is an exclusion.  Treatment by the investigator 
where indicated should be guided by findings and be consistent with local standard of care. 
Based on the limited Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 


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and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the limited Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from this trial.  Patients with a positive hepatitis B or C 
test or a history of alcohol dependence will also be excluded. 
Based on the limited Phase 1 SAD study (BOS161721-01), hepatic function abnormality in 
subjects who received BOS161721 was not observed. 
1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen; however, it is worth noting that 
BOS161721 administration did not produce any remarkable changes in anti-KLH antibody data 
for IgM, IgG1, IgG3, and IgG4 or anti-tetanus toxoid (TT) antibody data for IgM, IgG, IgG1, or 
IgE during the dosing phase in the same study. 


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Clinical Study Protocol:  BOS161721-02 
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1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 
oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 4.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 4.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES AND ENDPOINTS 
This trial has separate objectives and endpoints for the MAD Phase 1b and POC Phase 2 portions 
of the study.  The primary, secondary, and exploratory objectives for each phase, as applicable, 
are described below with their corresponding endpoints. 
2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment, in order to estimate the optimal 
dose. 
Safety Endpoints 
• 
Incidence and severity of AEs and SAEs, related AEs, AEs 
leading to study drug discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
 
Secondary 
• 
To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with mild to moderate 
SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time point 
• 
Maximum observed concentration (Cmax), Tmax, area under 
the concentration-time curve (AUC), terminal elimination 
half-life (t½), systematic clearance (CL), volume of 
distribution (Vd) 


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Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from baseline to each visit in 
phosphorylated signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) from baseline in 
anti-double-stranded DNA (dsDNA), antinuclear antibodies 
(ANA), anti-Sjögren syndrome A and B (SSA, SSB), Smith 
(Sm), and antiphospholipid (APL) autoantibodies at each 
visit 
• 
Results and changes (or shifts) from baseline in abrogation 
of IL-21 gene signature at each indicated visit 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
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2.2 
Phase 2 Proof of Concept 
 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on the SRI-4  
Primary Efficacy Endpoint 
• 
The proportion of patients with a SRI-4 response at 
Day 210 (see Section 6.3.4.1) 
Secondary 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
(Section 6.3.4.2) 
- 
a sustained reduction of oral corticosteroid (CS) 
(≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B flares relative to 
baseline through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B flare compared to 
baseline through Day 210 
Safety 
• 
To assess safety and tolerability of repeat 
doses of BOS161721 (20, 60, and 
120 mg) administered SC in adult patients 
with moderately to severely active SLE 
on limited background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), related AEs, AEs leading to study 
drug discontinuation, AEs by severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Exploratory 


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3 STUDY PLAN 
3.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
moderately to severely active SLE.  After successfully completing a screening phase, eligible 
patients will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule 
will be monthly.   
The trial will consist of 2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visits at Days 210, 240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease activity.  Further details on the content and methods of data reports by the medical 
monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
3.1.1 
Multiple Ascending Dose Phase 1b 
The MAD portion will consist of 3 cohorts:  
• 
Cohort 1 (20 mg SC) will include 6 patients 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
  
 
• 
 
 
• 
 
 
• 
 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
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o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• 
Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
the MAD part of the study are projected not to exceed the mean exposure of that achieved in the 
SAD study.   
3.1.1.1 
Dose Escalation for the MAD Portion  
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow-up after the second dose, Cohort 2 
begins dosing (after the DMC evaluation of the safety and tolerability data from Cohort 1).  
Similarly, after 8 of the 12 patients in Cohort 2 have received 2 doses and have completed 
2 weeks of follow-up after the second dose, Cohort 3 begins dosing after the DMC evaluation of 
the safety and tolerability data from Cohorts 1 and 2.  Each cohort will continue at their assigned 
dose level through their respective 6-month treatment periods (See Study Schematic, 
Section 3.1).  If patients discontinue the study in a cohort prior to adequate safety follow-up, 
he/she may be replaced. 
Criteria for dose escalation are further described in the DMC Charter.  See Section 3.1.1.2 for 
additional details about DLTs.   
3.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia 
• Grade 3 neutropenic infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia 
Non-Hematologic: 
• 
Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals) 


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Clinical Study Protocol:  BOS161721-02 
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• 
Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 6.2.2.6.3 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances. 
3.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD part of the study, the DMC may provide the following 
recommendations to the sponsor: 
• 
Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort 
• 
Continuing a dose level for a given cohort 
• 
Escalating a dose level for a subsequent cohort 
• 
Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC portion, the DMC and Boston Pharmaceuticals will conduct a 
data review to determine which dose will be carried forward into the POC Phase 2 part of the 
study.  This POC dose decision will be based on evaluation of the PK, safety (inclusive of 
dose-limiting toxicity [DLT]), and tolerability data (and available PD/biomarker data) from 
Cohorts 1, 2, and 3; this dose will not exceed doses tested during the MAD portion.  The DMC 
will be reviewing all relevant data from Cohorts 1, 2, and 3 that is available 30 days after the last 
patient from Cohort 3 receives the third dose.  Details are provided in the DMC Charter.  
3.1.2 
POC Phase 2  
3.1.2.1 
BOS161721 Dose  
The optimal dose is chosen based on MAD Phase 1b safety, tolerability, immunogenicity, and 
PK and PD data.  The dose will be communicated by a letter to site investigators participating in 
the POC Phase 2 portion, and to the IRB/IEC. 
3.1.2.2 
POC Study Design 
For the POC part of the study, approximately 156 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments (Section 3.4).  Dose selection will be based 
on the DMC and sponsor’s assessment of safety, tolerability, immunogenicity, and PK and PD 
data from the MAD portion of 30 patients treated with BOS161721/placebo. 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
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DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
3.2 
Randomization and Blinding 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
portion and separately for each cohort in the Phase 1b and 2 portions as follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1b MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the interim analysis (IA) and the DMC safety reviews.  The DMC will review 
unblinded data during safety reviews and the IA.  A limited team at Boston Pharmaceuticals will 
review unblinded results from the Phase 1b MAD portion during the IA to determine the dose 
that will be used for the Phase 2 POC portion of the study.  Details regarding maintenance of the 
blinding and content of data reviews will be described in the DMC charter or related study 
documentation.   
 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
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3.3 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 
Day 0
24 week treatment phase
Dose 1
Dose TBD N=104 
Placebo N=52
Low Dose (20 mg) N=6 (5A, 1P) 
Monthly visits 
Medium Dose (60 mg) N=12 (9A, 3P) 
Dose 3
2 month
6 patients complete dose 2:  dose escalate Cohort 2 if safe
Dose 1
Dose 2
1 month
High Dose (120 mg) N=12  (9A, 3P)
Dose 1
Dose 3 + 30 days: 
•
Phase 2 POC dose determined
•
Continue dosing Cohort 3 if safe
Follow up 
Dose 6
5 month
Dose 7
6 month
Dose 7
6 month
Dose 7
6 month
Screening
Week -4
8 patients complete dose 2:
•
Dose escalate Cohort 3 if safe
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Day 0
Day 0
Multiple Ascending Dose (MAD)
Phase 1b 
Proof of Concept (POC)
Phase 2 
Dose Evaluation
Phase
Follow up
90 days
90 days
Follow up 
90 days
Follow up 
90 days
Dose 1
Day 1
Dose 3
2 month
Dose 6
5 month
Dose 7
6 month
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Dose 3
2 month
 
A = active drug (BOS161721); P = placebo 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
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3.4 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site 
reaction assessment 
 
Xf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
SLEDAI-2K 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)h 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3l 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xm 
Xm 
Xm 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)n 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test 
(QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis 
B and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool sampleo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CCI


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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
PK Labs 
Predose 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Predose PK 
Window 
 
60m 
 
 
± 3d 
 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
 
 
 
 
 
Postdose 
 
Xp 
X 
X 
Xp 
 
 
 
 
 
Xp 
X 
X 
X 
X 
X 
Postdose PK 
Window 
 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
± 1d 
± 3d 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
 
 
 
 
 
4h ± 
30m 
8h ± 
45m 
24h ± 
60m 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SAE = serious adverse event; 
SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 7, 187, and 195).  When the timing 
of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
i 
When clinically indicated for hemolytic anemia. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
k 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
l 
Predose (trough) samples only. 
m 
Only 
 collected during safety follow-up visits.  
n 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
o 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
p 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180. 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC)  
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo dosing  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessment 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory assessments 
(hematology and clinical 
chemistry)h 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Whole blood for leukocyte 
immunophenotype 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xl 
Xl 
Xl 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)m 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
TB test (QuantiFERON-TB Gold 
In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Stool samplen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for protein/creatinine 
ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labso 
Predose 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Predose PK Window 
 
60m 
 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Predose PK Window 
 
 
± 3d 
 
 
 
 
 
 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; h = hour; HR = heart rate; HIV = human immunodeficiency virus; 
IgG = immunoglobulin G; IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; m = minute; nAb  = neutralizing antibody; PGA = Physician’s 
Global Assessment; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity 
Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; 
TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the 
daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after eligibility 
confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 187 and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
i 
When clinically indicated for hemolytic anemia. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed (analyzed) if the patient had a positive ADA on Day 90. 
k 
nAb is collected for all patients, though will only be analyzed by central lab if patient is positive for ADA at Day 90. 
l 
Only 
 collected during safety follow-up visits. 
m 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
n 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, 
and cryptosporidium. 
o 
PK samples will only be collected at the investigational sites that will be participating in the PK portion of the study. 
 
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3.5 
End of Study  
End of Study (Individual Patient): A patient is considered at the end of study if he/she has 
withdrawn, prematurely discontinued, or completed all of the study procedures including the last 
visit. 
End of Study (End of trial): The end of the study is defined as the date of the last visit of the 
last patient in the study globally, or the date of which the last patient withdraws or discontinues if 
all prior enrolled patients have already completed/withdrawn. 
4 POPULATION 
4.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
4.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b portion, and approximately 156 additional patients will be randomized in the POC Phase 2 
portion.  Note that approximately 24 dropouts are assumed.   
4.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Section 3.4]) for this study must be 
performed between Day -28 and Day -1. 
4.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 


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immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory 
c. C3 or C4 levels below normal as determined by central lab 
5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) must be ≥ 6, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis 
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of SLE, as defined 
by the BILAG criteria as modified for use in this study, which must be confirmed by the 
central data reviewer:  
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis in ≥ 2 joints with marked loss of functional range of movements and 
significant impairment of basic activities of daily living that has been present on 
several days cumulatively over the past 30 days, including at the time of the 
screening visit.  See APPENDIX 5 for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require assistance or 
assistive devices, (at least 1 must be present and documented in source): 


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o Ambulation, toileting, grooming- including bathing and dressing; feeding 
oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional range of movements 
which lead to some loss of functional range of motion as manifested by effects on 
instrumental ADLs such as: 
• Cooking, driving, using the telephone or computer, shopping, cleaning, etc, and 
has been present on several days over the last 30 days, and is present at the time 
of the screening visit 
If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to signing consent) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at screening for a patient 
to be eligible and must be stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 0 (randomization) (see APPENDIX 3) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after treatment completion 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 5 half-lives of 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
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4.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic scleroderma, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any elective 
surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 0 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to require additional 
systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is allowed 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 4.6 for prohibited 
concomitant medication) 
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
parenteral antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV) unless patient 
received curative treatment for HCV and has a documented negative viral load, known 
human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-
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12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 350/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to lupus 
based on the investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, might place a patient 
at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer 


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30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
4.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen of other 
concomitant medications for the treatment of SLE (eg, analgesics, NSAIDs, statins, ACE 
inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments are 
clinically indicated.  Use of any other drugs for non-SLE conditions, including over-the-counter 
medications and herbal preparations, should remain stable unless change or addition is clinically 
necessary.  Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
4.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, 
however, the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days 
prior to Day 0 (randomization day). 
After Day 0 (after initiation of study therapy), no up-titration above 10 mg/day is allowed except 
for up to 1 CS burst for increased disease activity.  
Tapering of steroids during the course of the study will be encouraged and should be evaluated at 
all visits.  
• 
Once a patient has received the first dose of study drug, prednisone (or prednisone 
equivalent) may be tapered down at the discretion of the investigator 
o Tapering is allowed after randomization except within 60 days of the primary (Day 210) 
and secondary (Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant. 
A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed during the 
study between Day 0 and Day 60, according to the following:   


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• 
An oral CS “burst” between Day 0 and Day 60; (an increase of ≤ 40 mg/day of prednisone or 
equivalent), which must be tapered down to a maximum of 10 mg/day within 2 weeks of 
initiation of the “burst” 
o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o The course of the oral CS “burst” is not permitted to extend beyond Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any other route, is allowed.  Other 
concomitant medications for SLE need to be taken at stable doses as per the inclusion criteria 
(Section 4.4). 
4.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and during the 
study are described below, and washout requirements are provided in APPENDIX 4.  
Medications taken within 30 days prior to screening must be recorded on the eCRF. 
1. Prior exposure to BOS161721 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
24 weeks of screening; recovery of B cells (CD19+) must be documented (record absolute 
number of CD19+ B cells) 
3. Patients who have received treatment with cyclophosphamide within the 24 weeks prior to 
screening 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria within 4 weeks for oral use or 8 weeks for topical use of screening 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 24 weeks prior to screening 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc, may be used 
according to local guidelines during treatment period 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation 
4.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 


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See Section 4.7.2 for detailed information regarding contraceptive requirements for WOCBP. 
4.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   
4.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 5 half-lives of study drug 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
At a minimum, patients must agree to the use of 1 method of highly effective contraception from 
the following: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who 
are WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• 
IUDs, such as ParaGard® 
• 
Vasectomy 
• 
Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception.  Women who are abstinent while participating in the study 
must continue to have pregnancy tests.  Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego complete 
abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, they must still undergo pregnancy testing. 


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4.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient to continue 
or withdrawal from the study medication.    
See Section 6.8 for additional details.  
4.8.1 
Patient Withdrawal and Replacement 
See Section 5.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD part of the study after discussion between the principal investigator or designee 
and sponsor. 
5 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
5.1 
Screening 
Screening will be the same for both the MAD and POC portions of the study. 
Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria, listed in Section 4.4 and Section 4.5 respectively, will be enrolled in 
the study.  Screened patients who drop out of the clinical study before randomization will be 
recorded as screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• 
Medical history documentation 
• 
Review of inclusion and exclusion criteria 
o Patient medical records must contain documentation of SLE diagnosis 
o C-SSRS   
• 
Concomitant medication documentation 
• 
Demographics 
• 
Full physical examination 


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• 
Vital signs 
• 
Chest x-ray (a prior x-ray can be used if taken within 12 weeks of screening date) 
• 
Laboratory evaluations (non-fasting): 
o Hematology and clinical chemistry 
o Serology (Hepatitis B and C; HIV-1/2 combination) 
o TB test 
o CRP 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, 
 
 
o Serum pregnancy test (WOCBP) 
o FSH (postmenopausal women) 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
o Stool sample  
• 
12-lead ECG 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity 
Screening procedures are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
5.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• 
medically indicated 
• 
there is evidence a laboratory sample was mislabeled, indeterminate, inadequately processed, 
and/or deteriorated in transit to the central laboratory 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
5.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.   
Prior to randomization, the study site should confirm that the patient still meets 
inclusion/exclusion criteria (especially SLE disease activity and treatment).  The site will obtain 
a randomization number when registering the patient in IWRS.  All patients will receive 
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BOS161721 or placebo according to the kit number assigned by the IWRS randomization 
scheme.    
After randomization, procedures include: 
• 
PROs:  
 
• 
C-SSRS 
• 
Laboratory evaluations (fasting): 
o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype 
o ADA 
o pSTAT3 (predose [trough] samples only in Phase 1b)  
o 
 
o 
 
o 
 
o See Table 1 and Table 2 for details of PK sampling in the MAD and POC portions 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Full physical examination 
• 
Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 0) 
• 
12-lead ECG (prior to PK blood draw) 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, PGA) 
• 
SLICC/ACR damage index 
• 
Study drug administration: 
o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 7.3 
• 
Injection site reaction assessment performed at 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
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5.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of Assessments 
(Table 1 and Table 2).  See Schedule of Assessment tables for allowable windows for each visit.   
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
PROs:  
 
• 
Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
• 
Injection site reaction assessments will be performed predose  
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Spot urine for protein to creatinine ratio 
• 
Urinalysis 
• 
 
• 
Plasma 
 
• 
PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
• 
SLICC/ACR Damage Index will be completed at Day 180 
• 
C-SSRS 
• 
ECGs prior to PK blood draw 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
• 
Fasting hematology and chemistry assessments  
• 
The CD4+ count and total IgG and IgM levels  
• 
Plasma 
 & 
, ADA, and whole blood for leukocyte immunophenotype 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
nAb will be analyzed by central lab if patient is positive for ADA 
• 
CRP 
• 
 
5.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270.  These visits will include the 
following assessments as indicated in the Schedule of Assessments (Table 1 and Table 2):  
• 
PROs:  
 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Injection site reactions 
• 
Targeted physical examination 
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• 
Vital signs (prior to PK blood draw) 
• 
Spot urine for protein/creatinine ratio and urinalysis 
• 
Concomitant medication documentation 
• 
BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
• 
Fasting clinical laboratory assessments (hematology and clinical chemistry) 
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Plasma 
 
• 
 
• 
12-lead ECG (prior to PK blood draw) 
• 
CRP 
• 
ADA 
• 
 
• 
Urine pregnancy test 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC portions, 
respectively 
5.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Day 180) and a last follow-up visit 90 days after dosing should be scheduled 
(Day 270).  Safety follow-up visit procedures based on the Schedule of Assessments 
(see Section 5.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• 
AE/SAE 
• 
Protocol deviation 
• 
Lost to follow-up 
• 
Patient withdraws consent at their own request 
• 
Investigator decision 
• 
Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
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6 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
6.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• 
General medical history 
• 
Documentation of SLE diagnosis 
• 
Historical medication therapy for SLE 
The following demographic information will be recorded:  
• 
Age 
• 
Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• 
Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• 
Height (without shoes, in cm) 
• 
Body weight, without shoes (kg) 
• 
Body mass index (BMI [kg/m2]) 
Other baseline characteristics will be recorded as follows: 
• 
Concomitant medication documentation (see Section 4.6) 
• 
Status of child bearing potential and contraception 
6.2 
Safety Assessments 
6.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Section 3.4).  Patient eligibility will be determined based on these tests at screening.  
Unscheduled clinical labs may be obtained at any time during the study to assess any perceived 
safety concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests) to ensure accuracy 
and consistency in test results.  Laboratory/analyte results that could unblind the study (ie, 
biomarker results) will not be reported to investigative sites.  Urinalysis will be performed on 


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midstream, clean catch specimens.  Some biomarkers listed above will not be drawn at some 
sites due to geographical logistical challenges.  See the laboratory manual for details. 
Endpoint analyses will be based on changes from baseline assessments at Days 120 and 210. 
Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test 
(QFT-G)d 
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
Serum pregnancy test 
 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
Prothrombin 
time/international 
normalized ratio (repeat) 
Creatine kinase (repeat) 
 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only in Phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
& 
 
Whole blood for leukocyte 
immunophenotype  
 
 
Antibodies 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
;; FSH = follicle stimulating hormone; 
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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; 
nAb = neutralizing antibody; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; 
PT = prothrombin time; qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; SAE = serious 
adverse event; SC = subcutaneous; 
; TB = tuberculosis.  
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for 
ova, parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 6.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated for hemolytic anemia. 
 
6.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or 
continued and a further negative urine pregnancy test results will then be required at the baseline 
visit before the patient may receive the investigational product.  Urine pregnancy tests will also 
be routinely repeated at study drug administration visits prior to study drug administration, at the 
last follow up visit day (Day 270) and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected.  In the case of a positive pregnancy test or 
confirmed pregnancy, the patient will be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after last dose should be scheduled 
(Day 270).  Safety follow-up visit procedures (see Section 5.4) are specified in the Schedule of 
Assessments (see Section 3.4). 
See Section 6.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
6.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 4.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 0). 
6.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
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tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 
study.  If a repeat test is indeterminate again, the patient is a screen failure.  The procedure for 
using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
6.2.2 
Adverse Events 
6.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 6.2.2.5). 
6.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset, date of AE outcome, and action taken for the AE will be documented together 
with the principal investigator’s assessment of the seriousness of the AE and causal relationship 
to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
6.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 


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and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 
6.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 4) should be selected based on medical 
judgment, considering the definitions below and all contributing factors. 
Table 4. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation (positive dechallenge), or the 
symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that there are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
6.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• 
Requires hospitalization or prolongation in existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly or birth defect 
• 
Is another important medical event (see below) 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 


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may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• 
Development of drug dependency or drug abuse 
Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
6.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Grades 2 to 5 injection site reaction, including erythema, pain, and induration 
(See APPENDIX 6) 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, and 
disseminated tuberculosis 
6. Cryptosporidiasis 
6.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 


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2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline 
6.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These will include Grades 2 to 5 
injection site erythema, pain, and induration (see APPENDIX 6), which are also captured as 
Adverse Events of Special Interest (See Section 6.2.2.6).  The investigator should provide a clear 
description of the observed or reported AE including location and severity.  All concomitant 
treatments used to treat injection site reactions should be recorded and captured in the eCRF, 
together with the AE of injection site reactions.   
6.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.2.2.7.2 for reporting details). 
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 


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2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 5× ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 
• 
ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
• 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
6.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 6.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue, the investigator and/or consultant(s) should contact the 
sponsor clinicians or designee to discuss the issue and any decisions as soon as possible. 


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6.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, shingles, disseminated herpes simplex, or disseminated 
tuberculosis will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
6.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 6.2.2.7.2. 
6.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 
adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 


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6.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Day 270).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• 
Study number 
• 
Patient number 
• 
Details of the SAE (verbatim details are sufficient for immediate notification) 
• 
Criterion for classification as ‘serious’ 
• 
Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 
obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   
6.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becoming aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 


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Potential DILI will be reported based on specifications mentioned in Section 6.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate, and is further outlined in Section 6.2.2.7.2. 
6.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 6.2.2.7.1 for details related to follow-up of pregnancy.  See Section 6.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 6.2.2.6.4 for details related to 
follow-up of malignancy. 
6.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Section 3.4).  Vital signs will be assessed on Day 0 at predose and at 
Day 0, 1 and 2 hours postdose, as well as on each of the scheduled visit days during the study 
(excluding PK-only site visits).  Supine BP and heart rate recordings will be made after the 
patient has been recumbent and at rest ≥ 5 minutes.  When the timing of these measurements 
coincides with a blood collection, vital signs should be obtained prior to the time of the blood 
collection. 
6.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Section 3.4).  ECG recording 
will initiate after the patient has been supine for at least 5 minutes.  On days of PK blood draws, 
the ECG will be collected before scheduled PK blood draws, though timing will be such that PK 
draws are collected on their scheduled times where possible. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 
6.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 


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thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at all other visits as indicated in 
the Schedule of Assessments (Section 3.4).  It includes evaluation of patient complaints and SLE 
disease-related issues, and will exclude the genitourinary system. 
6.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments 
(Section 3.4).  Patients with recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 is exclusionary at screening 
will be excluded from the study.  Patients with recent or active suicidal ideation or behavior at 
subsequent study visits will have responses to the C-SSRS reviewed in detail to assess patient 
risk, and appropriate consultative mental health services will be provided. 
6.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule of 
Assessments (Section 3.4).  Local injection site reactions will be assessed at 2 hours postdose at 
baseline, and predose for each injection after baseline.  Injection site reactions should be 
managed according to the standard of care.  Injection site reactions, Grades 2 to 5, are to be 
reported as AEs of special interest (see Section 6.2.2.7.3). 
6.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in the 
Schedule of Assessments (Section 3.4).  Blood samples (4 mL) to provide approximately 1.5 mL 
of plasma for anti BOS161721 antibody analysis will be collected into appropriately labeled 
tubes containing K2EDTA.  The presence or absence of ADA will be determined in the serum 
samples using validated bioanalytical methods.  Blood samples for ADA analysis will be 
collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all 
patients but only analyzed by a central lab if the patient had a positive ADA on Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, a sample 
from this patient will be further analyzed in the neutralizing antibody (nAb) assay by a central 
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6.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of Assessments 
(Section 3.4). 
6.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
6.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 
4 weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, 
worksheet, clinic notes, and labs) at each visit. 
See APPENDIX 5 for detailed specifications. 
6.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.  PGA worsening is defined as an increase of > 30 mm from baseline. 
When scoring the PGA, the assessor should always look back at the score from the previous 
visit. 


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6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
6.3.4.1 
SRI-4 Response 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 30 mm.  The SRI-4 response in patients with moderate to severe SLE is 
associated with broad improvements in clinical and patient-reported outcomes.45  
6.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal five-point or six-point improvement in 
SLEDAI-2K being required, respectively.46 
6.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 
For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined. 
6.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 
6.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 


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6.4 
Other Variables 
6.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Days 0 
and 180. 
6.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
 and will be assessed as 
specified in the Schedule of Assessments (Section 3.4). 
 
50     
 
.   
6.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) parts of the study, 
blood samples for PK analysis of BOS161721 or placebo concentration will be collected 
according to Table 1 and Table 2. 
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration actual time profiles.   
6.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the Schedule of 
Assessments (Section 3.4) for each of the following parameters: 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
Antibodies:  
  
• 
Plasma complement (
)  
• 
Plasma 
 and 
  
• 
Whole blood for leukocyte immunophenotype  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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6.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
6.8 
Protocol Deviations 
Protocol deviations will be documented during the study.   
7 STUDY DRUG MANAGEMENT 
7.1 
Description 
7.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
7.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
7.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
7.3 
Dose and Administration 
Details of dosing are provided in Section 3.1. 
Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
CCI
CCI
CCI


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appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
7.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Products returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed.  The returned products should be marked as ‘returned’ 
and kept separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
7.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 4.6 and APPENDIX 4 and will be 
listed as protocol violations if taken when not permitted. 
7.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
investigator.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. 
8 STATISTICS 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC part of the study.   
• The final analysis will be performed when all patients have completed the POC safety 
follow-up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
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content and format of the safety review meetings will be described in the SAP and/or 
DMC charter. 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9 
or higher.   
The following standards will be applied for the analysis unless otherwise specified.  Data will be 
summarized descriptively by treatment and overall for each study portion.  For the MAD part of 
the study, BOS161721 will be summarized overall and by each dose level, and placebo patients 
from each cohort will be combined.  Select parameters may be summarized using patients from 
both study parts.  Statistical testing will be performed on data from the Phase 2 portion only. 
Continuous data will be summarized using number, mean, standard deviation (SD), 25th and 75th 
percentiles, minimum, median, and maximum.  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage).  Time to event data will be 
summarized using counts, medians, 25th and 75th percentiles, and standard error.  All data will be 
listed for all patients. 
Statistical inference will be based on a 2-tailed test with an overall 0.10 level of significance, 
unless stated otherwise.   
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data will be conducted as 
deemed appropriate.  Any deviations from the planned analyses will be described and justified in 
the final integrated CSR. 
Protocol deviations and prohibited medications that define medication failures will be fully 
assigned and documented before database lock and unblinding.  
Further details of the analysis, including the handling of missing data, transformations and other 
data handling procedures will be provided in the SAP.   
8.1 
Sample Size 
Sample size in the Phase 1b part of the study is based on operational consideration. 
The sample size in the Phase 2 portion is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable patients in the FAS.  This assumes 
24 patients will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 patients are randomized into the FAS.    
A total of 132 patients randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes of a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 


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from most recent non-missing result and patients are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all patients who receive at 
least 1 dose of study treatment and at have least 1 evaluable post-baseline efficacy evaluation.  
FAS analyses will be conducted on the basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol violations from the 
efficacy analysis.  The PP Population will include all patients from the FAS except those with 
major violations to the protocol deemed to impact the analysis of the primary endpoint.  These 
violations will be identified based on blinded data prior to study unblinding.  PP analyses will be 
conducted on the basis of the randomized treatment. 
Safety analyses will be based on the safety analysis set (SS), defined as all patients who receive 
at least 1 dose of study treatment.  Safety analyses will be conducted on the basis of actual 
treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, defined as the FAS with 
sufficient concentration data for the calculation of PK parameters.   
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all randomized patients.   
8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will be assessed via 
Pearson’s chi-squared analysis.  The primary efficacy endpoint will be analyzed using the FAS 
and if needed repeated in the PP analysis set.  Missing values will be addressed by employing a 
last observation carried forward (LOCF) analysis.  Other imputation methods may be employed 
as a sensitivity analysis and will be described in the SAP.  Additional analyses exploring impact 
of baseline factors such as baseline disease severity, race, and other characteristics may be 
performed.  
Patients that received prohibited medications or unallowable CS usage as described in 
Section 4.6 will be considered “medication failures” and will be treated as non-responders for the 
primary efficacy analysis.  Patients that received an allowable CS burst but having missing data 
at Day 210 will considered a medication failure and will be treated as non-responders for the 
primary efficacy analysis.  The determination of medication failures will be reviewed using 
blinded data and finalized prior to unblinding.   
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
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Secondary and exploratory endpoints for this POC portion will be evaluated based on the same 
statistical hypothesis. 
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared analysis.  Continuous 
efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of covariance 
(ANCOVA) and treatment will be compared using the F-test.  Repeated measures mixed models 
may be performed to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be compared using the log-
rank test.  The secondary efficacy endpoints will be analyzed on the FAS and if needed repeated 
in the PP analysis set.  Details including handling of missing data and “medication failures” will 
be available in the SAP. 
8.2.5 
Analysis of Safety 
8.2.5.1 
Safety Analysis 
Safety analyses will be performed on the SS.  AE data will be coded to system organ class and 
preferred term using MedDRA.  The number and percentage of patients experiencing any 
treatment-emergent AE, overall, and by system organ class and preferred term, will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and relationship.   
Concomitant medications will be coded using the WHO Drug dictionary.  Observed values and 
changes from baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters will be summarized at each individual visit.   
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 
Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected during the MAD Phase 1b 
portion of the study using non-compartmental analysis and include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 
• 
A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 
• 
A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 


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8.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Exploratory analyses examining the relationship between PD parameters and PK concentration 
and PK parameters will be performed.   
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the POC decision for dose 
selection. 
Since there is no IA during the POC part of the study, there is no impact on the type 1 error.   
9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
9.2 
DMC 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC (ie, 
dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
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accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in Section 3.1.1.3. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.3 
Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) must meet the 
guidelines set out by the U.S. Food and Drug Administration (FDA) and conform to local laws 
and customs where appropriate.  Written IRB/IEC approval for the protocol and the signed ICF 
must be obtained and transmitted to Boston Pharmaceuticals or representative before the study 
can be initiated.  The IRB/IEC must be informed of and approve all protocol amendments.  The 
investigator will ensure that this study is conducted in full conformance with all applicable local 
and regional laws and regulations.  The complete text of the World Medical Association 
Declaration of Helsinki is given in APPENDIX 2. 
9.4 
Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the written 
informed consent will be obtained according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the principal investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient should be informed that he/she is free to withdraw from the study 
at any time.  He/she will receive all information that is required by federal regulations and ICH 
guidelines.  The principal investigator or designee will provide the sponsor with a copy of the 
IRB-approved ICF prior to the start of the study.   
The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 
study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   


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If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future patients enrolled in the clinical study will be required to 
sign this revised ICF. 
9.5 
Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 
9.6 
Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 


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must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
9.7 
Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
10 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 
study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 


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implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
12 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 
The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
13 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 
maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
metalloproteinase production in human intestinal fibroblasts by interleukin 21.  
Gut. 2006;55(12):1774-80. 
26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
contributes to the generation of plasma B-cells.  Clin Exp Rheumatol.  2013;31(2):172-9. 
 
 


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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 
28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
pathogenesis of primary Sjögren’s syndrome:  increased serum levels of interleukin-21 
and its expression in the labial salivary glands.  Arthritis Res Ther. 2011;13(5):R179. 
30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
Interleukin-21 modulates Th1 and Th17 responses in gianT-cell arteritis.  Arthritis 
Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
erythematosus.  J Rheumatol. 2012b;39(9):1819-28. 
32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
33 Wang W, Wang EQ, Balthasar JP.  Monoclonal Antibody Pharmacokinetics and 
Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
35 Elsaesser H, Sauer K, Brooks DG.  IL-21 is required to control chronic viral infection.  
Science.  2009;324(5934):1569-72 
36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.  
J Exp Med. 2013;210(3):433-43. 
37 Hunter PR, Nichols G.  Epidemiology and clinical features of Cryptosporidium infection in 
immunocompromised patients.  Clinical microbiology reviews.  2002;15(1):145-54. 
38 Desjardins M, Mazer BD.  B-cell memory and primary immune deficiencies:  interleukin-21 
related defects.  Curr Opin Allergy Clin Immunol. 2013;13(6):639-45. 
39 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
 
 


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40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US:  
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 
41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
doi:10.1136/lupus-2013-000005. 
47 Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M,et al.  Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
Cutaneous Lupus Erythematosus.  J Invest Derm. 2005;125(5):889-94. 
49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
Pulmonary Organ Scores are Predictors of Sever Outcome in Patients with Systemic 
Lupus Erythematosus.  Br J Rheumatol.  1996;35:248-54. 
50 
 
. 
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16 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 400 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
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In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 


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subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 


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informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Dose Equivalence 
Prednisone 
20 mg 
Cortisone 
100 mg 
Hydrocortisone 
80 mg 
Prednisolone 
20 mg 
Methylprednisolone 
16 mg 
Triamcinolone 
16 mg 
Budesonide 
4 mg 
Dexamethasone 
3 mg 
Bethamethasone 
2.4 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS  
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
24 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks for oral and 8 weeks for topical 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with 
cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE 
Adverse event 
Injection site reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Definition:  A disorder 
characterized by an 
intense adverse reaction 
(usually immunologic) 
developing at the site of 
an injection 
Tenderness with 
or without 
associated 
symptoms (eg, 
warmth, 
erythema, 
itching) 
Pain; 
Lipodystrophy; 
Edema; 
phlebitis 
Ulceration or 
necrosis;  
Severe tissue 
damage; 
Operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
 limiting self-
care ADL 
- 
- 
Rash 
maculopapular/Erythema
/Induration 
 
Definition:  A disorder 
characterized by the 
presence of macules 
(flat) and papules 
(elevated).  Also known 
as morbillform rash, it is 
one of the most common 
cutaneous adverse 
events, frequently 
affecting the upper trunk, 
spreading centripetally, 
and associated with 
pruritus. 
Macules/papules 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Erythema 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, burning, 
tightness) 
Macules/papules 
covering 10% - 
30% BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL; 
Erythema 30% 
BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL 
Macules/papul
es covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-care ADL 
 
Erythema 
covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-careADL 
- 
- 
ADL = active daily living 
 
 


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APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES 
The protocol summary of changes was moved to the end of the protocol for easier readability.   
Significant changes are described in the table below.  Changed text is displayed for the first 
major occurrence only.  Deleted text is presented in strikethrough format, and added text is 
presented in bold format.   
Section 
Description of Changes 
Rationale 
Global 
Replace: 
Protocol Date and Version:  21 March 2018; V3.0 
With: 
Protocol Date and Version:  27 July 2018; V4.0 
Administrative 
Global 
Change: 
Changed Version number from V3.0 (Amendment 2) to V4.0 
(Amendment 3) and Version date from 21 March 2018 to 27 July 2018. 
Administrative 
Global 
Made administrative and editorial (formatting, typographical, and 
grammatical) updates. 
Administrative 
Global 
Replaced subjects with patients. 
Corrected 
wording used 
to refer to 
those 
participating 
in study with 
SLE. 
Global 
All references directly or contextually to MAD/POC “phase” or “study” 
have been replaced with “MAD portion/part/part of the study)” or 
“POC portion/part/part of the study”. 
Clarifies that 
MAD and 
POC are 
2 portions of 
this 1 study 
and not 
2 separate 
studies. 
Global 
When referring to the DMC and Boston Pharmaceuticals conducting a 
data review to determine POC dose, all instances of the phrase “suggest 
which dose should” have been replaced with “determine which dose 
will”. 
Protocol 
clarification. 
Title Page 
Appendix 1 
Replace: 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 401 
Cambridge, MA 02142 
Administrative 


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Section 
Description of Changes 
Rationale 
United States of America (USA) 
With: 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 400 
Cambridge, MA 02142 
United States of America (USA) 
CLINICAL 
PROTOCOL 
APPROVAL FORM 
Add: 
Name and Title 
, MD, PhD 
Chief Medical Officer 
Boston Pharmaceuticals 
, MD, FACR 
Vice President, Clinical 
Development 
Boston Pharmaceuticals 
Administrative 
CONFIDENTIALITY 
AND 
INVESTIGATOR 
STATEMENT 
Replace: 
I have read the protocol (V3.0 [Amendment 2], dated 21 March 2018), 
including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described. 
With: 
I have read the protocol (Version 4.0, dated 27 July 2018), including all 
appendices, and I agree that it contains all of the necessary information 
for me and my staff to conduct this study as described.   
Administrative 
PROTOCOL 
SUMMARY, 
Background and 
Rationale 
Replace: 
The no observed adverse effect levels (NOAELs) in Cynomolgus 
monkeys were determined to be 100 mg/kg IV and 50 mg/kg SC, the 
highest doses tested.  No SC animals had injection reactions. 
With: 
The no observed adverse effect level (NOAEL) in Cynomolgus monkeys 
was determined to be 100 mg/kg (SC and IV), the highest dose tested.  
There were no injection site reactions in animals dosed 
subcutaneously. 
Updated based 
on new data 
describing 
NOAEL based 
on 6-month 
study data. 
PPD
PPD


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Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Background and 
Rationale 
Section 1.2.2.3, 
Clinical Studies 
Delete: 
Overall, there were no clinically significant safety or tolerability findings 
from this study, following an interim cut and review of the data at Day 
90 postdose. 
Removed 
since this date 
has been 
superseded. 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Safety 
Endpoints 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Safety 
Endpoints 
Section 2.1, Phase 1b 
Multiple Ascending 
Dose, Safety 
Endpoints 
Section 2.2, Phase 2 
Proof of Concept, 
Safety Endpoints 
Delete: 
• 
Concomitant medication usage 
Removed as 
not a safety 
endpoint. 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, MAD 
Phase 1b, Efficacy 
Endpoints 
Section 2.1, Phase 1b 
Multiple Ascending 
Dose, Efficacy 
Endpoints 
 
Replace: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical 
clarification. 
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Section 
Description of Changes 
Rationale 
- 
 
 
 
 
 
 
 
 
 
 
 
With: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints, POC 
Phase 2, Secondary 
Efficacy Endpoints 
Section 2.2, Phase 2 
Proof of Concept, 
Secondary Efficacy 
Endpoints 
Add: 
• 
The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit (Section 6.3.4.2) 
- 
a sustained reduction of oral corticosteroid (CS) (≤ 10 mg/day 
and ≤ Day 0 dose) between Day 120 and Day 210 
- 
new BILAG A flare or > 1 BILAG B flares relative to baseline 
through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
Statistical 
clarification. 
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Section 
Description of Changes 
Rationale 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• 
Time to medication failure 
• 
Duration of longest SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B flare compared to baseline 
through Day 210 
PROTOCOL 
SUMMARY, Study 
Design 
Section 1.2.4, 
Risk-Benefit 
Assessment 
Replace: 
Two weeks after the last patient in Cohort 3 receives the second dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to suggest 
which dose should be carried forward into the POC Phase 2 study.   
With: 
Thirty days after the last patient in Cohort 3 receives the third dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to 
determine which dose will be carried forward into the POC part of the 
study.   
To include 
more data 
from the 
120 mg cohort 
in data review 
to determine 
POC dose. 
PROTOCOL 
SUMMARY, Study 
Design 
Section 3.1, Study 
Design 
Add: 
After successfully completing a screening phase, eligible patients will be 
randomized to a specified dose of BOS161721 or placebo.   
Protocol 
clarification. 
PROTOCOL 
SUMMARY, 
Inclusion Criteria 
Section 4.4,  Inclusion 
Criteria 
Add: 
4 At screening, patients must have at least 1 of the following: 
a. 
Elevated ANA ≥ 1:80 via immunofluorescent assay at the 
central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level 
as determined by the central laboratory 
c. 
C3 or C4 levels below normal as determined by the central lab 
Protocol 
clarification. 
PROTOCOL 
SUMMARY, 
Exclusion Criteria 
Section 4.5,  
Exclusion Criteria 
Add: 
9 Active and clinically significant infection (bacterial, fungal, viral, or 
other) within 60 days prior to first dose of study drug.  Clinically 
significant is defined as requiring systemic parenteral antibiotics or 
hospitalization 
11 Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C 
(HCV) unless patient received curative treatment for HCV and 
has a documented negative viral load, known human 
immunodeficiency virus (HIV), or acquired immunodeficiency 
syndrome (AIDS)-related illness 
Protocol 
clarification. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 107 of 118 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Exclusion Criteria 
Section 4.5,  
Exclusion Criteria 
Replace: 
15 CD4+ count < 500/µL at screening 
With: 
15 CD4+ count < 350/µL at screening 
DMC recommendation:  The cut off for 
CD4+ T cells of 500 absolute count/µL 
was based on normal circulating levels in 
healthy individuals.  The current trial is 
enrolling Systemic Lupus Erythematosus 
patients that, due to the disease, are 
known to have lymphopenia and 
specifically CD4+ lymphopenia with 
values typically below 500 cells/µL.  
According to the “WHO case definitions 
of HIV for surveillance and revised 
clinical staging and immunological 
classification of HIV-related disease in 
adults and children”, CD4+ count 
< 350 cell/µL in adults is classified as 
significant immunodeficiency, thus the 
proposed cutoff threshold for exclusion 
criteria will be < 350 CD4+ cells/ µL. 
PROTOCOL 
SUMMARY, 
Exclusion Criteria 
Section 4.5,  
Exclusion Criteria 
Delete: 
17 Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia 
related to SLE 
Text removed 
as lab values 
would already 
qualify as 
anemic. 
PROTOCOL 
SUMMARY, 
Statistical 
Considerations 
Replace: 
Two analyses are planned:  1) an interim analysis to select the Phase 2 
dose based on Phase 1 data, and 2) a final analysis at study completion.  
Additionally, DMC safety analyses will be performed after each Phase 1 
cohort and throughout Phase 2 to monitor patient safety.   
Unless stated otherwise, statistical testing will only be performed on the 
Phase 2 data and will be done using 2-sided overall alpha of 0.10.   
With: 
Two analyses are planned:  1) an interim analysis to select the POC dose 
based on the MAD data, and 2) a final analysis at study completion.  
Additionally, DMC safety analyses will be performed for each MAD 
cohort and throughout the POC to monitor patient safety as described in 
the DMC charter.   
Unless stated otherwise, statistical testing will only be performed on the 
POC data and will be done using 2-sided overall alpha of 0.10.   
Protocol 
clarification to 
confirm DMC 
will meet after 
each cohort is 
enrolled and 
not after each 
cohort is 
complete. 
Minor text 
changes and 
additions to 
provide 
further clarity 
to Phase 1 and 
2 being MAD 
and POC. 
Section 1.2.2, 
BOS161721 
Development 
Add: 
Boston Pharmaceuticals is developing BOS161721 for the treatment of 
SLE.  BOS161721 is a humanized immunoglobulin G1 (IgG1) mAb with 
extended half-life directed against human IL-21.   
Protocol 
clarification. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 108 of 118 
Section 
Description of Changes 
Rationale 
Section 1.2.2,2 
Preclinical Studies 
Replace: 
The NOAELs were determined to be 100 mg/kg IV and 50 mg/kg SC, 
the highest doses tested. 
With: 
The NOAEL was determined to be 100 mg/kg (SC and IV), the highest 
dose tested. 
Updated based 
on new data 
describing 
NOAEL based 
on 6-month 
study data. 
Section 1.2.2,2 
Preclinical Studies 
Add: 
An additional GLP, repeat-dose toxicity study was conducted in 
Cynomolgus monkeys (4 males and 4 females per dose group) 
following every 2 weeks (Q2W) administration by SC (10, 30, and 
100 mg/kg) injection for a total of 14 doses.  
 
 
 
 
 
 There were no BOS161721-related effects on 
survival, clinical signs, male body weights, ophthalmologic 
parameters, electrocardiogram (ECG) findings, clinical pathology, 
macroscopic observations, organ weights, or microscopic 
observations. 
 
 
 
 
 
  The 
100 mg/kg/dose was the NOAEL and
 
 
Data from a 
6 month GLP 
Toxicology 
study 
conducted in 
Cynomolgus 
monkeys was 
not available 
at the time the 
original 
protocol was 
written. 
Section 1.2.3, Study 
Dose Selection 
Add: 
Doses have been selected for the multiple ascending dose (MAD) 
Phase 1b portion based on a 90-day safety, tolerability, PK, and PD data 
review from the Phase 1 SAD study (BOS161721-01); the SDMT 
reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 
120 [SC], or 240 [SC] mg), along with the accumulated safety and 
available PK/PD data from all subjects in the previous dose cohorts, to 
make a decision on whether to proceed to the next higher dose level, 
repeat a dose level, or stop dose escalation.   
Protocol 
clarification. 
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 109 of 118 
Section 
Description of Changes 
Rationale 
Section 1.2.5, 
Potential Risks 
Delete: 
ADAs could result in immune complex disease (with manifestations such 
as arthralgias, serum-sickness, and vasculitis), autoimmunity, or altered 
BOS161721 levels or activity. 
Protocol 
clarification. 
Section 1.2.5.2, 
Injection Site 
Reactions 
Replace: 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, 
BOS161721 was administered every 2 weeks by IV or SC (50 mg/kg) for 
3 months (a total of 7 doses); no SC animals had injection reactions. 
With: 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, 
BOS161721 was administered every 2 weeks by IV or SC for 3 months 
(a total of 7 doses).  There were no injection site reactions in animals 
dosed subcutaneously.  Further, there were no reports of injection 
site reactions in the 26-week GLP toxicology study in Cynomolgus 
monkeys. 
Data was not 
available at 
the time the 
original 
protocol was 
written. 
 
Section 1.2.5.4, 
Infections 
Replace: 
Since the risk of opportunistic cryptosporidium 
infection increases with low levels of CD4+ T-cells,37 
patients with a CD4+ count < 500 cell/mm3 were 
excluded from the Phase 1 SAD study (BOS161721-
01), and will be excluded from the proposed 
MAD/POC studies.   
With: 
Since the risk of opportunistic cryptosporidium 
infection increases with low levels of CD4+ T-cells,37 
patients with a CD4+ count < 500 cell/mm3 were 
excluded from the Phase 1 SAD study (BOS161721-
01), and CD4 + < 350 cells/mm3 will be excluded from 
the MAD/POC parts of the study.   
DMC recommendation:  The 
cut off for CD4+ T cells of 
500 absolute count/µL was 
based on normal circulating 
levels in healthy individuals.  
The current trial is enrolling 
Systemic Lupus Erythematosus 
patients that, due to the disease, 
are known to have lymphopenia 
and specifically CD4+ 
lymphopenia with values 
typically below 500 cells/µL.  
According to the “WHO case 
definitions of HIV for 
surveillance and revised clinical 
staging and immunological 
classification of HIV-related 
disease in adults and children”, 
CD4+ count < 350 cell/µL in 
adults is classified as 
significant immunodeficiency, 
thus the proposed cutoff 
threshold for exclusion criteria 
will be < 350 CD4+ cells/µL. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 110 of 118 
Section 
Description of Changes 
Rationale 
Section 1.2.5.6, 
Hepatic Function 
Abnormality 
Replace: 
However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or 
bilirubin at screening (ALT/AST > 2 × upper limit of normal [ULN]; 
total bilirubin > 1.5 × [ULN] and judged by the investigator to be 
clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from the MAD study.   
With: 
However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or 
bilirubin at screening (ALT/AST > 2 × upper limit of normal [ULN]; 
total bilirubin > 1.5 × [ULN] and judged by the investigator to be 
clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from this trial.   
Protocol 
clarification - 
MAD and 
POC have the 
same entrance 
criteria. 
Section 3.1, Study 
Design 
Replace: 
The scope of responsibility includes, but is not limited to, review and 
confirmation of “A” and “B” BILAG system organ disease, confirmation 
of clinical components of the SLEDAI-2K score at screening and during 
the study, and cross-validation of the instruments used in this study to 
assess the disease being studied. 
With: 
The scope of responsibility includes, but is not limited to, review and 
confirmation of “A” and “B” BILAG system organ disease, confirmation 
of clinical components of the SLEDAI-2K score at screening and during 
the study, and cross-validation of the instruments used in this study to 
assess the disease activity. 
Protocol 
clarification. 
Section 3.1.1, 
Multiple Ascending 
Dose Phase 1b Study 
Add: 
All doses selected for the MAD part of the study are projected not to 
exceed the mean exposure of that achieved in the SAD study.   
Protocol 
clarification. 
Section 3.1.1.3, DMC 
Recommendations 
Replace: 
The DMC will be reviewing all relevant data from Cohorts 1, 2, and 3 
that is available at the time the last patient in Cohort 3 completes the 
Day 44 visit (2 weeks after dose 2). 
With: 
The DMC will be reviewing all relevant data from Cohorts 1, 2, and 3 
that is available 30 days after the last patient from Cohort 3 receives 
the third dose. 
To include 
more data 
from the 
120 mg cohort 
in data review 
to determine 
the POC dose. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 111 of 118 
Section 
Description of Changes 
Rationale 
Section 3.1.2.1, 
BOS161721 Dose 
Delete: 
The optimal dose evaluation is chosen based on MAD Phase 1b safety, 
tolerability, immunogenicity, and PK and PD data.   
Protocol 
clarification. 
Section 3.2, 
Randomization and 
blinding, Table 
footnote 
Replace: 
*Additional patients may be enrolled to confirm sufficient numbers of 
patients are in the full analysis set (FAS). 
With: 
*Additional patients may be enrolled to ensure sufficient numbers of 
patients are in the full analysis set (FAS). 
Protocol 
clarification. 
Section 3.2, 
Randomization and 
blinding 
Add: 
Similarly, patients in the Phase 1b MAD will be assigned to the cohort 
which is active.   
Protocol 
clarification. 
Section 3.3, Study 
Schematic 
Replace: 
Figure 2. Study Diagram for MAD Phase 1b and POC Phase 2 Studies 
 
With: 
Figure 2. Study Diagram for MAD Phase 1b and POC Phase 2 
 
Protocol 
clarification. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 112 of 118 
Section 
Description of Changes 
Rationale 
Section 3.4, Schedule 
of Assessments, 
Table 1, Safety 
Follow-Up column 
Add: 
 
Safety Follow-Up 
Days 
210 (± 3) 
240 (± 3) 
270 (± 3) 
Visit Number 
11 
12 
13 
Urine pregnancy 
test (women)n 
 
 
X 
 
Protocol 
clarification.  
Urine 
pregnancy test 
added at day 
270 to ensure 
patient is not 
pregnant at 
end of 90 day 
follow-up due 
to 41 day 
half-life of 
study drug.  
Section 3.4, Schedule 
of Assessments, 
Table 1, PK Labs 
Windows 
Add: 
 
Adding PK 
windows for 
added 
flexibility. 
Section 3.4, Schedule 
of Assessments, 
Table 1 footnotes 
Section 3.4, Schedule 
of Assessments, 
Table 2 footnotes 
Add: 
j 
Blood samples for ADA analysis will be collected up to Day 90 
from all patients.  Subsequent ADA samples will be collected from 
all patients but only assayed (analyzed) if the patient had a positive 
ADA on Day 90. 
Protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 1 footnotes 
Section 3.4, Schedule 
of Assessments, 
Table 2 footnotes 
Replace: 
k 
nAb is assessed if patient is positive for ADA. 
With: 
k 
nAb is collected for all patients, though will only be analyzed by 
central lab if patient is positive for ADA at Day 90. 
Protocol 
clarification. 
Section 3.4, Schedule 
of Assessments, 
Table 1 footnotes 
Add: 
m 
Only 
 collected during safety follow-up visits. 
Protocol 
clarification. 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 113 of 118 
Section 
Description of Changes 
Rationale 
Section 3.4, Schedule 
of Assessments, 
Table 2 Safety 
Follow-Up column 
Add: 
 
Safety Follow-Up 
Days 
210 (± 3) 
240 (± 3) 
270 (± 3) 
Visit Number 
10 
11 
12 
Urine pregnancy 
test (women)m 
 
 
X 
 
Protocol 
clarification - 
urine 
pregnancy test 
added at day 
270 to ensure 
patient is not 
pregnant at 
end of 90 day 
follow-up due 
to 41 day 
half-life of 
study drug. 
Section 3.4, Schedule 
of Assessments, 
Table 2, PK Labs 
Window 
Add: 
 
Adding PK 
windows for 
added 
flexibility. 
Section 3.4, Schedule 
of Assessments, 
Table 2 footnotes 
Add: 
l 
Only 
 collected during safety follow-up visits. 
Protocol 
clarification. 
Section 3.5, End of 
Study 
Add: 
3.5 End of Study 
End of Study (Individual Patient): A patient is considered at the end 
of study if he/she has withdrawn, prematurely discontinued, or 
completed all of the study procedures including the last visit. 
End of Study (End of trial): The end of the study is defined as the 
date of the last visit of the last patient in the study globally, or the 
date of which the last patient withdraws or discontinues if all prior 
enrolled patients have already completed/withdrawn. 
Added end of 
study 
definitions in 
alignment 
with recent 
agency 
protocol 
authoring 
guidance. 
Section 4.6.2, Other 
Prohibited and/or 
Restricted Treatments 
Replace: 
2 
Patients who have received treatment with anti-CD20 monoclonal 
antibodies within 6 months of screening; recovery of B cells 
(CD19+) must be documented (record absolute number of CD19+ 
B cells) 
3 
Patients who have received treatment with cyclophosphamide 
within the 1 year prior to screening 
4 
Patients who have received treatment with cyclosporine (with 
exception of ophthalmic use), any other calcineurin inhibitor or 
other immunosuppressive medication not specified in the inclusion 
criteria (oral or topical) within 3 months of screening 
5 
Patients who are currently receiving or are scheduled to receive 
Protocol 
clarification to 
align with 
appendices, 
align with 
other windows 
in protocol, 
and further 
clarification in 
#4 for sites to 
differentiate 
between oral 
and topical 
washout. 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 114 of 118 
Section 
Description of Changes 
Rationale 
plasmapheresis or lymphapheresis therapy, or have received such 
therapy within 8 weeks prior to screening 
With: 
2 
Patients who have received treatment with anti-CD20 monoclonal 
antibodies within 24 weeks of screening; recovery of B cells 
(CD19+) must be documented (record absolute number of CD19+ 
B cells) 
3 
Patients who have received treatment with cyclophosphamide 
within the 24 weeks prior to screening 
4 
Patients who have received treatment with cyclosporine (with 
exception of ophthalmic use), any other calcineurin inhibitor or 
other immunosuppressive medication not specified in the inclusion 
criteria within 4 weeks for oral use or 8 weeks for topical use of 
screening 
5 
Patients who are currently receiving or are scheduled to receive 
plasmapheresis or lymphapheresis therapy, or have received such 
therapy within 24 weeks prior to screening 
Section 5.1, Screening 
Add: 
• 
Chest x-ray (a prior x-ray can be used if taken within 12 weeks of 
screening date) 
Protocol 
clarification. 
Section 5.2, 
Enrollment/ 
Randomization and 
Day 0 Treatment 
Replace: 
The study site will obtain a randomization number when registering the 
patient in IWRS.   
With: 
Prior to randomization, the study site should confirm that the 
patient still meets inclusion/exclusion criteria (especially SLE disease 
activity and treatment).  The site will obtain a randomization number 
when registering the patient in IWRS.   
Added text to 
ensure 
eligibility 
prior to 
randomization 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits 
Replace: 
• 
CRP and nAb will be assessed if patient is positive for ADA 
With: 
• 
nAb will be analyzed by central lab if patient is positive for ADA 
• 
CRP 
Protocol 
clarification. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 115 of 118 
Section 
Description of Changes 
Rationale 
Section 5.4, Safety 
Follow-Up Visits 
Add: 
• 
Urine pregnancy test 
Urine 
pregnancy test 
added at 
day 270 to 
ensure patient 
is not pregnant 
at end of 90 
day follow up 
due to 41 day 
half-life of 
study drug. 
Section 6.2.1, 
Laboratory 
Assessments 
Delete: 
A central laboratory will be used (with the exception of urine pregnancy 
tests and stool analysis) to ensure accuracy and consistency in test 
results.  The central laboratory will transmit all results for protocol tests, 
scheduled and unscheduled, to the clinical data base.   
Central data is 
not being 
transmitted 
into the 
clinical 
database. 
Section 6.2.1, 
Laboratory 
Assessments, Table 3, 
Other Safety Tests 
column 
Add: 
Other Safety Tests 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test (QFT-G)d  
Serologyd (Hepatitis B and C; HIV-1/2 combination) 
Stool samplee 
Serum pregnancy test 
Protocol 
clarification to 
align with 
Schedule of 
Assessments. 
Section 6.2.1, 
Laboratory 
Assessments, Table 3, 
Additional Tests 
column 
Add: 
Additional Testsf   
(potential Hy’s Law) 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase (repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
Prothrombin time/international normalized ratio (repeat) 
Creatine kinase (repeat) 
Protocol 
clarification to 
align with 
Schedule of 
Assessments. 
Section 6.2.1.1, 
Pregnancy Testing 
Add: 
Urine pregnancy tests will also be routinely repeated at study drug 
administration visits prior to study drug administration, at the last follow 
up visit day (Day 270) and additionally whenever 1 menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.   
Urine 
pregnancy test 
added at 
day 270 to 
ensure patient 
is not pregnant 
at end of 90 
day follow up 
due to 41 day 
half-life of 
study drug. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 116 of 118 
Section 
Description of Changes 
Rationale 
Section 6.2.2.2, 
Recording of Adverse 
Events 
Delete: 
The details of the AE, date of AE onset (and time, if known), date of AE 
outcome (and time, if known), and action taken for the AE will be 
documented together with the principal investigator’s assessment of the 
seriousness of the AE and causal relationship to the study drug and/or the 
study procedure. 
Exact time of 
adverse event 
is not needed 
for this study.  
If serious 
adverse event, 
time of onset 
will be 
provided in 
narrative. 
Section 6.2.2.6.2, 
Injection Site 
Reactions 
Add: 
These will include Grades 2 to 5 injection site erythema, pain, and 
induration (see APPENDIX 6), which are also captured as Adverse 
Events of Special Interest (See Section 6.2.2.6). 
Protocol 
clarification. 
Section 6.2.3, Vital 
Signs 
Add: 
Vital signs will be assessed on Day 0 at predose and at Day 0, 1 and 
2 hours postdose, as well as on each of the scheduled visit days during 
the study (excluding PK-only site visits). 
Protocol 
clarification. 
Section 6.2.8, 
Immunogenicity 
Replace: 
Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
After the first dose, if a patient tests positive in the validated 
confirmatory ADA assay, the sample from this patient will be further 
analyzed in the neutralizing antibody (nAb) assay. 
With: 
Subsequent ADA samples will be collected from all patients but only 
analyzed by a central lab if the patient had a positive ADA on Day 90. 
After the first dose, if a patient tests positive in the validated 
confirmatory ADA assay, a sample from this patient will be further 
analyzed in the neutralizing antibody (nAb) assay by a central lab. 
Protocol 
clarification. 
Section 6.3.3, PGA of 
Disease Activity 
Add: 
PGA worsening is defined as an increase of > 30 mm from baseline. 
Added 
definition of 
worsening 
PGA. 
Section 6.3.4.1, SRI-4 
Response 
Replace: 
no deterioration from baseline in the PGA by ≥ 0.3 points 
With: 
no deterioration from baseline in the PGA by ≥ 30 mm 
Unit was 
incorrectly 
presented in 
previous 
protocol 
version. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 117 of 118 
Section 
Description of Changes 
Rationale 
Section 6.3.4.2, SRI-5 
and SRI-6 Response 
Replace: 
However, the SRI-5 and SRI-6 are computed with a minimal three-point 
or five-point improvement in SLEDAI-2K being required, respectively. 
With: 
However, the SRI-5 and SRI-6 are computed with a minimal five-point 
or six-point improvement in SLEDAI-2K being required, respectively. 
Units 
incorrectly 
presented in 
previous 
protocol 
version. 
Section 6.4.2, PROs 
Add: 
 
 
Protocol 
clarification. 
Section 8, Statistics 
Add: 
• 
The final analysis will be performed when all patients have 
completed the POC safety follow-up or withdrawn from the study.   
Protocol 
clarification. 
Section 8, Statistics 
Replace: 
Select parameters will be summarized using patients from both study 
phases. 
With: 
Select parameters may be summarized using patients from both study 
parts. 
If an 
interpolated 
dose is 
selected for 
POC, dose 
levels may not 
be combined. 
Section 8.2.3, Primary 
Efficacy Endpoint(s) 
Delete: 
If the proportion of SRI-4 responders for the selected POC dose in 
BOS161721 arm is higher than that of the placebo arm, then BOS161721 
will be considered superior to placebo if the 2-sided p-value is less than 
or equal to 0.10. 
Statistical 
inference will 
be based on a 
2-tailed test 
with an overall 
0.10 level of 
significance. 
Appendix 1 
Replace: 
 
 
 
 
With: 
 
Administrative 
CCI
PPD
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  27 July 2018; V4.0 
Confidential 
 
Page 118 of 118 
Section 
Description of Changes 
Rationale 
 
 
 
 
 
Appendix 4 
Add: 
Cyclosporine (except for CSA 
eye drops) 
4 weeks for oral and 8 weeks for 
topical 
Protocol 
clarification. 
 
PPD
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 1 of 143 
  
 
A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 401 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721  
PROTOCOL NUMBER: 
BOS161721-02  
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
06 October 2017 
VERSION NUMBER: 
V3.0 (Amendment 2) 
VERSION DATE: 
21 March 2018 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 2 of 143 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited 
Standard of Care 
Study No:  BOS161721-02  
Original Protocol Date:  06 October 2017 
Protocol Version No:  v2.0 (Amendment 1) 
Protocol Version Date:  14 November 2017 
Protocol Version No:  v3.0 (Amendment 2) 
Protocol Version Date:  21 March 2018 
This study protocol was subject to critical review and has been approved by sponsor.  The 
information contained in this protocol is consistent with: 

The current risk-benefit evaluation of the investigational product.

The moral, ethical and scientific principles governing clinical research as set out in the
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to
applicable local requirements.
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature and Date 
, MD 
Vice President, Clinical Development 
Boston Pharmaceuticals 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
, MD, PhD 
Vice President, Clinical Development and Safety 
Officer 
Boston Pharmaceuticals 
PPD
PPD
PPD
PPD
PPD
PPD


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BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol (V3.0 [Amendment 2], dated 21 March 2018), including all appendices, 
and I agree that it contains all of the necessary information for me and my staff to conduct this 
study as described.  I will conduct this study as outlined herein, in accordance with the 
regulations stated in the Federal Code of Regulations for Good Clinical Practices and 
International Council for Harmonisation (ICH) guidelines, and will make a reasonable effort to 
complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


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Protocol Date and Version:  21 March 2018; V3.0 
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PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple 
Dose Escalation Study of BOS161721 in Systemic Lupus Erythematosus 
(SLE) Patients on a Background of Limited Standard of Care 
Indication 
Adults with moderately to severely active SLE 
Background 
and Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the disease, 
and that T-cell-derived cytokines such as interleukin-21 (IL-21) are involved 
in the SLE-associated inflammatory pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple mutation 
monoclonal antibody (mAb) intended to have an extended terminal 
elimination half-life (t1/2) that selectively binds to and neutralizes IL-21, 
which acts on multiple cell types that drive inflammation and autoimmunity.  
In vivo, BOS161721 inhibits T-cell dependent antigen responses of B-cells 
and is being developed as a potential treatment for adults with moderately to 
severely active SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics (PD), 
toxicokinetics (TK), pharmacokinetics (PK), and immunogenicity of 
BOS161721 administered intravenously (IV) and subcutaneously (SC).  The 
no observed adverse effect levels (NOAELs) in Cynomolgus monkeys were 
determined to be 100 mg/kg IV and 50 mg/kg SC, the highest doses tested.  
No SC animals had injection reactions. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  This 
double-blind, placebo-controlled study evaluated 8 ascending dose levels 
(1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg) for safety, tolerability, PK, PD and immunogenicity.  Overall, 
there were no clinically significant safety or tolerability findings from this 
study, following an interim cut and review of the data at Day 90 postdose.  
Results from the Phase 1 SAD study informed the dose regimens used for the 
multiple ascending doses (MAD) Phase 1b study in this trial.  The MAD 
study will involve 3 cohorts.  The Phase 2 portion will be a proof of concept 
(POC) study, where dose selection will be based on the data monitoring 
committee (DMC) and sponsor’s assessment of safety, tolerability, 
immunogenicity, and PK and PD data from the MAD study of 30 patients 
treated with BOS161721/placebo.  The purpose of the study is to establish 
safe and effective dosages for adult patients with moderately to severely 
active SLE. 


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Objectives and 
Endpoints: 
MAD Phase 1b Study 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients 
with moderately to severely active 
SLE on limited background 
standard of care treatment, in order 
to estimate the optimal dose. 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide severity Rating Scale 
(C-SSRS) 
• 
12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
Anti-drug antibodies (ADAs) 
• 
Study drug exposure/compliance 
• 
Concomitant medication usage 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the optimal 
dose of BOS161721 based on 
safety, PK, and PD effects in 
patients with mild to moderate 
SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time 
point 
• 
Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), t½, systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• 
Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• 
Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit  
Exploratory 
• 
 
 
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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
 
 
• 
 
POC Phase 2 Study 
OBJECTIVES 
ENDPOINTS 
Primary 
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• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on the SLE Responder 
Index 4 (SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of subjects with a SRI-4 
response at Day 210 (see Section 6.3.4.1) 
Secondary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for 
response on clinical indicators of 
SLE activity, in adult patients with 
moderately to severely active SLE 
on limited background standard of 
care treatment 
Secondary Efficacy Endpoints 
• 
The proportion of subjects with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response (Section 
6.3.4.2) 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B 
flares relative to baseline through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
- 
Time to medication failure 
• 
Duration of SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B 
flare compared to baseline through Day 210 
Safety 


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• 
To assess safety and tolerability of 
repeat doses of BOS161721 (20, 
60, and 120 mg) administered SC 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each 
visit and change from baseline 
• 
Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
• 
Clinical laboratory results and change from 
baseline 
• 
Physical examinations changes from 
baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
Concomitant medication usage 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
• 
 
 
 
• 
 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, 
placebo-controlled trial to study the clinical efficacy, safety, and PK of 
multiple SC doses of BOS161721 in adult patients with moderately to 
severely active SLE.  After successfully completing a screening phase, 
patients will be randomized to a specified dose of BOS161721 or placebo.  
The dosing schedule will be monthly.  The trial will consist of 
2 double-blinded studies:  MAD Phase 1b and POC Phase 2.  Patients may 
receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 
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120, 150, and 180, followed by safety follow-up visits at Days 210, 240, and 
270.   
The MAD Phase 1b study phase will consist of 3 cohorts, with Cohort 1 
containing 6 patients, where 5 of these patients will receive BOS161721 
(active), and 1 will receive placebo.  Cohorts 2 and 3 will each contain 
12 patients, including 9 active and 3 placebo patients.  Dose selection for each 
cohort is based on 90-day safety, tolerability, PK, and PD data review from 
the Phase 1 SAD study (BOS161721-01) in healthy subjects.  Each of the 
3 doses (20, 60, and 120 mg) selected for the MAD study are projected not to 
exceed the mean exposure of that achieved in the SAD study following the 
single 240 mg SC dose.  Each patient may receive a total of 7 SC monthly 
doses on Days 0, 30, 60, 90, 120, 150, and 180.   
The MAD study design is staggered, where after the 6 patients in Cohort 1 
have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 2 begins dosing (after a DMC evaluates the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in 
Cohort 2 have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing after DMC evaluation of the 
safety and tolerability data from Cohort 2 and Cohort 1.  Two weeks after the 
last patient in Cohort 3 receives the second dose, the DMC and Boston 
Pharmaceuticals will conduct a data review to suggest which dose should be 
carried forward into the POC Phase 2 study.  This dose will not exceed doses 
tested during the MAD study.   
For the POC study, approximately 156 additional patients will be randomized 
to active or placebo groups in a 2:1 ratio.  As in the MAD study, each patient 
in the POC study may receive a total of 7 SC monthly doses on Days 0, 30, 
60, 90, 120, 150, and 180.   
A maximum daily dose of 30 mg/day of oral CS will be acceptable for 
eligibility for the study, however, daily dose must be tapered down to a 
maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization 
day).  One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 60.  Tapering of steroids during the 
course of the study will be encouraged and should be evaluated at all visits.  
Tapering may occur after randomization except within 60 days of the primary 
(Day 210) and secondary (Day 120) endpoint assessments.  Between Day 60 
and Day 120, and between Day 150 and Day 210, oral CS doses must be held 
constant. 
DMC safety reviews will be conducted periodically throughout the study as 
described in the DMC charter. 
Main Criteria 
for Inclusion 
Inclusion Criteria: 


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and Exclusion 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be 
evidence of a personally signed and dated informed consent document 
indicating that the patient has been informed of all pertinent aspects of the 
study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus 
International Collaborating Clinics (SLICC) classification criteria for SLE 
(with at least 1 clinical and 1 immunologic criterion OR Lupus nephritis 
as the sole clinical criterion in the presence of antinuclear antibodies 
[ANA] or anti- double-stranded deoxyribonucleic acid [dsDNA] 
antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central 
laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as 
determined by the central laboratory 
c. C3 or C4 below normal as determined by the central lab 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis  
i. 
Excluding parameters which require central laboratory results:  
(hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 
decreased complement, thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome will also 
be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 
1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and 
vasculitis 
i. 
Excluding parameters which require central laboratory results:  
hematuria, pyuria, urinary casts, proteinuria, positive anti-dsDNA, 
decreased complement, thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also 


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be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, 
which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active 
polyarthritis as defined in the protocol Section 4.4 
If only one “B” and no “A” score is present in the mucocutaneous body 
system or in the musculoskeletal body system due to arthritis, then at least 
1 “B” must be present in the other body systems for a total of 2 “B” 
BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at 
least 56 days (8 weeks prior to signing consent) of the following 
permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic 
acid, chloroquine, hydroxychloroquine, or methotrexate 
(MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at 
screening for a patient to be eligible and must be stable at a maximum 
of 10 mg/day for at least 5 days prior to Day 0 (randomization) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full 
information regarding WOCBP, definition of menopause, and 
contraception): 
a. Must have a negative serum pregnancy test at screening.  Urine 
pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug plus 5 half-lives of study 
drug BOS161721 plus 30 days (duration of ovulatory cycle) for a total 
of 36 weeks after treatment completion 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with study drug plus 5 half-lives of BOS161721 plus 90 days (duration of 


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sperm turnover) for a total of 44 weeks after treatment completion 
11. Patients must demonstrate willingness and ability to comply with the 
scheduled study visits, treatment plans, laboratory tests, and other 
procedures 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this 
study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid 
arthritis [RA], multiple sclerosis [MS], systemic scleroderma, or vasculitis 
not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are 
allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), 
or any elective surgery planned during the course of the study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube 
(QFT-G) or other diagnostic test in the absence of clinical 
manifestations.  Latent TB is not excluded if the patient has 
documented completion of adequate course of prophylactic treatment 
with regimen recommended by local health authority guideline, or the 
patient has started treatment with isoniazid, or other regimen 
recommended by local health authority guidelines for at least 1 month 
before Day 0 and continues to receive the prophylactic treatment 
during study until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, including but 
not limited to any condition defined by BILAG A criteria, with the 
exception of mononeuritis multiplex and polyneuropathy, which are 
allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires 
or may require induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to 
require additional systemic glucocorticosteroid therapy during the study, 
(eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is 
allowed 


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8. Use or planned use of concomitant medication outside of standard of 
baseline treatment for SLE from Day -1 or for any time during the study 
9. Active and clinically significant infection (bacterial, fungal, viral, or 
other) within 60 days prior to first dose of study drug.  Clinically 
significant is defined as requiring systemic antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe 
disseminated herpes zoster or disseminated herpes simplex within the last 
3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C 
(HCV), known human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS)-related illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 500/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if 
related to SLE, at screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia related to 
SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of 
proteinuria as assessed by protein/creatinine ratio (3 mg/mg or 
339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) 
< 40 ml/minute based on Cockcroft-Gault calculation 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the investigator’s 
judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related to lupus 
myositis  
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s 
syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, 
might place a patient at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of components of 
mAbs 
25. History substance and/or alcohol abuse, or dependence within the past 1 
year, at the investigator’s judgment 


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26. History of cancer within the last 5 years (except for cutaneous basal cell or 
squamous cell cancer, or cervical cancer in situ resolved by excision 
27. Any other severe acute or chronic medical or psychiatric condition, 
including recent (within the past year) medical conditions (eg, 
cardiovascular conditions, respiratory illnesses) that may increase the risk 
associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate 
for entry into this study 
28. Investigational site staff members directly involved in the conduct of the 
trial and their family members, site staff members otherwise supervised by 
the investigator, or patients who are employees of the sponsor or directly 
involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional 
(drug or device) clinical study within 30 days or 5 half-lives of baseline, 
whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior 
based on patient responding “yes” to question 3, 4, or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a 
psychiatric or physical (eg, infectious disease) illness 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be found in 
Section 8. 
Two analyses are planned:  1) an interim analysis to select the Phase 2 dose 
based on Phase 1 data, and 2) a final analysis at study completion.  
Additionally, DMC safety analyses will be performed after each Phase 1 
cohort and throughout Phase 2 to monitor patient safety.   
Unless stated otherwise, statistical testing will only be performed on the 
Phase 2 data and will be done using 2-sided overall alpha of 0.10.  Data will 
be summarized descriptively by treatment and overall for each study phase.  
For the MAD phase, BOS161721 will be summarized overall and by each 
dose level and placebo patients from each cohort will be combined.   
The descriptive summaries for the categorical data will include number and 
percentage.  The descriptive summaries for the continuous data will include 
number, mean, median, standard deviations (SD), 25th and 75th percentiles, 
minimum, median, and maximum.  Counts, medians, 25th and 75th 
percentiles, and standard error will be presented for time-to-event data. 
All safety analyses will be performed using the safety analysis set (SS), 
defined as all patients who receive at least 1 dose of study treatment.  All 
efficacy analyses will be performed using the full analysis set (FAS), defined 


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as all patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  Select efficacy analyses may 
also be performed on the per protocol (PP) set. 
Binary efficacy endpoints, including the primary efficacy endpoint, will be 
assessed via Pearson’s chi-squared analysis.   
Continuous efficacy endpoints will be assessed via analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA) when applicable, adjusting 
for the baseline value.  Repeated measures mixed models may be performed 
to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be 
compared using the log-rank test.   
Adverse event data will be coded to system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The 
number and percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class and preferred term will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and 
relationship.   
Concomitant medications will be summarized, based on coded terms, using 
frequency and percentage of patients.  Observed values and changes from 
baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters, will be summarized at each individual visit. 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................3 
PROTOCOL SUMMARY ...............................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF IN-TEXT TABLES ........................................................................................................19 
LIST OF IN-TEXT FIGURES.......................................................................................................19 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION AND RATIONALE .................................................................................24 
1.1 
Indication ...........................................................................................................................24 
1.2 
Background and Rationale .................................................................................................24 
1.2.1 
Overview of the Disease State .....................................................................................24 
1.2.2 
BOS161721 Development ...........................................................................................24 
1.2.2.1 
Interleukin-21 .........................................................................................................25 
1.2.2.2 
Preclinical Studies ..................................................................................................26 
1.2.2.3 
Clinical Studies ......................................................................................................27 
1.2.3 
Study Dose Selection ...................................................................................................28 
1.2.4 
Risk-Benefit Assessment .............................................................................................29 
1.2.5 
Potential Risks .............................................................................................................29 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................30 
1.2.5.2 
Injection Site Reactions .........................................................................................30 
1.2.5.3 
Immune Complex Disease .....................................................................................31 
1.2.5.4 
Infections................................................................................................................31 
1.2.5.5 
Malignancy ............................................................................................................32 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................32 
1.2.5.7 
Failure of Vaccination............................................................................................33 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................33 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................33 
2 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................33 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................34 
2.2 
Phase 2 Proof of Concept ...................................................................................................35 
3 
STUDY PLAN........................................................................................................................37 
3.1 
Study Design ......................................................................................................................37 
3.1.1 
Multiple Ascending Dose Phase 1b Study ...................................................................37 
3.1.1.1 
Dose Escalation for the MAD Study .....................................................................38 
3.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................38 
3.1.1.3 
DMC Recommendations ........................................................................................39 


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3.1.2 
POC Phase 2 Study ......................................................................................................39 
3.1.2.1 
BOS161721 Dose...................................................................................................39 
3.1.2.2 
POC Study Design .................................................................................................39 
3.2 
Randomization and Blinding .............................................................................................40 
3.3 
Study Schematic.................................................................................................................41 
3.4 
Schedule of Assessments ...................................................................................................42 
4 
POPULATION .......................................................................................................................50 
4.1 
Participant Recruitment .....................................................................................................50 
4.2 
Number of Patients ............................................................................................................50 
4.3 
Patient Screening ...............................................................................................................50 
4.4 
Inclusion Criteria ...............................................................................................................50 
4.5 
Exclusion Criteria ..............................................................................................................52 
4.6 
Concomitant Medications ..................................................................................................54 
4.6.1 
Oral Corticosteroid Dose .............................................................................................55 
4.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................56 
4.7 
Women of Childbearing Potential .....................................................................................56 
4.7.1 
Determination of Menopause .......................................................................................56 
4.7.2 
Contraception ...............................................................................................................57 
4.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................57 
4.8.1 
Patient Withdrawal and Replacement ..........................................................................58 
5 
STUDY PROCEDURES ........................................................................................................58 
5.1 
Screening............................................................................................................................58 
5.1.1 
Retesting During Screening Period ..............................................................................59 
5.2 
Enrollment/Randomization and Day 0 Treatment .............................................................59 
5.3 
Treatment Period/Follow-Up Visits ...................................................................................60 
5.4 
Safety Follow-Up Visits ....................................................................................................61 
5.5 
Premature Discontinuation.................................................................................................62 
6 
ASSESSMENTS.....................................................................................................................62 
6.1 
Medical History, Demographic and Other Baseline Information ......................................62 
6.2 
Safety Assessments ............................................................................................................63 
6.2.1 
Laboratory Assessments ..............................................................................................63 
6.2.1.1 
Pregnancy testing ...................................................................................................65 
6.2.1.2 
Tuberculosis Screening ..........................................................................................65 
6.2.2 
Adverse Events ............................................................................................................66 
6.2.2.1 
Definitions..............................................................................................................66 
6.2.2.2 
Recording of Adverse Events ................................................................................66 
6.2.2.3 
Severity of Adverse Events ....................................................................................66 
6.2.2.4 
Causality of Adverse Events ..................................................................................67 
6.2.2.5 
Seriousness of Adverse Events ..............................................................................67 
6.2.2.6 
Adverse Events of Special Interest ........................................................................68 
6.2.2.7 
Reporting of Adverse Events .................................................................................71 


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6.2.2.8 
Follow Up of Adverse Events ................................................................................73 
6.2.3 
Vital Signs ....................................................................................................................73 
6.2.4 
12-Lead Electrocardiograms ........................................................................................73 
6.2.5 
Physical Examinations .................................................................................................73 
6.2.6 
C-SSRS ........................................................................................................................74 
6.2.7 
Injection Site Reactions ...............................................................................................74 
6.2.8 
Immunogenicity ...........................................................................................................74 
6.3 
Efficacy Assessments.........................................................................................................75 
6.3.1 
SLEDAI-2K .................................................................................................................75 
6.3.2 
BILAG 2004 ................................................................................................................75 
6.3.3 
PGA of Disease Activity ..............................................................................................75 
6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................76 
6.3.4.1 
SRI-4 Response ......................................................................................................76 
6.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................76 
6.3.4.3 
BICLA Response ...................................................................................................76 
6.3.5 
CLASI Response ..........................................................................................................76 
6.3.6 
ACR-28 Joint Count ....................................................................................................76 
6.4 
Other Variables ..................................................................................................................77 
6.4.1 
SLICC/ACR Damage Index ........................................................................................77 
6.4.2 
PROs ............................................................................................................................77 
6.5 
Pharmacokinetic Assessments ...........................................................................................77 
6.6 
Pharmacodynamic Assessments ........................................................................................77 
6.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................78 
6.8 
Protocol Deviations ............................................................................................................78 
7 
STUDY DRUG MANAGEMENT .........................................................................................78 
7.1 
Description .........................................................................................................................78 
7.1.1 
Formulation ..................................................................................................................78 
7.1.2 
Storage .........................................................................................................................78 
7.2 
Packaging and Shipment ....................................................................................................78 
7.3 
Dose and Administration ...................................................................................................78 
7.4 
Accountability ....................................................................................................................79 
7.5 
Prohibited Concomitant Therapy .......................................................................................79 
7.6 
Compliance ........................................................................................................................79 
8 
STATISTICS ..........................................................................................................................79 
8.1 
Sample Size ........................................................................................................................80 
8.2 
Statistical Methods .............................................................................................................81 
8.2.1 
Analysis Populations ....................................................................................................81 
8.2.2 
Demographics and Baseline Characteristics ................................................................81 
8.2.3 
Primary Efficacy Endpoint(s) ......................................................................................81 
8.2.4 
Secondary Efficacy Endpoint(s) ..................................................................................82 
8.2.5 
Analysis of Safety ........................................................................................................82 


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8.2.5.1 
Safety Analysis ......................................................................................................82 
8.2.6 
Pharmacokinetic and Pharmacodynamic Data .............................................................82 
8.2.6.1 
Analysis of Pharmacokinetic Data .........................................................................82 
8.2.6.2 
Analysis of Pharmacodynamic Data ......................................................................83 
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ..................................83 
8.3 
Interim Analysis and Power ...............................................................................................83 
9 
ETHICS AND RESPONSIBILITIES .....................................................................................83 
9.1 
Good Clinical Practice .......................................................................................................83 
9.2 
DMC ..................................................................................................................................83 
9.3 
Institutional Review Board/Independent Ethics Committee..............................................84 
9.4 
Informed Consent...............................................................................................................84 
9.5 
Records Management.........................................................................................................85 
9.6 
Source Documentation .......................................................................................................85 
9.7 
Study Files and Record Retention......................................................................................86 
10 AUDITING AND MONITORING ........................................................................................86 
11 AMENDMENTS ....................................................................................................................86 
12 STUDY REPORT AND PUBLICATIONS ...........................................................................87 
13 STUDY DISCONTINUATION .............................................................................................87 
14 CONFIDENTIALITY ............................................................................................................87 
15 REFERENCES .......................................................................................................................88 
16 APPENDICES ........................................................................................................................92 
APPENDIX 1 
NAMES OF STUDY PERSONNEL ...............................................................92 
APPENDIX 2 
DECLARATION OF HELSINKI....................................................................93 
APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ......................97 
APPENDIX 4 
MEDICATION WASHOUT PERIODS..........................................................98 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA).........................99 
APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE ...................................100 
APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES ...................................................101 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .........................42 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study .....................46 
Table 3. 
Laboratory Tests ....................................................................................................64 
Table 4. 
Causality Definitions .............................................................................................67 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................28 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies ..............................41 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
CS 
corticosteroids 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
 
 
FAS 
full analysis set 
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Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
INFγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MedDRA 
Medical Dictionary of Regulatory Activities 
MS 
multiple sclerosis 
MTX 
methotrexate 


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NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PP 
per protocol 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-
wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS  
safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
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STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
TT 
tetanus toxoid 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1. INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids (CS), immunosuppressants, and cytotoxic 
agents.1  However, some of the morbidity in patients with SLE is related to its treatment.  
Comparison of early and late outcomes in patients with SLE demonstrate that death in early 
disease is most commonly due to infections and active SLE causing multi-system organ damage, 
while thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb directed against human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t1/2) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies.  
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses).  
 
 
 
 
 
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  The NOAELs were determined to be 100 mg/kg IV and 50 mg/kg SC, the highest 
doses tested. 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: 
placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 
30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first 
cohort, after the first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 
48 hours before the remaining subjects from that cohort were dosed, to allow for an initial review 
of any emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not 
sooner than 8 days after all the subjects in the prior cohort had been dosed and were based on a 
review of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included electrocardiograms (ECGs), vital signs (blood pressure [BP], heart rate, and 
temperature), safety laboratory assessments, blood sampling for ADAs, total IgG and 
immunoglobulin M (IgM) levels, CD4+ count, and full and targeted physical examinations.  
Overall, there were no clinically significant findings from this study, following an interim cut 
and review of the data at Day 90 postdose.  Adverse events reported as related to the study drug, 
particularly infections, were expected for the compound, and there were no clinically relevant 
changes in laboratory and ECG results or vital signs.  There was 1 serious adverse event (SAE; 
death due to pulmonary embolism) that occurred 127 days after a single administration of 
240 mg SC dose of BOS161721.  The causality of this single SAE was not attributed to study 
drug and further information can be found in the Investigator’s Brochure.  PK data from the SAD 
study demonstrates BOS161721 has an extended t1/2 (provisional single dose data indicates this 
to be approximately 42-46 days) which supports evaluation of monthly dosing.  
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1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1 study based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose 
level, repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant 
safety or tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD phase of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median first time to maximum concentration (Tmax) of 6 days and an apparent 
terminal half-life of 44 days.  Furthermore, pSTAT3 suppression, a marker of IL-21 target 
engagement, follows a similar time course of the mAb levels, with maximal and sustained 
suppression apparent with doses greater than 30 mg SC (Figure 1).   
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 


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Clinical Study Protocol:  BOS161721-02 
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All doses selected for the MAD study are projected not to exceed the mean exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD 
study.  Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered 
study design, the data monitoring committee (DMC) will perform a scheduled review of safety 
data and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC and 
Boston Pharmaceuticals will conduct a data review to suggest which dose should be carried 
forward into the proof of concept (POC) Phase 2 study.  This POC dose decision will be based 
on evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD study (see 
Section 3.1.1.1).     
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD study.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  
Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Two weeks after the last patient in Cohort 3 receives the second dose, the 
DMC and Boston Pharmaceuticals will conduct a data review to suggest which dose should be 
carried forward into the POC Phase 2 study.  This POC dose decision will be based on evaluation 
of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3 during the MAD study.  Thereafter, DMC safety 
reviews will be conducted periodically throughout the study as described in the DMC charter.  
With the agreement of the DMC and sponsor, this schedule may be modified depending on the 
rate of patient accrual.  Additional details can be found in the DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), autoimmunity, or altered BOS161721 levels or activity.  Further details can be found 


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in the current Investigator’s Brochure (IB) for BOS161721, which contains comprehensive 
toxicology, preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational 
products.  Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to 
the study drug, particularly infections (flu-like symptoms, etc), were expected for the compound, 
and there were no clinically relevant changes in laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 
this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 6.2.2.6.1. 
Based on the limited Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic 
reactions in subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) for 3 months (a total of 7 doses); no SC animals had 
injection reactions. 


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Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 6.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 
ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 
Based on the limited Phase 1 SAD study (BOS161721-01), immune complex disease in subjects 
who received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 


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Clinical Study Protocol:  BOS161721-02 
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BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and will be excluded from the proposed MAD/POC studies.  
Patients exposed to investigational product who develop diarrhea during the course of the study 
should immediately undergo an assessment for opportunistic infection including stool for ova 
and parasites and stool examination for cryptosporidium.  Positive cryptosporidium in stool 
sample at screening is an exclusion.  Treatment by the investigator where indicated should be 
guided by findings and be consistent with local standard of care. 
Based on the limited Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 
and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the limited Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from the MAD study.  Patients with a positive hepatitis 
B or C test or a history of alcohol dependence will also be excluded. 
Based on the limited Phase 1 SAD study (BOS161721-01), hepatic function abnormality in 
subjects who received BOS161721 was not observed. 


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1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen; however, it is worth noting that 
BOS161721 administration did not produce any remarkable changes in anti-KLH antibody data 
for IgM, IgG1, IgG3, and IgG4 or anti-tetanus toxoid (TT) antibody data for IgM, IgG, IgG1, or 
IgE during the dosing phase in the same study. 
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 
oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 4.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 4.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES AND ENDPOINTS 
This trial has separate objectives and endpoints for the MAD Phase 1b and POC Phase 2 studies.  
The primary, secondary, and exploratory objectives for each phase, as applicable, are described 
below with their corresponding endpoints. 


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2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered SC in adult patients with 
moderately to severely active SLE on 
limited background standard of care 
treatment, in order to estimate the optimal 
dose. 
Safety Endpoints 
• 
Incidence and severity of AEs and SAEs, related AEs, AEs 
leading to study drug discontinuation, AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide severity Rating Scale (C-SSRS) 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
• 
Concomitant medication usage 
Secondary 
• 
To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with mild to moderate 
SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by visit and time point 
• 
Maximum observed concentration (Cmax), Tmax, area under 
the concentration-time curve (AUC), terminal elimination 
half-life (t½), systematic clearance (CL), volume of 
distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) from baseline to each visit in 
phosphorylated signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) from baseline in anti-
double-stranded DNA (dsDNA), antinuclear antibodies 
(ANA), anti-Sjögren syndrome A and B (SSA, SSB), Smith 
(Sm), and antiphospholipid (APL) autoantibodies at each 
visit 
• 
Results and changes (or shifts) from baseline in abrogation 
of IL-21 gene signature at each indicated visit 


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Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
 
2.2 
Phase 2 Proof of Concept 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on the SRI-4  
Primary Efficacy Endpoint 
• 
The proportion of subjects with a SRI-4 response at 
Day 210 (see Section 6.3.4.1) 
Secondary 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
Secondary Efficacy Endpoints 
• 
The proportion of subjects with: 
- 
SRI-4 response at each visit 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
- 
SRI-5 and SRI-6 response (Section 6.3.4.2) 
- 
a sustained reduction of oral corticosteroid (CS) 
(≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B flares relative to 
baseline through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
- 
Time to medication failure 
• 
Duration of SRI-4 response 
• 
Time to first SRI-4 response 
• 
Time to BILAG A flare or > 1 BILAG B flare compared to 
baseline through Day 210 
Safety 
• 
To assess safety and tolerability of repeat 
doses of BOS161721 (20, 60, and 120 
mg) administered SC in adult patients 
with moderately to severely active SLE 
on limited background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs), related AEs, AEs leading to study 
drug discontinuation, AEs by severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter results at each visit and change 
from baseline 
• 
Vital signs (blood pressure [BP], heart rate, and 
temperature) parameter results at each visit and change 
from baseline 
• 
Clinical laboratory results and change from baseline 
• 
Physical examinations changes from baseline 
• 
ADAs 
• 
Study drug exposure/compliance 
• 
Concomitant medication usage 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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3 STUDY PLAN 
3.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
moderately to severely active SLE.  After successfully completing a screening phase, patients 
will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule will be 
monthly.   
The trial will consist of 2 double-blinded studies:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visits at Days 210, 240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease being studied.  Further details on the content and methods of data reports by the medical 
monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
3.1.1 
Multiple Ascending Dose Phase 1b Study 
The MAD study will consist of 3 cohorts:  
• 
Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• 
Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
 
• 
 
  
 
• 
 
 
• 
 
 
• 
 
CCI
CCI
CCI
CCI
CCI


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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the MAD study are projected not to exceed the mean exposure of that achieved in the SAD 
study.   
3.1.1.1 
Dose Escalation for the MAD Study  
The MAD study design is staggered, where after the 6 patients in Cohort 1 have received 2 doses 
and have completed 2 weeks of follow-up after the second dose, Cohort 2 begins dosing (after 
DMC evaluation of the safety and tolerability data from Cohort 1).  Similarly, after 8 of the 
12 patients in Cohort 2 have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing after DMC evaluation of the safety and tolerability data 
from Cohorts 1 and 2.  Each cohort will continue at their assigned dose level through their 
respective 6-month treatment periods (See Study Schematic, Section 3.1).  If patients discontinue 
the study in a cohort prior to adequate safety follow-up, he/she may be replaced. 
Criteria for dose escalation are further described in the DMC Charter.  See Section 3.1.1.2 for 
additional details about DLTs.   
3.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia 
• Grade 3 neutropenic infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia 
Non-Hematologic: 
• 
Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals) 
• 
Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 6.2.2.6.3 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances. 


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3.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD study, the DMC may provide the following recommendations to the 
sponsor: 
• 
Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort 
• 
Continuing a dose level for a given cohort 
• 
Escalating a dose level for a subsequent cohort 
• 
Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC study, the DMC and Boston Pharmaceuticals will conduct a 
data review to suggest which dose should be carried forward into the POC Phase 2 study.  This 
POC dose decision will be based on evaluation of the PK, safety (inclusive of dose-limiting 
toxicity [DLT]), and tolerability data (and available PD/biomarker data) from Cohorts 1, 2, and 
3; this dose will not exceed doses tested during the MAD study.  The DMC will be reviewing all 
relevant data from Cohorts 1, 2, and 3 that is available at the time the last patient in Cohort 3 
completes the Day 44 visit (2 weeks after dose 2).  Details are provided in the DMC Charter.  
3.1.2 
POC Phase 2 Study 
3.1.2.1 
BOS161721 Dose  
The optimal dose evaluation is chosen based on MAD Phase 1b safety, tolerability, 
immunogenicity, and PK and PD data.  The dose will be communicated by a letter to site 
investigators participating in the POC Phase 2 study, and to the IRB/IEC. 
3.1.2.2 
POC Study Design 
For the POC study, approximately 156 additional patients will be randomized to active or 
placebo groups in a 2:1 ratio.   
As in the MAD study, each patient in the POC study may receive a total of 7 SC monthly doses 
of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be completed 
according to the Schedule of Assessments (Section 3.4).  Dose selection will be based on the 
DMC and sponsor’s assessment of safety, tolerability, immunogenicity, and PK and PD data 
from the MAD study of 30 patients treated with BOS161721/placebo. 
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 


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Clinical Study Protocol:  BOS161721-02 
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3.2 
Randomization and Blinding 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
phase and separately for each cohort in the Phase 1b and 2 portions as follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to confirm sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study phase which is active at time of enrollment.  
Similarly, patients in the Phase 1 MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the interim analysis (IA) and the DMC safety reviews.  The DMC will review 
unblinded data during safety reviews and the IA.  A limited team at Boston Pharmaceuticals will 
review unblinded results from the Phase 1b MAD portion during the IA to determine the dose 
that will be used for the Phase 2 POC portion of the study.  Details regarding maintenance of the 
blinding and content of data reviews will be described in the DMC charter or related study 
documentation.   
 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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3.3 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies 
 
A = active drug (BOS161721); P = placebo 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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3.4 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site 
reaction assessment 
 
Xf 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 43 of 143 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
SLEDAI-2K 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)h 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3l 
 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 44 of 143 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xm 
Xm 
Xm 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)n 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
TB test 
(QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis 
B and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool sampleo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labs 
Predose 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
Xq 
X 
X 
Xq 
 
 
 
 
 
Xq 
X 
X 
X 
X 
X 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 45 of 143 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SAE = serious adverse event; SC = subcutaneous; 
 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; 
 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 7, 187, and 195).  When the timing 
of these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
i 
When clinically indicated for hemolytic anemia. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
k 
nAb is assessed if patient is positive for ADA. 
l 
Predose (trough) samples only. 
m 
Only dsDNA collected during safety follow-up visits.  
n 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
o 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
p 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180. 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 46 of 143 
 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo dosing  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessment 
 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 47 of 143 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory assessments 
(hematology and clinical 
chemistry)h 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Whole blood for leukocyte 
immunophenotype 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xl 
Xl 
Xl 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)m 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
TB test (QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 48 of 143 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Spot urine for protein/creatinine 
ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labso 
Predose 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb  = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; 
SLICC = Systemic Lupus International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell 
dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the 
daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 4.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after eligibility 
confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 187 and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
i 
When clinically indicated for hemolytic anemia. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
CCI
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 49 of 143 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
k 
nAb is assessed if patient is positive for ADA. 
l 
Only 
 collected during safety follow-up visits. 
m 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
n 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, 
and cryptosporidium. 
o 
PK samples will only be collected at the investigational sites that will be participating in the PK portion of the study. 
 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 50 of 143 
4 POPULATION 
4.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
4.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b study, and approximately 156 additional patients will be randomized in the POC Phase 2 
study.  Note that approximately 24 dropouts are assumed.   
4.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Section 3.4]) for this study must be 
performed between Day -28 and Day -1. 
4.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 
immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory 
c. C3 or C4 below normal as determined by central lab 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 51 of 143 
5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) must be ≥ 6, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis 
i. 
Excluding parameters which require central laboratory results:  hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
7. Patients must have at least 1A or 2Bs from the following manifestations of SLE, as defined 
by the BILAG criteria as modified for use in this study, which must be confirmed by the 
central data reviewer:  
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis in ≥ 2 joints with marked loss of functional range of movements and 
significant impairment of basic activities of daily living that has been present on 
several days cumulatively over the past 30 days, including at the time of the 
screening visit.  See APPENDIX 5 for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require assistance or 
assistive devices, (at least 1 must be present and documented in source): 
o Ambulation, toileting, grooming- including bathing and dressing; feeding 
oneself 
ii. “BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional range of movements 
which lead to some loss of functional range of motion as manifested by effects on 
instrumental ADLs such as: 


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• Cooking, driving, using the telephone or computer, shopping, cleaning, etc, and 
has been present on several days over the last 30 days, and is present at the time 
of the screening visit 
If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to signing consent) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at screening for a patient 
to be eligible and must be stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 0 (randomization) (see APPENDIX 3) 
9. Women of childbearing potential (WOCBP; see Section 4.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after treatment completion 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 5 half-lives of 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
treatment plans, laboratory tests, and other procedures 
4.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic scleroderma, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any elective 
surgery planned during the course of the study 


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4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 0 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to require additional 
systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is allowed 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 4.6 for prohibited 
concomitant medication) 
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV), known human 
immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related 
illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 500/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol) 


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19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to lupus 
based on the investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, might place a patient 
at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the C-SSRS 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
4.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen of other 
concomitant medications for the treatment of SLE (eg, analgesics, NSAIDs, statins, ACE 
inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments are 


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clinically indicated.  Use of any other drugs for non-SLE conditions, including over-the-counter 
medications and herbal preparations, should remain stable unless change or addition is clinically 
necessary.  Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
4.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, 
however, the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days 
prior to Day 0 (randomization day). 
After Day 0 (after initiation of study therapy), no up-titration above 10 mg/day is allowed except 
for up to 1 CS burst for increased disease activity.  
Tapering of steroids during the course of the study will be encouraged and should be evaluated at 
all visits.  
• 
Once a patient has received the first dose of study drug, prednisone (or prednisone 
equivalent) may be tapered down at the discretion of the investigator 
o Tapering is allowed after randomization except within 60 days of the primary (Day 210) 
and secondary (Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant. 
A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed during the 
study between Day 0 and Day 60, according to the following:   
• 
An oral CS “burst” between Day 0 and Day 60; (an increase of ≤ 40 mg/day of prednisone or 
equivalent), which must be tapered down to a maximum of 10 mg/day within 2 weeks of 
initiation of the “burst” 
o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o The course of the oral CS “burst” is not permitted to extend beyond Day 60 
Treatment with inhalational CS therapy (eg, for asthma), or by any other route, is allowed.  Other 
concomitant medications for SLE need to be taken at stable doses as per the inclusion criteria 
(Section 4.4). 


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4.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and during the 
study are described below, and washout requirements are provided in APPENDIX 4.  
Medications taken within 30 days prior to screening must be recorded on the eCRF. 
1. Prior exposure to BOS161721 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
6 months of screening; recovery of B cells (CD19+) must be documented (record absolute 
number of CD19+ B cells) 
3. Patients who have received treatment with cyclophosphamide within the 1 year prior to 
screening 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria (oral or topical) within 3 months of screening 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 8 weeks prior to screening 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc, may be used 
according to local guidelines during treatment period 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation 
4.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 
See Section 4.7.2 for detailed information regarding contraceptive requirements for WOCBP. 
4.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   


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4.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 5 half-lives of study drug 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
At a minimum, patients must agree to the use of 1 method of highly effective contraception from 
the following: 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who 
are WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• 
IUDs, such as ParaGard® 
• 
Vasectomy 
• 
Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception.  Women who are abstinent while participating in the study 
must continue to have pregnancy tests.  Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego complete 
abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, they must still undergo pregnancy testing. 
4.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient continue or 
withdrawal from the study medication.    
See Section 6.8 for additional details.  


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4.8.1 
Patient Withdrawal and Replacement 
See Section 5.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD study after discussion between the principal investigator or designee and 
sponsor. 
5 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
5.1 
Screening 
Screening will be the same for both the MAD and POC studies. 
Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria, listed in Section 4.4 and Section 4.5 respectively, will be enrolled in 
the study.  Screened patients who drop out of the clinical study before randomization will be 
recorded as screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• 
Medical history documentation 
• 
Review of inclusion and exclusion criteria 
o Patient medical records must contain documentation of SLE diagnosis 
o C-SSRS   
• 
Concomitant medication documentation 
• 
Demographics 
• 
Full physical examination 
• 
Vital signs 
• 
Chest x-ray 
• 
Laboratory evaluations (nonfasting): 
o Hematology and clinical chemistry 
o Serology (Hepatitis B and C; HIV-1/2 combination) 
o TB test 
o CRP 


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o Direct Coomb’s test (if indicated for hemolytic anemia) 
o CD4+ count, total IgG and IgM levels, plasma 
, 
 
 
o Serum pregnancy test (WOCBP) 
o FSH (postmenopausal women) 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
o Stool sample  
• 
12-lead ECG 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity 
Screening procedures are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
5.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• 
medically indicated 
• 
there is evidence a laboratory sample was mislabeled, indeterminate, inadequately processed, 
and/or deteriorated in transit to the central laboratory 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
5.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.   
The study site will obtain a randomization number when registering the patient in IWRS.  All 
patients will receive BOS161721 or placebo according to the kit number assigned by the IWRS 
randomization scheme.    
After randomization, procedures include: 
• 
PROs:  
 
• 
C-SSRS 
• 
Laboratory evaluations (fasting): 
o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated for hemolytic anemia) 
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o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype 
o ADA 
o pSTAT3 (predose [trough] samples only in Phase 1b)  
o 
 
o 
 
o 
 
o See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Full physical examination 
• 
Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 0) 
• 
12-lead ECG (prior to PK blood draw) 
• 
SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, PGA) 
• 
SLICC/ACR damage index 
• 
Study drug administration: 
o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 7.3 
• 
Injection site reaction assessment performed at 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Section 3.4), and details are 
provided in Section 6. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
5.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of Assessments (Table 
1 and Table 2).  See Schedule of Assessment tables for allowable windows for each visit.   
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Concomitant medication documentation 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
PROs:  
 
• 
Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
• 
Injection site reaction assessments will be performed predose  
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• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Spot urine for protein to creatinine ratio 
• 
Urinalysis 
• 
 
• 
Plasma 
 
• 
PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
• 
SLICC/ACR Damage Index will be completed at Day 180 
• 
C-SSRS 
• 
ECGs prior to PK blood draw 
• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
• 
Fasting hematology and chemistry assessments  
• 
The CD4+ count and total IgG and IgM levels  
• 
Plasma 
 & 
, ADA, and whole blood for leukocyte immunophenotype 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
CRP and nAb will be assessed if patient is positive for ADA 
• 
 
5.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270.  These visits will include the 
following assessments as indicated in the Schedule of Assessments (Table 1 and Table 2):  
• 
PROs:  
 
• 
Documentation of AEs and SAEs (see Section 6.2.2.5 on SAE reporting requirements) 
• 
Injection site reactions 
• 
Targeted physical examination 
• 
Vital signs (prior to PK blood draw) 
• 
Spot urine for protein/creatinine ratio and urinalysis 
• 
Concomitant medication documentation 
• 
BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
• 
Fasting clinical laboratory assessments (hematology and clinical chemistry) 
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
• 
Plasma 
 
• 
 
• 
12-lead ECG (prior to PK blood draw) 
• 
CRP 
• 
ADA 
• 
 
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• 
See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
5.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Day 180) and a last follow-up visit 90 days after dosing should be scheduled 
(Day 270).  Safety follow-up visit procedures based on the Schedule of Assessments (see 
Section 5.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• 
AE/SAE 
• 
Protocol deviation 
• 
Lost to follow-up 
• 
Patient withdraws consent at their own request 
• 
Investigator decision 
• 
Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
6 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
6.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• 
General medical history 


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• 
Documentation of SLE diagnosis 
• 
Historical medication therapy for SLE 
The following demographic information will be recorded:  
• 
Age 
• 
Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• 
Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• 
Height (without shoes, in cm) 
• 
Body weight, without shoes (kg) 
• 
Body mass index (BMI [kg/m2]) 
Other baseline characteristics will be recorded as follows: 
• 
Concomitant medication documentation (see Section 4.6) 
• 
Status of child bearing potential and contraception 
6.2 
Safety Assessments 
6.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Section 3.4).  Patient eligibility will be determined based on these tests at screening.  
Unscheduled clinical labs may be obtained at any time during the study to assess any perceived 
safety concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests and stool analysis) 
to ensure accuracy and consistency in test results.  The central laboratory will transmit all results 
for protocol tests, scheduled and unscheduled, to the clinical data base.  Laboratory/analyte 
results that could unblind the study (ie, biomarker results) will not be reported to investigative 
sites.  Urinalysis will be performed on midstream, clean catch specimens.  Some biomarkers 
listed above will not be drawn at some sites due to geographical logistical challenges.  See the 
laboratory manual for details. 
Endpoint analyses will be based on changes from baseline assessments at Days 120 and 210. 
 
 


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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test 
(QFT-G)  
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only in Phase 1b) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte 
immunophenotype  
 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
dsDNA = double-stranded deoxyribonucleic acid;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; 
nAb = neutralizing antibody; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; 
PT = prothrombin time; qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; SAE = serious 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
adverse event; SC = subcutaneous; 
; TB = tuberculosis.  
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for 
ova, parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 6.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated for hemolytic anemia. 
 
6.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or 
continued and a further negative urine pregnancy test results will then be required at the baseline 
visit before the patient may receive the investigational product.  Urine pregnancy tests will also 
be routinely repeated at study drug administration visits prior to study drug administration, and 
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive pregnancy test or confirmed pregnancy, the patient will be 
discontinued from study drug, an EOT visit should be performed (Day 180), and a last follow-up 
visit 90 days after last dose should be scheduled (Day 270).  Safety follow-up visit procedures 
based on the Schedule of Assessments (see Section 5.4). 
See Section 6.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
6.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 4.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 0). 
6.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
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Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 
study.  If a repeat test is indeterminate again, the patient is a screen failure.  The procedure for 
using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
6.2.2 
Adverse Events 
6.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 6.2.2.5). 
6.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset (and time, if known), date of AE outcome (and time, if known), and action 
taken for the AE will be documented together with the principal investigator’s assessment of the 
seriousness of the AE and causal relationship to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
6.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 
and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 


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6.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 4) should be selected based on medical 
judgment, considering the definitions below and all contributing factors. 
Table 4. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation (positive dechallenge), or the 
symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that there are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists (for 
example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
6.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• 
Requires hospitalization or prolongation in existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Is a congenital anomaly or birth defect 
• 
Is another important medical event (see below) 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 


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• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• 
Development of drug dependency or drug abuse 
Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
6.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Grades 2 to 5 injection site reaction, including erythema, pain, and induration (See 
APPENDIX 6) 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, and 
disseminated tuberculosis 
6. Cryptosporidiasis 
6.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 


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2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline 
6.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These will include Grades 2 to 5 
injection site erythema, pain, and induration (see APPENDIX 6).  The investigator should 
provide a clear description of the observed or reported AE including location and severity.  All 
concomitant treatments used to treat injection site reactions should be recorded and captured in 
the eCRF, together with the AE of injection site reactions.   
6.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 6.2.2.7.2 for reporting details). 
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 


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2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• 
ALT or AST > 8 × ULN 
• 
ALT or AST > 5× ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 
• 
ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
• 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
6.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 6.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue, the investigator and/or consultant(s) should contact the 
sponsor clinicians or designee to discuss the issue and any decisions as soon as possible. 


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6.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, shingles, disseminated herpes simplex, or disseminated 
tuberculosis will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
6.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 6.2.2.7.2. 
6.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 
adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 


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6.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Day 270).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• 
Study number 
• 
Patient number 
• 
Details of the SAE (verbatim details are sufficient for immediate notification) 
• 
Criterion for classification as ‘serious’ 
• 
Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 
obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   
6.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becomes aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 


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Potential DILI will be reported based on specifications mentioned in Section 6.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate, and is further outlined in Section 6.2.2.7.2. 
6.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 6.2.2.7.1 for details related to follow-up of pregnancy.  See Section 6.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 6.2.2.6.4 for details related to follow-
up of malignancy. 
6.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Section 3.4).  Vital signs will be assessed on Day 0 at predose and at 
1 and 2 hours postdose, as well as on each of the scheduled visit days during the study 
(excluding PK-only site visits).  Supine BP and heart rate recordings will be made after the 
patient has been recumbent and at rest ≥ 5 minutes.  When the timing of these measurements 
coincides with a blood collection, vital signs should be obtained prior to the time of the blood 
collection. 
6.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Section 3.4).  ECG recording 
will initiate after the patient has been supine for at least 5 minutes.  On days of PK blood draws, 
the ECG will be collected before scheduled PK blood draws, though timing will be such that PK 
draws are collected on their scheduled times where possible. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 
6.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 


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thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at all other visits as indicated in 
the Schedule of Assessments (Section 3.4).  It includes evaluation of patient complaints and SLE 
disease-related issues, and will exclude the genitourinary system. 
6.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments 
(Section 3.4).  Patients with recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 is exclusionary at screening 
will be excluded from the study.  Patients with recent or active suicidal ideation or behavior at 
subsequent study visits will have responses to the C-SSRS reviewed in detail to assess patient 
risk, and appropriate consultative mental health services will be provided. 
6.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule of 
Assessments (Section 3.4).  Local injection site reactions will be assessed at 2 hours postdose at 
baseline, and predose for each injection after baseline.  Injection site reactions should be 
managed according to the standard of care.  Injection site reactions, Grades 2 to 5, are to be 
reported as AEs of special interest (see Section 6.2.2.7.3). 
6.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in the 
Schedule of Assessments (Section 3.4).  Blood samples (4 mL) to provide approximately 1.5 mL 
of plasma for anti BOS161721 antibody analysis will be collected into appropriately labeled 
tubes containing K2EDTA.  The presence or absence of ADA will be determined in the serum 
samples using validated bioanalytical methods.  Blood samples for ADA analysis will be 
collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all 
patients but only assayed if the patient had a positive ADA on Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, the 
sample from this patient will be further analyzed in the neutralizing antibody (nAb) assay. 


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6.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of Assessments 
(Section 3.4). 
6.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
6.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 
4 weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, 
worksheet, clinic notes, and labs) at each visit. 
See APPENDIX 5 for detailed specifications. 
6.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.   
When scoring the PGA, the assessor should always look back at the score from the previous 
visit. 


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6.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
6.3.4.1 
SRI-4 Response 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 0.3 points.  The SRI-4 response in patients with moderate to severe 
SLE is associated with broad improvements in clinical and patient-reported outcomes.45  
6.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal three-point or five-point improvement in 
SLEDAI-2K being required, respectively.46 
6.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 
For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined. 
6.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 
6.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 


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6.4 
Other Variables 
6.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Days 0 
and 180. 
6.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
 and will be assessed as 
specified in the Schedule of Assessments (Section 3.4). 
 
     
 
.   
6.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) studies, blood samples 
for PK analysis of BOS161721 or placebo concentration will be collected according to Table 1 
and Table 2. 
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration actual time profiles.   
6.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the Schedule of 
Assessments (Section 3.4) for each of the following parameters: 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
• 
Antibodies:  
  
• 
Plasma complement (
)  
• 
Plasma 
 and 
  
• 
Whole blood for leukocyte immunophenotype  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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6.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
6.8 
Protocol Deviations 
Protocol deviations will be documented during the study.   
7 STUDY DRUG MANAGEMENT 
7.1 
Description 
7.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
7.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
7.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
7.3 
Dose and Administration 
Details of dosing are provided in Section 3.1. 
Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
CCI
CCI
CCI


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appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
7.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Products returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed.  The returned products should be marked as ‘returned’ 
and kept separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
7.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 4.6 and APPENDIX 4 and will be 
listed as protocol violations if taken when not permitted. 
7.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
investigator.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. 
8 STATISTICS 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD phase to determine dose 
selection for the POC phase.   
• The final analysis will be performed when all patients have completed the safety 
follow-up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
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content and format of the safety review meetings will be described in the SAP and/or 
DMC charter. 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9 
or higher.   
The following standards will be applied for the analysis unless otherwise specified.  Data will be 
summarized descriptively by treatment and overall for each study phase.  For the MAD phase, 
BOS161721 will be summarized overall and by each dose level, and placebo patients from each 
cohort will be combined.  Select parameters will be summarized using patients from both study 
phases.  Statistical testing will be performed on data from the Phase 2 study only. 
Continuous data will be summarized using number, mean, standard deviation (SD), 25th and 
75th percentiles, minimum, median, and maximum.  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage).  Time to event data will be 
summarized using counts, medians, 25th and 75th percentiles, and standard error.  All data will 
be listed for all patients. 
Statistical inference will be based on a 2-tailed test with an overall 0.10 level of significance, 
unless stated otherwise.   
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data will be conducted as 
deemed appropriate.  Any deviations from the planned analyses will be described and justified in 
the final integrated CSR. 
Protocol deviations and prohibited medications that define medication failures will be fully 
assigned and documented before database lock and unblinding.  
Further details of the analysis, including the handling of missing data, transformations and other 
data handling procedures will be provided in the SAP.   
8.1 
Sample Size 
Sample size in the Phase 1b study is based on operational consideration. 
The sample size in the Phase 2 study is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable subjects in the FAS.  This assumes 
24 subjects will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 subjects are randomized into the FAS.    
A total of 132 subjects randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes of a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 


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from most recent non-missing result and subjects are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all patients who receive at 
least 1 dose of study treatment and at have least 1 evaluable post-baseline efficacy evaluation.  
FAS analyses will be conducted on the basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol violations from the 
efficacy analysis.  The PP Population will include all patients from the FAS except those with 
major violations to the protocol deemed to impact the analysis of the primary endpoint.  These 
violations will be identified based on blinded data prior to study unblinding.  PP analyses will be 
conducted on the basis of the randomized treatment. 
Safety analyses will be based on the safety analysis set (SS), defined as all patients who receive 
at least 1 dose of study treatment.  Safety analyses will be conducted on the basis of actual 
treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, defined as the FAS with 
sufficient concentration data for the calculation of PK parameters.   
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all randomized patients.   
8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will be assessed via 
Pearson’s chi-squared analysis.  The primary efficacy endpoint will be analyzed using the FAS 
and if needed repeated in the PP analysis set.  Missing values will be addressed by employing a 
last observation carried forward (LOCF) analysis.  Other imputation methods may be employed 
as a sensitivity analysis and will be described in the SAP.  Additional analyses exploring impact 
of baseline factors such as baseline disease severity, race, and other characteristics may be 
performed.  
Patients that received prohibited medications or unallowable CS usage as described in 
Section 4.6 will be considered “medication failures” and will be treated as non-responders for the 
primary efficacy analysis.  Patients that received an allowable CS burst but having missing data 
at Day 210 will considered a medication failure and will be treated as non-responders for the 
primary efficacy analysis.  The determination of medication failures will be reviewed using 
blinded data and finalized prior to unblinding.   
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than or 


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equal to 0.10.  Secondary and exploratory endpoints for this POC study will be evaluated based 
on the same statistical hypothesis. 
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared analysis.  Continuous 
efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of covariance 
(ANCOVA) and treatment will be compared using the F-test.  Repeated measures mixed models 
may be performed to evaluate data collected at each visit and overall.  Time-to-event endpoints 
will be assessed via Kaplan-Meier methodology and treatment will be compared using the log-
rank test.  The secondary efficacy endpoints will be analyzed on the FAS and if needed repeated 
in the PP analysis set.  Details including handling of missing data and “medication failures” will 
be available in the SAP. 
8.2.5 
Analysis of Safety 
8.2.5.1 
Safety Analysis 
Safety analyses will be performed on the SS.  AE data will be coded to system organ class and 
preferred term using MedDRA.  The number and percentage of patients experiencing any 
treatment-emergent AE, overall, and by system organ class an preferred term, will be tabulated.  
Treatment-emergent AEs will also be summarized by severity and relationship.   
Concomitant medications will be coded using the WHO Drug dictionary.  Observed values and 
changes from baseline in vital signs, ECG readings, and hematology and clinical chemistry 
parameters will be summarized at each individual visit.   
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 
Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected during the MAD Phase 1b 
using non-compartmental analysis and include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 
• 
A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 
• 
A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 


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8.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Exploratory analyses examining the relationship between PD parameters and PK concentration 
and PK parameters will be performed.   
8.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the POC decision for dose 
selection. 
Since there is no IA during the POC phase, there is no impact on the type 1 error.   
9 ETHICS AND RESPONSIBILITIES 
9.1 
Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
9.2 
DMC 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC (ie, 
dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 


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accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in Section 3.1.1.3. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.3 
Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) must meet the 
guidelines set out by the U.S. Food and Drug Administration (FDA) and conform to local laws 
and customs where appropriate.  Written IRB/IEC approval for the protocol and the signed ICF 
must be obtained and transmitted to Boston Pharmaceuticals or representative before the study 
can be initiated.  The IRB/IEC must be informed of and approve all protocol amendments.  The 
investigator will ensure that this study is conducted in full conformance with all applicable local 
and regional laws and regulations.  The complete text of the World Medical Association 
Declaration of Helsinki is given in APPENDIX 2. 
9.4 
Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the written 
informed consent will be obtained according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the principal investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient should be informed that he/she is free to withdraw from the study 
at any time.  He/she will receive all information that is required by federal regulations and ICH 
guidelines.  The principal investigator or designee will provide the sponsor with a copy of the 
IRB-approved ICF prior to the start of the study.   
The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 
study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   


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If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future patients enrolled in the clinical study will be required to 
sign this revised ICF. 
9.5 
Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 
9.6 
Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 


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must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
9.7 
Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
10 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 
study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
11 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 


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implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
12 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 
The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
13 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
14 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 
maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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15 REFERENCES 
                                                          
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4 Kanta H, Mohan C.  Three Checkpoints in lupus development:  central tolerance in adaptive 
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6 Spolski R, Leonard WJ.  The Yin and Yang of interleukin-21 in allergy, autoimmunity and 
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7 Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, et al.  Cutting edge:  the 
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8 Habib T, Senadheera S, Weinberg K, Kaushansky K.  The common gamma chain (gamma c) is 
a required signaling component of the IL-21 receptor and supports IL-21-induced cell 
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9 Spolski R, Leonard WJ.  Interleukin-21:  basic biology and implications for cancer and 
autoimmunity.  Annu Rev Immunol. 2008b;26:57-79. 
10 Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, et al.  B-cell-helper neutrophils 
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11 Costanzo A, Chimenti MS, Botti E, Caruso R, Sarra M, Monteleone G.  IL-21 in the 
pathogenesis and treatment of skin diseases.  J Dermatol Sci.  2010;60(2):61-6. 
12 Avery DT, Bryant VL, Ma CS, de Waal Malefy R, Tangye SG.  IL-21-induced isotype 
switching to IgG and IgA by human naive B cells is differentially regulated by IL-4.  
J Immunol.  2008;181:1767-79. 
13 Rasmussen TK, Andersen T, Bak, RO, Yiu G, Sorensen CM, Stengaard-Pedersen K, et al.  
Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 
production in systemic lupus erythematosus.  Arthritis Research & Therapy 2015;17(154) 
 


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14 Ettinger R, Kuchen S, Lipsky PE.  The role of IL-21 in regulating B-cell function in health 
and disease.  Immunol Rev. 2008;223:60-86. 
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17 Tangye SG, Ma CS, Brink R, Deenick EK.  The good, the bad and the ugly - TFH cells in 
human health and disease.  Nat Rev Immunol. 2013;13(6):412-26. 
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experimental colitis by modulating the balance between Treg and Th17 cells.  Eur J 
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19 Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al.  IL-21 
counteracts the regulatory T-cell-mediated suppression of human CD4+ T lymphocytes.  J 
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20 Hippen KL, Bucher C, Schirm DK, Bearl AM, Brender T, Mink KA, et al.  Blocking IL-21 
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21 Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, et al.  An open- 
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22 Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, et al.  
IL-21 induces in vivo immune activation of NK cells and CD8(+) T-cells in patients with 
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23 Karrich JJ, Jachimowski LC, Nagasawa M, Kamp A, Balzarolo M, Wolkers MC, et al.  
IL-21- stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs 
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24 Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TF, et al.  
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25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
metalloproteinase production in human intestinal fibroblasts by interleukin 21.  
Gut. 2006;55(12):1774-80. 
26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
contributes to the generation of plasma B-cells.  Clin Exp Rheumatol.  2013;31(2):172-9. 
 


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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 
28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
pathogenesis of primary Sjögren’s syndrome:  increased serum levels of interleukin-21 
and its expression in the labial salivary glands.  Arthritis Res Ther. 2011;13(5):R179. 
30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
Interleukin-21 modulates Th1 and Th17 responses in gianT-cell arteritis.  Arthritis 
Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
erythematosus.  J Rheumatol. 2012b;39(9):1819-28. 
32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
33 Wang W, Wang EQ, Balthasar JP.  Monoclonal Antibody Pharmacokinetics and 
Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
35 Elsaesser H, Sauer K, Brooks DG.  IL-21 is required to control chronic viral infection.  
Science.  2009;324(5934):1569-72 
36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.  
J Exp Med. 2013;210(3):433-43. 
37 Hunter PR, Nichols G.  Epidemiology and clinical features of Cryptosporidium infection in 
immunocompromised patients.  Clinical microbiology reviews.  2002;15(1):145-54. 
38 Desjardins M, Mazer BD.  B-cell memory and primary immune deficiencies:  interleukin-21 
related defects.  Curr Opin Allergy Clin Immunol. 2013;13(6):639-45. 
39 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
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40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US:  
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41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
doi:10.1136/lupus-2013-000005. 
47 Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M,et al.  Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
Cutaneous Lupus Erythematosus.  J Invest Derm. 2005;125(5):889-94. 
49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
Pulmonary Organ Scores are Predictors of Sever Outcome in Patients with Systemic 
Lupus Erythematosus.  Br J Rheumatol.  1996;35:248-54. 
50 
 
. 
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16 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 401 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
quality. 


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In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 


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subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 


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informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Dose Equivalence 
Prednisone 
20 mg 
Cortisone 
100 mg 
Hydrocortisone 
80 mg 
Prednisolone 
20 mg 
Methylprednisolone 
16 mg 
Triamcinolone 
16 mg 
Budesonide 
4 mg 
Dexamethasone 
3 mg 
Bethamethasone 
2.4 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS  
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
24 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with 
cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 6 
INJECTION SITE REACTION GRADING SCALE 
Adverse event 
Injection site reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Definition:  A disorder 
characterized by an 
intense adverse reaction 
(usually immunologic) 
developing at the site of 
an injection 
Tenderness with 
or without 
associated 
symptoms (eg, 
warmth, 
erythema, 
itching) 
Pain; 
Lipodystrophy; 
Edema; 
phlebitis 
Ulceration or 
necrosis;  
Severe tissue 
damage; 
Operative 
intervention 
indicated 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Pain 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
 limiting self-
care ADL 
- 
- 
Rash 
maculopapular/Erythem
a/Induration 
 
Definition:  A disorder 
characterized by the 
presence of macules 
(flat) and papules 
(elevated).  Also known 
as morbillform rash, it is 
one of the most 
common cutaneous 
adverse events, 
frequently affecting the 
upper trunk, spreading 
centripetally, and 
associated with pruritus. 
Macules/papules 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, 
burning, 
tightness) 
Erythema 
covering <10% 
BSA with or 
without 
symptoms (eg, 
pruritus, 
burning, 
tightness) 
Macules/papules 
covering 10% - 30% 
BSA with or 
without symptoms 
(eg, pruritus, 
burning, tightness); 
limiting 
instrumental ADL; 
Erythema 30% BSA 
with or without 
symptoms (eg, 
pruritus, burning, 
tightness); limiting 
instrumental ADL 
Macules/papul
es covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-care ADL 
 
Erythema 
covering 
> 30% BSA 
with or 
without 
associated 
symptoms; 
limiting 
self-careADL 
- 
- 
ADL = active daily living 
 
 


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APPENDIX 7 
PROTOCOL SUMMARY OF CHANGES 
The protocol summary of changes was moved to the end of the protocol for easier readability.   
Significant changes are described in the table below.  Changed text is displayed for the first 
major occurrence only.  Deleted text is presented in strikethrough format, and added text is 
presented in bold format.   
Section 
Description of Changes 
Rationale 
Global 
Add: 
Added ‘Protocol Date and Version:  21 March 2018; V3.0’ to the 
header. 
Administrative 
Global 
Change: 
Changed Version number from V2.0 (Amendment 1) to V3.0 
(Amendment 2) and Version date from 14 November 2017 to 
21 March 2018. 
Administrative 
Global 
Change: 
Changed subjects to patients. 
Replaced 
‘subjects’ to 
‘patients’ since 
the enrolled 
participants 
are with SLE 
condition 
Global 
Made administrative and editorial (formatting, typographical, and 
grammatical) updates. 
Administrative 
PROTOCOL 
SUMMARY, 
Background and 
Rationale 
 
Add: 
The Phase 2 portion will be a proof of concept (POC) study, where dose 
selection will be based on the data monitoring committee (DMC) and 
sponsor’s assessment of safety, tolerability, immunogenicity, and PK and 
PD data from the MAD study of 30 patients treated with 
BOS161721/placebo 
Clarification 
that POC dose 
selection will 
be based on 
DMC and 
sponsor 
assessment 
PROTOCOL 
SUMMARY, 
Objectives and 
Endpoints 
The objectives and endpoints sections were combined together and are 
now represented in a table format in order to demonstrate which endpoints 
correspond to each objective.  Only primary and secondary objectives and 
endpoints are listed within the synopsis.  Additional edits were made to 
some objectives and endpoints.  Some new endpoints were added to the 
study. 
An exploratory objective, to examine PK and PD effects of BOS161721 in 
subjects with mild to moderate SLE, was changed to ‘secondary 
objective’. 
Changes to the objectives and endpoints are noted below: 
MAD Phase 1b Study 
Updated for 
clarity and to 
provide a 
comprehensive 
list of 
endpoints 
identified in 
the protocol 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 102 of 143 
Section 
Description of Changes 
Rationale 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses 
of BOS161721 (20, 60, and 120 
mg) administered SC in adult 
patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment, in order to estimate the 
optimal dose. 
Safety Endpoints 
• 
Incidence and severity of 
adverse events (AEs) and 
serious adverse events (SAEs), 
related AEs, AEs leading to 
study drug discontinuation, 
AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide severity 
Rating Scale (C-SSRS) 
• 
12-lead electrocardiograms 
(ECGs) parameter results at 
each visit and change from 
baseline 
• 
Vital signs (blood pressure 
[BP], heart rate, and 
temperature) parameter results 
at each visit and change from 
baseline 
• 
Clinical laboratory results and 
change from baseline 
• 
Physical examinations changes 
from baseline 
• 
Anti-drug antibodies (ADAs) 
• 
Study drug 
exposure/compliance 
• 
Concomitant medication 
usage 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the 
optimal dose of BOS161721 
based on safety, PK, and PD 
effects in patients with mild to 
moderate SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by 
visit and time point 
• 
Maximum observed 
concentration (Cmax), first time 
to maximum concentration 
(Tmax), area under the 
concentration-time curve 
(AUC), t½, systematic clearance 
(CL), volume of distribution 
(Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) 
from baseline to each visit in 
phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3), C3 
and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) 
from baseline in anti-double-
stranded DNA (dsDNA), 
antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 103 of 143 
Section 
Description of Changes 
Rationale 
(SSA, SSB), Smith (Sm), and 
antiphospholipid (APL) 
autoantibodies at each visit 
• 
Results and changes (or shifts) 
from baseline in abrogation of 
IL-21 gene signature at each 
indicated visit  
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
- 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The rules for 
CS usage 
during the 
trial, as well as 
limitations of 
other 
prohibited 
medications, 
are applied on 
the analytical 
end to ensure 
SRI-4 
responders 
meet all 
necessary 
criteria. 
CCI
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 104 of 143 
Section 
Description of Changes 
Rationale 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
  
 
• 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
• 
 
POC Phase 2 Study 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE Responder Index 4 
(SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of subjects 
with a SRI-4 response at 
Day 210 (see 
Section 6.3.4.1) 
Secondary 
CCI
CCI
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 105 of 143 
Section 
Description of Changes 
Rationale 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Secondary Efficacy 
Endpoints 
• 
The proportion of subjects 
with: 
- 
SRI-4 response at each 
visit 
- 
SRI-5 and SRI-6 
response 
(Section 6.3.4.2) 
- 
a sustained reduction 
of oral corticosteroid 
(CS) (≤ 10 mg/day and 
≤ Day 0 dose) between 
Day 120 and Day 210 
- 
new BILAG A flare or 
> 1 BILAG B flares 
relative to baseline 
through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from 
baseline in: 
- 
CLASI 
- 
swollen and tender 
joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage 
index 
• 
Time to medication failure 
• 
Duration of SRI-4 response 
• 
Time to first SRI-4 
response 
• 
Time to BILAG A flare or 
> 1 BILAG B flare 
compared to baseline 
through Day 210 
Safety 
• 
To assess safety and tolerability 
of repeat doses of BOS161721 
(20, 60, and 120 mg) 
administered SC in adult 
patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of 
adverse events (AEs) 
and serious adverse 
events (SAEs), related 
AEs, AEs leading to 
study drug 
discontinuation, AEs by 
severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter 
results at each visit and 
change from baseline 
• 
Vital signs (blood 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 106 of 143 
Section 
Description of Changes 
Rationale 
pressure [BP], heart rate, 
and temperature) 
parameter results at 
each visit and change 
from baseline 
• 
Clinical laboratory 
results and change from 
baseline 
• 
Physical examinations 
changes from baseline 
• 
ADAs 
• 
Study drug 
exposure/compliance 
• 
Concomitant 
medication usage 
Exploratory 
• 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 107 of 143 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Study Design 
 
Replace: 
The trial will consist of a staggered MAD Phase 1b and POC Phase 2 
studies.  Both studies will be double blinded with each patient having the 
same number of doses (7), and visits; the duration will be 180 days, 
followed by a 90-day follow-up safety observation period.   
With: 
The trial will consist of 2 double-blinded studies:  MAD Phase 1b and 
POC Phase 2.  Patients may receive a total of 7 SC monthly doses of 
study drug on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety 
follow-up visits at Days 210, 240, and 270.   
 
Clarification 
that patients 
will not have 
the same 
number of 
visits in both 
studies. 
PROTOCOL 
SUMMARY, 
Study Design 
Section 1.2.4, 
Risk-Benefit 
Assessment 
Delete: 
Two weeks after the last patient in Cohort 3 receives the second dose, the 
DMC and Boston Pharmaceuticals will conduct a data review for the first 
interim analysis (IA1).  At that time, a decision will be made to suggest 
which dose should be carried forward into the POC Phase 2 study. 
The futility 
analysis was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half of 
the study 
(before week 
24) when 
futility 
analysis was 
planned 
PROTOCOL 
SUMMARY, 
Study Design 
Section 3.1.2.2, 
POC Study 
Design 
Add: 
For the POC study, approximately 156 additional patients will be 
randomized to active or placebo groups in a 2:1 ratio. 
Clarification 
on POC 
sample size 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 108 of 143 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Study Design 
Replace: 
Data from 60 patients, including the 12 from the MAD study, or 6 fewer if 
the low dose is chosen, who are in the cohort of the chosen dose for the 
POC study who complete 3 months of treatment will be used in a second 
IA (IA2) at Day 90 to assess if the trial could stop for an early futility 
conclusion.  If futility is not claimed in the IA2, the POC study will 
continue to approximately 156 patients. 
Following the 6 month treatment period, primary and secondary efficacy 
endpoints will be assessed for each patient, after providing their Day 180 
disease activity assessments.  DMC monitoring will be conducted 
periodically throughout the study as described in the DMC charter. 
With: 
DMC safety reviews will be conducted periodically throughout the study 
as described in the DMC charter. 
Removed 
assessment 
information 
from section, 
and the futility 
analysis   was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response)  is 
known to 
occur during 
the first half of 
the study 
(before 
week 24) when 
FA was 
planned 
PROTOCOL 
SUMMARY, 
Main Criteria for 
Inclusion and 
Exclusion 
(inclusion 
criterion 6, sub-
bullet ii) 
Section 4.4, 
Inclusion Criteria 
(inclusion 
criterion 6, 
sub-bullet ii) 
Replace: 
ii 
Points from lupus headache and organic brain syndrome 
are also excluded 
With: 
ii 
Points from lupus headache and organic brain syndrome 
will also be excluded 
Corrected to 
maintain 
consistency 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 109 of 143 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Main Criteria for 
Inclusion and 
Exclusion 
(inclusion 
criterion 7, sub-
bullets a and b) 
Replace: 
7 
Patients must have at least 1 of the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, 
which must be confirmed by the central data reviewer: 
a. 
BILAG A or B score in the mucocutaneous body system 
b. 
BILAG A or B score in the musculoskeletal body 
system due to active polyarthritis as defined in the 
protocol Section 4.4. 
c 
If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal 
body system due to arthritis, then at least 1 “B” must be 
present in the other body systems for a total of 2 “B” 
BILAG body system scores 
With:  
7 
Patients must have at least 1A or 2Bs from the following 
manifestations of SLE, as defined by the BILAG criteria as modified for 
use in this study, which must be confirmed by the central data reviewer: 
a 
BILAG A or B score in the mucocutaneous body system  
b 
BILAG A or B score in the musculoskeletal body 
system due to active polyarthritis as defined in the 
protocol Section 4.4. 
If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal body 
system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system 
scores 
Text updated 
to clarify that a 
minimum 
BILAG 1 ‘A’ 
or 2 ‘B’ scores 
is required for 
screening 
PROTOCOL 
SUMMARY, 
Statistical 
Considerations 
Replace: 
Baseline and patient characteristics will be summarized via appropriate 
summary statistics by treatment group and overall, for each phase of the 
trial. 
Binary efficacy endpoints will be compared between treatments via 
Cochran-Mantel-Haenszel (CMH) analysis.  Continuous efficacy 
endpoints will be assessed via analysis of covariance (ANCOVA) repeated 
measures mixed model analysis with factors including treatment, time, 
treatment-by-time interaction, baseline covariate, and covariate-by-time 
interaction.  Summary statistics will be provided by dose/treatment for all 
safety endpoints.  Details will be provided in the statistical analysis plan 
(SAP).   
Two IAs are planned for this study.  The initial IA (IA1) will be conducted 
at the time of the POC decision for dose selection.  The second IA (IA2) 
The futility 
analysis was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half of 
the study 
(before week 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 110 of 143 
Section 
Description of Changes 
Rationale 
will be performed for futility.  IA2 is planned to be conducted when SRI-4 
response is determined for approximately 60 patients (including all 
patients at the same dose level/matching placebo from the MAD study) 
after completing 3 months of treatment.  The purpose of IA2 is to assess if 
the trial could stop for an early futility conclusion, or continue.  Since 
there is no plan to stop the trial for an early efficacy conclusion, there is 
no impact on the type 1 error level.   
AEs will be summarized by counts and percentages of patients by 
treatment group.  Laboratory data and vital signs will be summarized by 
treatment group as summary statistics for value and change from baseline 
at each individual time point.  Summary statistics will include n, 
arithmetic mean, median, arithmetic SD, minimum, and maximum. 
The PK parameter data will be listed and summarized descriptively in 
tabular format.  Binary PD endpoints will be assessed for the full analysis 
set (FAS) population via CMH analysis.  Continuous PD endpoints will be 
assessed via ANCOVA repeated measures mixed model analysis with 
multiple factors.  PK and PD relationships will be explored graphically 
and where appropriate model based methods of analysis will used. 
With: 
Two analyses are planned:  1) an interim analysis to select the Phase 2 
dose based on Phase 1 data, and 2) a final analysis at study 
completion.  Additionally, DMC safety analyses will be performed 
after each Phase 1 cohort and throughout Phase 2 to monitor patient 
safety.   
Unless stated otherwise, statistical testing will only be performed on 
the Phase 2 data and will be done using 2-sided overall alpha of 0.10.  
Data will be summarized descriptively by treatment and overall for 
each study phase.  For the MAD phase, BOS161721 will be 
summarized overall and by each dose level and placebo patients from 
each cohort will be combined.   
The descriptive summaries for the categorical data will include 
number and percentage.  The descriptive summaries for the 
continuous data will include number, mean, standard deviations (SD), 
25th and 75th percentiles, minimum, median, and maximum.  Counts 
medians, 25th and 75th percentiles, and standard error will be 
presented for time-to-event data. 
All safety analyses will be performed using the safety analysis set (SS), 
defined as all patients who receive at least 1 dose of study treatment.  
All efficacy analyses will be performed using the full analysis set 
(FAS), defined as all patients who have receive at least 1 dose of study 
treatment and have at least 1 evaluable post-baseline efficacy 
evaluation.  Select efficacy analyses may also be performed on the per 
protocol (PP) set. 
Binary efficacy endpoints, including the primary efficacy endpoint, will 
24) when 
futility 
analysis was 
planned 
 
 
 
 
 
 
 
 
Text updated 
to allow use of 
testing 
procedures 
that are not 
typical/straight
forward as 1-
sided (such as 
CMH).  
 
 
 
 
 
 
 
 
 Simplification 
and 
consistency 
with binary 
endpoints. 
Allows more 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 111 of 143 
Section 
Description of Changes 
Rationale 
be assessed via Pearson’s chi-squared analysis.   
Continuous efficacy endpoints will be assessed via analysis of variance 
(ANOVA) or analysis of covariance (ANCOVA) when applicable, 
adjusting for the baseline value.  Repeated measures mixed models may 
be performed to evaluate data collected at each visit and overall.  
Time-to-event endpoints will be assessed via Kaplan-Meier 
methodology and treatment will be compared using the log-rank test.   
Adverse event data will be coded to system organ class and preferred 
term using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of patients experiencing any 
treatment-emergent AE, overall, and by system organ class and 
preferred term will be tabulated.  Treatment-emergent AEs will also 
be summarized by severity and relationship.   
Concomitant medications will be summarized, based on coded terms, 
using frequency and percentage of patients.  Observed values and 
changes from baseline in vital signs, ECG readings, and hematology 
and clinical chemistry parameters, will be summarized at each 
individual visit. 
flexibility in 
handling 
missing data. 
 
List of 
Abbreviations 
Add: 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
CS 
corticosteroids 
 
 
FAS 
full analysis set 
MedDRA 
Medical Dictionary of Regulatory Activities 
PP 
per protocol 
SS 
safety analysis set 
Updated to 
align with 
abbreviations 
added 
throughout the 
protocol 
List of 
Abbreviations 
Delete: 
RNP 
ribonucleoprotein 
 
Updated to 
align with 
abbreviations 
deleted 
throughout the 
protocol 
Section 1.2.3, 
Study Dose 
Selection 
Delete: 
In addition, the DMC and Boston Pharmaceuticals will conduct a data 
review for the first interim analysis (IA1).  At that time, a decision will be 
made to suggest which dose should be carried forward into the proof of 
concept (POC) Phase 2 study. 
The futility 
analysis was 
removed 
due to the 
modest size 
of the trial 
but more 
importantly 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 112 of 143 
Section 
Description of Changes 
Rationale 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half 
of the study 
(before 
week 24) 
when 
futility 
analysis was 
planned 
Section 1.2.4, 
Risk-Benefit 
Assessment 
Replace: 
Thereafter, DMC monitoring will be conducted periodically throughout 
the study as described in the DMC charter. 
With: 
Thereafter, DMC safety reviews will be conducted periodically 
throughout the study as described in the DMC charter. 
Text updated 
for 
clarification 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 113 of 143 
Section 
Description of Changes 
Rationale 
Section 2, Study 
Objectives And 
Endpoints 
Replace: 
This trial has separate primary and secondary objectives for the MAD 
Phase 1b and POC Phase 2 studies. 
With: 
This trial has separate objectives and endpoints for the MAD Phase 1b 
and POC Phase 2 studies.  The primary, secondary, and exploratory 
objectives for each phase, as applicable, are described below with 
their corresponding endpoints. 
Text updated 
to 
appropriately 
setup table 
Section 2, Study 
Objectives And 
Endpoints 
The objectives and endpoints sections (Section 2 and 3 in Amendment 1) 
were combined into 1 section (Section 2 of Amendment 2) and the 
objectives and endpoints are now in a table format to easily distinguish 
which endpoints align with each objective.  Additional edits were made to 
the objectives and endpoints.  Some new endpoints were added to the 
study.   
An exploratory objective, to examine PK and PD effects of BOS161721 in 
subjects with mild to moderate SLE, was changed to ‘secondary 
objective’. 
Changes to the objectives and endpoints are noted below: 
2.1 
Phase 1b Multiple Ascending Dose 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To assess safety, tolerability, and 
immunogenicity of repeat doses 
of BOS161721 (20, 60, and 120 
mg) administered SC in adult 
patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment, in order to estimate the 
optimal dose. 
Safety Endpoints 
• 
Incidence and severity of 
adverse events (AEs) and 
serious adverse events (SAEs), 
related AEs, AEs leading to 
study drug discontinuation, 
AEs by severity and 
relatedness 
• 
Injection site reactions 
• 
Columbia Suicide severity 
Rating Scale (C-SSRS) 
• 
12-lead electrocardiograms 
(ECGs) parameter results at 
each visit and change from 
baseline 
• 
Vital signs (blood pressure [BP], 
heart rate, and temperature) 
parameter results at each visit 
and change from baseline 
• 
Clinical laboratory results and 
change from baseline 
• 
Physical examinations changes 
from baseline 
• 
ADAs 
• 
Study drug 
Updated for 
clarity and to 
provide a 
comprehensive 
list of 
endpoints 
identified in 
the protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 114 of 143 
Section 
Description of Changes 
Rationale 
exposure/compliance 
• 
Concomitant medication usage 
Secondary 
• 
To characterize the PK of 
BOS161721 and select the 
optimal dose of BOS161721 
based on safety, PK, and PD 
effects in patients with mild to 
moderate SLE. 
Pharmacokinetic Endpoints 
• 
BOS161721 concentration by 
visit and time point 
• 
Maximum observed 
concentration (Cmax), Tmax, area 
under the concentration-time 
curve (AUC), terminal 
elimination half-life (t½) 
systematic clearance (CL), 
volume of distribution (Vd) 
Pharmacodynamic Endpoints 
• 
Results and changes (or shifts) 
from baseline to each visit in 
phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3), C3 
and C4 levels, and leukocyte 
immunophenotype 
• 
Results and changes (or shifts) 
from baseline in anti-double-
stranded DNA (dsDNA), 
antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B 
(SSA, SSB), Smith (Sm), and 
antiphospholipid (APL) 
autoantibodies at each visit 
• 
Results and changes (or shifts) 
from baseline in abrogation of 
IL-21 gene signature at each 
indicated visit  
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 115 of 143 
Section 
Description of Changes 
Rationale 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
 
• 
 
2.2 
Phase 2 Proof of Concept 
OBJECTIVES 
ENDPOINTS 
Primary 
• 
To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE Responder Index 4 
(SRI-4)  
Primary Efficacy Endpoint 
• 
The proportion of subjects 
with a SRI-4 response at 
Day 210 (see 
Section 6.3.4.1) 
Secondary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The rules for 
CS usage 
during the 
trial, as well as 
limitations of 
other 
prohibited 
medications, 
are applied on 
CCI
CCI
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 116 of 143 
Section 
Description of Changes 
Rationale 
To demonstrate a superior effect of 
BOS161721 at the chosen dose compared 
with placebo for response on clinical 
indicators of SLE activity, in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Secondary Efficacy 
Endpoints 
• 
The proportion of subjects 
with: 
- 
SRI-4 response at each 
visit 
- 
SRI-5 and SRI-6 
response (Section 
6.3.4.2) 
- 
a sustained reduction 
of oral corticosteroid 
(CS) (≤ 10 mg/day and 
≤ Day 0 dose) between 
Day 120 and Day 210 
- 
new BILAG A flare or 
> 1 BILAG B flares 
relative to baseline 
through Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• 
Results and changes from 
baseline in: 
- 
CLASI 
- 
swollen and tender 
joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage 
index 
• 
Time to medication failure 
• 
Duration of SRI-4 response 
• 
Time to first SRI-4 
response 
• 
Time to BILAG A flare or 
> 1 BILAG B flare 
compared to baseline 
through Day 210 
Safety 
• 
To assess safety and 
tolerability of repeat doses of 
BOS161721 (20, 60, and 120 
mg) administered SC in adult 
patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment 
Safety Endpoints 
• 
Incidence and severity of 
adverse events (AEs) and 
serious adverse events 
(SAEs), related AEs, AEs 
leading to study drug 
discontinuation, AEs by 
severity and relatedness 
• 
Injection site reactions 
• 
C-SSRS 
• 
12-lead ECGs parameter 
results at each visit and 
change from baseline 
• 
Vital signs (blood pressure 
the analytical 
end to ensure 
SRI-4 
responders 
meet all 
necessary 
criteria. 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 117 of 143 
Section 
Description of Changes 
Rationale 
[BP], heart rate, and 
temperature) parameter 
results at each visit and 
change from baseline 
• 
Clinical laboratory results 
and change from baseline 
• 
Physical examinations 
changes from baseline 
• 
ADAs 
• 
Study drug 
exposure/compliance 
• 
Concomitant medication 
usage 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
 
• 
 
 
• 
 
 
 
Section 3.1, Study 
Design 
Replace: 
The trial will consist of 2 studies:  MAD Phase 1b, and POC Phase 2.  
Both studies will be double-blinded, and patients will have the same 
number of visits.  Patients may receive a total of 7 SC monthly doses of 
study drug on Days 0, 30, 60, 90, 120, 150, and 180, followed by a 90-day 
safety follow-up visit.   
Text updated 
to correspond 
with POC 
portion having 
1 less visit. 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 118 of 143 
Section 
Description of Changes 
Rationale 
With: 
The trial will consist of 2 double-blinded studies:  MAD Phase 1b and 
POC Phase 2.  Patients may receive a total of 7 SC monthly doses of study 
drug on Days 0, 30, 60, 90, 120, 150, and 180, followed by safety 
follow-up visits at Days 210, 240, and 270. 
Section 3.1.1.1, 
Dose Escalation 
for the MAD 
Study 
Replace: 
If > 3 patients discontinue the study in a cohort, he/she may be replaced. 
With: 
If patients discontinue the study in a cohort prior to adequate safety 
follow-up, he/she may be replaced. 
Updated text 
to clarify that 
replacement 
may occur if 
any amount of 
subjects 
discontinue 
too early to 
establish 
safety 
Section 3.1.1.3, 
DMC 
Recommendations 
Delete: 
For the POC study, the DMC and Boston Pharmaceuticals will conduct a 
data review for the IA1 to suggest which dose should be carried forward 
into the POC Phase 2 study. 
The futility 
analysis was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half of 
the study 
(before week 
24) when FA 
was planned. 
Section 3.1.2.2, 
POC Study 
Design 
Add: 
Dose selection will be based on the DMC and sponsor’s assessment of 
safety, tolerability, immunogenicity, and PK and PD data from the MAD 
study of 30 patients treated with BOS161721/placebo. 
Clarification 
that POC dose 
selection will 
be based on 
DMC and 
sponsor 
assessment 
Section 3.1.2.2, 
POC Study 
Design 
Replace: 
Data from approximately 60 patients (including the 12 from the MAD 
study, or 6 fewer if the low dose is chosen who are in the cohort of the 
chosen dose for the POC study) who complete 3 months of treatment will 
be used in the IA2 at Day 90 to assess if the trial could stop for an early 
futility conclusion (see Section 9.3 for details regarding the IA).  If futility 
is not claimed in the IA2, the POC study will continue to approximately 
Removed 
assessment 
information 
from section 
and the futility 
analysis was 
removed due 
to the modest 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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Page 119 of 143 
Section 
Description of Changes 
Rationale 
156 patients. 
Following the 6-month treatment period, primary and secondary efficacy 
endpoints will be assessed for each patient after providing their Day 180 
disease activity assessments. 
DMC monitoring will be conducted periodically throughout the study as 
described in the DMC charter. 
With: 
DMC safety reviews will be conducted periodically throughout the study 
as described in the DMC charter. 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response)  is 
known to 
occur during 
the first half of 
the study 
(before week 
24) when FA 
was planned 
Section 3.2, 
Randomization 
and Blinding (new 
section) 
Add: 
3.2 
Randomization and Blinding 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally 
randomized to either placebo or BOS161721 using an IWRS 
according to a randomization list generated by an independent, non-
study statistician.  Randomization will be performed separately for 
each study phase and separately for each cohort in the Phase 1b and 2 
portion as follows: 
 
 
 
 
 
 
*Additional patients may be enrolled to confirm sufficient numbers of 
patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study phase which is active at 
time of enrollment.  Similarly, patients in the Phase 1 MAD will be 
assigned to the cohort which is active.  Each patient will be assigned a 
unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded 
to treatment assignment.  An independent biostatistician not 
otherwise involved on the study will be unblinded and prepare 
materials for the interim analysis (IA) and the DMC safety reviews.  
Phase/Cohort 
Number of 
Patients 
Randomization Ratio 
BOS161721:Placebo 
Phase 
1b/Cohort 1 
6 
5:1 
Phase 
1b/Cohort 2 
12 
3:1 
Phase 
1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
Text was 
added to 
clarify 
randomization 
and blinding 
process 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 120 of 143 
Section 
Description of Changes 
Rationale 
The DMC will review unblinded data during safety reviews and the 
IA.  A limited team at Boston Pharmaceuticals will review unblinded 
results from the Phase 1b MAD portion during the IA to determine 
the dose that will be used for the Phase 2 POC portion of the study.  
Details regarding maintenance of the blinding and content of data 
reviews will be described in the DMC charter or related study 
documentation.  
Section 3.3, Study 
Schematic 
Replace: 
 
With: 
 
The futility 
analysis was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half of 
the study 
(before week 
24) when 
futility 
analysis was 
planned 
Section 3.4, 
Schedule of 
Assessments 
(Table 1) 
Replace: 
 
Screena 
Enroll 
Treatment Period 
Follow-Up  
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
Injection site reaction 
assessmentf 
 
X 
X 
 
X 
Plasma 
 & 
 
X 
X 
 
X 
X 
Whole blood for 
X 
X 
 
X 
X 
Clarification 
of when 
certain 
assessments 
will be 
collected 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 121 of 143 
Section 
Description of Changes 
Rationale 
leukocyte 
immunophenotype 
 
 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
With: 
 
Screena 
Enroll 
Treatment Period 
Follow-Up  
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
Injection site reaction 
assessment 
 
Xf 
X 
 
X 
Plasma 
 & 
 
 
X 
 
X 
X 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
X 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 122 of 143 
Section 
Description of Changes 
Rationale 
Section 3.4, 
Schedule of 
Assessments 
(Table 1) 
Replace: 
 
Treatment Period Follow-Up 
Safety Follow-up 
Days 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
Visit 
number 
9 
10 
-- 
-- 
11 
12 
pSTAT3 
X 
 
 
 
 
X 
With: 
 
Treatment Period Follow-Up 
Safety Follow-up 
Days 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
Visit 
number 
9 
10 
-- 
-- 
11 
12 
pSTAT3l 
 
 
 
 
 
 
Clarification 
of when 
certain 
assessments 
will be 
collected 
Section 3.4, 
Schedule of 
Assessments 
(Table 1 
footnotes) 
Add: 
i 
When clinically indicated for hemolytic anemia. 
l 
Predose (trough) samples only. 
Text added to 
maintain 
consistency 
throughout the 
document. 
Section 3.4, 
Schedule of 
Assessments 
(Table 1 and its 
footnotes) 
Delete: 
- 
Predoseo 
f 
Injection site reaction assessments to be performed predose and 
at 2 hours postdose. 
o 
Predose samples occur on study drug administration visit days. 
 
Clarified that 
no need for 
predose 
injection site 
reaction 
assessment at 
baseline and 
definition of 
‘o’ was deleted 
as it was 
redundant. 
Section 3.4, 
Schedule of 
Assessments 
(Table 2) 
Replace: 
 
Screena 
Enroll 
Treatment Period 
Follow-Up  
Days 
-28 
to -1 
0 
15  
(± 3) 
30 
(± 3) 
60 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
Injection site reaction 
assessmentf 
 
X 
 
X 
X 
Plasma 
 & 
 
X 
X 
X 
X 
X 
Whole blood for 
leukocyte 
immunophenotype 
X 
X 
X 
X 
X 
Clarification 
of when 
certain 
assessments 
will be 
collected 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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Section 
Description of Changes 
Rationale 
 
 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
With: 
 
Screena 
Enroll 
Treatment Period 
Follow-Up  
Days 
-28 
to -1 
0 
15  
(± 3) 
30 
(± 3) 
60 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
Injection site reaction 
assessment 
 
Xf 
 
X 
X 
Plasma 
 & 
 
 
X 
X 
X 
 
Whole blood for 
leukocyte 
immunophenotype 
 
X 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
X 
X 
Section 3.4, 
Schedule of 
Assessments 
(Table 2 
footnotes) 
Add: 
i 
When clinically indicated for hemolytic anemia. 
Text added to 
maintain 
consistency 
throughout the 
document. 
Section 3.4, 
Schedule of 
Assessments 
(Table 2 
footnotes) 
Delete: 
pSTAT3lPredoseq 
f 
Injection site reaction assessments to be performed predose and 
at 2 hours postdose. 
l 
l 
Predose (trough) samples only. 
q 
Predose samples occur on study drug administration visit days. 
 
Clarified that 
no need for 
predose 
injection site 
reaction 
assessment at 
baseline, 
definition of 
‘q’ was deleted 
as it was 
redundant, and 
footnote ‘l’ 
was removed 
to align with 
removal of 
pSTAT3 from 
the table 
Section 4.2, 
Number of 
Patients 
Add: 
Approximately 30 patients will be randomized for the MAD Phase 1b 
study, and approximately 156 additional patients will be randomized in 
Clarification 
on POC 
sample size 
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BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
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Section 
Description of Changes 
Rationale 
the POC Phase 2 study. 
Section 4.2, 
Number of 
Patients 
Replace: 
Note that approximately 30 dropouts are assumed. 
With: 
Note that approximately 24 dropouts are assumed. 
Text updated 
to clarify new 
number of 
dropouts 
assumed for 
the study 
Section 4.4, 
Inclusion Criteria 
(Inclusion 
criterion 7, part b, 
subparts i and ii) 
Replace: 
7 
Patients must have at least 1 of the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this study, 
which must be confirmed by the central data reviewer: 
a 
BILAG A or B score in the mucocutaneous body system 
b 
BILAG A or B score in the musculoskeletal body system due to 
active polyarthritis defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 
41), manifested by observed active synovitis in ≥ 2 joints with 
marked loss of functional range of movements and significant 
impairment of basic activities of daily living that has been present 
on several days cumulatively over the past 4 weeks, including at 
the time of the screening visit.  See APPENDIX 5 for additional 
detailed specifications. 
• 
Basic ADLs are defined as the following activities 
which require assistance or assistive devices, (at least 1 
must be present and documented in source): 
o 
Ambulation, toileting, grooming- including bathing 
and dressing; feeding oneself, (and not responsive 
to steroids up to 10 mg/day, antimalarials, NSAIDs) 
ii. 
“BILAG B:” Moderate Arthritis, Tendonitis or 
Tenosynovitis, (BILAG item number 42), defined as 
tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional 
range of movements which lead to some loss of functional range 
of motion as manifested by effects on instrumental ADLs such as: 
• 
Cooking, driving, using the telephone or computer, 
shopping, cleaning, etc, and has been present on several 
days over the last 4 weeks, and is present at the time of 
the screening visit 
c 
If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal body system 
due to arthritis, then at least 1 “B” must be present in the other body 
Text updated 
to clarify that a 
minimum 
BILAG 1 ‘A’ 
or 2 ‘B’ scores 
is required for 
screening 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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Section 
Description of Changes 
Rationale 
systems for a total of 2 “B” BILAG body system scores 
With: 
7 
Patients must have at least 1A or 2Bs from the following 
manifestations of SLE, as defined by the BILAG criteria as modified for 
use in this study, which must be confirmed by the central data reviewer: 
a 
BILAG A or B score in the mucocutaneous body system 
b 
BILAG A or B score in the musculoskeletal body system due to 
active polyarthritis defined as follows: 
i 
“BILAG A:” Severe Arthritis, (BILAG item number 
41), manifested by observed active synovitis in ≥ 2 joints with 
marked loss of functional range of movements and significant 
impairment of basic activities of daily living that has been 
present on several days cumulatively over the past 30 days, 
including at the time of the screening visit.  See APPENDIX 5 
for additional detailed specifications. 
• 
Basic ADLs are defined as the following activities 
which require assistance or assistive devices, (at least 1 
must be present and documented in source): 
o 
Ambulation, toileting, grooming- including bathing 
and dressing; feeding oneself 
ii 
“BILAG B:” Moderate Arthritis, Tendonitis or 
Tenosynovitis, (BILAG item number 42), defined as 
tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional 
range of movements which lead to some loss of functional range 
of motion as manifested by effects on instrumental ADLs such 
as: 
• 
Cooking, driving, using the telephone or computer, 
shopping, cleaning, etc, and has been present on several 
days over the last 30 days, and is present at the time of 
the screening visit 
If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal body 
system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system 
scores 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
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Section 
Description of Changes 
Rationale 
Section 5.1, 
Screening 
Section 5.2, 
Enrollment/Rando
mization and Day 
0 Treatment 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits 
Section 5.4, 
Safety Follow-Up 
Visits 
Add: 
• 
Direct Coomb’s test (if indicated for hemolytic anemia) 
Text updated 
to clarity 
Section 5.1, 
Screening 
Delete: 
• 
CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
 whole blood for leukocyte 
immunophenotype;
 
) 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 5.1.1, 
Retesting During 
Screening Period 
Add: 
• 
there is evidence a laboratory sample was mislabeled, indeterminate, 
inadequately processed, and/or deteriorated in transit to the central 
laboratory 
 
Text added for 
further 
clarification 
Section 5.2, 
Enrollment/Rando
mization and Day 
0 Treatment 
 
Replace: 
o 
pSTAT3 (predose [trough] samples only in Phase 2)  
With: 
o 
pSTAT3 (predose [trough] samples only in Phase 1b) 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 5.2, 
Enrollment/Rando
mization and Day 
0 Treatment 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits 
Delete: 
• 
 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 5.2, 
Enrollment/Rando
mization and Day 
Replace: 
- 
Injection site reaction assessment, predose, and 2 hours post dose 
Clarified that 
no need for 
predose 
injection site 
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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
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Section 
Description of Changes 
Rationale 
0 Treatment 
With: 
Injection site reaction assessment, performed at 2 hours postdose 
reaction 
assessment at 
baseline 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits 
Delete: 
• 
Injection site reaction assessments will be performed predose and 
2 hours postdose 
Clarified that 
no need for 
predose 
injection site 
reaction 
assessment at 
baseline 
Section 5.3, 
Treatment 
Period/Follow-Up 
Visits 
Section 5.4, 
Safety Follow-Up 
Visits 
Section 6.6, 
Pharmacodynamic 
Assessments 
Add: 
• 
pSTAT3 (predose [trough] samples only Phase 1b) 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 5.4, 
Safety Follow-Up 
Visits 
Delete: 
• 
pSTAT3 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 6.2.1, 
Laboratory 
Assessments 
(Table 3) 
Delete: 
Hematology 
Reticulocytes (%) 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 6.2.1, 
Laboratory 
Assessments 
(Table 3) 
Replace: 
Immunogenicity, PD and other Biomarker Tests 
pSTAT3 (predose [trough] samples only, in Phase 2) 
With: 
Immunogenicity, PD and other Biomarker Tests 
pSTAT3 (predose [trough] samples only in Phase 1b) 
Updated to 
clarify the 
planned 
laboratory 
assessments 
Section 6.2.1, 
Laboratory 
Assessments 
(Table 3 
footnotes) 
Add: 
h 
If clinically indicated for hemolytic anemia. 
Text updated 
to clarify when 
Coomb’s test 
direct will be 
collected 


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Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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Section 
Description of Changes 
Rationale 
Section 6.2.2.6, 
Adverse Events of 
Special Interest 
Replace: 
2 
Injection site reaction, including erythema, pain, and induration 
With: 
2 
Grades 2 to 5 injection site reaction, including erythema, pain, 
and induration (See APPENDIX 6) 
Clarify that 
Grades 2 to 5 
injection site 
reactions are 
AEs of special 
interest 
Section 6.2.2.6.2, 
Injection Site 
Reactions 
Replace: 
These may include injection site erythema, pain, and induration. 
With: 
These will include Grades 2 to 5 injection site erythema, pain, and 
induration (see APPENDIX 6). 
Clarify that 
Grades 2 to 5 
injection site 
reactions are 
AEs of special 
interest 
Section 6.2.7, 
Injection Site 
Reaction 
Replace: 
Local injection site reactions will be assessed predose and at 2 hours 
postdose.  Injection site reactions should be managed according to the 
standard of care.  Injection site reactions are to be reported as AEs of 
special interest (see Section 6.2.2.7.3). 
With: 
Local injection site reactions will be assessed at 2 hours postdose at 
baseline, and predose for each injection after baseline.  Injection site 
reactions should be managed according to the standard of care.  Injection 
site reactions, Grades 2 to 5, are to be reported as AEs of special interest 
(see Section 6.2.2.7.3). 
Clarify that 
Grades 2 to 5 
injection site 
reactions are 
AEs of special 
interest 
Section 6.3.4.1, 
SRI-4 Response 
Delete: 
Patients will be evaluated for SRI-4 scores at Day 210, with evaluation for 
sustained reduction of oral CS (≤ 10 mg/day and ≤ Day 0 dose) between 
Day 120 and Day 210. 
Differentiate 
assessment of 
SRI-4 and CS 
usage. 
Section 6.3.4.1, 
SRI-4 Response 
Delete: 
Each patient, after providing their Day 210 visit SRI 4 response, will be 
evaluated as either a responder or non-responder.   
Remove 
analysis item 
from 
assessment 
section 


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Protocol Date and Version:  21 March 2018; V3.0 
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Section 
Description of Changes 
Rationale 
Section 6.3.4.2, 
SRI-5 and SRI-6 
Response 
Delete: 
The SRI-5 and SRI-6 are evaluated for response at Day 180, along with a 
sustained reduction of oral CS (≤ 10 mg/day and ≤ Day 0 dose) between 
Day 120 and Day 210. 
Differentiate 
assessment of 
SRI-4 and CS 
usage. 
 
Remove 
analysis item 
from 
assessment 
section 
Section 6.5, 
Pharmacokinetic 
Assessments 
Delete: 
PK parameters include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
Plasma concentrations of BOS161721 will be measured using a validated 
immunoassay.  The PK parameters will be calculated from the plasma 
concentration-nominal time profiles for the IA2 and actual time profiles 
for the final analysis.  The non-compartmental analysis will be performed 
using appropriately validated PK/PD software. 
Remove 
analysis item 
from 
assessment 
section 
Section 6.6, 
Pharmacodynamic 
Assessments 
Delete: 
• 
Antibodies:  
 
• 
IgG and IgM and CD4+ count 
Updated to 
clarify the 
planned PD 
assessments 
Section 6.8, 
Protocol 
Deviations 
Delete: 
Per the statistical analysis plan (SAP), these will be listed by patient and 
summarized by deviation category by treatment group. 
Remove 
analysis item 
from 
assessment 
section 
Section 8, 
Statistics (entire 
section) 
Replace: 
9 
STATISTICS 
There are 2 IAs planned for the study.  The first IA will be conducted at 
the time of the POC decision for dose selection.  The second IA will be 
performed for futility (see Section 9.3).  Before the first IA, a SAP will be 
finalized, providing detailed methods for the analyses outlined below.  
Any deviations from the planned analyses will be described and justified 
in the final integrated CSR. 
The following standards will be applied for the analysis unless otherwise 
specified.  Continuous data will be summarized by treatment group using 
descriptive statistics (number, mean, standard deviation [SD], minimum, 
median, and maximum).  Categorical data will be summarized by 
Updated 
section to 
clarify 
statistical 
analysis plan 
for the study 
 
 
 
 
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Protocol Date and Version:  21 March 2018; V3.0 
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Section 
Description of Changes 
Rationale 
treatment group using frequency tables (number and percentage). 
9.1 
Sample Size 
Sample size in the Phase 1b study is based on operational consideration. 
A summary of the power in the trial for the chosen sample size is provided 
in Table 5, with N = 132 randomized 89:43 to the chosen dose for the 
POC study and placebo, respectively; this includes 12 patients from the 
MAD study who were in the cohort of the mid or high dose if chosen for 
the POC study. 
Table 5. 
Sample Size 
Type 1 
Error 
(1-
Sided) 
TRUE 
Underlying 
Response Rate 
(%) 
Overall 
Power 
Minimum OBSERVED 
Response Rates 
Yielding Statistical 
Significance 
Placebo 
Treat
ment 
Placebo 
Treatment 
0.025 
40 
60 
0.54 
40 
60 
40 
65 
0.75 
40 
70 
0.9 
0.05 
40 
60 
0.63 
40 
58 
40 
65 
0.81 
40 
70 
0.93 
Total sample size of approximately 156 patients is planned for analysis, 
but may be adjusted upward according to the dropout (noncompliance) 
rate, which will be monitored in a blinded fashion in an ongoing basis.  
Note that approximately 36 dropouts are assumed. 
8.2 
Statistical Methods 
9.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the full analysis set (FAS), 
defined to be all patients with at least 1 baseline and post-baseline efficacy 
evaluation.  A per protocol (PP) analysis set may be defined to exclude 
major protocol violations from the efficacy analysis.  The PP Population 
will include all patients from the FAS except those with major violations 
to the protocol deemed to impact the analysis of the primary endpoint.  
These violations will be identified based on blinded data prior to 
unblinding the final analysis dataset.  Safety analyses will be based on all 
patients who receive test treatment.  Pharmacokinetic analysis will be 
conducted on the PK analysis set (PK), defined as the FAS with sufficient 
concentration data for the calculation of PK parameters.  All analyses will 
combine data from the MAD and POC studies and focus on the active 
treatment dose chosen for the POC study versus placebo.  The 0.05 
1-sided type 1 error level is included for POC, and the 0.025 1-sided 
type 1 error level for potential use of this trial to support regulatory filing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
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Section 
Description of Changes 
Rationale 
9.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized via appropriate 
summary statistics by treatment group and overall, for each phase of the 
trial.   
9.2.3 
Primary Endpoint(s) 
The proportion of patients who achieve treatment response (measured by 
SRI-4 at Day 210 along with a sustained reduction of oral CS) will be 
analyzed via Cochran-Mantel-Haenszel (CMH) analysis.  The primary 
endpoint will be analyzed on the FAS and if needed the PP analysis set.  
In addition, missing values will be addressed by employing a last 
observation carried forward (LOCF) analysis and/or other appropriate 
analytic approaches as a sensitivity analysis.  Details will be available in 
the SAP. 
9.2.4 
Secondary Endpoint(s) 
Binary efficacy endpoints will be assessed via CMH analysis.  Continuous 
efficacy endpoints will be assessed via analysis of covariance (ANCOVA) 
repeated measures mixed model analysis with factors including treatment, 
time, treatment-by-time interaction, baseline covariate, and 
covariate-by-time interaction.  The secondary efficacy endpoint will be 
analyzed on the FAS and if needed the PP analysis set.  Details will be 
available in the SAP. 
9.2.5 
Analysis of Safety 
9.2.5.1 Safety Analysis 
Safety analyses will be performed on the Safety Analysis Set.  AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary.  Incidences (number and percent) of AEs will be presented by 
treatment group.  Incidences of AEs will also be presented by maximum 
severity and relationship to study medication.  For the MAD study, the 
placebo patients from each cohort will be combined for the summaries.  If 
there is a clear increase in AE rates for placebo patients across the cohorts, 
the AEs will also be summarized by cohort. 
AEs will be summarized by counts and percentages of patients by 
treatment group.  Laboratory data and vital signs will be summarized by 
treatment group as summary statistics for value and change from baseline 
at each individual time point.  Summary statistics will include n, 
arithmetic mean, median, arithmetic SD, minimum, and maximum. 
Additional safety parameters will be analyzed descriptively by treatment 
group.  Descriptive statistics (n, mean, standard deviation (SD), median, 
minimum, maximum) will be calculated by treatment group and time point 
for continuous variables.  Frequencies and percentages will be presented 
by treatment group for categorical and ordinal variables. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
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Section 
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Rationale 
9.2.5.2 Data Monitoring Committee 
This study will use an external DMC.  The DMC is an independent 
committee established to provide oversight of safety considerations in 
study and to provide advice to the sponsor regarding actions the 
committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the 
continuing validity and scientific merit of the study results.  The DMC is 
charged with assessing such actions in light of an acceptable benefit/risk 
profile for anti-IL-21 mAb.  The recommendations made by the DMC (ie, 
dose escalation, etc.) will be forwarded to the sponsor for final decision.  
The sponsor will forward such decisions, which may include summaries of 
safety data which are not endpoints, to regulatory authorities, as 
appropriate. 
The DMC will have access to unblinded treatment information during the 
clinical trial.  Details regarding management and process of this 
committee are found in the DMC Charter. 
The DMC may recommend termination of an anti-IL-21 mAb treatment 
arm or the entire BOS161721 MAD/POC trial for any safety concern that 
is felt to outweigh potential benefits.  The recommendation must be 
supported by the sponsor as indicated in the DMC Charter. 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data 
9.2.6.1 Analysis of Pharmacokinetic Data 
The PK parameter data will be listed and summarized descriptively in 
tabular format. 
If data permit, the following analyses will be performed for plasma 
BOS161721 concentration data: 
• 
A listing of all plasma BOS161721 concentrations by patient at actual 
times post dose; 
• 
A descriptive summary of plasma BOS161721 concentrations.  
Summary statistics of geometric mean, % coefficient of variation, 
standard deviation, median, minimum, and maximum will be 
tabulated by study days with PK assessments. 
Details will be available in the SAP.   
9.2.6.2 Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in 
tabular format. 
Binary PD endpoints will be assessed for the FAS population.  Binary PD 
endpoints will be assessed via CMH analysis.  Continuous PD endpoints 
will be assessed via analysis of covariance (ANCOVA) repeated measures 
mixed model analysis with factors including treatment, time, treatment-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 133 of 143 
Section 
Description of Changes 
Rationale 
by-time interaction, baseline covariate, and covariate-by-time interaction.  
Normality will be assessed via diagnostic residual plots and Shapiro-Wilk 
statistic, but not as a formal statistical test of normality.  If substantial 
departures from normality are observed, transformation will be used (eg, 
log and/or rank). 
Details will be available in the SAP. 
9.2.6.3 Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on 
Y-axis and each relevant PK parameter on X-axis will be examined for 
relationship.  If relationships are revealed by these diagnostic plots, PK 
and PD data from this study may be analyzed using modeling approaches 
to describe the relationship and may also be pooled with data from other 
studies to investigate any association between BOS161721 exposure and 
biomarkers or significant safety endpoints. 
Details will be available in the SAP.     
9.3 
Interim Analysis and Power 
Two IAs are planned for this study.  The initial IA will be conducted at the 
time of the POC decision for dose selection. 
The second IA will be performed for futility.  IA2 is planned to be 
conducted at Day 90 when SRI-4 response is determined for 
approximately 60 patients (including all patients at the same dose 
level/matching placebo from the MAD study) after completing 3 months 
of treatment.  The purpose of the IA2 is to assess if the trial could stop for 
an early futility conclusion, or continue.  Since there is no plan to stop the 
trial for an early efficacy conclusion, there is no impact on the type 1 
error.  If that intention changes, then p < 0.0001 is required for an early 
efficacy conclusion at the IA2 in order to not impact the planned type 1 
error level. 
Nominal time profiles will be used for calculating PK parameters in the 
IA2.  Details will be available in the SAP. 
With: 
8 
STATISTICS 
The following analyses are planned: 
• 
An IA will be performed during the last cohort of the MAD phase 
to determine dose selection for the POC phase.   
• 
The final analysis will be performed when all patients have 
completed the safety follow-up or withdrawn from the study.   
• 
Safety analyses will be performed for DMC reviews throughout 
the study to evaluate dose escalation decisions and accumulating 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Updated to 
clarify that 
single alpha 
for a single 
primary 
hypothesis at a 
significance 


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Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
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Section 
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Rationale 
safety data.  The frequency and details of the content and format 
of the safety review meetings will be described in the SAP and/or 
DMC charter. 
All statistical analyses will be performed using Statistical Analysis 
Software (SAS®) Version 9 or higher.   
The following standards will be applied for the analysis unless otherwise 
specified.  Data will be summarized descriptively by treatment and 
overall for each study phase.  For the MAD phase, BOS161721 will be 
summarized overall and by each dose level, and placebo patients from 
each cohort will be combined.  Select parameters will be summarized 
using patients from both study phases.  Statistical testing will be 
performed on data from the Phase 2 study only. 
Continuous data will be summarized using number, mean, standard 
deviation (SD), 25th and 75th percentiles, minimum, median, and 
maximum.  Categorical data will be summarized by treatment group using 
frequency tables (number and percentage).  Time to event data will be 
summarized using counts, medians, 25th and 75th percentiles, and 
standard error.  All data will be listed for all patients. 
Statistical inference will be based on a 2-tailed test with an overall 
0.10 level of significance, unless stated otherwise.   
The effects of noncompliance, background therapy use, treatment 
discontinuations, premature withdrawal from study and covariates 
will be assessed to determine the impact on the general applicability of 
results from this study.    Exploratory analyses of the data will be 
conducted as deemed appropriate.  Any deviations from the planned 
analyses will be described and justified in the final integrated CSR. 
Protocol deviations and prohibited medications that define medication 
failures will be fully assigned and documented before database lock 
and unblinding.  
Further details of the analysis, including the handling of missing data, 
transformations and other data handling procedures will be provided 
in the SAP. 
8.1 
Sample Size 
Sample size in the Phase 1b study is based on operational consideration. 
The sample size in the Phase 2 study is based on the primary 
endpoint, SRI-4 Response at Day 210.  Approximately 156 additional 
patients will be randomized in a 2:1 ratio to BOS161721 versus 
placebo to achieve 132 evaluable subjects in the FAS.  This assumes 
24 subjects will drop prior to having received treatment and an 
evaluable post-baseline efficacy measure.  Enrollment and 
randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 subjects are randomized into the FAS.  
level is 
acceptable for 
PoC study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Text updated 
to express in 
terms of power 
for selected 
sample size 
and primary 
hypothesis 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 135 of 143 
Section 
Description of Changes 
Rationale 
A total of 132 subjects randomized provides more than 80% power to 
detect a treatment difference of 25% in SRI-4 response rates at 
Day 210, based on a targeted 2-sided significance level of 10% and 
using a 2-sided Pearson’s chi-squared test.  This assumes of a 
response rate of 65% for BOS161721 and 40% for placebo, where 
missing data at Day 210 is carried forward from most recent non-
missing result and subjects are treated as a non-responder if a 
prohibited medication defined as a medication failure occurs. 
8.2 
Statistical Methods 
8.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the FAS, defined as all 
patients who receive at least 1 dose of study treatment and have at least 
1 evaluable post-baseline efficacy evaluation.  FAS analyses will be 
conducted on the basis of the randomized treatment.  
A per protocol (PP) analysis set may be defined to exclude major protocol 
violations from the efficacy analysis.  The PP Population will include all 
patients from the FAS except those with major violations to the protocol 
deemed to impact the analysis of the primary endpoint.  These violations 
will be identified based on blinded data prior study to unblinding.  PP 
analyses will be conducted on the basis of the randomized treatment. 
Safety analyses will be based on the safety analysis set (SS), defined as 
all patients who receive at least 1 dose of study treatment.  Safety 
analyses will be conducted on the basis of actual treatment received.  
Pharmacokinetic analysis will be conducted on the PK analysis set, 
defined as the FAS with sufficient concentration data for the calculation of 
PK parameters. 
8.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized using all 
randomized patients.   
8.2.3 
Primary Efficacy Endpoint(s) 
The proportion of patients who achieve a SRI-4 response at Day 210 will 
be assessed via Pearson’s chi-squared analysis.  The primary efficacy 
endpoint will be analyzed using the FAS and if needed repeated in the PP 
analysis set.  Missing values will be addressed by employing a last 
observation carried forward (LOCF) analysis.  Other imputation methods 
may be employed as a sensitivity analysis and will be described in the 
SAP.  Additional analyses exploring impact of baseline factors such as 
baseline disease severity, race, and other characteristics may be 
performed. 
Patients that received prohibited medications or unallowable CS 
usage as described in Section 4.6 will be considered “medication 
failures” and will be treated as non-responders for the primary 
test, as well as 
describe alpha, 
beta, treatment 
effect 
assumptions 
used, and 
statistical test 
used for power 
calculation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Text updated 
to clarify that 
CMH is 
stratified 
analysis, and 
no 
stratification 
factors were 
used at 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
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Section 
Description of Changes 
Rationale 
efficacy analysis.  Patients that received an allowable CS burst but 
having missing data at Day 210 will considered a medication failure 
and will be treated as non-responders for the primary efficacy 
analysis.  The determination of medication failures will be reviewed 
using blinded data and finalized prior to unblinding.   
The superiority of BOS161721 relative to placebo will be evaluated.  If 
the proportion of SRI-4 responders for the selected POC dose in 
BOS161721 arm is higher than that of the placebo arm, then 
BOS161721 will be considered superior to placebo if the 2-sided 
p-value is less than or equal to 0.10.  Secondary and exploratory 
endpoints for this POC study will be evaluated based on the same 
statistical hypothesis. 
8.2.4 
Secondary Efficacy Endpoint(s) 
Binary efficacy endpoints will be assessed via Pearson’s chi-squared 
analysis.  Continuous efficacy endpoints will be assessed via analysis of 
variance (ANOVA) or analysis of covariance (ANCOVA) and 
treatment will be compared using the F-test.  Repeated measures 
mixed models may be performed to evaluate data collected at each 
visit and overall.  Time-to-event endpoints will be assessed via 
Kaplan-Meier methodology and treatment will be compared using the 
log-rank test.  The secondary efficacy endpoints will be analyzed on the 
FAS and if needed repeated in the PP analysis set.  Details including 
handling of missing data and “medication failures” will be available in 
the SAP. 
8.2.5 
Analysis of Safety 
8.2.5.1 Safety Analysis 
Safety analyses will be performed on the SS.  AE data will be coded to 
system organ class and preferred term using MedDRA.  The number 
and percentage of patients experiencing any treatment-emergent AE, 
overall, and by system organ class an preferred term, will be 
tabulated.  Treatment-emergent AEs will also be summarized by 
severity and relationship. 
Concomitant medications will be coded using the WHO Drug 
dictionary.  Observed values and changes from baseline in vital signs, 
ECG readings, and hematology and clinical chemistry parameters will 
be summarized at each individual visit.   
8.2.6 
Pharmacokinetic and Pharmacodynamic Data 
8.2.6.1 Analysis of Pharmacokinetic Data 
PK parameters will be calculated from concentration data collected 
during the MAD Phase 1b using non-compartmental analysis and 
include the following:  
randomization. 
Population is 
expected to be 
relatively 
homogenous, 
so Pearson chi-
square as 
primary and 
secondary 
analyses may 
be conducted 
with factors 
for adjustment. 
 
 
 
Text updated 
to simplify and 
maintain 
consistency 
with binary 
endpoints. 
Allows more 
flexibility in 
handling 
missing data. 
 
 
 
 
 
 
 
 
 
 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 137 of 143 
Section 
Description of Changes 
Rationale 
• 
Cmax, Tmax, AUC, t½, CL, Vd 
The PK parameter data will be listed and summarized descriptively in 
tabular format. 
If data permit, the following analyses will be performed for plasma 
BOS161721 concentration data: 
• 
A listing of all plasma BOS161721 concentrations by patient at actual 
times post dose; 
• 
A descriptive summary of plasma BOS161721 concentrations.  
Summary statistics of geometric mean, % coefficient of variation, 
standard deviation, median, minimum, and maximum will be 
tabulated by study days with PK assessments. 
8.2.6.2 Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in 
tabular format. 
Exploratory analyses examining the relationship between PD 
parameters and PK concentration and PK parameters will be 
performed.   
8.2.6.3 Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on 
Y-axis and each relevant PK parameter on X-axis will be examined for 
relationship.  If relationships are revealed by these diagnostic plots, PK 
and PD data from this study may be analyzed using modeling approaches 
to describe the relationship and may also be pooled with data from other 
studies to investigate any association between BOS161721 exposure and 
biomarkers or significant safety endpoints 
8.3 
Interim Analysis and Power 
One IA is planned for this study and will be conducted at the time of the 
POC decision for dose selection. 
Since there is no IA during the POC phase, there is no impact on the 
type 1 error.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The futility 
analysis was 
removed due 
to the modest 
size of the trial 
but more 
importantly 
because the 
least reliable 
data (high 
placebo 
response) is 
known to 
occur during 
the first half of 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
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Section 
Description of Changes 
Rationale 
the study 
(before week 
24) when 
futility 
analysis was 
planned 
Section 9.2, DMC 
Replace: 
The sponsor will appoint a DMC for the periodic review of available study 
data.  The DMC is an independent group of experts that advises the 
sponsor and the study investigators.  The members of the DMC serve in an 
individual capacity and provide their expertise and recommendations.  The 
primary responsibilities of the DMC are to (1) periodically review and 
evaluate the accumulated study data for participant safety, study conduct, 
and progress, (2) make recommendations to the sponsor concerning the 
continuation, modification, or termination of the study and (3) suggest 
dose for POC portion of the study. 
The DMC considers study-specific data as well as relevant background 
knowledge about the disease, test agent, or patient population under study.  
The DMC is responsible for defining its deliberative processes, including 
event triggers that would call for an unscheduled review, stopping 
guidelines, unmasking (unblinding), and voting procedures prior to 
initiating any data review.  The DMC is also responsible for maintaining 
the confidentiality of its internal discussions and activities as well as the 
contents of reports provided to it. 
With: 
This study will use an external DMC.  The DMC is an independent 
committee established to provide oversight of safety considerations in 
study and to provide advice to the sponsor regarding actions the 
committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the 
continuing validity and scientific merit of the study results.  The DMC 
is charged with assessing such actions in light of an acceptable 
benefit/risk profile for BOS161721.  The recommendations made by 
the DMC (ie, dose escalation, etc.) will be forwarded to the sponsor 
for final decision.  The sponsor will forward such decisions, which 
may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study 
data.  The DMC is an independent group of experts that advises the 
sponsor and the study investigators.  The members of the DMC serve in an 
individual capacity and provide their expertise and recommendations.  The 
primary responsibilities of the DMC are to (1) periodically review and 
evaluate the accumulated study data for participant safety, study conduct, 
and progress, (2) make recommendations to the sponsor concerning the 
continuation, modification, or termination of the study and (3) suggest 
dose for POC portion of the study as described in Section 3.1.1.3. 
The DMC considers study-specific data as well as relevant background 
Clarification 
and to remove 
redundant text 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 139 of 143 
Section 
Description of Changes 
Rationale 
knowledge about the disease, test agent, or patient population under study.  
The DMC is responsible for defining its deliberative processes, including 
event triggers that would call for an unscheduled review, stopping 
guidelines, unmasking (unblinding), and voting procedures prior to 
initiating any data review.  The DMC is also responsible for maintaining 
the confidentiality of its internal discussions and activities as well as the 
contents of reports provided to it. 
The DMC will have access to unblinded treatment information during 
the clinical trial.  Details regarding management and process of this 
committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm 
or the entire BOS161721 MAD/POC trial for any safety concern that 
is felt to outweigh potential benefits.  The recommendation must be 
supported by the sponsor as indicated in the DMC Charter. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 140 of 143 
Section 
Description of Changes 
Rationale 
Appendix 1, 
Names of Study 
Personnel 
Replace: 
Clinical Research Organizations: 
 
 
  
 
 
 
 
 
With: 
Clinical Research Organizations: 
 
 
 
  
 
 
 
 
 
 
 
Updated to 
represent 
change in 
personnel 
Appendix 4, 
Medication 
Washout Periods 
Replace: 
Medication 
Discontinuing Prior to Signing 
Consent 
Belimumab 
48 weeks 
With: 
Medication 
Discontinuing Prior to Signing 
Consent 
Belimumab 
24 weeks 
Updated text 
to clarify when 
medication 
had to be 
discontinued 
prior to study 
initiation 
Appendix 5, 
BILAG-2004 
(STUDY-
SPECIFIC 
MODIFIED 
CRITERIA) 
Replace: 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 141 of 143 
Section 
Description of Changes 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 142 of 143 
Section 
Description of Changes 
Rationale 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 6, 
INJECTION 
SITE REACTION 
GRADING 
SCALE 
Add: 
Adverse event 
Injection site 
reaction 
Grade 1 
Grade 2 
Grade 3 
Grade 
4 
Grade 
5 
Definition:  A 
disorder 
characterized by 
an intense 
adverse reaction 
(usually 
immunologic) 
developing at 
the site of an 
injection 
Tenderness 
with or 
without 
associated 
symptoms 
(eg, 
warmth, 
erythema, 
itching) 
Pain; 
Lipodystr
ophy; 
Edema; 
phlebitis 
Ulceratio
n or 
necrosis;  
Severe 
tissue 
damage; 
Operativ
e 
intervent
ion 
indicated 
Life-
threat
ening 
conseq
uences
; 
urgent 
interve
ntion 
indicat
ed 
Death 
 
Pain 
Mild pain 
Moderat
e pain; 
limiting 
instrume
ntal ADL 
Severe 
pain;  
limiting 
self-care 
ADL 
- 
- 
Rash 
maculopapular/
Macules/pa
pules 
Macules/
papules 
Macules/
papules 
- 
- 
Added table to 
clarify the 
grading scale 
for injection 
site reactions 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Protocol Date and Version:  21 March 2018; V3.0 
Confidential 
Page 143 of 143 
Section 
Description of Changes 
Rationale 
Erythema/Indur
ation 
 
Definition:  A 
disorder 
characterized by 
the presence of 
macules (flat) 
and papules 
(elevated).  Also 
known as 
morbillform 
rash, it is one of 
the most 
common 
cutaneous 
adverse events, 
frequently 
affecting the 
upper trunk, 
spreading 
centripetally, 
and associated 
with pruritus. 
covering 
<10% BSA 
with or 
without 
symptoms 
(eg, 
pruritus, 
burning, 
tightness) 
Erythema 
covering 
<10% BSA 
with or 
without 
symptoms 
(eg, 
pruritus, 
burning, 
tightness) 
covering 
10% - 
30% BSA 
with or 
without 
symptom
s (eg, 
pruritus, 
burning, 
tightness
); limiting 
instrume
ntal ADL; 
Erythema 
30% BSA 
with or 
without 
symptom
s (eg, 
pruritus, 
burning, 
tightness
); limiting 
instrume
ntal ADL 
covering 
> 30% 
BSA with 
or 
without 
associate
d 
symptom
s; 
limiting 
self-care 
ADL 
 
Erythema 
covering 
> 30% 
BSA with 
or 
without 
associate
d 
symptom
s; 
limiting 
self-care 
ADL 
ADL = active daily living 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 1 of 118 
A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 401 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721 
PROTOCOL NUMBER: 
BOS161721-02  
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
05 October 2017 
VERSION NUMBER: 
V2.0 (Amendment 1) 
VERSION DATE: 
08 November 2017 


BOS161721 
Boston Pharmaceuticals, Inc.  
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 2 of 118 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study 
of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of 
Care 
 
Study No:  BOS161721-02  
Original Protocol Date:  05 October 2017 
Protocol Version No:  v2.0 (Amendment 1) 
Protocol Version Date:  08 November 2017 
This study protocol was subject to critical review and has been approved by sponsor.  The 
information contained in this protocol is consistent with: 
 The current risk-benefit evaluation of the investigational product. 
 The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to 
applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature 
Date 
, MD 
Vice President, Clinical Development 
Boston Pharmaceuticals 
 
 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
 
 
, MD, PhD 
Vice President, Clinical Development and Safety 
Officer 
Boston Pharmaceuticals 
 
 
 
 
DocuSign Envelope ID: FB31453E-5D5A-49BC-8318-4673D9F4179F
PPD
PPD
PPD
PPD
PPD
PPD


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 3 of 118 
SUMMARY OF CHANGES 
Section 
Description of Changes 
Rationale 
Global 
Change: 
Changed Version number from V1.0 to V2.0 (Amendment 1) 
and Version date from 05 October 2017 to 08 November 2017. 
Administrative 
Global 
Change: 
Removed use of “Months” and “Weeks” to describe study site 
visits and dosing.  Changed to Day X throughout protocol. 
For clarity, site visits 
are based on study day 
number only. 
Global 
Change: 
Changed randomization day from Day 1 to Day 0. 
Clarification (as dose is 
given every 30 days) 
Global 
Made administrative and editorial (formatting, typographical, and 
grammatical) updates. 
Administrative 
PROTOCOL 
SUMMARY, 
Background and 
Rationale 
Section 1.2.2.3, 
Clinical Studies 
Replace: 
Overall, there were no clinically significant findings from this 
study; there were no serious adverse events (SAEs), deaths, or 
discontinuations due to AEs during the study, AEs reported as 
related to the study drug, particularly infections (flu-like 
symptoms, etc), were expected for the compound, and there were 
no clinically relevant changes in laboratory and ECG results or 
vital signs. 
With: 
Overall, there were no clinically significant findings from this 
study, following an interim cut and review of the data at 
Day 90 postdose.  Adverse events reported as related to the 
study drug, particularly infections, were expected for the 
compound, and there were no clinically relevant changes in 
laboratory and ECG results or vital signs.  There was 1 serious 
adverse event (SAE; death due to pulmonary embolism) that 
occurred 127 days after a single administration of 240 mg SC 
dose of BOS161721.  The causality of this single SAE was not 
attributed to study drug and further information can be 
found in the Investigator’s Brochure. 
Clarification and 
updated with new 
safety data. 
 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 4 of 118 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY, 
Study Design 
Section 1.2.3, 
Study Dose Section 
Section 4.1.1, 
Multiple Ascending 
Dose Phase 1b 
Study 
Delete: 
Each of the 3 doses (20 mg, 60 mg, and 120 mg) selected for the 
MAD study are projected not to exceed the mean peak levels or 
exposures of that achieved in the SAD study following the single 
240 mg SC dose. 
Clarification to correct 
level of exposure 
PROTOCOL 
SUMMARY,  
Study Design 
 
Replace: 
Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing (based on the dose level 
determined after DMC evaluation of the safety and tolerability 
data from Cohort 2 and Cohort 1).  Two weeks after the last 
patient in Cohort 3 receives the second dose, the DMC will 
conduct a data review for the first interim analysis (IA1) to 
determine which dose will be carried forward into the POC 
Phase 2 study.  This POC dose decision will be based on 
evaluation of the PK, safety (inclusive of dose-limiting toxicity 
[DLT]), and tolerability data (and available PD/biomarker data) 
from Cohorts 1, 2 and 3; this dose will not exceed doses tested 
during the MAD study.  The DMC will be reviewing all relevant 
data from Cohorts 1, 2, and 3 that is available when the last 
patient in Cohort 3 reaches 60 days (dose 2).  This dose will not 
exceed doses tested during the MAD study. 
With: 
Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing after DMC evaluation of the 
safety and tolerability data from Cohort 2 and Cohort 1.  Two 
weeks after the last patient in Cohort 3 receives the second dose, 
the DMC and Boston Pharmaceuticals will conduct a data 
review for the first interim analysis (IA1).  At that time, a 
decision will be made to suggest which dose should be carried 
forward into the POC Phase 2 study.  This dose will not exceed 
doses tested during the MAD study.   
Removed erroneous 
text and added clarity 
that Boston 
Pharmaceuticals will 
review data along with 
DMC for POC Dose 
selection. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 5 of 118 
Section 
Description of Changes 
Rationale 
PROTOCOL 
SUMMARY,  
Study Design 
Section 4.1.2.2, 
POC Study Design 
Section 9.1, Sample 
Size 
Add: 
…approximately 156 patients… 
Clarification to allow 
flexibility in exact 
number enrolled. 
PROTOCOL 
SUMMARY, 
 Study Design 
 
Replace: 
One oral CS “burst” for increased SLE disease activity may occur 
during the study either between Weeks 1 and 8 or between 
Weeks 16 and 20. 
With: 
One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 60. 
Second period for 
allowed CS “burst” 
removed as it conflicts 
with study endpoints. 
PROTOCOL 
SUMMARY, 
 Study Design 
Section 5.6.1, Oral 
Corticosteroid 
Dose 
Replace: 
Tapering may occur after randomization except within 8 weeks of 
the primary (Week 28) and secondary (Week 16) endpoint 
assessments. 
With: 
Tapering may occur after randomization except within 60 days of 
the primary (Day 210) and secondary (Day 120) endpoint 
assessments. 
Replaced weeks with 
days to be consistent 
with protocol. 
Section 1.2.3; 
Study Dose Section 
Replace: 
In addition, the DMC will conduct a data review for the first 
interim analysis (IA1) to determine which dose will be carried 
forward into the proof of concept (POC) Phase 2 study. 
With: 
In addition, the DMC and Boston Pharmaceuticals will conduct 
a data review for the first interim analysis (IA1).  At that time, a 
decision will be made to suggest which dose should be carried 
forward into the proof of concept (POC) Phase 2 study. 
Clarification that 
Boston Pharmaceuticals 
will review data along 
with DMC for POC 
Dose selection. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 6 of 118 
Section 
Description of Changes 
Rationale 
Section 1.2.4, 
Risk-Benefit 
Assessment 
Replace: 
Two weeks after the last patient in Cohort 3 receives the second 
dose, the DMC will conduct a data review for the IA1 to 
determine which dose will be carried forward into the POC 
Phase 2 study. 
With: 
Two weeks after the last patient in Cohort 3 receives the second 
dose, the DMC and Boston Pharmaceuticals will conduct a data 
review for the IA1.  At that time, a decision will be made to 
suggest which dose should be carried forward into the POC 
Phase 2 study. 
Clarification that 
Boston Pharmaceuticals 
will review data along 
with DMC for POC 
Dose selection. 
Section 4.1.1.1; 
Dose Escalation for 
the MAD Study 
Delete: 
Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing (based on the dose level 
determined after DMC evaluation of the safety and tolerability 
data from Cohorts 1 and 2).  Two weeks after the last patient in 
Cohort 3 receives the second dose, the DMC will conduct a data 
review for the IA1 to determine which dose will be carried 
forward into the POC Phase 2 study.  This POC dose decision 
will be based on evaluation of the PK, safety (inclusive of dose-
limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2, and 3; this dose will not 
exceed doses tested during the MAD study.  The DMC will be 
reviewing all relevant data from Cohorts 1, 2, and 3 that is 
available when the last patient in Cohort 3 reaches 60 days 
(dose 2). 
Removed, as this 
information does not fit 
this section. 
Section 4.1.1.1; 
Dose Escalation for 
the MAD Study 
Replace: 
If > 3 patients discontinue the study in a cohort, he/she will be 
replaced. 
With: 
If > 3 patients discontinue the study in a cohort, he/she may be 
replaced. 
Clarified statement as it 
is not definitive that 
these patients would be 
replaced. 
Section 4.1.1.2; 
Dose Limiting 
Toxicity (DLT) 
Delete: 
Investigators should always manage their patients according to 
their medical judgment which may include interruption of study 
drug based on the particular clinical circumstances.  All dose 
modifications/adjustments must be clearly documented in the 
patient's source notes and electronic Case Report Form (eCRF). 
Dose modifications/ 
adjustments are not 
allowed in this study. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 7 of 118 
Section 
Description of Changes 
Rationale 
Section 4.1.1.3; 
DMC 
Recommendations 
Replace: 
For the POC study, the DMC will conduct a data review for the 
IA1 to determine which dose will be carried forward into the 
POC Phase 2 study.  This POC dose decision will be based on 
evaluation of the PK, safety (inclusive of dose-limiting toxicity 
[DLT]), and tolerability data (and available PD/biomarker data) 
from Cohorts 1, 2, and 3; this dose will not exceed doses tested 
during the MAD study.  The DMC will be reviewing all relevant 
data from Cohorts 1, 2, and 3 that is available when the last 
patient in Cohort 3 reaches 60 days (dose 2).  Details are 
provided in the DMC Charter. 
With: 
For the POC study, the DMC and Boston Pharmaceuticals will 
conduct a data review for the IA1 to suggest which dose should 
be carried forward into the POC Phase 2 study.  This POC dose 
decision will be based on evaluation of the PK, safety (inclusive 
of dose-limiting toxicity [DLT]), and tolerability data (and 
available PD/biomarker data) from Cohorts 1, 2, and 3; this dose 
will not exceed doses tested during the MAD study.  The DMC 
will be reviewing all relevant data from Cohorts 1, 2, and 3 that is 
available at the time the last patient in Cohort 3 completes the 
Day 44 visit (2 weeks after dose 2).  Details are provided in the 
DMC Charter. 
Corrected error, data 
cut for the DMC review 
will be 2 weeks after 
dose 2 (Day 44 visit). 
Section 4.1.2.1; 
BOS161721 Dose 
Replace: 
The optimal dose evaluation is chosen based on MAD Phase 1b 
safety results.  The dose will be communicated by a letter to site 
investigators participating in the POC Phase 2 study, and to the 
IRB/IEC.  Once the POC dose decision has been made, screening 
for the POC study can begin. 
With: 
The optimal dose evaluation is chosen based on MAD Phase 1b 
safety, tolerability, immunogenicity, and PK and PD data.  
The dose will be communicated by a letter to site investigators 
participating in the POC Phase 2 study, and to the IRB/IEC. 
Updated for 
consistency with rest of 
protocol. 
Section 4.2, Study 
Schematic, 
Figure 2 
Change: 
Study schematic was updated to reflect use of “Days” for dosing 
as well as a correction to the time point for dose escalation 
(change from “Day 60” to “Day 44”). 
To reflect changes 
made to protocol body. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 8 of 118 
Section 
Description of Changes 
Rationale 
Section 4.3, 
Schedule of 
Assessments, 
Table 1, Table 2 
Change: 
Schedule of Assessments was reorganized so that all assessments 
are categorized as:  General, Safety, Efficacy, Laboratory, or PK 
Labs.  Footnotes were relettered accordingly. 
Reorganized for better 
clarity 
Section 4.3, 
Schedule of 
Assessments, 
Table 2 
Change: 
Removed columns for Day 7 and Day 44 in POC Schedule of 
Assessments. 
These visits are not 
applicable in the POC 
portion of this study. 
Section 4.3, 
Schedule of 
Assessments, 
Table 1, Table 2 
Change: 
Added assessments on Days 7 (MAD only), 187, and 195 for 
concomitant medications, AEs and SAEs, and injection site 
reactions. 
Safety information 
should be collected 
even on PK-only visits. 
Section 4.3, 
Schedule of 
Assessments, 
Table 1, Table 2 
Section 6.1, 
Screening 
Section 7.2.1, 
Laboratory 
Assessments, 
Table 3 
Delete: 
FSH and estradiol (postmenopausal women) 
Estradiol is removed as 
FSH is sufficient to 
determine menopause 
Section 4.3, 
Schedule of 
Assessments, 
Table 1, Table 2, 
footnote g 
Section 7.2.3, Vital 
Signs 
Add: 
Vital signs will be assessed on Day 0 at predose and at 1 and 
2 hours postdose, as well as on each of the scheduled outpatient 
days in the table above (excluding PK-only site visits at Days 7, 
187, and 195). 
Clarification 
Section 4.3, 
Schedule of 
Assessments, 
Table 1, Table 2, 
footnote h 
Replace: 
Clinical laboratory assessments will include a fasting glucose and 
lipid panel during screening and Week 28. 
With: 
Clinical laboratory assessments will include a fasting glucose and 
lipid panel, with exception of screening (Visit 1) which will be 
nonfasting. 
Clarification 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 9 of 118 
Section 
Description of Changes 
Rationale 
Section 5.6.1, Oral 
Corticosteroid 
Dose 
Delete: 
A maximum of 1 oral CS “burst” for increased SLE disease 
activity will be allowed during the study either between Day 0 
and Day 60 or between Weeks 16 and 20, according to the 
following: 
Second period for 
allowed CS “burst” 
removed as it conflicts 
with study endpoints. 
Section 5.6.1, Oral 
Corticosteroid 
Dose 
Delete: 
• 
An oral CS “burst” between Week 16 and Week 20 (an 
increase of ≤ 20 mg/day prednisone or equivalent), which 
must be tapered down to a maximum of 10 mg/day within 2 
weeks of initiation of the “burst”. 
o 
Alternatively, a single IM dose of methylprednisolone 
(40 mg or equivalent) is permitted. 
Second period for 
allowed CS “burst” 
removed as it conflicts 
with study endpoints. 
Section 5.6.2, 
Other Prohibited 
and/or Restricted 
Treatments 
Replace: 
Prohibited and/or restricted medications taken prior to study drug 
administration in the study are described below, and washout 
requirements are provided in APPENDIX 4. 
With: 
Prohibited and/or restricted medications taken prior to study drug 
administration and during the study are described below, and 
washout requirements are provided in APPENDIX 4. 
Clarification – this list 
includes not only 
prohibited medication 
prior to first dose, but 
also restrictions during 
the study. 
Section 5.8.2, 
Exception for Non-
Responders 
Delete: 
5.8.2 
Exception for Non-Responders 
Patients will be classified as non-responders if they (1) receive a 
second rescue medication at any time in the study or (2) take 
rescue medications between Week 8 and Week 16 or between 
Week 20 and Week 28 (as described in Section 5.6.1).  If a 
patient has been deemed a non-responder, they will discontinue 
from treatment and all End of Treatment assessments will be 
performed.  The patient will then enter the safety follow-up 
period.  The use of rescue medications in the case of 
non-responders is not to be considered a protocol violation 
(exclusion criteria 8).  Protocol violations will be identified based 
on blinded data prior to unblinding the final analysis dataset. 
Section deleted.  
Patients requiring 
corticosteroid outside 
of the protocol allowed 
time should be included 
in safety analysis and 
therefore continue in 
study.  Use of 
corticosteroid excluded 
from protocol windows 
would be documented 
as protocol violations. 
Section 6.1, 
Screening 
Delete: 
Screening will be the same for both the MAD and POC studies.  
Screening for the POC study cannot begin until the POC dose 
decision has been made. 
Screening for POC 
study can begin while 
dose decision is being 
made. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 10 of 118 
Section 
Description of Changes 
Rationale 
Section 6.1, 
Screening 
Add: 
• 
Chest x-ray 
• 
Laboratory evaluations (nonfasting): 
Chest x-ray was added 
as it was missing from 
V1.0 list of 
assessments.  
“(nonfasting)” was 
added as clarification. 
Section 6.2, 
Enrollment/Rando
mization and Day 0 
Treatment 
Add: 
• 
Laboratory evaluations (fasting): 
Clarification 
Section 6.3, 
Treatment 
Period/Follow-Up 
Visits 
Replace: 
See Section 4.3 for allowable windows for each visit.  The 
following procedures will be performed at every study drug 
administration visit (Weeks 4, 8, 12, 16, 20, and 24) and 
follow-up visits during the treatment period (Weeks 2 and 6): 
With: 
The following procedures will be performed as indicated in the 
Schedule of Assessments (Table 1 and Table 2).  See Schedule 
of Assessment tables for allowable windows for each visit. 
Clarification 
Section 6.3, 
Treatment 
Period/Follow-Up 
Visits 
Change: 
Based on change above (ie, cross-reference to Schedule of 
Assessments), removed timing of assessments from bulleted 
listed. 
Clarification 
Section 6.3, 
Treatment 
Period/Follow-Up 
Visits 
Replace: 
• 
Hematology and chemistry assessments will be performed at 
Weeks 4 and 6 (Visits 4 and 5) for the MAD study, only, and 
at Weeks 8, 12, 16, 20, and 24 (Visits 6 through 10) for both 
studies. 
With: 
• 
Fasting hematology and chemistry assessments 
Clarification 
Section 6.4, Safety 
Follow-Up Visits 
Add: 
These visits will include the following assessments as indicated 
in the Schedule of Assessments (Table 1 and Table 2): 
Clarification 
Section 6.4, Safety 
Follow-Up Visits 
Change: 
Based on change above (ie, cross-reference to Schedule of 
Assessments), removed timing of assessments from bulleted 
listed. 
Clarification 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 11 of 118 
Section 
Description of Changes 
Rationale 
Section 6.4, Safety 
Follow-Up Visits 
Add: 
• 
Fasting clinical laboratory assessments (hematology and 
clinical chemistry) 
Clarification 
Section 7.2.1, 
Laboratory 
Assessments 
Delete: 
Laboratory/analyte results that could unblind the study (ie, 
biomarker results) will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.  
Urinalysis will be performed on midstream, clean catch 
specimens. 
Text removed as 
Boston Pharmaceuticals 
will be reviewing 
biomarker data for POC 
dose selection. 
Section 7.2.1, 
Laboratory 
Assessments 
Add: 
Endpoint analyses will be based on changes from baseline 
assessments at Days 120 and 210. 
Moved from redundant 
laboratory assessment 
section that was deleted 
from protocol. 
Section 7.2.1, 
Laboratory 
Assessments, 
Table 3 
Add: 
 
Clarification (genotype 
needed to establish 
gene signature) 
Section 7.2.1.1, 
Pregnancy testing 
Replace: 
Urine pregnancy tests will also be routinely repeated at study 
drug administration visits (Visits 2, 4, 6, 7, 8, 9, and 10) prior to 
study drug administration, and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive pregnancy test or confirmed 
pregnancy, the patient will be withdrawn from study drug but 
may remain in the study for safety monitoring. 
With: 
Urine pregnancy tests will also be routinely repeated at study 
drug administration visits prior to study drug administration, and 
additionally whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  In the case of a 
positive pregnancy test or confirmed pregnancy, the patient will 
be discontinued from study drug, an EOT visit should be 
performed (Day 180), and a last follow-up visit 90 days after 
last dose should be scheduled (Day 270).  Safety follow-up 
visit procedures based on the Schedule of Assessments (see 
Section 6.4). 
To clarify how the 
patient should complete 
the study.  Also 
removed Visit numbers 
as beginning of section 
cross-references 
Schedule of 
Assessments. 
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 12 of 118 
Section 
Description of Changes 
Rationale 
Section 7.2.4, 
12-Lead 
Electrocardiograms 
Replace: 
ECG will be performed at screening, and Visits 2, 4, and 7, and 
13. 
With: 
ECG will be assessed as specified in the Schedule of 
Assessments (Section 4.3). 
Clarification 
Section 7.2.5, 
Physical 
Examination 
Replace: 
The targeted (limited) physical examination will be completed at 
Visits 3 through 13. 
With: 
The targeted (limited) physical examination will be completed at 
all other visits as indicated in the Schedule of Assessments 
(Section 4.3). 
Clarification 
Section 7.2.6, 
C-SSRS 
Replace: 
The C-SSRS evaluation will be performed at screening, Visit 2 
(Day 1) and at Visits 7 and 10 (Weeks 12 and 24, respectively). 
With: 
The C-SSRS evaluation will be performed as specified in the 
Schedule of Assessments (Section 4.3). 
Clarification 
Section 7.2.7, 
Injection Site 
Reactions 
Replace: 
Patients will be monitored for local injection site reactions at 
dosing administration visits, Visits 2 (Day 1), Visit 4 (Week 4), 
and Visits 6 through 10 (Weeks 8, 12, 16, 20, and 24).  Patients 
will also be monitored for local injection site reactions at the 
safety follow-up visits, Visits 11, 12, and 13 (Weeks 28, 32, and 
36, respectively). 
With: 
Patients will be monitored for local injection site reactions as 
specified in the Schedule of Assessments (Section 4.3). 
Clarification 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 13 of 118 
Section 
Description of Changes 
Rationale 
Section 7.2.8, 
Immunogenicity 
Replace: 
The serum samples to measure the presence of ADA will be 
collected as Visits 2, 3, 4, 6, 7, 10, and 13 (Week 0, 2, 4, 8, 12, 
24, and 36, respectively). 
With: 
The serum samples to measure the presence of ADA will be 
collected as specified in the Schedule of Assessments 
(Section 4.3). 
Clarification 
Section 7.3, 
Efficacy 
Assessments 
Add: 
All efficacy assessments will be performed at times defined in 
the Schedule of Assessments (Section 4.3). 
Clarification (allows 
for deletion of visit 
days from each 
subsection). 
Section 7.3.1, 
SLEDAI-2K 
Delete: 
The SLEDAI-2K is completed at screening, at Visit 2, Visit 4, 
and Visits 6 through 13. 
Removed based on 
cross-reference to 
Schedule of 
Assessments provided 
in Section 7.3. 
Section 7.3.2, 
BILAG 2004 
Delete: 
The BILAG-2004 is completed at screening, Visit 2, 4, and 6 
through 13. 
Removed based on 
cross-reference to 
Schedule of 
Assessments provided 
in Section 7.3. 
Section 7.3.3, PGA 
of Disease Activity 
Delete: 
The PGA is completed at screening, Visit 2, 4, and Visits 6 
through 13. 
Removed based on 
cross-reference to 
Schedule of 
Assessments provided 
in Section 7.3. 
Section 7.3.6, 
ACR-28 Joint 
Count 
Delete: 
The ACR-28 joint count will be performed at screening, Visit 2, 
4, and 6 through 13. 
Removed based on 
cross-reference to 
Schedule of 
Assessments provided 
in Section 7.3. 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 14 of 118 
Section 
Description of Changes 
Rationale 
Section 7.3.7, 
Laboratory 
Assessments 
Delete: 
7.3.7 
Laboratory Assessments 
Patients will be evaluated for laboratory parameters as specified 
in the Schedule of Assessments (Section 4.3), including:  Fasting 
glucose and lipid panels, pSTAT3 (predose samples in Phase 2), 
total IgG & IgM, complement:  
, Plasma 
 & 
, whole blood for leukocyte immunophenotype and 
RNA, 
, and antibodies:  (
 
). 
Endpoint analyses will be based on changes from baseline 
assessments at Week 16 and Week 28. 
Deletion of redundant 
information already 
presented in Section 
7.2.1. 
Section 7.4.2, 
PROs 
Add: 
The PROs include the 
 and the 
 and will be 
assessed as specified in the Schedule of Assessments 
(Section 4.3). 
Delete: 
The 
 is completed by patients at screening and Day 1 
(Visit 2), Week 4 (Visit 4), Week 8 (Visit 6) through Week 36 
(Visit 13). 
Delete: 
The 
 is administered at screening, and Day 1 (Visit 2) Week 
4 (Visit 4), Week 8 (Visit 6) through Week 36 (Visit 13). 
Clarification 
Section 7.5, 
Pharmacokinetic 
Assessments 
Delete: 
PK parameters include the following:  
• 
Cmax, Tmax, AUC, t½, CL, Vd 
In addition to samples collected at the scheduled times, an 
additional blood sample should be collected from patients 
experiencing unexpected AEs and/or SAEs and the date and time 
documented in the eCRF. 
This language is not 
applicable under PK 
section. 
Section 7.6, 
Pharmacodynamic 
Assessments 
Add: 
Blood samples for PD parameters (plasma) will be collected at 
times indicated in the Schedule of Assessments (Section 4.3) for 
each of the following parameters: 
Clarification 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 15 of 118 
Section 
Description of Changes 
Rationale 
Section 7.6, 
Pharmacodynamic 
Assessments 
Change: 
Based on change above (ie, cross-reference to Schedule of 
Assessments), removed timing of assessments from bulleted 
listed. 
Clarification 
Section 8.5, 
Prohibited 
Concomitant 
Therapy 
Add: 
Prohibited concomitant medications are discussed in Section 5.6 
and APPENDIX 4 and will be listed as protocol violations if 
taken when not permitted. 
Clarification 
Section 9.2.5.2, 
Data Monitoring 
Committee 
Delete: 
The DMC will have access to unblinded treatment information 
during the clinical trial.  To prevent inadvertent unblinding of 
sponsor staff, reports to the DMC will describe each treatment 
group by a coded identifier rather than actual treatment group 
assignment.  Details regarding management and process of this 
committee are found in the DMC Charter. 
Removed text, exact 
details will be provided 
in charter. 
Section 9.3, Interim 
Analysis and Power 
Delete: 
Two IAs are planned for this study.  The initial IA will be 
conducted at the time of the POC decision for dose selection.  
The DMC will review safety and tolerability, and 
PK/PD/biomarkers for dose selection.  Efficacy data will not be 
reviewed for dose selection so there should be no impact on the 
type 1 error. 
Removed as efficacy 
data will be reviewed 
by Boston 
Pharmaceuticals in 
order to make informed 
dose selection decision. 
Section 9.3, Interim 
Analysis and Power 
Add: 
Nominal time profiles will be used for calculating PK parameters 
in the IA2.  Details will be available in the SAP. 
Clarification 
Section 10.2, DMC 
Replace: 
The primary responsibilities of the DMC are to (1) periodically 
review and evaluate the accumulated study data for participant 
safety, study conduct, and progress, (2) make recommendations 
to the sponsor concerning the continuation, modification, or 
termination of the study and (3) make a dose recommendation for 
POC portion of the study. 
With: 
The primary responsibilities of the DMC are to (1) periodically 
review and evaluate the accumulated study data for participant 
safety, study conduct, and progress, (2) make recommendations 
to the sponsor concerning the continuation, modification, or 
termination of the study and (3) suggest dose for POC portion of 
the study. 
Clarification 


BOS161721 
Boston Pharmaceuticals, Inc. 
Clinical Study Protocol:  BOS161721-02 
Confidential 
Page 16 of 118 
Section 
Description of Changes 
Rationale 
Section 10.4, 
Informed Consent 
Replace: 
Before each patient is enrolled in the clinical study, written 
informed consent will be obtained from the patient according to 
the regulatory and legal requirements of the participating country. 
With: 
Before each patient undergoes any protocol required 
assessments or procedure, the written informed consent will be 
obtained according to the regulatory and legal requirements of the 
participating country. 
Clarification 
 


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BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described.  I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Council for Harmonisation (ICH) guidelines, and will 
make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


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PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered 
Multiple Dose Escalation Study of BOS161721 in Systemic Lupus 
Erythematosus (SLE) Patients on a Background of Limited Standard 
of Care 
Indication 
Adults with moderately to severely active SLE 
Background and 
Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the 
disease, and that T-cell-derived cytokines such as interleukin-21 
(IL-21) are involved in the SLE-associated inflammatory 
pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple 
mutation monoclonal antibody (mAb) intended to have an extended 
terminal elimination half-life (t1/2) that selectively binds to and 
neutralizes IL-21, which acts on multiple cell types that drive 
inflammation and autoimmunity.  In vivo, BOS161721 inhibits 
T-cell dependent antigen responses of B-cells and is being developed 
as a potential treatment for adults with moderately to severely active 
SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics 
(PD), toxicokinetics (TK), pharmacokinetics (PK), and 
immunogenicity of BOS161721 administered intravenously (IV) and 
subcutaneously (SC).  The no observed adverse effect levels 
(NOAELs) in Cynomolgus monkeys were determined to be 
100 mg/kg IV and 50 mg/kg SC, the highest doses tested.  No SC 
animals had injection reactions. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  
This double-blind, placebo-controlled study evaluated 8 ascending 
dose levels (1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 
120 [SC], or 240 [SC] mg) for safety, tolerability, PK, PD and 
immunogenicity.  Overall, there were no clinically significant safety 
or tolerability findings from this study, following an interim cut and 
review of the data at Day 90 postdose.  
Results from the Phase 1 SAD study informed the dose regimens 
used for the multiple ascending doses (MAD) Phase 1b study in this 
trial.  The MAD study will involve 3 cohorts.  The Phase 2 portion 
will be a proof of concept (POC) study, where dose selection will be 
based on the sponsor’s assessment of safety, tolerability, 


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immunogenicity, and PK and PD data from the MAD study of 
30 patients treated with BOS161721/placebo.  The purpose of the 
study is to establish safe and effective dosages for adult patients with 
moderately to severely active SLE. 


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Objectives:  
MAD Phase 1b Study 
Primary Objective: 
To assess safety, tolerability, and immunogenicity of repeat doses of 
BOS161721 (20 mg, 60 mg, and 120 mg) administered SC in adult 
patients with moderately to severely active SLE on limited 
background standard of care treatment, in order to estimate the 
optimal dose. 
POC Phase 2 Study 
Primary Objective: 
To demonstrate a superior effect of BOS161721 at the chosen dose 
compared with placebo for response on the SLE Responder Index 4 
(SRI-4), with sustained reduction of oral corticosteroids (CS), in 
adult patients with moderately to severely active SLE on limited 
background standard of care treatment. 
Secondary Objectives:  
To demonstrate a superior effect of BOS161721 at the chosen dose 
compared with placebo for response on clinical indicators of SLE 
activity, in adult patients with moderately to severely active SLE on 
limited background standard of care treatment, including: 
• Changes in SLE-specific autoantibody titers 
• Changes in complement 3 and 4 (C3 and C4) levels 
• Responses on SRI-4, SLE Responder Index 5 and 6 (SRI-5, and 
SRI-6), with sustained reduction of oral CS 
• Response on the British Isles Lupus Assessment Group 
(BILAG)-based Composite Lupus Assessment (BICLA) 
• Response on the Cutaneous Lupus Erythematosus Area and 
Severity Index (CLASI) 
• Changes in the SLE Disease Activity Index 2000 (SLEDAI-2K) 
• Changes in the American College of Rheumatology (ACR)-28 
joint count 


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Endpoints:  
Phase 1b MAD Study 
Primary Endpoints:  
Evaluation of safety, tolerability, and immunogenicity at each dose 
level, to determine the optimal dose, will include the recording of the 
following parameters: 
• Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs) 
• 12-lead electrocardiograms (ECGs) 
• Vital signs (blood pressure [BP], heart rate, and temperature) 
• Clinical laboratory assessments 
• Physical examinations 
• Evaluation for anti-drug antibodies (ADAs) 
Exploratory Endpoints: 
• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
Other Endpoints: 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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• 
 
 
• 
 
 
 
• 
 
PRO Endpoints: 
• 
 
 
• 
 
Phase 2 POC Study 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients who 
achieve treatment response as measured by the SRI-4 at Day 210, 
along with a sustained reduction of oral CS (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and Day 210. 
Secondary Efficacy Endpoints: 
• The proportion of patients who achieve treatment response for 
the SRI-5 and SRI-6 at Day 210, along with a sustained reduction 
of oral CS (≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and 
Day 210 
• Changes from baseline in dsDNA, ANA, SSA, SSB, RNP, Sm, 
APL autoantibodies, at Day 120 and Day 210 
• Changes from baseline in C3 and C4 levels at Day 120 and 
Day 210 
• Changes from baseline in the SLEDAI-2K at Day 210 
• Time to BILAG A or B flare 
• Changes from baseline in the CLASI at Day 210 
• The proportion of patients with a BICLA response at Day 210 
• The proportion of patients with CLASI response at Day 210 
CCI
CCI
CCI
CCI
CCI


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• Changes from baseline (percentage) in swollen joints and tender 
joints ACR-28 joint count 
• Assessment of safety, tolerability, and immunogenicity as 
described for the primary endpoint in the MAD Phase 1b study 
Exploratory Endpoints:  
• 
 
• 
 
Other Endpoints: 
• 
 
• 
 
• 
 
PRO Endpoints: 
• 
 
 
• 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, 
double-blind, placebo-controlled trial to study the clinical efficacy, 
safety, and PK of multiple SC doses of BOS161721 in adult patients 
with moderately to severely active SLE.  After successfully 
completing a screening phase, patients will be randomized to a 
specified dose of BOS161721 or placebo.  The dosing schedule will 
be monthly.  The trial will consist of a staggered MAD Phase 1b and 
POC Phase 2 studies.  Both studies will be double-blinded with each 
patient having the same number of doses (7), and visits; the duration 
will be 180 days, followed by a 90-day follow-up safety observation 
period.   
The MAD Phase 1b study phase will consist of 3 cohorts, with 
Cohort 1 containing 6 patients, where 5 of these patients will receive 
BOS161721 (active), and 1 will receive placebo.  Cohorts 2 and 3 
will each contain 12 patients, including 9 active and 3 placebo 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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patients.  Dose selection for each cohort is based on 90-day safety, 
tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01) in healthy subjects.  Each of the 3 doses (20 mg, 
60 mg, and 120 mg) selected for the MAD study are projected not to 
exceed the mean exposure of that achieved in the SAD study 
following the single 240 mg SC dose.  Each patient may receive a 
total of 7 SC monthly doses on Days 0, 30, 60, 90, 120, 150, and 
180.   
The MAD study design is staggered, where after the 6 patients in 
Cohort 1 have received 2 doses and have completed 2 weeks of 
follow-up after the second dose, Cohort 2 begins dosing (after a data 
monitoring committee [DMC] evaluates the safety and tolerability 
data from Cohort 1).  Similarly, after 8 of the 12 patients in Cohort 2 
have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing after DMC evaluation 
of the safety and tolerability data from Cohort 2 and Cohort 1.  Two 
weeks after the last patient in Cohort 3 receives the second dose, the 
DMC and Boston Pharmaceuticals will conduct a data review for the 
first interim analysis (IA1).  At that time, a decision will be made to 
suggest which dose should be carried forward into the POC Phase 2 
study.  This dose will not exceed doses tested during the MAD study.  
For the POC study, approximately 156 patients will be randomized 
to active or placebo groups in a 2:1 ratio.  As in the MAD study, 
each patient in the POC study may receive a total of 7 SC monthly 
doses on Days 0, 30, 60, 90, 120, 150, and 180.  A maximum daily 
dose of 30 mg/day of oral CS will be acceptable for eligibility for the 
study, however, daily dose must be tapered down to a maximum of 
10 mg/day for at least 5 days prior to Day 0 (randomization day).  
One oral CS “burst” for increased SLE disease activity may occur 
during the study between Day 0 and Day 60.  Tapering of steroids 
during the course of the study will be encouraged and should be 
evaluated at all visits.  Tapering may occur after randomization 
except within 60 days of the primary (Day 210) and secondary 
(Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant 
otherwise the patient will be declared a non-responder in efficacy 
assessments. 
Data from 60 patients, including the 12 from the MAD study, or 
6 fewer if the low dose is chosen, who are in the cohort of the chosen 
dose for the POC study who complete 3 months of treatment will be 
used in a second IA (IA2) at Day 90 to assess if the trial could stop 
for an early futility conclusion.  If futility is not claimed in the IA2, 
the POC study will continue to approximately 156 patients. 


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Following the 6-month treatment period, primary and secondary 
efficacy endpoints will be assessed for each patient, after providing 
their Day 180 disease activity assessments.  DMC monitoring will be 
conducted periodically throughout the study as described in the 
DMC charter. 
Main Criteria for 
Inclusion and Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there 
must be evidence of a personally signed and dated informed 
consent document indicating that the patient has been informed 
of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic 
Lupus International Collaborating Clinics (SLICC) classification 
criteria for SLE (with at least 1 clinical and 1 immunologic 
criterion OR Lupus nephritis as the sole clinical criterion in the 
presence of ANA or anti-dsDNA antibodies), either sequentially 
or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the 
central laboratory 
b. Positive anti-dsDNA or anti-Sm above the normal level as 
determined by the central laboratory 
c. C3 or C4 below normal as determined by the central lab 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from 
at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory 
results:  (hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome 
will also be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at 


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least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, and vasculitis 
i. 
Excluding parameters which require central laboratory 
results:  hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia and leukopenia 
ii. 
Points from lupus headache and organic brain syndrome 
are also excluded 
7. Patients must have at least 1 of the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this 
study, which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis as defined in the protocol Section 5.4 
c. If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal body 
system due to arthritis, then at least 1 “B” must be present in 
the other body systems for a total of 2 “B” BILAG body 
system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose 
for at least 56 days (8 weeks prior to signing consent) of the 
following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or 
mycophenolic acid, chloroquine, hydroxychloroquine, 
or methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 
30 mg/day at screening for a patient to be eligible and must 
be stable at a maximum of 10 mg/day for at least 5 days prior 
to Day 0 (randomization) 
9. Women of childbearing potential (WOCBP; see Section 5.7 for 
full information regarding WOCBP, definition of menopause, 
and contraception): 
a. Must have a negative serum pregnancy test at screening.  


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Urine pregnancy test must be negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug 
plus 5 half-lives of study drug BOS1617219 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after 
treatment completion 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of BOS161721 plus 
90 days (duration of sperm turnover) for a total of 44 weeks after 
treatment completion 
11. Patients must demonstrate willingness and ability to comply with 
the scheduled study visits, treatment plans, laboratory tests, and 
other procedures 
Exclusion Criteria 
Patients presenting with any of the following will not be included in 
this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, 
rheumatoid arthritis [RA], multiple sclerosis [MS], systemic 
scleroderma, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome 
are allowed 
3. Any major surgery within 6 weeks of study drug administration, 
(Day 0), or any elective surgery planned during the course of the 
study 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of 
active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold 
In-Tube (QFT-G) or other diagnostic test in the absence of 
clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of 
prophylactic treatment with regimen recommended by local 
health authority guideline, or the patient has started treatment 


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with isoniazid, or other regimen recommended by local 
health authority guidelines for at least 1 month before Day 0 
and continues to receive the prophylactic treatment during 
study until the treatment course is completed 
5. Active or unstable lupus neuropsychiatric manifestations, 
including but not limited to any condition defined by BILAG A 
criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which 
requires or may require induction treatment with cytotoxic agents 
or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is 
likely to require additional systemic glucocorticosteroid therapy 
during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy 
is allowed 
8. Use or planned use of concomitant medication outside of 
standard of baseline treatment for SLE from Day -1 or for any 
time during the study 
9. Active and clinically significant infection (bacterial, fungal, viral, 
or other) within 60 days prior to first dose of study drug.  
Clinically significant is defined as requiring systemic antibiotics 
or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or 
severe disseminated herpes zoster or disseminated herpes 
simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and 
hepatitis C (HCV), known human immunodeficiency virus 
(HIV), or acquired immunodeficiency syndrome (AIDS)-related 
illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 500/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 
(35 × 109/L) if related to SLE, at screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia 
related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent 
level of proteinuria as assessed by protein/creatinine ratio 


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(3 mg/mg or 339 mg/mmol) 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine 
clearance (CrCL) < 40 ml/minute based on Cockcroft-Gault 
calculation 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the 
investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related 
to lupus myositis  
22. Direct bilirubin > 1.5 × ULN at screening (unless related to 
Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the 
Investigator, might place a patient at unacceptable risk for 
participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of 
components of mAbs 
25. History substance and/or alcohol abuse, or dependence within the 
past 1 year, at the investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous 
basal cell or squamous cell cancer, or cervical cancer in situ 
resolved by excision 
27. Any other severe acute or chronic medical or psychiatric 
condition, including recent (within the past year) medical 
conditions (eg, cardiovascular conditions, respiratory illnesses) 
that may increase the risk associated with study participation or 
investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the 
investigator, would make the patient inappropriate for entry into 
this study 
28. Investigational site staff members directly involved in the 
conduct of the trial and their family members, site staff members 
otherwise supervised by the investigator, or patients who are 
employees of the sponsor or directly involved in the conduct of 
the trial 
29. Currently participating in, or who have participated in other 
interventional (drug or device) clinical study within 30 days or 
5 half-lives of baseline, whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 


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on the Columbia Suicide severity Rating Scale (C-SSRS) 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of 
either a psychiatric or physical (eg, infectious disease) illness 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be 
found in Section 9. 
Baseline and patient characteristics will be summarized via 
appropriate summary statistics by treatment group and overall, for 
each phase of the trial. 
Binary efficacy endpoints will be compared between treatments via 
Cochran-Mantel-Haenszel (CMH) analysis.  Continuous efficacy 
endpoints will be assessed via analysis of covariance (ANCOVA) 
repeated measures mixed model analysis with factors including 
treatment, time, treatment-by-time interaction, baseline covariate, 
and covariate-by-time interaction.  Summary statistics will be 
provided by dose/treatment for all safety endpoints.  Details will be 
provided in the statistical analysis plan (SAP).   
Two IAs are planned for this study.  The initial IA (IA1) will be 
conducted at the time of the POC decision for dose selection.  The 
second IA (IA2) will be performed for futility.  IA2 is planned to be 
conducted when SRI-4 response is determined for approximately 
60 patients (including all patients at the same dose level/matching 
placebo from the MAD study) after completing 3 months of 
treatment.  The purpose of IA2 is to assess if the trial could stop for 
an early futility conclusion, or continue.  Since there is no plan to 
stop the trial for an early efficacy conclusion, there is no impact on 
the type 1 error level.   
AEs will be summarized by counts and percentages of patients by 
treatment group.  Laboratory data and vital signs will be summarized 
by treatment group as summary statistics for value and change from 
baseline at each individual time point.  Summary statistics will 
include n, arithmetic mean, median, arithmetic SD, minimum, and 
maximum. 
The PK parameter data will be listed and summarized descriptively 
in tabular format.  Binary PD endpoints will be assessed for the full 
analysis set (FAS) population via CMH analysis.  Continuous PD 
endpoints will be assessed via ANCOVA repeated measures mixed 
model analysis with multiple factors.  PK and PD relationships will 
be explored graphically and where appropriate model based methods 
of analysis will used. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
SUMMARY OF CHANGES ...........................................................................................................3 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT ...................................................17 
PROTOCOL SUMMARY .............................................................................................................18 
TABLE OF CONTENTS ...............................................................................................................31 
LIST OF IN-TEXT TABLES ........................................................................................................35 
LIST OF IN-TEXT FIGURES.......................................................................................................35 
LIST OF ABBREVIATIONS ........................................................................................................36 
1 
INTRODUCTION AND RATIONALE .................................................................................40 
1.1 
Indication ...........................................................................................................................40 
1.2 
Background and Rationale .................................................................................................40 
1.2.1 
Overview of the Disease State .....................................................................................40 
1.2.2 
BOS161721 Development ...........................................................................................40 
1.2.2.1 
Interleukin-21 .........................................................................................................41 
1.2.2.2 
Preclinical Studies ..................................................................................................42 
1.2.2.3 
Clinical Studies ......................................................................................................43 
1.2.3 
Study Dose Selection ...................................................................................................44 
1.2.4 
Risk-Benefit Assessment .............................................................................................45 
1.2.5 
Potential Risks .............................................................................................................45 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................46 
1.2.5.2 
Injection Site Reactions .........................................................................................46 
1.2.5.3 
Immune Complex Disease .....................................................................................47 
1.2.5.4 
Infections................................................................................................................47 
1.2.5.5 
Malignancy ............................................................................................................48 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................48 
1.2.5.7 
Failure of Vaccination............................................................................................49 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................49 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................49 
2 
STUDY OBJECTIVES ..........................................................................................................49 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................49 
2.1.1 
Primary Objective ........................................................................................................49 
2.2 
Phase 2 Proof of Concept ...................................................................................................50 
2.2.1 
Primary Objective ........................................................................................................50 
2.2.2 
Secondary Objectives ...................................................................................................50 
3 
STUDY ENDPOINTS ............................................................................................................50 
3.1 
Phase 1b MAD Study.........................................................................................................50 
3.1.1 
Primary Endpoints .......................................................................................................50 
3.1.2 
Exploratory Endpoints .................................................................................................51 


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3.1.3 
Other Endpoints ...........................................................................................................51 
3.1.4 
PRO Endpoints.............................................................................................................52 
3.2 
Phase 2 POC Study ............................................................................................................52 
3.2.1 
Primary Efficacy Endpoint ..........................................................................................52 
3.2.2 
Secondary Efficacy Endpoints .....................................................................................52 
3.2.3 
Exploratory Endpoints .................................................................................................53 
3.2.4 
Other Endpoints ...........................................................................................................53 
3.2.5 
PRO Endpoints.............................................................................................................53 
4 
STUDY PLAN ........................................................................................................................53 
4.1 
Study Design ......................................................................................................................53 
4.1.1 
Multiple Ascending Dose Phase 1b Study ...................................................................54 
4.1.1.1 
Dose Escalation for the MAD Study .....................................................................54 
4.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................55 
4.1.1.3 
DMC Recommendations ........................................................................................55 
4.1.2 
POC Phase 2 Study ......................................................................................................56 
4.1.2.1 
BOS161721 Dose...................................................................................................56 
4.1.2.2 
POC Study Design .................................................................................................56 
4.2 
Study Schematic.................................................................................................................57 
4.3 
Schedule of Assessments ...................................................................................................58 
5 
POPULATION .......................................................................................................................66 
5.1 
Participant Recruitment .....................................................................................................66 
5.2 
Number of Patients ............................................................................................................66 
5.3 
Patient Screening ...............................................................................................................66 
5.4 
Inclusion Criteria ...............................................................................................................66 
5.5 
Exclusion Criteria ..............................................................................................................68 
5.6 
Concomitant Medications ..................................................................................................70 
5.6.1 
Oral Corticosteroid Dose .............................................................................................71 
5.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................72 
5.7 
Women of Childbearing Potential .....................................................................................72 
5.7.1 
Determination of Menopause .......................................................................................72 
5.7.2 
Contraception ...............................................................................................................73 
5.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................73 
5.8.1 
Patient Withdrawal and Replacement ..........................................................................74 
6 
STUDY PROCEDURES ........................................................................................................74 
6.1 
Screening............................................................................................................................74 
6.1.1 
Retesting During Screening Period ..............................................................................75 
6.2 
Enrollment/Randomization and Day 0 Treatment .............................................................76 
6.3 
Treatment Period/Follow-Up Visits ...................................................................................77 
6.4 
Safety Follow-Up Visits ....................................................................................................78 
6.5 
Premature Discontinuation .................................................................................................79 
7 
ASSESSMENTS .....................................................................................................................80 


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7.1 
Medical History, Demographic and Other Baseline Information ......................................80 
7.2 
Safety Assessments ............................................................................................................81 
7.2.1 
Laboratory Assessments ..............................................................................................81 
7.2.1.1 
Pregnancy testing ...................................................................................................83 
7.2.1.2 
Tuberculosis Screening ..........................................................................................83 
7.2.2 
Adverse Events ............................................................................................................84 
7.2.2.1 
Definitions..............................................................................................................84 
7.2.2.2 
Recording of Adverse Events ................................................................................84 
7.2.2.3 
Severity of Adverse Events ....................................................................................84 
7.2.2.4 
Causality of Adverse Events ..................................................................................85 
7.2.2.5 
Seriousness of Adverse Events ..............................................................................85 
7.2.2.6 
Adverse Events of Special Interest ........................................................................86 
7.2.2.7 
Reporting of Adverse Events .................................................................................89 
7.2.2.8 
Follow Up of Adverse Events ................................................................................91 
7.2.3 
Vital Signs ....................................................................................................................91 
7.2.4 
12-Lead Electrocardiograms ........................................................................................91 
7.2.5 
Physical Examinations .................................................................................................92 
7.2.6 
C-SSRS ........................................................................................................................92 
7.2.7 
Injection Site Reactions ...............................................................................................92 
7.2.8 
Immunogenicity ...........................................................................................................92 
7.3 
Efficacy Assessments .........................................................................................................93 
7.3.1 
SLEDAI-2K .................................................................................................................93 
7.3.2 
BILAG 2004 ................................................................................................................93 
7.3.3 
PGA of Disease Activity ..............................................................................................94 
7.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................94 
7.3.4.1 
SRI-4 Response ......................................................................................................94 
7.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................94 
7.3.4.3 
BICLA Response ...................................................................................................94 
7.3.5 
CLASI Response ..........................................................................................................95 
7.3.6 
ACR-28 Joint Count ....................................................................................................95 
7.4 
Other Variables ..................................................................................................................95 
7.4.1 
SLICC/ACR Damage Index ........................................................................................95 
7.4.2 
PROs ............................................................................................................................95 
7.5 
Pharmacokinetic Assessments ...........................................................................................96 
7.6 
Pharmacodynamic Assessments ........................................................................................96 
7.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................96 
7.8 
Protocol Deviations ............................................................................................................96 
8 
STUDY DRUG MANAGEMENT .........................................................................................97 
8.1 
Description .........................................................................................................................97 
8.1.1 
Formulation ..................................................................................................................97 
8.1.2 
Storage .........................................................................................................................97 


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8.2 
Packaging and Shipment ....................................................................................................97 
8.3 
Dose and Administration ...................................................................................................97 
8.4 
Accountability ....................................................................................................................98 
8.5 
Prohibited Concomitant Therapy .......................................................................................98 
8.6 
Compliance ........................................................................................................................98 
9 
STATISTICS ..........................................................................................................................98 
9.1 
Sample Size ........................................................................................................................98 
9.2 
Statistical Methods .............................................................................................................99 
9.2.1 
Analysis Populations ....................................................................................................99 
9.2.2 
Demographics and Baseline Characteristics ................................................................99 
9.2.3 
Primary Endpoint(s) ...................................................................................................100 
9.2.4 
Secondary Endpoint(s) ...............................................................................................100 
9.2.5 
Analysis of Safety ......................................................................................................100 
9.2.5.1 
Safety Analysis ....................................................................................................100 
9.2.5.2 
Data Monitoring Committee ................................................................................100 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data ...........................................................101 
9.2.6.1 
Analysis of Pharmacokinetic Data .......................................................................101 
9.2.6.2 
Analysis of Pharmacodynamic Data ....................................................................101 
9.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ................................101 
9.3 
Interim Analysis and Power .............................................................................................102 
10 ETHICS AND RESPONSIBILITIES ...................................................................................102 
10.1 
Good Clinical Practice .....................................................................................................102 
10.2 
DMC ................................................................................................................................102 
10.3 
Institutional Review Board/Independent Ethics Committee ............................................103 
10.4 
Informed Consent.............................................................................................................103 
10.5 
Records Management .......................................................................................................103 
10.6 
Source Documentation .....................................................................................................104 
10.7 
Study Files and Record Retention....................................................................................104 
11 AUDITING AND MONITORING ......................................................................................104 
12 AMENDMENTS ..................................................................................................................105 
13 STUDY REPORT AND PUBLICATIONS .........................................................................105 
14 STUDY DISCONTINUATION ...........................................................................................106 
15 CONFIDENTIALITY ..........................................................................................................106 
16 REFERENCES .....................................................................................................................107 
17 APPENDICES ......................................................................................................................111 
APPENDIX 1 
NAMES OF STUDY PERSONNEL .............................................................111 
APPENDIX 2 
DECLARATION OF HELSINKI..................................................................112 
APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ....................116 
APPENDIX 4 
MEDICATION WASHOUT PERIODS........................................................117 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) ......................118 
 


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LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .........................58 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study .....................62 
Table 3. 
Laboratory Tests ....................................................................................................82 
Table 4. 
Causality Definitions .............................................................................................85 
Table 5. 
Sample Size ............................................................................................................99 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................44 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies ..............................57 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
C 
complement 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CD 
cluster of differentiation 
CK 
creatine kinase 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 


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GLP 
Good Laboratory Practice 
GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
INFγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MS 
multiple sclerosis 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 


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OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RNP 
ribonucleoprotein 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
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Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
TT 
tetanus toxoid 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids, immunosuppressants, and cytotoxic agents.1  
However, some of the morbidity in patients with SLE is related to its treatment.  Comparison of 
early and late outcomes in patients with SLE demonstrate that death in early disease is most 
commonly due to infections and active SLE causing multi-system organ damage, while 
thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb directed against human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t1/2) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies. 
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses). 
 
 
 
 
 
 
 
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  The NOAELs were determined to be 100 mg/kg IV and 50 mg/kg SC, the highest 
doses tested. 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: 
placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 
30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first 
cohort, after the first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 
48 hours before the remaining subjects from that cohort were dosed, to allow for an initial review 
of any emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not 
sooner than 8 days after all the subjects in the prior cohort had been dosed and were based on a 
review of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included electrocardiograms (ECGs), vital signs (blood pressure, heart rate, and 
temperature), safety laboratory assessments, blood sampling for ADAs, total IgG and IgM levels, 
CD4+ count, and full and targeted physical examinations.  Overall, there were no clinically 
significant findings from this study, following an interim cut and review of the data at Day 90 
postdose.  Adverse events reported as related to the study drug, particularly infections, were 
expected for the compound, and there were no clinically relevant changes in laboratory and ECG 
results or vital signs.  There was 1 serious adverse event (SAE; death due to pulmonary 
embolism) that occurred 127 days after a single administration of 240 mg SC dose of 
BOS161721.  The causality of this single SAE was not attributed to study drug and further 
information can be found in the Investigator’s Brochure.  PK data from the SAD study 
demonstrates BOS161721 has an extended t1/2 (provisional single dose data indicates this to be 
approximately 42-46 days) which supports evaluation of monthly dosing.  
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1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1 study based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose 
level, repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant 
safety or tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD phase of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median Tmax of 6 days and an apparent terminal half-life of 44 days.  Furthermore, 
pSTAT3 suppression, a marker of IL-21 target engagement, follows a similar time course of the 
mAb levels, with maximal and sustained suppression apparent with doses greater than 30 mg SC 
(Figure 1).   
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 


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All doses selected for the MAD study are projected not to exceed the mean exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD 
study.  Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered 
study design, the data monitoring committee (DMC) will perform a scheduled review of safety 
data and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC and 
Boston Pharmaceuticals will conduct a data review for the first interim analysis (IA1).  At that 
time, a decision will be made to suggest which dose should be carried forward into the proof of 
concept (POC) Phase 2 study.  This POC dose decision will be based on evaluation of the PK, 
safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD study (see Section 4.1.1.1).     
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD study.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  
Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Two weeks after the last patient in Cohort 3 receives the second dose, the 
DMC and Boston Pharmaceuticals will conduct a data review for the IA1.  At that time, a 
decision will be made to suggest which dose should be carried forward into the POC Phase 2 
study.  This POC dose decision will be based on evaluation of the PK, safety (inclusive of dose-
limiting toxicity [DLT]), and tolerability data (and available PD/biomarker data) from Cohorts 1, 
2 and 3 during the MAD study.  Thereafter, DMC monitoring will be conducted periodically 
throughout the study as described in the DMC charter.  With the agreement of the DMC and 
sponsor, this schedule may be modified depending on the rate of patient accrual.  Additional 
details can be found in the DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), autoimmunity, or altered BOS161721 levels or activity.  Further details can be found 


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in the current Investigator’s Brochure (IB) for BOS161721, which contains comprehensive 
toxicology, preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational 
products.  Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to 
the study drug, particularly infections (flu-like symptoms, etc), were expected for the compound, 
and there were no clinically relevant changes in laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 
this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 7.2.2.6.1. 
Based on the limited Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic 
reactions in subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) for 3 months (a total of 7 doses); no SC animals had 
injection reactions. 


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Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 7.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 
ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 
Based on the limited Phase 1 SAD study (BOS161721-01), immune complex disease in subjects 
who received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 


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BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and will be excluded from the proposed MAD/POC studies.  
Patients exposed to investigational product who develop diarrhea during the course of the study 
should immediately undergo an assessment for opportunistic infection including stool for ova 
and parasites and stool examination for cryptosporidium.  Positive cryptosporidium in stool 
sample at screening is an exclusion.  Treatment by the investigator where indicated should be 
guided by findings and be consistent with local standard of care. 
Based on the limited Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 
and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the limited Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However, as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from the MAD study.  Patients with a positive hepatitis 
B or C test or a history of alcohol dependence will also be excluded. 
Based on the limited Phase 1 SAD study (BOS161721-01), hepatic function abnormality in 
subjects who received BOS161721 was not observed. 


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1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen; however, it is worth noting that 
BOS161721 administration did not produce any remarkable changes in anti-KLH antibody data 
for IgM, IgG1, IgG3, and IgG4 or anti-tetanus toxoid (TT) antibody data for IgM, IgG, IgG1, or 
IgE during the dosing phase in the same study. 
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 
oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 5.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 5.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES 
This trial has separate primary and secondary objectives for the MAD Phase 1b and POC Phase 2 
studies. 
2.1 
Phase 1b Multiple Ascending Dose  
2.1.1 
Primary Objective 
To assess safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20 mg, 60 mg, 
and 120 mg) administered SC in adult patients with moderately to severely active SLE on limited 
background standard of care treatment, in order to estimate the optimal dose.   


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2.2 
Phase 2 Proof of Concept 
2.2.1 
Primary Objective 
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for 
response on the SLE Responder Index 4 (SRI-4), with sustained reduction of oral CS, in adult 
patients with moderately to severely active SLE on limited background standard of care 
treatment. 
2.2.2 
Secondary Objectives 
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for 
response on clinical indicators of SLE activity, in adult patients with moderately to severely 
active SLE on limited background standard of care treatment, including: 
• Changes in SLE-specific autoantibody titers 
• Changes in complement 3 and 4 (C3 and C4) levels 
• Responses on SRI-4, SRI-5, and SRI-6, with sustained reduction of oral CS 
• Response on the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus 
Assessment (BICLA) 
• Response on the Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
• Changes in the SLE Disease Activity Index 2000 (SLEDAI-2K) 
• Changes in American College of Rheumatology (ACR)-28 joint count 
3 STUDY ENDPOINTS  
This trial has separate primary and secondary endpoints for the MAD Phase 1b and POC Phase 2 
studies. 
3.1 
Phase 1b MAD Study 
3.1.1 
Primary Endpoints 
Evaluation of safety, tolerability, and immunogenicity at each dose level, to determine the 
optimal dose, will include the recording of the following parameters: 
• Incidence and severity of AEs, AEs of special interest, and SAEs 
• 12-lead ECGs 
• Vital signs (blood pressure [BP], heart rate, and temperature) 


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• Clinical laboratory assessments 
• Physical examinations 
• Evaluation for ADAs 
3.1.2 
Exploratory Endpoints 
• 
 
• 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
3.1.3 
Other Endpoints 
• 
 
 
 
• 
 
 
• 
 
. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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3.1.4 
PRO Endpoints 
• 
 
• 
 
3.2 
Phase 2 POC Study 
3.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients who achieve treatment response as 
measured by the SRI-4 at Day 210, along with a sustained reduction of oral CS (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and Day 210 
3.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The proportion of patients who achieve treatment response for the SRI-5 and SRI-6 at 
Day 210, along with a sustained reduction of oral CS (≤ 10 mg/day and ≤ Day 0 dose) 
between Day 120 and Day 210 
• Changes from baseline in dsDNA, ANA, SSA, SSB, RNP, Sm, APL autoantibodies, at 
Day 120 and Day 210 
• Changes from baseline in C3 and C4 levels at Day 120 and Day 210 
• Changes from baseline in the SLEDAI-2K at Day 210 
• Time to BILAG A or B flare  
• Changes from baseline in the CLASI at Day 210 
• The proportion of patients with a BICLA response at Day 210 
• The proportion of patients with CLASI response at Day 210 
• Changes from baseline (percentage) in swollen joints and tender joints ACR-28 joint count 
• Incidence and severity of AEs, AEs of special interest, and SAEs 
• 12-lead ECGs 
• Vital signs (BP, heart rate, and temperature) 
• Clinical laboratory assessments 
CCI
CCI


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• Physical examinations and targeted physical examinations 
• Evaluation for ADAs 
3.2.3 
Exploratory Endpoints  
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
 
• 
 
3.2.4 
Other Endpoints 
• 
 
 
 
 
 
 
3.2.5 
PRO Endpoints 
• 
 
• 
 
4 STUDY PLAN 
4.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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moderately to severely active SLE.  After successfully completing a screening phase, patients 
will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule will be 
monthly.   
The trial will consist of 2 studies:  MAD Phase 1b, and POC Phase 2.  Both studies will be 
double-blinded, and patients will have the same number of visits.  Patients may receive a total of 
7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180, followed by a 
90-day safety follow-up visit.   
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease being studied.  Further details on the content and methods of data reports by the medical 
monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
4.1.1 
Multiple Ascending Dose Phase 1b Study 
The MAD study will consist of 3 cohorts:  
• Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
the MAD study are projected not to exceed the mean exposure of that achieved in the SAD 
study.   
4.1.1.1 
Dose Escalation for the MAD Study  
The MAD study design is staggered, where after the 6 patients in Cohort 1 have received 2 doses 
and have completed 2 weeks of follow-up after the second dose, Cohort 2 begins dosing (after 
DMC evaluation of the safety and tolerability data from Cohort 1).  Similarly, after 8 of the 
12 patients in Cohort 2 have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing after DMC evaluation of the safety and tolerability data 
from Cohorts 1 and 2.  Each cohort will continue at their assigned dose level through their 
respective 6-month treatment periods (See Study Schematic, Section 4.1).  If > 3 patients 
discontinue the study in a cohort, he/she may be replaced. 


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Criteria for dose escalation are further described in the DMC Charter.  See Section 4.1.1.2 for 
additional details about DLTs.   
4.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia 
• Grade 3 neutropenic infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia 
Non-Hematologic: 
• Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals) 
• Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 7.2.2.6.3 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances. 
4.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD study, the DMC may provide the following recommendations to the 
sponsor: 
• Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort 
• Continuing a dose level for a given cohort 
• Escalating a dose level for a subsequent cohort 
• Termination of current or previous cohort(s) 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC study, the DMC and Boston Pharmaceuticals will conduct a 
data review for the IA1 to suggest which dose should be carried forward into the POC Phase 2 


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study.  This POC dose decision will be based on evaluation of the PK, safety (inclusive of dose-
limiting toxicity [DLT]), and tolerability data (and available PD/biomarker data) from Cohorts 1, 
2, and 3; this dose will not exceed doses tested during the MAD study.  The DMC will be 
reviewing all relevant data from Cohorts 1, 2, and 3 that is available at the time the last patient in 
Cohort 3 completes the Day 44 visit (2 weeks after dose 2).  Details are provided in the DMC 
Charter.  
4.1.2 
POC Phase 2 Study 
4.1.2.1 
BOS161721 Dose  
The optimal dose evaluation is chosen based on MAD Phase 1b safety, tolerability, 
immunogenicity, and PK and PD data.  The dose will be communicated by a letter to site 
investigators participating in the POC Phase 2 study, and to the IRB/IEC. 
4.1.2.2 
POC Study Design 
For the POC study, approximately 156 patients will be randomized to active or placebo groups in 
a 2:1 ratio.   
As in the MAD study, each patient in the POC study may receive a total of 7 SC monthly doses 
of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be completed 
according to the Schedule of Assessments (Section 4.3).  Dose selection will be based on the 
sponsor’s assessment of safety, tolerability, immunogenicity, and PK and PD data from the 
MAD study of 30 patients treated with BOS161721/placebo. 
Data from approximately 60 patients (including the 12 from the MAD study, or 6 fewer if the 
low dose is chosen who are in the cohort of the chosen dose for the POC study) who complete 
3 months of treatment will be used in the IA2 at Day 90 to assess if the trial could stop for an 
early futility conclusion (see Section 9.3 for details regarding the IA).  If futility is not claimed in 
the IA2, the POC study will continue to approximately 156 patients. 
Following the 6-month treatment period, primary and secondary efficacy endpoints will be 
assessed for each patient after providing their Day 180 disease activity assessments.     
DMC monitoring will be conducted periodically throughout the study as described in the DMC 
charter. 
 


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4.2 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies 
 
A = active drug (BOS161721); P = placebo 


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4.3 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessmentf 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 


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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
SLEDAI-2K 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR Damage 
Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry)h 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Whole blood RNA 
collection 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xl 
Xl 
Xl 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test 
(women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(women)m 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
TB test 
(QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B 
and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labs 
Predoseo 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
Xp 
X 
X 
Xp 
 
 
 
 
 
Xp 
X 
X 
X 
X 
X 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
Treatment Period Follow-Up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
-- 
3 
4 
5 
6 
7 
8 
9 
10 
-- 
-- 
11 
12 
13 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; RNA = ribonucleic acid; RNP = ribonucleoprotein; 
SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus 
International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 5.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to screening 
or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled PK 
blood draws. 
f 
Injection site reaction assessments to be performed predose and at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 7, 187, and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
i 
When clinically indicated. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
k 
nAb is assessed if patient is positive for ADA. 
l 
Only dsDNA collected during safety follow-up visits.  
m 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
n 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
o 
Predose samples occur on study drug administration visit days. 
p 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 0, 30, and 180. 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medicationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or placebo dosing  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
SAFETY ASSESSMENTS 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
AEs and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
Injection site reaction 
assessmentf 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted physical examination 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, and 
temperature)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
EFFICACY ASSESSMENTS 
BILAG-2004 Index 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
SLICC/ACR Damage Index 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
LABORATORY ASSESSMENTS 
CD4+ count 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory assessments 
(hematology and clinical 
chemistry)h 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Coomb’s test directi 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for leukocyte 
immunophenotype 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
ADAj 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
nAbk 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3l 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Whole blood RNA collection 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Xm 
Xm 
Xm 
CRP 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum pregnancy test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (postmenopausal women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (women)n 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
TB test (QuantiFERON-TB 
Gold In-Tube)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B and C, 
HIV-1/2 combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
Stool sampleo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for protein/creatinine 
ratio 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PK Labsp 
Predoseq 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb  = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; RNA = ribonucleic acid; RNP = ribonucleoprotein; 
SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus 
International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen 
response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the 
daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 0 (randomization day).  See Section 5.6.1 for further details. 
c 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after 
eligibility confirmation or the morning of Day 0 prior to dosing for logistical purposes. 
d 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to 
screening or during the screening period must be documented in study records prior to randomization (Day 0). 
e 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled 
PK blood draws. 
f 
Injection site reaction assessments to be performed predose and at 2 hours postdose. 
g 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 0 at predose and at 1 and 2 hours 
postdose, as well as on each of the scheduled outpatient days in the table above (excluding PK-only site visits at Days 187 and 195).  When the timing of 
these measurements coincides with a blood collection, vital signs should be obtained prior to the time of the blood collection. 
h 
Clinical laboratory assessments will include a fasting glucose and lipid panel, with exception of screening (Visit 1) which will be nonfasting. 
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Clinical Study Protocol:  BOS161721-02 
Confidential 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
Treatment Period Follow-up  
Safety Follow-Up 
Days 
-28 
to -1 
0 
15 
(± 3) 
30 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
-- 
-- 
10 
11 
12 
i 
When clinically indicated. 
j 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
k 
nAb is assessed if patient is positive for ADA. 
l 
Predose (trough) samples only. 
m 
Only 
 collected during safety follow-up visits. 
n 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
o 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, 
and cryptosporidium. 
p 
PK samples will only be collected at the investigational sites that will be participating in the PK portion of the study. 
q 
Predose samples occur on study drug administration visit days. 
 
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5 POPULATION 
5.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
5.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b study, and approximately 156 patients will be randomized in the POC Phase 2 study.  Note 
that approximately 30 dropouts are assumed.   
5.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Section 4.3]) for this study must be 
performed between Day -28 and Day -1. 
5.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 
immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the central laboratory 
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory 
c. C3 or C4 below normal as determined by central lab 


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5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) must be ≥ 6, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory results:  (hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded 
6. On Day 0, the SLEDAI-2K must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis 
i. 
Excluding parameters which require central laboratory results:  (hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome are also excluded 
7. Patients must have at least 1 of the following manifestations of SLE, as defined by the 
BILAG criteria as modified for use in this study, which must be confirmed by the central 
data reviewer: 
a. BILAG A or B score in the mucocutaneous body system 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis in ≥ 2 joints with marked loss of functional range of movements 
and significant impairment of basic activities of daily living that has been present 
on several days cumulatively over the past 4 weeks, including at the time of the 
screening visit.  See APPENDIX 5 for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require 
assistance or assistive devices, (at least 1 must be present and 
documented in source): 
o Ambulation, toileting, grooming- including bathing and dressing; 
feeding oneself, (and not responsive to steroids up to 10 mg/day, 
antimalarials, NSAIDs) 
ii. 
“BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional range of 
movements which lead to some loss of functional range of motion as manifested 
by effects on instrumental ADLs such as: 


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• Cooking, driving, using the telephone or computer, shopping, cleaning, 
etc, and has been present on several days over the last 4 weeks, and is 
present at the time of the screening visit 
c. If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system scores 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to signing consent) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX) 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at screening for a patient 
to be eligible and must be stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 0 (randomization) (see APPENDIX 3) 
9. Women of childbearing potential (WOCBP; see Section 5.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose 
b. Must not be breastfeeding 
c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after treatment completion 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 5 half-lives of 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
treatment plans, laboratory tests, and other procedures 
5.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic scleroderma, or vasculitis not related to SLE) 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed 
3. Any major surgery within 6 weeks of study drug administration, (Day 0), or any elective 
surgery planned during the course of the study 


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4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB 
b. History of active TB 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 0 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS 
7. Concomitant illness that, in the opinion of the investigator, is likely to require additional 
systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy is allowed 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 5.6 for prohibited 
concomitant medication) 
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
antibiotics or hospitalization 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV), known human 
immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related 
illness 
12. Cryptosporidium in the stool sample at screening 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening 
15. CD4+ count < 500/µL at screening 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia related to SLE 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol) 


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19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum ALT and/or serum AST > 2 × ULN at screening, unless explicitly related to lupus 
based on the investigator’s judgment 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome) 
23. Any other laboratory test results that, in the opinion of the Investigator, might place a patient 
at unacceptable risk for participating in this study 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgment 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision) 
27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer 
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the Columbia Suicide severity Rating Scale 
(C-SSRS) 
31. Current or pending incarceration 
32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
5.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen of other 
concomitant medications for the treatment of SLE (eg, analgesics, NSAIDs, statins, ACE 


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inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments are 
clinically indicated.  Use of any other drugs for non-SLE conditions, including over-the-counter 
medications and herbal preparations, should remain stable unless change or addition is clinically 
necessary.  Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
5.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, 
however, the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days 
prior to Day 0 (randomization day). 
After Day 0 (after initiation of study therapy), no up-titration above 10 mg/day is allowed except 
for up to 1 CS burst for increased disease activity.  
Tapering of steroids during the course of the study will be encouraged and should be evaluated at 
all visits.  
• Once a patient has received the first dose of study drug, prednisone (or prednisone 
equivalent) may be tapered down at the discretion of the investigator 
o Tapering is allowed after randomization except within 60 days of the primary (Day 210) 
and secondary (Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant otherwise the patient 
will be declared a non-responder in efficacy assessments. 
A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed during the 
study between Day 0 and Day 60, according to the following:   
• An oral CS “burst” between  Day 0 and Day 60; (an increase of ≤ 40 mg/day of prednisone 
or equivalent), which must be tapered down to a maximum of 10 mg/day within 2 weeks of 
initiation of the “burst” 
o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o The course of the oral CS “burst” is not permitted to extend beyond Day 60 


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Treatment with inhalational CS therapy (eg, for asthma), or by any other route, is allowed.  Other 
concomitant medications for SLE need to be taken at stable doses as per the inclusion criteria 
(Section 5.4). 
5.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration and during the 
study are described below, and washout requirements are provided in APPENDIX 4.  
Medications taken within 30 days prior to screening must be recorded on the eCRF. 
1. Prior exposure to BOS161721 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
6 months of screening; recovery of B cells (CD19+) must be documented (record absolute 
number of CD19+ B cells) 
3. Patients who have received treatment with cyclophosphamide within the 1 year prior to 
screening 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria (oral or topical) within 3 months of screening 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 8 weeks prior to screening 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc, may be used 
according to local guidelines during treatment period 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation 
5.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 
See Section 5.7.2 for detailed information regarding contraceptive requirements for WOCBP. 
5.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   


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5.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 5 half-lives of study drug 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
At a minimum, patients must agree to the use of 1 method of highly effective contraception from 
the following: 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who 
are WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• IUDs, such as ParaGard® 
• Vasectomy 
• Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception.  Women who are abstinent while participating in the study 
must continue to have pregnancy tests.  Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego complete 
abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, they must still undergo pregnancy testing. 
5.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient continue or 
withdrawal from the study medication.    


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See Section 7.8 for additional details.  
5.8.1 
Patient Withdrawal and Replacement 
See Section 6.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD study after discussion between the principal investigator or designee and 
sponsor. 
6 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
6.1 
Screening 
Screening will be the same for both the MAD and POC studies. 
Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria, listed in Section 5.4 and Section 5.5 respectively, will be enrolled in 
the study.  Screened patients who drop out of the clinical study before randomization will be 
recorded as screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• Medical history documentation 
• Review of inclusion and exclusion criteria 
o Patient medical records must contain documentation of SLE diagnosis 
o C-SSRS   
• Concomitant medication documentation 
• Demographics 
• Full physical examination 
• Vital signs 


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• Chest x-ray 
• Laboratory evaluations (nonfasting): 
o Hematology and clinical chemistry 
o Serology (Hepatitis B and C; HIV-1/2 combination) 
o TB test 
o CRP 
o Direct Coomb’s test (if indicated) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype; 
 
 
o Serum pregnancy test (WOCBP) 
o FSH (postmenopausal women) 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
o Stool sample  
• 12-lead ECG 
• SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity 
Screening procedures are listed in the Schedule of Assessments (Section 4.3), and details are 
provided in Section 7. 
6.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• medically indicated 
• there is evidence a laboratory sample was mislabeled, inadequately processed, and/or 
deteriorated in transit to the central laboratory 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
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represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
6.2 
Enrollment/Randomization and Day 0 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.   
The study site will obtain a randomization number when registering the patient in IWRS.  All 
patients will receive BOS161721 or placebo according to the kit number assigned by the IWRS 
randomization scheme.    
After randomization, procedures include: 
• PROs:  
 
• C-SSRS 
• Laboratory evaluations (fasting): 
o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype 
o ADA 
o pSTAT3 (predose [trough] samples only in Phase 2)  
o 
 
o Whole blood RNA collection 
o 
 
o See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration 
o Spot urine for protein/creatinine ratio 
o Urinalysis 
• Concomitant medication documentation 
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements) 
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• Full physical examination 
• Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 0) 
• 12-lead ECG (prior to PK blood draw) 
• SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, PGA) 
• SLICC/ACR damage index 
• Study drug administration: 
o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 8.3 
• Injection site reaction assessment, predose, and 2 hours postdose 
Procedures on Day 0 are listed in the Schedule of Assessments (Section 4.3), and details are 
provided in Section 7. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
6.3 
Treatment Period/Follow-Up Visits 
The following procedures will be performed as indicated in the Schedule of Assessments 
(Table 1 and Table 2).  See Schedule of Assessment tables for allowable windows for each visit.   
• Targeted physical examination 
• Vital signs (prior to PK blood draw) 
• Concomitant medication documentation 
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements) 
• PROs:  
 
• Urine pregnancy tests will be collected on WOCBP prior to study drug administration 
• Injection site reaction assessments will be performed predose and 2 hours postdose 
• Direct Coomb’s test (if indicated) 
• Spot urine for protein to creatinine ratio 
• Urinalysis 
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• 
 
• Plasma 
 
• PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed 
• SLICC/ACR Damage Index will be completed at Day 180 
• C-SSRS 
• ECGs prior to PK blood draw 
• See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
• Fasting hematology and chemistry assessments  
• The CD4+ count and total IgG and IgM levels  
• Plasma 
 & 
, ADA, and whole blood for leukocyte immunophenotype 
• pSTAT3   
• Whole blood RNA 
• CRP and nAb will be assessed if patient is positive for ADA 
• 
 
6.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Days 210, 240, and 270.  These visits will include the 
following assessments as indicated in the Schedule of Assessments (Table 1 and Table 2):  
• PROs:  
 
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements) 
• Injection site reactions 
• Targeted physical examination 
• Vital signs (prior to PK blood draw) 
• Spot urine for protein/creatinine ratio and urinalysis 
• Concomitant medication documentation 
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• BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA 
• Fasting clinical laboratory assessments (hematology and clinical chemistry) 
• Direct Coomb’s test (if indicated) 
• Plasma 
 
• 
 
• pSTAT3 
• 12-lead ECG (prior to PK blood draw) 
• CRP 
• ADA 
• Whole blood RNA collection 
• See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively 
6.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Day 180) and a last follow-up visit 90 days after dosing should be scheduled 
(Day 270).  Safety follow-up visit procedures based on the Schedule of Assessments (see 
Section 6.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• AE/SAE 
• Protocol deviation 
• Lost to follow-up 
• Patient withdraws consent at their own request 
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• Investigator decision 
• Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up) 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
7 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
7.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• General medical history 
• Documentation of SLE diagnosis 
• Historical medication therapy for SLE 
The following demographic information will be recorded:  
• Age 
• Ethnic origin (Hispanic/Latino or not Hispanic/not Latino) 
• Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American) 
• Height (without shoes, in cm) 
• Body weight, without shoes (kg) 
• Body mass index (BMI [kg/m2]) 
Other baseline characteristics will be recorded as follows: 
• Concomitant medication documentation (see Section 5.6) 
• Status of child bearing potential and contraception 


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7.2 
Safety Assessments 
7.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Section 4.3).  Patient eligibility will be determined based on these tests at screening.  
Unscheduled clinical labs may be obtained at any time during the study to assess any perceived 
safety concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests and stool analysis) 
to ensure accuracy and consistency in test results.  The central laboratory will transmit all results 
for protocol tests, scheduled and unscheduled, to the clinical data base.  Laboratory/analyte 
results that could unblind the study (ie, biomarker results) will not be reported to investigative 
sites.  Urinalysis will be performed on midstream, clean catch specimens.  Some biomarkers 
listed above will not be drawn at some sites due to geographical logistical challenges.  See the 
laboratory manual for details. 
Endpoint analyses will be based on changes from baseline assessments at Days 120 and 210. 
 
 


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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Reticulocytes (%) 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
Spot urine for protein/creatinine ratio 
FSHb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test 
(QFT-G)  
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only, in Phase 2) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte 
immunophenotype and RNA 
 
 
Antibodies 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
dsDNA = double-stranded deoxyribonucleic acid;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; nAb = neutralizing 
antibody; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; PT = prothrombin time; 
qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; RNA = ribonucleic acid; 
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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
RNP = ribonucleoprotein; SAE = serious adverse event; SC = subcutaneous; 
 
; TB = tuberculosis.  
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for ova, 
parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 7.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated. 
 
7.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or continued 
and a further negative urine pregnancy test results will then be required at the baseline visit 
before the patient may receive the investigational product.  Urine pregnancy tests will also be 
routinely repeated at study drug administration visits prior to study drug administration, and 
additionally whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise 
suspected.  In the case of a positive pregnancy test or confirmed pregnancy, the patient will be 
discontinued from study drug, an EOT visit should be performed (Day 180), and a last follow-up 
visit 90 days after last dose should be scheduled (Day 270).  Safety follow-up visit procedures 
based on the Schedule of Assessments (see Section 6.4). 
See Section 7.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
7.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 5.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 0). 
7.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
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Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 
study.  If a repeat test is indeterminate again, the patient is a screen failure.  The procedure for 
using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
7.2.2 
Adverse Events 
7.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 7.2.2.5). 
7.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset (and time, if known), date of AE outcome (and time, if known), and action 
taken for the AE will be documented together with the principal investigator’s assessment of the 
seriousness of the AE and causal relationship to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
7.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 
and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 


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7.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 4) should be selected based on medical 
judgment, considering the definitions below and all contributing factors. 
Table 4. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE 
disappear partially or completely, within a reasonable time from drug discontinuation (positive 
dechallenge), or the symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that 
there are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug relatedness 
clearly exists (for example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
7.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death 
• Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
• Requires hospitalization or prolongation in existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect 
• Is another important medical event (see below) 


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Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
• Development of drug dependency or drug abuse 
Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
7.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions 
2. Injection site reaction, including erythema, pain, and induration 
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law 
4. Malignancy 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, and 
disseminated tuberculosis 
6. Cryptosporidiasis 
7.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 


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a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline 
7.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These may include injection site 
erythema, pain, and induration.  The investigator should provide a clear description of the 
observed or reported AE including location and severity.  All concomitant treatments used to 
treat injection site reactions should be recorded and captured in the eCRF, together with the AE 
of injection site reactions.   
7.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 7.2.2.7.2 for reporting details). 


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Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 
3. No other immediately apparent possible causes of ALT or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• ALT or AST > 8 × ULN 
• ALT or AST > 5× ULN for more than 2 weeks 
Discontinuation of treatment must occur if: 
 
• ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 


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7.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 7.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue, the investigator and/or consultant(s) should contact the 
sponsor clinicians or designee to discuss the issue and any decisions as soon as possible. 
7.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, shingles, disseminated herpes simplex, or disseminated 
tuberculosis will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
7.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 7.2.2.7.2. 
7.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 


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Additional information about pregnancy outcomes that are reported as SAEs follows: 
• Spontaneous abortion includes miscarriage and missed abortion 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 
adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 
7.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Day 270).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• Study number 
• Patient number 
• Details of the SAE (verbatim details are sufficient for immediate notification) 
• Criterion for classification as ‘serious’ 
• Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification) 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 


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obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   
7.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becomes aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 
Potential DILI will be reported based on specifications mentioned in Section 7.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate, and is further outlined in Section 7.2.2.7.2. 
7.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 7.2.2.7.1 for details related to follow-up of pregnancy.  See Section 7.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 7.2.2.6.4 for details related to follow-
up of malignancy. 
7.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Section 4.3).  Vital signs will be assessed on Day 0 at predose and at 
1 and 2 hours postdose, as well as on each of the scheduled visit days during the study 
(excluding PK-only site visits).  Supine BP and heart rate recordings will be made after the 
patient has been recumbent and at rest ≥ 5 minutes.  When the timing of these measurements 
coincides with a blood collection, vital signs should be obtained prior to the time of the blood 
collection. 
7.2.4 
12-Lead Electrocardiograms 
ECG will be assessed as specified in the Schedule of Assessments (Section 4.3).  ECG recording 
will initiate after the patient has been supine for at least 5 minutes.  On days of PK blood draws, 
the ECG will be collected before scheduled PK blood draws, though timing will be such that PK 
draws are collected on their scheduled times where possible. 


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The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 
7.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Day 0.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 
thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at all other visits as indicated in 
the Schedule of Assessments (Section 4.3).  It includes evaluation of patient complaints and SLE 
disease-related issues, and will exclude the genitourinary system. 
7.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed as specified in the Schedule of Assessments 
(Section 4.3).  Patients with recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 is exclusionary at screening 
will be excluded from the study.  Patients with recent or active suicidal ideation or behavior at 
subsequent study visits will have responses to the C-SSRS reviewed in detail to assess patient 
risk, and appropriate consultative mental health services will be provided. 
7.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions as specified in the Schedule of 
Assessments (Section 4.3).  Local injection site reactions will be assessed predose and at 2 hours 
postdose.  Injection site reactions should be managed according to the standard of care.  Injection 
site reactions are to be reported as AEs of special interest (see Section 7.2.2.7.3). 
7.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as specified in the 
Schedule of Assessments (Section 4.3).  Blood samples (4 mL) to provide approximately 1.5 mL 


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of plasma for anti BOS161721 antibody analysis will be collected into appropriately labeled 
tubes containing K2EDTA.  The presence or absence of ADA will be determined in the serum 
samples using validated bioanalytical methods.  Blood samples for ADA analysis will be 
collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all 
patients but only assayed if the patient had a positive ADA on Day 90.  
After the first dose, if a patient tests positive in the validated confirmatory ADA assay, the 
sample from this patient will be further analyzed in the neutralizing antibody (nAb) assay. 
7.3 
Efficacy Assessments 
All efficacy assessments will be performed at times defined in the Schedule of Assessments 
(Section 4.3). 
7.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
7.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 
4 weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, 
worksheet, clinic notes, and labs) at each visit. 
See APPENDIX 5 for detailed specifications. 


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7.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.   
When scoring the PGA, the assessor should always look back at the score from the previous 
visit. 
7.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
7.3.4.1 
SRI-4 Response 
Patients will be evaluated for SRI-4 scores at Day 210, with evaluation for sustained reduction of 
oral CS (≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and Day 210. 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 0.3 points.  The SRI-4 response in patients with moderate to severe 
SLE is associated with broad improvements in clinical and patient-reported outcomes.45  
Each patient, after providing their Day 210 visit SRI-4 response, will be evaluated as either a 
responder or non-responder.   
7.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal three-point or five-point improvement in 
SLEDAI-2K being required, respectively.46 
The SRI-5 and SRI-6 are evaluated for response at Day 180, along with a sustained reduction of 
oral CS (≤ 10 mg/day and ≤ Day 0 dose) between Day 120 and Day 210. 
7.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 


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For the endpoints of BICLA response at Days 210, 240, and 270, patient scores will be 
completed and response determined. 
7.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 
For the secondary efficacy endpoint of CLASI response at Day 210, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 
7.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 
7.4 
Other Variables 
7.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Days 0 
and 180. 
7.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
 and will be assessed as 
specified in the Schedule of Assessments (Section 4.3). 
 
.      
 
.   
CCI
CCI
CCI
CCI


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7.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) studies, blood samples 
for PK analysis of BOS161721 or placebo concentration will be collected according to Table 1 
and Table 2. 
PK parameters include the following:  
• Cmax, Tmax, AUC, t½, CL, Vd 
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration-nominal time profiles for the IA2 
and actual time profiles for the final analysis.  The non-compartmental analysis will be 
performed using appropriately validated PK/PD software. 
7.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated in the Schedule of 
Assessments (Section 4.3) for each of the following parameters: 
• pSTAT3  
• Antibodies:  
  
• Plasma complement (
)  
• Plasma 
 and 
  
• Whole blood for leukocyte immunophenotype  
• Whole blood RNA  
• IgG and IgM and CD4+ count  
7.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
7.8 
Protocol Deviations 
Protocol deviations will be documented during the study.  Per the statistical analysis plan (SAP), 
these will be listed by patient and summarized by deviation category by treatment group. 
CCI
CCI
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8 STUDY DRUG MANAGEMENT 
8.1 
Description 
8.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
8.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
8.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
8.3 
Dose and Administration 
Details of dosing are provided in Section 4.1. 
Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
CCI
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After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
8.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Products returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed.  The returned products should be marked as ‘returned’ 
and kept separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
8.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 5.6 and APPENDIX 4 and will be 
listed as protocol violations if taken when not permitted. 
8.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
investigator.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. 
9 STATISTICS 
There are 2 IAs planned for the study.  The first IA will be conducted at the time of the POC 
decision for dose selection.  The second IA will be performed for futility (see Section 9.3).  
Before the first IA, a SAP will be finalized, providing detailed methods for the analyses outlined 
below.  Any deviations from the planned analyses will be described and justified in the final 
integrated CSR. 
The following standards will be applied for the analysis unless otherwise specified.  Continuous 
data will be summarized by treatment group using descriptive statistics (number, mean, standard 
deviation [SD], minimum, median, and maximum).  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage). 
9.1 
Sample Size 
Sample size in the Phase 1b study is based on operational consideration. 


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A summary of the power in the trial for the chosen sample size is provided in Table 5, with 
N = 132 randomized 89:43 to the chosen dose for the POC study and placebo, respectively; this 
includes 12 patients from the MAD study who were in the cohort of the mid or high dose if 
chosen for the POC study. 
Table 5. 
Sample Size 
Type 1 Error 
(1-Sided) 
TRUE Underlying 
Response Rate (%) 
Overall Power 
Minimum OBSERVED Response 
Rates Yielding Statistical 
Significance 
Placebo 
Treatment 
Placebo 
Treatment 
0.025 
40 
60 
0.54 
40 
60 
40 
65 
0.75 
40 
70 
0.9 
0.05 
40 
60 
0.63 
40 
58 
40 
65 
0.81 
40 
70 
0.93 
Total sample size of approximately 156 patients is planned for analysis, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Note that approximately 36 dropouts are assumed. 
9.2 
Statistical Methods 
9.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the full analysis set (FAS), defined to be all 
patients with at least 1 baseline and post-baseline efficacy evaluation.  A per protocol (PP) 
analysis set may be defined to exclude major protocol violations from the efficacy analysis.  The 
PP Population will include all patients from the FAS except those with major violations to the 
protocol deemed to impact the analysis of the primary endpoint.  These violations will be 
identified based on blinded data prior to unblinding the final analysis dataset.  Safety analyses 
will be based on all patients who receive test treatment.  Pharmacokinetic analysis will be 
conducted on the PK analysis set (PK), defined as the FAS with sufficient concentration data for 
the calculation of PK parameters.  All analyses will combine data from the MAD and POC 
studies and focus on the active treatment dose chosen for the POC study versus placebo.  The 
0.05 1-sided type 1 error level is included for POC, and the 0.025 1-sided type 1 error level for 
potential use of this trial to support regulatory filing. 
9.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized via appropriate summary statistics by 
treatment group and overall, for each phase of the trial.   


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9.2.3 
Primary Endpoint(s) 
The proportion of patients who achieve treatment response (measured by SRI-4 at Day 210 along 
with a sustained reduction of oral CS) will be analyzed via Cochran-Mantel-Haenszel (CMH) 
analysis.  The primary endpoint will be analyzed on the FAS and if needed the PP analysis set.  
In addition, missing values will be addressed by employing a last observation carried forward 
(LOCF) analysis and/or other appropriate analytic approaches as a sensitivity analysis.  Details 
will be available in the SAP. 
9.2.4 
Secondary Endpoint(s) 
Binary efficacy endpoints will be assessed via CMH analysis.  Continuous efficacy endpoints 
will be assessed via analysis of covariance (ANCOVA) repeated measures mixed model analysis 
with factors including treatment, time, treatment-by-time interaction, baseline covariate, and 
covariate-by-time interaction.  The secondary efficacy endpoint will be analyzed on the FAS and 
if needed the PP analysis set.  Details will be available in the SAP. 
9.2.5 
Analysis of Safety 
9.2.5.1 
Safety Analysis 
Safety analyses will be performed on the Safety Analysis Set.  AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Incidences (number and 
percent) of AEs will be presented by treatment group.  Incidences of AEs will also be presented 
by maximum severity and relationship to study medication.  For the MAD study, the placebo 
patients from each cohort will be combined for the summaries.  If there is a clear increase in AE 
rates for placebo patients across the cohorts, the AEs will also be summarized by cohort. 
AEs will be summarized by counts and percentages of patients by treatment group.  Laboratory 
data and vital signs will be summarized by treatment group as summary statistics for value and 
change from baseline at each individual time point.  Summary statistics will include n, arithmetic 
mean, median, arithmetic SD, minimum, and maximum. 
Additional safety parameters will be analyzed descriptively by treatment group.  Descriptive 
statistics (n, mean, standard deviation (SD), median, minimum, maximum) will be calculated by 
treatment group and time point for continuous variables.  Frequencies and percentages will be 
presented by treatment group for categorical and ordinal variables. 
9.2.5.2 
Data Monitoring Committee 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for anti-IL-21 mAb.  The recommendations made by the DMC 
(ie, dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 


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forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of an anti-IL-21 mAb treatment arm or the entire 
BOS161721 MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  
The recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data 
9.2.6.1 
Analysis of Pharmacokinetic Data 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 
• A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 
• A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 
Details will be available in the SAP.   
9.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Binary PD endpoints will be assessed for the FAS population.  Binary PD endpoints will be 
assessed via CMH analysis.  Continuous PD endpoints will be assessed via analysis of 
covariance (ANCOVA) repeated measures mixed model analysis with factors including 
treatment, time, treatment-by-time interaction, baseline covariate, and covariate-by-time 
interaction.  Normality will be assessed via diagnostic residual plots and Shapiro-Wilk statistic, 
but not as a formal statistical test of normality.  If substantial departures from normality are 
observed, transformation will be used (eg, log and/or rank). 
Details will be available in the SAP. 
9.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 


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Details will be available in the SAP.     
9.3 
Interim Analysis and Power 
Two IAs are planned for this study.  The initial IA will be conducted at the time of the POC 
decision for dose selection. 
The second IA will be performed for futility.  IA2 is planned to be conducted at Day 90 when 
SRI-4 response is determined for approximately 60 patients (including all patients at the same 
dose level/matching placebo from the MAD study) after completing 3 months of treatment.  The 
purpose of the IA2 is to assess if the trial could stop for an early futility conclusion, or continue.  
Since there is no plan to stop the trial for an early efficacy conclusion, there is no impact on the 
type 1 error.  If that intention changes, then p < 0.0001 is required for an early efficacy 
conclusion at the IA2 in order to not impact the planned type 1 error level. 
Nominal time profiles will be used for calculating PK parameters in the IA2.  Details will be 
available in the SAP. 
10 ETHICS AND RESPONSIBILITIES 
10.1 Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
10.2 DMC 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 


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10.3 Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) must meet the 
guidelines set out by the U.S. Food and Drug Administration (FDA) and conform to local laws 
and customs where appropriate.  Written IRB/IEC approval for the protocol and the signed ICF 
must be obtained and transmitted to Boston Pharmaceuticals or representative before the study 
can be initiated.  The IRB/IEC must be informed of and approve all protocol amendments.  The 
investigator will ensure that this study is conducted in full conformance with all applicable local 
and regional laws and regulations.  The complete text of the World Medical Association 
Declaration of Helsinki is given in APPENDIX 2. 
10.4 Informed Consent 
Before each patient undergoes any protocol required assessments or procedure, the written 
informed consent will be obtained according to the regulatory and legal requirements of the 
participating country.  As part of this procedure, the principal investigator must explain orally 
and in writing the nature, duration, and purpose of the study, and the action of the drug in such a 
manner that the study patient should be informed that he/she is free to withdraw from the study 
at any time.  He/she will receive all information that is required by federal regulations and ICH 
guidelines.  The principal investigator or designee will provide the sponsor with a copy of the 
IRB-approved ICF prior to the start of the study.   
The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 
study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   
If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future subjects enrolled in the clinical study will be required to 
sign this revised ICF. 
10.5 Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 


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The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 
validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 
10.6 Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 
must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
10.7 Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
11 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 


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study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
12 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
13 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 


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The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
14 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 
maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
metalloproteinase production in human intestinal fibroblasts by interleukin 21.  
Gut. 2006;55(12):1774-80. 
26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
contributes to the generation of plasma B-cells.  Clin Exp Rheumatol.  2013;31(2):172-9. 
 


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27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 
28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
pathogenesis of primary Sjögren’s syndrome:  increased serum levels of interleukin-21 
and its expression in the labial salivary glands.  Arthritis Res Ther. 2011;13(5):R179. 
30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
Interleukin-21 modulates Th1 and Th17 responses in gianT-cell arteritis.  Arthritis 
Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
erythematosus.  J Rheumatol. 2012b;39(9):1819-28. 
32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
33 Wang W, Wang EQ, Balthasar JP.  Monoclonal Antibody Pharmacokinetics and 
Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
35 Elsaesser H, Sauer K, Brooks DG.  IL-21 is required to control chronic viral infection.  
Science.  2009;324(5934):1569-72 
36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.  
J Exp Med. 2013;210(3):433-43. 
37 Hunter PR, Nichols G.  Epidemiology and clinical features of Cryptosporidium infection in 
immunocompromised patients.  Clinical microbiology reviews.  2002;15(1):145-54. 
38 Desjardins M, Mazer BD.  B-cell memory and primary immune deficiencies:  interleukin-21 
related defects.  Curr Opin Allergy Clin Immunol. 2013;13(6):639-45. 
39 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US:  
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5415a4.htm. 
 


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41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
doi:10.1136/lupus-2013-000005. 
47 Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M,et al.  Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
Cutaneous Lupus Erythematosus.  J Invest Derm. 2005;125(5):889-94. 
49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
Pulmonary Organ Scores are Predictors of Sever Outcome in Patients with Systemic 
Lupus Erythematosus.  Br J Rheumatol.  1996;35:248-54. 
50 
 
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17 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 401 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
quality. 


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In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 


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subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 


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informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Dose Equivalence 
Prednisone 
20 mg 
Cortisone 
100 mg 
Hydrocortisone 
80 mg 
Prednisolone 
20 mg 
Methylprednisolone 
16 mg 
Triamcinolone 
16 mg 
Budesonide 
4 mg 
Dexamethasone 
3 mg 
Bethamethasone 
2.4 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS  
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
48 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 COMBINED 
STAGGERED MULTIPLE DOSE ESCALATION STUDY OF BOS161721 
IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A 
BACKGROUND OF LIMITED STANDARD OF CARE 
 
SPONSOR 
Boston Pharmaceuticals, Inc. 
55 Cambridge Parkway, Suite 401 
Cambridge, MA 02142 
United States of America (USA) 
INVESTIGATIONAL COMPOUND: 
BOS161721  
PROTOCOL NUMBER: 
BOS161721-02  
PHASE 
Phase 1b/2 
INVESTIGATIONAL NEW DRUG (IND) 
NUMBER: 
131796 
ORIGINAL PROTOCOL DATE: 
05 October 2017 
VERSION NUMBER: 
V1.0 
VERSION DATE: 
06 October 2017  
 
 
 


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CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title:  A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation Study 
of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of 
Care 
 
Study No:  BOS161721-02  
Original Protocol Date:  05 October 2017 
Protocol Version No:  v1.0 
Protocol Version Date:  06 October 2017 
This study protocol was subject to critical review and has been approved by sponsor.  The 
information contained in this protocol is consistent with: 
 The current risk-benefit evaluation of the investigational product. 
 The moral, ethical and scientific principles governing clinical research as set out in the 
Declaration of Helsinki (APPENDIX 2), and principles of Good Clinical Practices (GCP) as 
described in 21 Code of Federal Regulations (CFR) parts 50, 54, 56 and 312 and according to 
applicable local requirements. 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
I agree with these statements and indicate my approval by signature for this protocol: 
Name and Title 
Signature 
Date 
, MD 
Vice President, Clinical Development 
Boston Pharmaceuticals 
 
 
 
Clinical Operations Lead 
Boston Pharmaceuticals 
 
 
, MD, PhD 
Vice President, Clinical Development and Safety 
Officer 
Boston Pharmaceuticals 
 
 
 
 
DocuSign Envelope ID: E0A86977-C5F7-4177-B16B-472A6FDE44D5
10/6/2017
10/6/2017
10/6/2017
PPD
PPD
PPD
PPD
PPD
PPD


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BOS161721-02  
A Randomized Double-Blind Phase 1b/2 Combined Staggered Multiple Dose Escalation 
Study of BOS161721 in Systemic Lupus Erythematosus (SLE) Patients on a Background of 
Limited Standard of Care 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to BOS161721 are 
the confidential and proprietary information of Boston Pharmaceuticals, Inc., and except as may 
be required by federal, state, or local laws or regulation, may not be disclosed to others without 
prior written permission of Boston Pharmaceuticals, Inc. 
I have read the protocol, including all appendices, and I agree that it contains all of the necessary 
information for me and my staff to conduct this study as described.  I will conduct this study as 
outlined herein, in accordance with the regulations stated in the Federal Code of Regulations for 
Good Clinical Practices and International Council for Harmonisation (ICH) guidelines, and will 
make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by Boston Pharmaceuticals, Inc., or 
specified designees.  I will discuss the material with them to ensure that they are fully informed 
about BOS161721 and the study. 
 
 
 
______________________________ 
______________________________ 
Principal Investigator Name (printed) 
Signature 
 
___________ ___________ 
Date 
 
Site Number 
 
 


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PROTOCOL SUMMARY 
Title:  
A Randomized Double-Blind Phase 1b/2 Combined Staggered 
Multiple Dose Escalation Study of BOS161721 in Systemic Lupus 
Erythematosus (SLE) Patients on a Background of Limited Standard 
of Care 
Indication 
Adults with moderately to severely active SLE 
Background and 
Rationale 
SLE is a chronic systemic autoimmune disease with considerable 
heterogeneity in clinical manifestations and disease course.  There is 
evidence that B- and T-cells are critical to the development of the 
disease, and that T-cell-derived cytokines such as interleukin-21 
(IL-21) are involved in the SLE-associated inflammatory 
pathological response.   
BOS161721 is a humanized immunoglobulin G1 (IgG1) triple 
mutation monoclonal antibody (mAb) intended to have an extended 
terminal elimination half-life (t1/2) that selectively binds to and 
neutralizes IL-21, which acts on multiple cell types that drive 
inflammation and autoimmunity.  In vivo, BOS161721 inhibits 
T-cell dependent antigen responses of B-cells and is being developed 
as a potential treatment for adults with moderately to severely active 
SLE.   
Nonclinical studies have evaluated the toxicity, pharmacodynamics 
(PD), toxicokinetics (TK), pharmacokinetics (PK), and 
immunogenicity of BOS161721 administered intravenously (IV) and 
subcutaneously (SC).  The no observed adverse effect levels 
(NOAELs) in Cynomolgus monkeys were determined to be 
100 mg/kg IV and 50 mg/kg SC, the highest doses tested.  No SC 
animals had injection reactions. 
In a Phase 1 single ascending dose (SAD) study, BOS161721 was 
administered IV and SC to healthy male and female adult subjects.  
This double-blind, placebo-controlled study evaluated 8 ascending 
dose levels (1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 
120 [SC], or 240 [SC] mg) for safety, tolerability, PK, PD and 
immunogenicity.  Overall, there were no clinically significant safety 
or tolerability findings from this study.  
Results from the Phase 1 SAD study informed the dose regimens 
used for the multiple ascending doses (MAD) Phase 1b study in this 
trial.  The MAD study will involve 3 cohorts.  The Phase 2 portion 
will be a proof of concept (POC) study, where dose selection will be 
based on the sponsor’s assessment of safety, tolerability, 
immunogenicity, and PK and PD data from the MAD study of 


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30 patients treated with BOS161721/placebo.  The purpose of the 
study is to establish safe and effective dosages for adult patients with 
moderately to severely active SLE. 


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Objectives:  
MAD Phase 1b Study 
Primary Objective: 
To assess safety, tolerability, and immunogenicity of repeat doses of 
BOS161721 (20 mg, 60 mg, and 120 mg) administered SC in adult 
patients with moderately to severely active SLE on limited 
background standard of care treatment, in order to estimate the 
optimal dose. 
POC Phase 2 Study 
Primary Objective: 
To demonstrate a superior effect of BOS161721 at the chosen dose 
compared with placebo for response on the SLE Responder Index 4 
(SRI-4), with sustained reduction of oral corticosteroids (CS), in 
adult patients with moderately to severely active SLE on limited 
background standard of care treatment. 
Secondary Objectives:  
To demonstrate a superior effect of BOS161721 at the chosen dose 
compared with placebo for response on clinical indicators of SLE 
activity, in adult patients with moderately to severely active SLE on 
limited background standard of care treatment, including: 
• Changes in SLE-specific autoantibody titers; 
• Changes in complement 3 and 4 (C3 and C4) levels; 
• Responses on SRI-4, SLE Responder Index 5 and 6 (SRI-5, and 
SRI-6), with sustained reduction of oral CS; 
• Response on the British Isles Lupus Assessment Group 
(BILAG)-based Composite Lupus Assessment (BICLA); 
• Response on the Cutaneous Lupus Erythematosus Area and 
Severity Index (CLASI); 
• Changes in the SLE Disease Activity Index 2000 (SLEDAI-2K);  
• Changes in the American College of Rheumatology (ACR)-28 
joint count. 


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Endpoints:  
Phase 1b MAD Study 
Primary Endpoints:  
Evaluation of safety, tolerability, and immunogenicity at each dose 
level, to determine the optimal dose, will include the recording of the 
following parameters: 
• Incidence and severity of adverse events (AEs) and serious 
adverse events (SAEs); 
• 12-lead electrocardiograms (ECGs); 
• Vital signs (blood pressure [BP], heart rate, and temperature); 
• Clinical laboratory assessments; 
• Physical examinations; 
• Evaluation for anti-drug antibodies (ADAs). 
Exploratory Endpoints: 
• 
 
 
 
• 
 
 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
 
• 
. 
 
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Other Endpoints: 
• 
 
 
 
• 
 
 
 
• 
 
 
PRO Endpoints: 
• 
 
 
• 
 
Phase 2 POC Study 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the proportion of patients who 
achieve treatment response as measured by the SRI-4 at Week 28, 
along with a sustained reduction of oral CS (≤ 10 mg/day and 
≤ Day 1 dose) between Week 16 and Week 28. 
Secondary Efficacy Endpoints: 
• The proportion of patients who achieve treatment response for 
the SRI-5 and SRI-6 at Week 28, along with a sustained 
reduction of oral CS (≤ 10 mg/day and ≤ Day 1 dose) between 
Week 16 and Week 28; 
• Changes from baseline in dsDNA, ANA, SSA, SSB, RNP, Sm, 
APL autoantibodies, at Week 16 and Week 28; 
• Changes from baseline in C3 and C4 levels at Week 16 and 
Week 28; 
• Changes from baseline in the SLEDAI-2K at Week 28; 
• Time to BILAG A or B flare;  
• Changes from baseline in the CLASI at Week 28; 
• The proportion of patients with a BICLA response at Week 28; 
CCI
CCI
CCI
CCI
CCI


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• The proportion of patients with CLASI response at Week 28; 
• Changes from baseline (percentage) in swollen joints and tender 
joints ACR-28 joint count; 
• Assessment of safety, tolerability, and immunogenicity as 
described for the primary endpoint in the MAD Phase 1b study. 
Exploratory Endpoints:  
• 
 
 
• 
 
Other Endpoints: 
• 
 
• 
 
 
• 
 
 
PRO Endpoints: 
• 
 
 
• 
 
Study Design: 
This is a Phase 1b/2 combined, randomized, multicenter, 
double-blind, placebo-controlled trial to study the clinical efficacy, 
safety, and PK of multiple SC doses of BOS161721 in adult patients 
with moderately to severely active SLE.  After successfully 
completing a screening phase, patients will be randomized to a 
specified dose of BOS161721 or placebo.  The dosing schedule will 
be monthly.  The trial will consist of a staggered MAD Phase 1b and 
POC Phase 2 studies.  Both studies will be double-blinded with each 
patient having the same number of doses (7), and visits; the duration 
will be 180 days, followed by a 90-day follow-up safety observation 
period.   
The MAD Phase 1b study phase will consist of 3 cohorts, with 
Cohort 1 containing 6 patients, where 5 of these patients will receive 
CCI
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BOS161721 (active), and 1 will receive placebo.  Cohorts 2 and 3 
will each contain 12 patients, including 9 active and 3 placebo 
patients.  Dose selection for each cohort is based on 90-day safety, 
tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01) in healthy subjects.  Each of the 3 doses (20 mg, 
60 mg, and 120 mg) selected for the MAD study are projected not to 
exceed the mean peak levels or exposures of that achieved in the 
SAD study following the single 240 mg SC dose.  Each patient may 
receive a total of 7 SC monthly doses on Days 1, 30, 60, 90, 120, 
150, and 180.   
The MAD study design is staggered, where after the 6 patients in 
Cohort 1 have received 2 doses and have completed 2 weeks of 
follow-up after the second dose, Cohort 2 begins dosing (after a data 
monitoring committee [DMC] evaluates the safety and tolerability 
data from Cohort 1).  Similarly, after 8 of the 12 patients in Cohort 2 
have received 2 doses and have completed 2 weeks of follow-up 
after the second dose, Cohort 3 begins dosing (based on the dose 
level determined after DMC evaluation of the safety and tolerability 
data from Cohort 2 and Cohort 1).  Two weeks after the last patient 
in Cohort 3 receives the second dose, the DMC will conduct a data 
review for the first interim analysis (IA1) to determine which dose 
will be carried forward into the POC Phase 2 study.  This POC dose 
decision will be based on evaluation of the PK, safety (inclusive of 
dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3; this dose will not 
exceed doses tested during the MAD study.  The DMC will be 
reviewing all relevant data from Cohorts 1, 2, and 3 that is available 
when the last patient in Cohort 3 reaches 60 days (dose 2).  Once the 
POC dose decision has been made, screening for the POC study can 
begin. 
For the POC study, 156 patients will be randomized to active or 
placebo groups in a 2:1 ratio.  As in the MAD study, each patient in 
the POC study may receive a total of 7 SC monthly doses on Days 1, 
30, 60, 90, 120, 150, and 180.  A maximum daily dose of 30 mg/day 
of oral CS will be acceptable for eligibility for the study, however, 
daily dose must be tapered down to a maximum of 10 mg/day for at 
least 5 days prior to Day 1 (randomization day).  One oral CS “burst” 
for increased SLE disease activity may occur during the study either 
between Weeks 1 and 8 or between Weeks 16 and 20.  Tapering of 
steroids during the course of the study will be encouraged and should 
be evaluated at all visits.  Tapering may occur after randomization 
except within 8 weeks of the primary (Week 28) and secondary 
(Week 16) endpoint assessments.  Between Week 8 and Week 16, 
and between Week 20 and Week 28, oral corticosteroid (OCS) doses 
must be held constant otherwise the patient will be declared a 


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non-responder in efficacy assessments. 
Data from 60 patients, including the 12 from the MAD study, or 
6 fewer if the low dose is chosen, who are in the cohort of the chosen 
dose for the POC study who complete 3 months of treatment will be 
used in a second IA (IA2) at Week 16 to assess if the trial could stop 
for an early futility conclusion.  If futility is not claimed in the IA2, 
the POC study will continue to 156 patients. 
Following the 6-month treatment period, primary and secondary 
efficacy endpoints will be assessed for each patient, after providing 
their 24-week disease activity assessments.  DMC monitoring will be 
conducted periodically throughout the study as described in the 
DMC charter. 
Main Criteria for 
Inclusion and Exclusion 
Inclusion Criteria: 
1. Men and women, ages 18 to 70 years, inclusive. 
2. Patients must be mentally capable of giving consent and there 
must be evidence of a personally signed and dated informed 
consent document indicating that the patient has been informed 
of all pertinent aspects of the study. 
3. Patients must have SLE as defined by meeting 4 of the Systemic 
Lupus International Collaborating Clinics (SLICC) classification 
criteria for SLE (with at least 1 clinical and 1 immunologic 
criterion OR Lupus nephritis as the sole clinical criterion in the 
presence of ANA or anti-dsDNA antibodies), either sequentially 
or simultaneously. 
4. At screening, patients must have at least 1 of the following: 
a. Elevated ANA ≥ 1:80 via immunofluorescent assay at the 
central laboratory;  
b. Positive anti-dsDNA or anti-Sm above the normal level as 
determined by the central laboratory; 
c. C3 or C4 below normal as determined by the central lab. 
5. At screening, the SLEDAI-2K must be ≥ 6, including points from 
at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory 


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results:  (hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia); 
ii. 
Points from lupus headache and organic brain syndrome 
will also be excluded. 
6. On Day 1, the SLEDAI-2K must be ≥ 6, including points from at 
least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, 
pericarditis, and vasculitis. 
i. 
Excluding parameters which require central laboratory 
results:  hematuria, pyuria, urinary casts, proteinuria, 
positive anti-dsDNA, decreased complement, 
thrombocytopenia and leukopenia; 
ii. 
Points from lupus headache and organic brain syndrome 
are also excluded. 
7. Patients must have at least 1 of the following manifestations of 
SLE, as defined by the BILAG criteria as modified for use in this 
study, which must be confirmed by the central data reviewer: 
a. BILAG A or B score in the mucocutaneous body system; 
b. BILAG A or B score in the musculoskeletal body system due 
to active polyarthritis as defined in the protocol Section 5.4; 
c. If only one “B” and no “A” score is present in the 
mucocutaneous body system or in the musculoskeletal body 
system due to arthritis, then at least 1 “B” must be present in 
the other body systems for a total of 2 “B” BILAG body 
system scores. 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose 
for at least 56 days (8 weeks prior to signing consent) of the 
following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or 
mycophenolic acid, chloroquine, hydroxychloroquine, 
or methotrexate (MTX). 
b. Prednisone (or prednisone-equivalent) cannot exceed 
30 mg/day at screening for a patient to be eligible and must 


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be stable at a maximum of 10 mg/day for at least 5 days prior 
to Day 1 (randomization). 
9. Women of childbearing potential (WOCBP; see Section 5.7 for 
full information regarding WOCBP, definition of menopause, 
and contraception): 
a. Must have a negative serum pregnancy test at screening.  
Urine pregnancy test must be negative prior to first dose. 
b. Must not be breastfeeding; 
c. Must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug 
plus 5 half-lives of study drug BOS1617219 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after 
treatment completion; 
10. Men who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of BOS161721 plus 
90 days (duration of sperm turnover) for a total of 44 weeks after 
treatment completion.  
11. Patients must demonstrate willingness and ability to comply with 
the scheduled study visits, treatment plans, laboratory tests, and 
other procedures. 
Exclusion Criteria 
Patients presenting with any of the following will not be included in 
this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE; 
2. Other systemic autoimmune disease (eg, erosive arthritis, 
rheumatoid arthritis [RA], multiple sclerosis [MS], systemic 
scleroderma, or vasculitis not related to SLE); 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome 
are allowed. 
3. Any major surgery within 6 weeks of study drug administration, 
(Day 1), or any elective surgery planned during the course of the 
study; 
4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of 
active TB; 


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b. History of active TB; 
c. Latent TB defined as positive QuantiFERON-TB Gold 
In-Tube (QFT-G) or other diagnostic test in the absence of 
clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of 
prophylactic treatment with regimen recommended by local 
health authority guideline, or the patient has started treatment 
with isoniazid, or other regimen recommended by local 
health authority guidelines for at least 1 month before Day 1 
and continues to receive the prophylactic treatment during 
study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, 
including but not limited to any condition defined by BILAG A 
criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed; 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which 
requires or may require induction treatment with cytotoxic agents 
or high dose CS; 
7. Concomitant illness that, in the opinion of the investigator, is 
likely to require additional systemic glucocorticosteroid therapy 
during the study, (eg, asthma), is exclusionary 
a. However, treatment for asthma with inhalational CS therapy 
is allowed. 
8. Use or planned use of concomitant medication outside of 
standard of baseline treatment for SLE from Day -1 or for any 
time during the study; 
9. Active and clinically significant infection (bacterial, fungal, viral, 
or other) within 60 days prior to first dose of study drug.  
Clinically significant is defined as requiring systemic antibiotics 
or hospitalization; 
10. A history of opportunistic infection, or a history of recurrent or 
severe disseminated herpes zoster or disseminated herpes 
simplex within the last 3 years; 
11. Chronic viral hepatitis including hepatitis B (HBV) and 
hepatitis C (HCV), known human immunodeficiency virus 
(HIV), or acquired immunodeficiency syndrome (AIDS)-related 
illness; 
12. Cryptosporidium in the stool sample at screening; 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at 
screening; 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening; 


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15. CD4+ count < 500/µL at screening; 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 
(35 × 109/L) if related to SLE, at screening; 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia 
related to SLE. 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent 
level of proteinuria as assessed by protein/creatinine ratio 
(3 mg/mg or 339 mg/mmol); 
19. Serum creatinine > 2.0 mg/dL at screening or creatinine 
clearance (CrCL) < 40 ml/minute based on Cockcroft-Gault 
calculation; 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate 
aminotransferase (AST) > 2 × the upper limit of normal (ULN) at 
screening, unless explicitly related to lupus based on the 
investigator’s judgment; 
21. Creatinine kinase (CK) > 3.0 × ULN at screening unless related 
to lupus myositis.   
22. Direct bilirubin > 1.5 × ULN at screening (unless related to 
Gilbert’s syndrome); 
23. Any other laboratory test results that, in the opinion of the 
Investigator, might place a patient at unacceptable risk for 
participating in this study; 
24. History of allergic or anaphylactic reaction to any therapeutic or 
diagnostic mAb (eg, IgG protein) or molecules made of 
components of mAbs; 
25. History substance and/or alcohol abuse, or dependence within the 
past 1 year, at the investigator’s judgement; 
26. History of cancer within the last 5 years (except for cutaneous 
basal cell or squamous cell cancer, or cervical cancer in situ 
resolved by excision; 
27. Any other severe acute or chronic medical or psychiatric 
condition, including recent (within the past year) medical 
conditions (eg, cardiovascular conditions, respiratory illnesses) 
that may increase the risk associated with study participation or 
investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the 
investigator, would make the patient inappropriate for entry into 
this study; 
28. Investigational site staff members directly involved in the 
conduct of the trial and their family members, site staff members 
otherwise supervised by the investigator, or patients who are 


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employees of the sponsor or directly involved in the conduct of 
the trial; 
29. Currently participating in, or who have participated in other 
interventional (drug or device) clinical study within 30 days or 
5 half-lives of baseline, whichever is longer; 
30. Recent (within the past 12 months) or active suicidal ideation or 
behavior based on patient responding “yes” to question 3, 4, or 5 
on the Columbia Suicide severity Rating Scale (C-SSRS); 
31. Current or pending incarceration; 
32. Current or pending compulsory detainment for treatment of 
either a psychiatric or physical (eg, infectious disease) illness. 
Statistical 
Considerations 
Below is a summary of the statistical methods.  Further details can be 
found in Section 9. 
Baseline and patient characteristics will be summarized via 
appropriate summary statistics by treatment group and overall, for 
each phase of the trial. 
Binary efficacy endpoints will be compared between treatments via 
Cochran-Mantel-Haenszel (CMH) analysis.  Continuous efficacy 
endpoints will be assessed via analysis of covariance (ANCOVA) 
repeated measures mixed model analysis with factors including 
treatment, time, treatment-by-time interaction, baseline covariate, 
and covariate-by-time interaction.  Summary statistics will be 
provided by dose/treatment for all safety endpoints.  Details will be 
provided in the statistical analysis plan (SAP).   
Two IAs are planned for this study.  The initial IA (IA1) will be 
conducted at the time of the POC decision for dose selection.  The 
second IA (IA2) will be performed for futility.  IA2 is planned to be 
conducted when SRI-4 response is determined for approximately 
60 patients (including all patients at the same dose level/matching 
placebo from the MAD study) after completing 3 months of 
treatment.  The purpose of IA2 is to assess if the trial could stop for 
an early futility conclusion, or continue.  Since there is no plan to 
stop the trial for an early efficacy conclusion, there is no impact on 
the type 1 error level.   
AEs will be summarized by counts and percentages of patients by 
treatment group.  Laboratory data and vital signs will be summarized 
by treatment group as summary statistics for value and change from 
baseline at each individual time point.  Summary statistics will 
include n, arithmetic mean, median, arithmetic SD, minimum, and 
maximum. 


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The PK parameter data will be listed and summarized descriptively 
in tabular format.  Binary PD endpoints will be assessed for the full 
analysis set (FAS) population via CMH analysis.  Continuous PD 
endpoints will be assessed via ANCOVA repeated measures mixed 
model analysis with multiple factors.  PK and PD relationships will 
be explored graphically and where appropriate model based methods 
of analysis will used. 
 
 
 


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TABLE OF CONTENTS 
A RANDOMIZED DOUBLE-BLIND PHASE 1B/2 COMBINED STAGGERED 
MULTIPLE DOSE ESCALATION STUDY OF BOS161721 IN SYSTEMIC 
LUPUS ERYTHEMATOSUS (SLE) PATIENTS ON A BACKGROUND OF 
LIMITED STANDARD OF CARE .........................................................................................1 
CLINICAL PROTOCOL APPROVAL FORM ..............................................................................2 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT .....................................................3 
PROTOCOL SUMMARY ...............................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................18 
LIST OF IN-TEXT TABLES ........................................................................................................22 
LIST OF IN-TEXT FIGURES.......................................................................................................22 
LIST OF ABBREVIATIONS ........................................................................................................23 
1 
INTRODUCTION AND RATIONALE .................................................................................27 
1.1 
Indication ...........................................................................................................................27 
1.2 
Background and Rationale .................................................................................................27 
1.2.1 
Overview of the Disease State .....................................................................................27 
1.2.2 
BOS161721 Development ...........................................................................................27 
1.2.2.1 
Interleukin-21 .........................................................................................................28 
1.2.2.2 
Preclinical Studies ..................................................................................................29 
1.2.2.3 
Clinical Studies ......................................................................................................30 
1.2.3 
Study Dose Selection ...................................................................................................31 
1.2.4 
Risk-Benefit Assessment .............................................................................................32 
1.2.5 
Potential Risks .............................................................................................................32 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions .........................................................33 
1.2.5.2 
Injection Site Reactions .........................................................................................33 
1.2.5.3 
Immune Complex Disease .....................................................................................34 
1.2.5.4 
Infections................................................................................................................34 
1.2.5.5 
Malignancy ............................................................................................................35 
1.2.5.6 
Hepatic Function Abnormality ..............................................................................35 
1.2.5.7 
Failure of Vaccination............................................................................................36 
1.2.5.8 
Potential for Drug-Drug Interactions .....................................................................36 
1.2.5.9 
Potential Risk to Fetal Development .....................................................................36 
2 
STUDY OBJECTIVES ..........................................................................................................36 
2.1 
Phase 1b Multiple Ascending Dose ...................................................................................36 
2.1.1 
Primary Objective ........................................................................................................36 
2.2 
Phase 2 Proof of Concept ...................................................................................................37 
2.2.1 
Primary Objective ........................................................................................................37 
2.2.2 
Secondary Objectives...................................................................................................37 
3 
STUDY ENDPOINTS ............................................................................................................38 
3.1 
Phase 1b MAD Study.........................................................................................................38 


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3.1.1 
Primary Endpoints .......................................................................................................38 
3.1.2 
Exploratory Endpoints .................................................................................................38 
3.1.3 
Other Endpoints ...........................................................................................................39 
3.1.4 
PRO Endpoints.............................................................................................................39 
3.2 
Phase 2 POC Study ............................................................................................................39 
3.2.1 
Primary Efficacy Endpoint ..........................................................................................39 
3.2.2 
Secondary Efficacy Endpoints .....................................................................................39 
3.2.3 
Exploratory Endpoints .................................................................................................40 
3.2.4 
Other Endpoints ...........................................................................................................40 
3.2.5 
PRO Endpoints.............................................................................................................41 
4 
STUDY PLAN........................................................................................................................41 
4.1 
Study Design ......................................................................................................................41 
4.1.1 
Multiple Ascending Dose Phase 1b Study ...................................................................41 
4.1.1.1 
Dose Escalation for the MAD Study .....................................................................42 
4.1.1.2 
Dose Limiting Toxicity (DLT) ..............................................................................42 
4.1.1.3 
DMC Recommendations ........................................................................................43 
4.1.2 
POC Phase 2 Study ......................................................................................................43 
4.1.2.1 
BOS161721 Dose...................................................................................................43 
4.1.2.2 
POC Study Design .................................................................................................43 
4.2 
Study Schematic.................................................................................................................45 
4.3 
Schedule of Assessments ...................................................................................................46 
5 
POPULATION .......................................................................................................................56 
5.1 
Participant Recruitment .....................................................................................................56 
5.2 
Number of Patients ............................................................................................................56 
5.3 
Patient Screening ...............................................................................................................56 
5.4 
Inclusion Criteria ...............................................................................................................56 
5.5 
Exclusion Criteria ..............................................................................................................58 
5.6 
Concomitant Medications ..................................................................................................60 
5.6.1 
Oral Corticosteroid Dose .............................................................................................61 
5.6.2 
Other Prohibited and/or Restricted Treatments ...........................................................62 
5.7 
Women of Childbearing Potential .....................................................................................62 
5.7.1 
Determination of Menopause .......................................................................................63 
5.7.2 
Contraception ...............................................................................................................63 
5.8 
Deviation from Inclusion/Exclusion Criteria .....................................................................64 
5.8.1 
Patient Withdrawal and Replacement ..........................................................................64 
5.8.2 
Exception for Non-Responders ....................................................................................64 
6 
STUDY PROCEDURES ........................................................................................................65 
6.1 
Screening............................................................................................................................65 
6.1.1 
Retesting During Screening Period ..............................................................................66 
6.2 
Enrollment/Randomization and Day 1 Treatment .............................................................66 
6.3 
Treatment Period/Follow-Up Visits ...................................................................................68 


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6.4 
Safety Follow-Up Visits ....................................................................................................69 
6.5 
Premature Discontinuation.................................................................................................70 
7 
ASSESSMENTS.....................................................................................................................71 
7.1 
Medical History, Demographic and Other Baseline Information ......................................71 
7.2 
Safety Assessments ............................................................................................................72 
7.2.1 
Laboratory Assessments ..............................................................................................72 
7.2.1.1 
Pregnancy testing ...................................................................................................74 
7.2.1.2 
Tuberculosis Screening ..........................................................................................74 
7.2.2 
Adverse Events ............................................................................................................75 
7.2.2.1 
Definitions..............................................................................................................75 
7.2.2.2 
Recording of Adverse Events ................................................................................75 
7.2.2.3 
Severity of Adverse Events ....................................................................................75 
7.2.2.4 
Causality of Adverse Events ..................................................................................75 
7.2.2.5 
Seriousness of Adverse Events ..............................................................................76 
7.2.2.6 
Adverse Events of Special Interest ........................................................................77 
7.2.2.7 
Reporting of Adverse Events .................................................................................80 
7.2.2.8 
Follow Up of Adverse Events ................................................................................82 
7.2.3 
Vital Signs ....................................................................................................................82 
7.2.4 
12-Lead Electrocardiograms ........................................................................................82 
7.2.5 
Physical Examinations .................................................................................................83 
7.2.6 
C-SSRS ........................................................................................................................83 
7.2.7 
Injection Site Reactions ...............................................................................................83 
7.2.8 
Immunogenicity ...........................................................................................................83 
7.3 
Efficacy Assessments.........................................................................................................84 
7.3.1 
SLEDAI-2K .................................................................................................................84 
7.3.2 
BILAG 2004 ................................................................................................................84 
7.3.3 
PGA of Disease Activity ..............................................................................................84 
7.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response ..........................85 
7.3.4.1 
SRI-4 Response ......................................................................................................85 
7.3.4.2 
SRI-5 and SRI-6 Response ....................................................................................85 
7.3.4.3 
BICLA Response ...................................................................................................85 
7.3.5 
CLASI Response ..........................................................................................................85 
7.3.6 
ACR-28 Joint Count ....................................................................................................86 
7.3.7 
Laboratory Assessments ..............................................................................................86 
7.4 
Other Variables ..................................................................................................................86 
7.4.1 
SLICC/ACR Damage Index ........................................................................................86 
7.4.2 
PROs ............................................................................................................................86 
7.5 
Pharmacokinetic Assessments ...........................................................................................87 
7.6 
Pharmacodynamic Assessments ........................................................................................87 
7.7 
Pharmacokinetic/Pharmacodynamic Relationship .............................................................87 
7.8 
Protocol Deviations ............................................................................................................87 


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8 
STUDY DRUG MANAGEMENT .........................................................................................88 
8.1 
Description .........................................................................................................................88 
8.1.1 
Formulation ..................................................................................................................88 
8.1.2 
Storage .........................................................................................................................88 
8.2 
Packaging and Shipment ....................................................................................................88 
8.3 
Dose and Administration ...................................................................................................88 
8.4 
Accountability ....................................................................................................................89 
8.5 
Prohibited Concomitant Therapy .......................................................................................89 
8.6 
Compliance ........................................................................................................................89 
9 
STATISTICS ..........................................................................................................................90 
9.1 
Sample Size ........................................................................................................................90 
9.2 
Statistical Methods .............................................................................................................90 
9.2.1 
Analysis Populations ....................................................................................................90 
9.2.2 
Demographics and Baseline Characteristics ................................................................91 
9.2.3 
Primary Endpoint(s) .....................................................................................................91 
9.2.4 
Secondary Endpoint(s) .................................................................................................91 
9.2.5 
Analysis of Safety ........................................................................................................91 
9.2.5.1 
Safety Analysis ......................................................................................................91 
9.2.5.2 
Data Monitoring Committee ..................................................................................92 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data .............................................................92 
9.2.6.1 
Analysis of Pharmacokinetic Data .........................................................................92 
9.2.6.2 
Analysis of Pharmacodynamic Data ......................................................................92 
9.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling ..................................93 
9.3 
Interim Analysis and Power ...............................................................................................93 
10 ETHICS AND RESPONSIBILITIES .....................................................................................94 
10.1 
Good Clinical Practice .......................................................................................................94 
10.2 
DMC ..................................................................................................................................94 
10.3 
Institutional Review Board/Independent Ethics Committee..............................................94 
10.4 
Informed Consent...............................................................................................................94 
10.5 
Records Management.........................................................................................................95 
10.6 
Source Documentation .......................................................................................................96 
10.7 
Study Files and Record Retention......................................................................................96 
11 AUDITING AND MONITORING ........................................................................................97 
12 AMENDMENTS ....................................................................................................................98 
13 STUDY REPORT AND PUBLICATIONS ...........................................................................99 
14 STUDY DISCONTINUATION ...........................................................................................100 
15 CONFIDENTIALITY ..........................................................................................................101 
16 REFERENCES .....................................................................................................................102 
17 APPENDICES ......................................................................................................................106 
APPENDIX 1 
NAMES OF STUDY PERSONNEL .............................................................106 
APPENDIX 2 
DECLARATION OF HELSINKI..................................................................107 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID EQUIVALENTS ....................111 
APPENDIX 4 
MEDICATION WASHOUT PERIODS........................................................112 
APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA).......................113 
 
LIST OF IN-TEXT TABLES 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose .........................46 
Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study .....................51 
Table 3. 
Laboratory Tests ....................................................................................................73 
Table 4. 
Causality Definitions .............................................................................................76 
Table 5. 
Sample Size ............................................................................................................90 
 
LIST OF IN-TEXT FIGURES 
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose .......................................................31 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies ..............................45 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
anti-drug antibody 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibodies 
ANC 
absolute neutrophil count 
APL 
antiphospholipid 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AZA 
azathioprine 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
blood pressure 
BUN 
blood urea nitrogen 
BW 
body weight 
CD 
cluster of differentiation 
CK 
creatine kinase 
C 
complement 
CL 
systematic clearance 
CLASI 
Cutaneous Lupus Erythematosus Area and Severity Index 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CS 
corticosteroids 
CSR 
clinical study report 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
dsDNA 
double-stranded deoxyribonucleic acid 
ECG 
electrocardiogram 
EOT 
end of treatment 
eCRF 
electronic case report form 
F 
female 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
eGFR 
estimated glomerular filtration rate 
GLP 
Good Laboratory Practice 


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GWAS 
genome-wide association studies 
γc 
gamma chain 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin  
IL 
interleukin 
IL-21R 
interleukin 21 receptor 
IM 
intramuscular 
INFγ 
interferon gamma 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
kg 
kilogram 
KLH 
keyhole limpet hemocyanin 
LOCF 
last observation carried forward 
M 
male 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPK 
mitogen-activated protein kinase 
MS 
multiple sclerosis 
MTX 
methotrexate 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network 
NK 
natural killer 
NOAEL 
no observed adverse event level 
NO 
nitric oxide 
OCS 
oral corticosteroid 


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OTC 
over-the-counter 
PD 
pharmacodynamics 
PEF 
peak expiratory flow 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
POC 
proof of concept 
PR 
(interval) from onset of the p-wave to the end of the r-wave 
pSS 
primary Sjögren’s syndrome 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
preferred term 
QRS 
(interval) from the onset of the q-wave to the end of the s-wave 
QT 
(interval) from onset of the QRS complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QFT-G 
QuantiFERON-TB Gold In-Tube  
RA 
rheumatoid arthritis 
RNP 
ribonucleoprotein 
RR 
(interval) from the onset of the r-wave to the onset of the next consecutive r-wave 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SDMT 
safety data monitoring board 
 
 
SLE 
systemic lupus erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
system organ class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
STAT3 
signal transducer and activator of transcription 3 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TB 
tuberculosis 
TDAR 
T-cell dependent antibody response 
Tfh 
T-follicular helper 
Th 
T-helper  
TK 
toxicokinetics 
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Tmax 
first time to maximum concentration  
Treg 
regulatory T-cell 
TT 
tetanus toxoid 
ULN 
upper limit of normal 
US 
United States 
Vd 
volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
YTE 
triple mutation 
 
 
 


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1 INTRODUCTION AND RATIONALE 
1.1 
Indication 
BOS161721 is a humanized monoclonal antibody (mAb), which binds to and inhibits 
interleukin-21 (IL-21) bioactivity, and is being developed for the treatment of moderately to 
severely active systemic lupus erythematosus (SLE) in adults.  
1.2 
Background and Rationale 
1.2.1 
Overview of the Disease State  
SLE is a chronic inflammatory autoimmune disease that has variable manifestations in multiple 
organ systems and follows a relapsing and remitting course.  The disease process includes 
abnormal immune responses mediated by tissue-binding autoantibodies and immune complex 
deposition, giving rise to tissue damage often resulting in end organ disease and even mortality.  
Survival of SLE has improved due to earlier detection, improved overall medical care, and 
standardized SLE treatment with corticosteroids, immunosuppressants, and cytotoxic agents.1  
However, some of the morbidity in patients with SLE is related to its treatment.  Comparison of 
early and late outcomes in patients with SLE demonstrate that death in early disease is most 
commonly due to infections and active SLE causing multi-system organ damage, while 
thromboses were the most common cause of death during later disease.2   
The reported prevalence of SLE in the United States (US) is 20 to 70 cases per 100,000 people.3  
More than 90% of cases of SLE occur in women, frequently starting at childbearing age.  
Women of color are disproportionately affected by SLE.  This suggests multiple genetic and 
environmental factors are at play.  Accordingly, a multifactorial view of the 
immunopathogenesis of SLE suggests more than 1 area of interest, including breach in central 
tolerance in the adaptive arm of the immune system, peripheral amplification of the autoimmune 
response by the innate immune system, and local processes in the target organ that facilitate 
end-organ disease.4  
1.2.2 
BOS161721 Development 
Boston Pharmaceuticals is developing BOS161721 for the treatment of SLE.  BOS161721 is a 
humanized immunoglobulin G1 (IgG1) mAb directed against human IL-21.   
Murine mAb 19E3, the progenitor of BOS161721, was generated using mouse hybridoma 
technology.  19E3 has subpicomolar (pM) affinity to human IL-21 and was selected for its potent 
neutralization of IL-21 bioactivity.  BOS161721 was generated by the humanization of mAb 
19E3 where its complementarity-determining regions were grafted onto a human IgG1 kappa 
backbone.  The fragment crystallizable (Fc) portion of BOS161721 contains a YTE 
(M252Y/S254T/T256E triple mutation) in the constant domain of the IgG1 heavy chain that was 
introduced into the parental molecule, 19E3, intended to prolong the in vivo terminal elimination 
half-life (t1/2) of the mAb.5  Thus, BOS161721 retains sub-pM binding to IL-21 and prevents 
IL-21 from binding to the IL-21 receptor (IL-21R), inhibiting IL-21 bioactivity.   


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BOS161721 binds to human IL-21 and Cynomolgus monkey IL-21, which are highly 
homologous, and neutralizes the bioactivity of both.  BOS161721 is specific for IL-21 as it does 
not bind to or inhibit the other gamma-chain (γc) family of cytokines, and acts to specifically 
neutralize the IL-21 pathway.  In in vitro studies, BOS161721 inhibited downstream IL-21-
induced signaling, IL-21-induced plasma cell differentiation, and IL-21-induced natural killer 
(NK) cell activation.  In in vivo studies, BOS161721 significantly inhibited the T-cell dependent 
antibody response (TDAR) to immunization with a protein antigen as well as B-cell expansion 
following a second protein antigen immunization in Cynomolgus monkeys.    
1.2.2.1 
Interleukin-21 
IL-21 is an inflammatory cytokine, which belongs to a family of cytokines that also includes 
IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private receptors in complex with the 
common cytokine receptor γc.6  Most cytokines in this family are critically important for both 
the maintenance and function of T-cell and B-cell responses.  IL-21 signals through a receptor 
complex consisting of its own private receptor, the IL-21R and γc.6,7  Engagement of the 
IL-21R/γc complex leads to the activation of several signaling pathways, including the Janus 
kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) 
and phosphoinositide 3-kinase pathways.8  IL-21 is produced mainly by T-cells and NK T-cells, 
but neutrophils have also been reported to produce IL-21.9,10  The IL-21R is expressed on a 
broad array of cell types, including B-cells, T-cells, NK-cells, macrophages and dendritic cells, 
as well as other hematopoietic and nonhematopoietic cells such as fibroblasts, keratinocytes, and 
intestinal epithelial cells.9,11  Activation of signal transducer and activator of transcription 3 
(STAT3) via phosphorylation is critical in regulating human B-cell responses to IL-2112; 
phosphorylated STAT3 (pSTAT3) forms a homodimer, which translocates to the nucleus where 
it initiates transcription of the IL-21 gene, forming an autocrine loop for IL-21 production via 
STAT3 phosphorylation.13  In addition, IL-21 has been shown to upregulate expression of its 
own receptor14 and induces an autocrine feedback loop.15 
IL-21 modulates various aspects of immune function.  It promotes cluster of differentiation 4 
(CD4+) T-cell differentiation and promotes the generation of T-helper (Th)1716 and T-follicular 
helper (Tfh) cells.15,17  In mice, IL-21 has been shown to regulate the balance between Th17 and 
regulatory T-cell (Treg), in that it increases Th17, while inhibiting Treg differentiation.18  Less is 
understood with regards to human Tregs, although IL-21 has been reported to counteract Treg 
suppression of human effector T-cells19 and blockade of IL-21 promotes Treg generation in a 
murine model of graft versus host disease induced by human T-cells.20  IL-21 upregulates CD8+ 
T-cell and NK-cell expansion and cytolytic activity by increasing granzyme B and perforin.21,22  
IL-21 also has been reported to increase granzyme B in plasmacytoid dendritic cells and B-cells 
resulting in inhibition of T-cell responses.23,24  IL-21 also has a variety of effects on 
nonhematopoietic cells, such as stromal cells and induces inflammation through matrix 
metalloproteinase release by gut intestinal fibroblasts.25 
One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation, 
or death during humoral immune responses.14  Furthermore, increased IL-21 production is 
characteristic of several autoimmune diseases and is likely to contribute to autoantibody 
production as well as pathologic features of autoimmune disease. 26  The critical role of IL-21 in 
promoting humoral and other immune responses makes it an important focus of potential 


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therapeutic interventions in conditions characterized by overproduction of pathogenic 
autoantibodies.  IL-21 production by Tfh cells in humans is believed to play a major role in 
driving the autoantibody production through its role in plasma cell differentiation.  Importantly, 
Tfh cell populations are expanded in patients with autoimmune diseases such as lupus, bullous 
pemphigoid, rheumatoid arthritis (RA) and primary Sjögren’s syndrome (pSS) and have been 
reported to correlate with IL-21 levels, autoantibodies, and disease severity.26,27,28,29  
Furthermore, loss of number and functionality of Tregs has been associated with autoimmune 
diseases such as SLE and giant cell arteritis, which IL-21 is expected to modulate.30,31  Thus, 
neutralization of IL-21 in settings of autoimmunity is expected to impact several cell populations 
believed to be involved in the pathogenesis of autoimmune disorders including SLE. 
BOS161721 selectively binds IL-21 with high affinity to neutralize IL-21, and due to its 
pleiotropic nature, neutralization of IL-21 is expected to impact several cell populations believed 
to be involved in the pathogenesis of SLE.  Importantly, patients with SLE have elevated IL-21 
plasma levels that correlate with the severity of the disease.  Recently, genome-wide association 
studies (GWAS) have provided convincing evidence that the chromosomal 4q 27 region harbors 
the IL-21 genes and is associated with chronic inflammatory disorders, including SLE.29   
1.2.2.2 
Preclinical Studies 
The pharmacokinetics (PK) of BOS161721 were characterized following single-dose intravenous 
(IV) administration of BOS161721 (0.01 to 30 mg/kg) in male Cynomolgus monkeys or repeat, 
every 2 weeks IV administration (15 to 100 mg/kg) and subcutaneous (SC) administration 
(50 mg/kg) in male and female Cynomolgus monkeys.  Systemic exposure was approximately 
dose-proportional within the tested dose range.  SC bioavailability was determined to be 64.3%.  
 
 
Two single-dose (IV) non-good laboratory practice (GLP) studies conducted in Cynomolgus 
monkeys evaluated the toxicity, pharmacodynamics (PD), toxicokinetics (TK), and 
immunogenicity of BOS161721.  Following a single IV administration (slow bolus), there were 
no BOS161721-related adverse changes, resulting in a no-observed-adverse-effect-level 
(NOAEL) value of 30 mg/kg, the highest dose tested among 2 studies.  
 
 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) administration for 3 months (a total of 7 doses).  
 
 
 
 
 
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  The NOAELs were determined to be 100 mg/kg IV and 50 mg/kg SC, the highest 
doses tested. 
1.2.2.3 
Clinical Studies 
BOS161721-01 was a double-blind, Phase 1, single ascending dose (SAD) study to assess the 
safety, PK, and PD of BOS161721 in healthy subjects.  The primary objective of the study was 
to characterize the safety and tolerability of IV and SC SADs of BOS161721 in an otherwise 
healthy subject population without concomitant illnesses, immune abnormalities, or concomitant 
medications.  Secondary objectives included characterization of the PK and immunogenicity of 
BOS161721, and exploratory objectives included the evaluation of the effect of BOS161721 on 
TDAR to keyhole limpet hemocyanin (KLH) (primary and secondary immunizations) in healthy 
subjects, the effects of BOS161721 on plasma levels of IL-21 (free and bound), and the 
evaluation of the effect of BOS161721 on IL-21 gene expression (via gene signature) in blood.  
This study consisted of 8 cohorts.  Subjects were randomized in a 3:1 ratio (BOS161721: 
placebo) and received either a single dose of BOS161721 (1 [IV], 3 [SC], 10 [SC], 22 [IV], 
30 [SC], 60 [SC], 120 [SC], or 240 [SC] mg) or placebo, with safety follow-up.  For the first 
cohort, after the first 2 subjects were dosed (1 active and 1 placebo), there was a minimum gap of 
48 hours before the remaining subjects from that cohort were dosed, to allow for an initial review 
of any emerging safety and tolerability data.  For all cohorts, escalation to the next dose was not 
sooner than 8 days after all the subjects in the prior cohort had been dosed and were based on a 
review of at least 7 days of safety and tolerability data by the Safety Data Monitoring Team 
(SDMT).   
Blood samples were collected at every in-house study visit for BOS161721 concentration 
determinations.  Blood samples were also collected for determination of IL-21 plasma levels 
(free and total).  Safety was assessed based on the occurrence of treatment-emergent AEs, 
hepatic function abnormality, and acute and delayed hypersensitivity reactions.  Other safety 
variables included electrocardiograms (ECGs), vital signs (blood pressure, heart rate, and 
temperature), safety laboratory assessments, blood sampling for ADAs, total IgG and IgM levels, 
CD4+ count, and full and targeted physical examinations.  Overall, there were no clinically 
significant findings from this study; there were no serious adverse events (SAEs), deaths, or 
discontinuations due to AEs during the study, AEs reported as related to the study drug, 
particularly infections (flu-like symptoms, etc), were expected for the compound, and there were 
no clinically relevant changes in laboratory and ECG results or vital signs.  PK data from the 
SAD study demonstrates BOS161721 has an extended t1/2 (provisional single dose data indicates 
this to be approximately 42-46 days) which supports evaluation of monthly dosing.  
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1.2.3 
Study Dose Selection 
Doses have been selected for the multiple ascending dose (MAD) Phase 1 study based on a 
90-day safety, tolerability, PK, and PD data review from the Phase 1 SAD study 
(BOS161721-01); the SDMT reviewed the blinded safety data from subjects for each dose cohort 
(8 cohorts, evaluating 1 [IV], 3 [SC], 10 [SC], 22 [IV], 30 [SC], 60 [SC], 120 [SC], or 
240 [SC] mg), along with the accumulated safety and available PK/PD data from all subjects in 
the previous dose cohorts, to make a decision on whether to proceed to the next higher dose 
level, repeat a dose level, or stop dose escalation.  Overall, there were no clinically significant 
safety or tolerability findings from this study. 
Based on the Day-90 interim cut of the PK and biomarker data in the BOS161721-01 study, the 
recommended doses for evaluation in the MAD phase of this study are 20, 60, and 120 mg SC 
monthly.  This dose recommendation is supported by evidence of linear PK with BOS161721 
resulting in a median Tmax of 6 days and an apparent terminal half-life of 44 days.  Furthermore, 
pSTAT3 suppression, a marker of IL-21 target engagement, follows a similar time course of the 
mAb levels, with maximal and sustained suppression apparent with doses greater than 30 mg SC 
(Figure 1).   
Figure 1. 
Individual pSTAT3 Cmin Levels Versus Dose 
 
IV = intravenous, pSTAT3 = phosphorylated signal transducer and activator of transcription 3; SC = subcutaneous 


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All doses selected for the MAD study are projected not to exceed peak levels or exposure of that 
achieved following the highest single dose of 240 mg SC administered in the Phase 1 SAD 
study.  Cohort 1 will include randomized treatment to the 20 mg dose.  Based on the staggered 
study design, the data monitoring committee (DMC) will perform a scheduled review of safety 
data and sequentially consider dose escalation for Cohorts 2 and 3.  In addition, the DMC will 
conduct a data review for the first interim analysis (IA1) to determine which dose will be carried 
forward into the proof of concept (POC) Phase 2 study.  This POC dose decision will be based 
on evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data 
(and available PD/biomarker data) from Cohorts 1, 2 and 3 from the MAD study (see 
Section 4.1.1.1).     
1.2.4 
Risk-Benefit Assessment 
The available preclinical data on BOS161721, the findings in clinical study BOS161721-01, and 
existing clinical information on IL-21 inhibitors suggest that the present clinical study has an 
acceptable risk-benefit ratio.  In this study, the risk-benefit assessment of BOS161721 in adult 
patients with moderately to severely active SLE will be ongoing, with step-wise evaluations 
during the staggered MAD study.  The DMC used in this study is charged with assessing such 
actions in light of an acceptable benefit-risk profile for BOS161721 as an anti-IL-21 mAb.  
Formal DMC monitoring meetings will occur as described in the DMC Charter.  Two weeks 
after Cohort 1 has received a second dose of study drug, the DMC will evaluate the safety and 
tolerability data from Cohort 1 to determine the recommended dose for Cohort 2.  Two weeks 
after 8 patients in Cohort 2 receive a second dose, the DMC will determine if dose escalation to 
Cohort 3 can proceed.  Two weeks after the last patient in Cohort 3 receives the second dose, the 
DMC will conduct a data review for the IA1 to determine which dose will be carried forward 
into the POC Phase 2 study.  This POC dose decision will be based on evaluation of the PK, 
safety (inclusive of dose-limiting toxicity [DLT]), and tolerability data (and available 
PD/biomarker data) from Cohorts 1, 2 and 3 during the MAD study.  Thereafter, DMC 
monitoring will be conducted periodically throughout the study as described in the DMC charter.  
With the agreement of the DMC and sponsor, this schedule may be modified depending on the 
rate of patient accrual.  Additional details can be found in the DMC Charter. 
The benefit of participation for all patients in this study is close monitoring of their medical 
condition and safety of their treatment.  Those randomized to the active treatment arm may 
potentially experience improvement in their SLE disease.  Those randomized to the placebo (in 
combination with standard of care) arm are not expected to obtain any additional benefit, beyond 
those of their background treatment, though close monitoring of their medical condition and 
safety may itself be associated with improving their SLE.   
1.2.5 
Potential Risks 
Potential risks based on the mechanism of action of BOS161721 include infections, risks 
associated with the administration of any foreign protein or biologic agent, including injection 
site reaction, anaphylaxis, serious allergic reaction, and development of ADAs.  ADAs could 
result in immune complex disease (with manifestations such as arthralgias, serum-sickness, and 
vasculitis), autoimmunity, or altered BOS161721 levels or activity.  Further details can be found 


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in the current Investigator’s Brochure (IB) for BOS161721, which contains comprehensive 
toxicology, preclinical and clinical information on BOS161721. 
Two investigational drug products are considered to be in the same pharmacological class as 
BOS161721 based on interruption of signaling through the IL-21 signaling pathway.  No 
potential risk generalizable across the class has been observed with these investigational 
products.  Based on the clinical Phase 1 SAD study (BOS161721-01), AEs reported as related to 
the study drug, particularly infections (flu-like symptoms, etc), were expected for the compound, 
and there were no clinically relevant changes in laboratory and ECG results or vital signs.  
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or 
receptor-mediated endocytosis.  This type of endocytosis and elimination is a form of 
target-mediated disposition where the interaction of the drug and its pharmacological target 
(eg, a target receptor) serves as a significant contributor to the kinetics of antibody distribution 
and elimination.  Renal elimination, which is a primary pathway of clearance of small-molecule 
drugs, is relatively unimportant for IgG, as its large size prevents efficient filtration through the 
glomerulus.  Secretion into the bile is an important pathway of elimination of IgA antibodies, but 
this route is not a significant contributor to the elimination of IgG antibodies.  Thus, risk to renal 
and hepatic systems due to metabolism of BOS161721 is low.33 
1.2.5.1 
Anaphylaxis and Serious Allergic Reactions 
As with the administration of any foreign protein and/or other biological agents, acute 
hypersensitivity reactions, including acute anaphylactic/hypersensitivity, severe allergic, and 
anaphylactoid reactions may follow infusion of mAbs and can be caused by various mechanisms.  
These acute hypersensitivity reactions may be severe and result in death. 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria,34 and are discussed in 
Section 7.2.2.6.1. 
Based on the limited Phase 1 SAD study (BOS161721-01), anaphylaxis and serious allergic 
reactions in subjects who received BOS161721 was not observed.   
Patients with a known history of allergy or severe hypersensitivity reaction to any component of 
BOS161721 formulation or patients with a history of anaphylaxis to any other biological therapy 
such as mAbs will be excluded from studies with BOS161721.  In addition, appropriate drugs 
and medical equipment to treat acute hypotensive, bronchoconstrictive, or anaphylactic reactions 
will be immediately available at the unit and study personnel will be trained to recognize and 
treat these reactions. 
1.2.5.2 
Injection Site Reactions 
In a repeat-dose GLP toxicology study in Cynomolgus monkeys, BOS161721 was administered 
every 2 weeks by IV or SC (50 mg/kg) for 3 months (a total of 7 doses); no SC animals had 
injection reactions. 


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Based on the Phase 1 SAD study (BOS161721-01), incidence of injection site reactions in 
subjects who received BOS161721 was similar to placebo.   
Patients will be monitored for local injection site reactions in this study.  See Section 7.2.7.  
1.2.5.3 
Immune Complex Disease 
The potential risk of immune complex disease for BOS161721 is theoretical, based on the known 
risks associated with mAbs.  The administration of a mAb can result in the formation of ADAs.  
Administration of the mAb in the presence of ADA may result in the formation of circulating 
antibody-antigen complexes potentially resulting in altered BOS161721 levels or activity or 
deposition of the complexes in microvasculature.  Complement is frequently involved in the 
latter setting, and the breakdown products of complement attract polymorphonuclear leukocytes 
to the site of deposition where they can provoke local tissue damage through specific or 
nonspecific release of enzymes.  Two of the more common end-organ targets are the blood 
vessels (vasculitis) and kidney (nephritis).  These clinical manifestations represent immune 
complex disease or Type III hypersensitivity.  Although BOS161721 is a humanized mAb, 
ADAs may develop; however, the likelihood of occurrence of immune complex disease with 
BOS161721 is low.  The findings of immune complex disease are typically reversible when mAb 
administration stops and the antibody-antigen complexes are cleared from the body. 
Based on the limited Phase 1 SAD study (BOS161721-01), immune complex disease in subjects 
who received BOS161721 was not observed. 
1.2.5.4 
Infections 
BOS161721 is expected to diminish the activity of T-cell, B-cell and NK-cell lines.  Like other 
medications modulating immune response, BOS161721 may increase the potential risk for 
infection, including serious infections.  IL-21 produced by CD4+ Th cells is required to sustain 
the anti-viral function of CD8+ T-cells against chronic viral infections.  Nonclinical evidence 
suggests that the risk of chronic viral infection recurrence or increased severity may occur with 
IL-21 inhibition.35 
These conditions will be fully characterized with clinical descriptions and routine laboratory 
and/or specialty testing and treated where indicated with appropriate local standard of care. 
Patients with a history of opportunistic infection, including recurrent or severe disseminated 
herpes zoster or disseminated herpes simplex within the last 3 years, or any other underlying 
pathology predisposing to serious infection, are excluded from studies with BOS161721 (for 
further details please refer to the current IB for BOS161721). 
Patients will be assessed for hepatitis B, and C, and HIV-1/2 combination, at screening. 
Cryptosporidium Infection 
Cryptosporidium infection was noted in patients with an IL-21 receptor loss-of-function gene 
mutation and similar findings of cryptosporidium infection have been observed in 
immunosuppressed liver transplant and human immunodeficiency virus patients.36,37  Since 


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BOS161721 is expected to diminish the immunosurveillance activity of T-cell, B-cell, and 
NK-cell lines, a similar risk is biologically plausible with prolonged exposure to BOS161721. 
Since the risk of opportunistic cryptosporidium infection increases with low levels of 
CD4+ T-cells,37 patients with a CD4+ count < 500 cell/mm3 were excluded from the Phase 1 
SAD study (BOS161721-01), and will be excluded from the proposed MAD/POC studies.  
Patients exposed to investigational product who develop diarrhea during the course of the study 
should immediately undergo an assessment for opportunistic infection including stool for ova 
and parasites and stool examination for cryptosporidium.  Positive cryptosporidium in stool 
sample at screening is an exclusion.  Treatment by the investigator where indicated should be 
guided by findings and be consistent with local standard of care. 
Based on the limited Phase 1 SAD study (BOS161721-01), infections in subjects who received 
BOS161721 was not observed. 
1.2.5.5 
Malignancy 
The stimulatory effect of IL-21 on NK cells and CD8+ T-cells suggests the cytokine may have 
anti-tumor activity.  Nonclinical studies have demonstrated significant anti-tumor effects of 
IL-21 in a number of tumor models.  IL-21 therapy of human metastatic melanoma and renal cell 
carcinoma has demonstrated POC with significant increases in levels of perforin, granzyme B, 
and interferon gamma (IFNγ) expression in CD8+ T-cells and NK T-cells.  Clinical response has 
been limited in these generally unmanageable diseases. 
The impact of treatment with anti-IL-21 therapy on the development or growth of malignancies 
is not known; however, as with other immunomodulatory biologic agents, treatment with 
BOS161721 may result in an increase in the risk of malignancies.  NK cell suppression by IL-21 
neutralization may represent a biological mechanism for a potential risk for malignancy.  
Patients with a history or current diagnosis of cancer within the past 5 years, with the exception 
of non-melanoma skin cancer or cervical cancer in situ treated with apparent success with 
curative therapy, are excluded from the study. 
Based on the limited Phase 1 SAD study (BOS161721-01), malignancy in subjects who received 
BOS161721 was not observed.   
1.2.5.6 
Hepatic Function Abnormality 
There is no substantial evidence suggesting BOS161721 is associated with liver function 
abnormality.  However as a precaution, patients with a history of abnormal alanine 
aminotransferase (ALT) and/or aspartate aminotransferase (AST), or bilirubin at screening 
(ALT/AST > 2 × upper limit of normal [ULN]; total bilirubin > 1.5 × [ULN] and judged by the 
investigator to be clinically significant) were excluded from the Phase 1 SAD study 
(BOS161721-01), and will be excluded from the MAD study.  Patients with a positive hepatitis 
B or C test or a history of alcohol dependence will also be excluded. 
Based on the limited Phase 1 SAD study (BOS161721-01), hepatic function abnormality in 
subjects who received BOS161721 was not observed. 


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1.2.5.7 
Failure of Vaccination 
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting plasma cells.  
Abnormal signaling through the IL-21R/Janus Kinase (JAK)3/signal transducer and activator of 
transcription (STAT3) pathway leads to defective humoral immune responses to both 
T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell 
memory.  Abnormal signaling through the pathway has been related to decreased specific 
antibody responses following vaccination, and to increased susceptibility to encapsulated 
bacterial infections.38 
The effect of BOS161721 was evaluated in in vivo single dose studies in Cynomolgus monkey in 
which the animals received vaccination to T-cell dependent KLH antigen to stimulate a TDAR.  
These in vivo studies demonstrated that BOS161721 significantly inhibited B-cell proliferation 
and IgG antibody responses to the KLH protein antigen; however, it is worth noting that 
BOS161721 administration did not produce any remarkable changes in anti-KLH antibody data 
for IgM, IgG1, IgG3, and IgG4 or anti-tetanus toxoid (TT) antibody data for IgM, IgG, IgG1, or 
IgE during the dosing phase in the same study. 
1.2.5.8 
Potential for Drug-Drug Interactions 
Drug-drug interactions were not evaluated in the Phase 1 SAD study (BOS161721-01), which 
included only healthy adult subjects.  Use of prescription medications (with the exceptions of 
oral contraceptives), and over-the-counter (OTC) treatments including herbal supplements such 
as St John’s Wort (except multivitamins), in the 2 weeks prior to screening was prohibited in the 
SAD study.   
See Section 5.5 for other specific exclusion criteria which support lowered risk of interactions, 
and Section 5.6.1 for corticosteroid (CS) dosing.  In addition, Section 1.2.5.6 describes 
considerations for hepatic function for this study.  
1.2.5.9 
Potential Risk to Fetal Development 
No data on preclinical reproductive toxicity are available at the time of this study.   
2 STUDY OBJECTIVES 
This trial has separate primary and secondary objectives for the MAD Phase 1b and POC Phase 2 
studies. 
2.1 
Phase 1b Multiple Ascending Dose  
2.1.1 
Primary Objective 
To assess safety, tolerability, and immunogenicity of repeat doses of BOS161721 (20 mg, 60 mg, 
and 120 mg) administered SC in adult patients with moderately to severely active SLE on limited 
background standard of care treatment, in order to estimate the optimal dose.   


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2.2 
Phase 2 Proof of Concept 
2.2.1 
Primary Objective 
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for 
response on the SLE Responder Index 4 (SRI-4), with sustained reduction of oral CS, in adult 
patients with moderately to severely active SLE on limited background standard of care 
treatment. 
2.2.2 
Secondary Objectives 
To demonstrate a superior effect of BOS161721 at the chosen dose compared with placebo for 
response on clinical indicators of SLE activity, in adult patients with moderately to severely 
active SLE on limited background standard of care treatment, including: 
• Changes in SLE-specific autoantibody titers; 
• Changes in complement 3 and 4 (C3 and C4) levels; 
• Responses on SRI-4, SRI-5, and SRI-6, with sustained reduction of oral CS; 
• Response on the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus 
Assessment (BICLA); 
• Response on the Cutaneous Lupus Erythematosus Area and Severity Index (CLASI); 
• Changes in the SLEDAI-2K;  
• Changes in American College of Rheumatology (ACR)-28 joint count. 
 
 


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3 STUDY ENDPOINTS  
This trial has separate primary and secondary endpoints for the MAD Phase 1b and POC Phase 2 
studies. 
3.1 
Phase 1b MAD Study 
3.1.1 
Primary Endpoints 
Evaluation of safety, tolerability, and immunogenicity at each dose level, to determine the 
optimal dose, will include the recording of the following parameters: 
• Incidence and severity of AEs, AEs of special interest, and SAEs; 
• 12-lead ECGs; 
• Vital signs (blood pressure [BP], heart rate, and temperature); 
• Clinical laboratory assessments; 
• Physical examinations; 
• Evaluation for ADAs. 
3.1.2 
Exploratory Endpoints 
• 
 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
• 
 
• 
 
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• 
 
• 
 
• 
 
3.1.3 
Other Endpoints 
• 
 
 
  
• 
 
 
• 
 
 
3.1.4 
PRO Endpoints 
• 
 
• 
 
3.2 
Phase 2 POC Study 
3.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of patients who achieve treatment response as 
measured by the SRI-4 at Week 28, along with a sustained reduction of oral CS (≤ 10 mg/day 
and ≤ Day 1 dose) between Week 16 and Week 28. 
3.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The proportion of patients who achieve treatment response for the SRI-5 and SRI-6 at 
Week 28, along with a sustained reduction of oral CS (≤ 10 mg/day and ≤ Day 1 dose) 
between Week 16 and Week 28; 
• Changes from baseline in dsDNA, ANA, SSA, SSB, RNP, Sm, APL autoantibodies, at 
Week 16 and Week 28; 
• Changes from baseline in C3 and C4 levels at Week 16 and Week 28; 
• Changes from baseline in the SLEDAI-2K at Week 28; 
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• Time to BILAG A or B flare;  
• Changes from baseline in the CLASI at Week 28; 
• The proportion of patients with a BICLA response at Week 28; 
• The proportion of patients with CLASI response at Week 28; 
• Changes from baseline (percentage) in swollen joints and tender joints ACR-28 joint count; 
• Incidence and severity of AEs, AEs of special interest, and SAEs; 
• 12-lead ECGs;  
• Vital signs (BP, heart rate, and temperature); 
• Clinical laboratory assessments; 
• Physical examinations and targeted physical examinations; 
• Evaluation for ADAs. 
3.2.3 
Exploratory Endpoints  
• 
 
• 
 
• 
 
 
• 
 
• 
 
; 
• 
 
• 
 
3.2.4 
Other Endpoints 
• 
 
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• 
 
• 
 
 
3.2.5 
PRO Endpoints 
• 
 
 
• 
 
4 STUDY PLAN 
4.1 
Study Design 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of SC doses of BOS161721 in adult patients with 
moderately to severely active SLE.  After successfully completing a screening phase, patients 
will be randomized to a specified dose of BOS161721 or placebo.  The dosing schedule will be 
monthly.   
The trial will consist of 2 studies:  MAD Phase 1b, and POC Phase 2.  Both studies will be 
double-blinded, and patients will have the same number of visits.  Patients may receive a total of 
7 SC monthly doses of study drug on Days 1, 30, 60, 90, 120, 150, and 180, followed by a 
90-day safety follow-up visit.   
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” BILAG 
system organ disease, confirmation of clinical components of the SLEDAI-2K score at screening 
and during the study, and cross-validation of the instruments used in this study to assess the 
disease being studied.  Further details on the content and methods of data reports by the medical 
monitor and sponsor will be outlined in the Medical Data Review Plan along with the processes 
and procedures that will be followed.   
4.1.1 
Multiple Ascending Dose Phase 1b Study 
The MAD study will consist of 3 cohorts:  
• Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
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• Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 SAD study (BOS161721-01) in healthy subjects.  All doses selected for 
the MAD study are projected not to exceed the mean peak levels or exposures of that achieved in 
the SAD study.   
4.1.1.1 
Dose Escalation for the MAD Study  
The MAD study design is staggered, where after the 6 patients in Cohort 1 have received 2 doses 
and have completed 2 weeks of follow-up after the second dose, Cohort 2 begins dosing (after 
DMC evaluation of the safety and tolerability data from Cohort 1).  Similarly, after 8 of the 
12 patients in Cohort 2 have received 2 doses and have completed 2 weeks of follow-up after the 
second dose, Cohort 3 begins dosing (based on the dose level determined after DMC evaluation 
of the safety and tolerability data from Cohorts 1 and 2).  Two weeks after the last patient in 
Cohort 3 receives the second dose, the DMC will conduct a data review for the IA1 to determine 
which dose will be carried forward into the POC Phase 2 study.  This POC dose decision will be 
based on evaluation of the PK, safety (inclusive of dose-limiting toxicity [DLT]), and tolerability 
data (and available PD/biomarker data) from Cohorts 1, 2, and 3; this dose will not exceed doses 
tested during the MAD study.  The DMC will be reviewing all relevant data from Cohorts 1, 2, 
and 3 that is available when the last patient in Cohort 3 reaches 60 days (dose 2).  Each cohort 
will continue at their assigned dose level through their respective 6-month treatment periods (See 
Study Schematic, Section 4.1).  If > 3 patients discontinue the study in a cohort, he/she will be 
replaced. 
Criteria for dose escalation are further described in the DMC Charter.  See Section 4.1.1.2 for 
additional details about DLTs.   
4.1.1.2 
Dose Limiting Toxicity (DLT) 
Severity of adverse events will be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  For the purpose of dose 
escalation, any of the following AEs occurring after study drug administration, which are 
attributable to the study drug, will be considered DLTs: 
Hematologic: 
• Grade 4 neutropenia; 
• Grade 3 neutropenic infection; 
• Grade 3 thrombocytopenia with bleeding; 
• Grade 4 thrombocytopenia. 


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Non-Hematologic: 
• Grade 3 or above toxicities, persisting after optimal treatment with standard medical therapy 
(eg, anti-emetics, anti-diarrheals); 
• Drug-induced liver injury ([DILI], Hy’s Law), as defined in Section 7.2.2.6.3. 
Investigators should always manage their patients according to their medical judgment which 
may include interruption of study drug based on the particular clinical circumstances.  All dose 
modifications/adjustments must be clearly documented in the patient's source notes and 
electronic Case Report Form (eCRF). 
4.1.1.3 
DMC Recommendations  
During scheduled meetings, the DMC will review relevant study data for safety or benefit-risk 
concern.  During the MAD study, the DMC may provide the following recommendations to the 
sponsor: 
• Expanding a cohort at a specific dosing level, or repeating a lower dose in a subsequent 
cohort; 
• Continuing a dose level for a given cohort; 
• Escalating a dose level for a subsequent cohort; 
• Termination of current or previous cohort(s). 
Further dosing in a given cohort will be halted if 2 or more DLTs are identified intra- and 
inter-patients dosed.  For the POC study, the DMC will conduct a data review for the IA1 to 
determine which dose will be carried forward into the POC Phase 2 study.  This POC dose 
decision will be based on evaluation of the PK, safety (inclusive of dose-limiting toxicity 
[DLT]), and tolerability data (and available PD/biomarker data) from Cohorts 1, 2, and 3; this 
dose will not exceed doses tested during the MAD study.  The DMC will be reviewing all 
relevant data from Cohorts 1, 2, and 3 that is available when the last patient in Cohort 3 reaches 
60 days (dose 2).  Details are provided in the DMC Charter.  
4.1.2 
POC Phase 2 Study 
4.1.2.1 
BOS161721 Dose  
The optimal dose evaluation is chosen based on MAD Phase 1b safety results.  The dose will be 
communicated by a letter to site investigators participating in the POC Phase 2 study, and to the 
IRB/IEC.  Once the POC dose decision has been made, screening for the POC study can begin. 
4.1.2.2 
POC Study Design 
For the POC study, 156 patients will be randomized to active or placebo groups in a 2:1 ratio.   


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As in the MAD study, each patient in the POC study may receive a total of 7 SC monthly doses 
of study drug on Days 1, 30, 60, 90, 120, 150, and 180.  Assessments will be completed 
according to the Schedule of Assessments (Section 4.3).  Dose selection will be based on the 
sponsor’s assessment of safety, tolerability, immunogenicity, and PK and PD data from the 
MAD study of 30 patients treated with BOS161721/placebo. 
Data from approximately 60 patients (including the 12 from the MAD study, or 6 fewer if the 
low dose is chosen who are in the cohort of the chosen dose for the POC study) who complete 
3 months of treatment will be used in the IA2 at Week 16 to assess if the trial could stop for an 
early futility conclusion (see Section 9.3 for details regarding the IA).  If futility is not claimed in 
the IA2, the POC study will continue to 156 patients. 
Following the 6-month treatment period, primary and secondary efficacy endpoints will be 
assessed for each patient after providing their 24-week disease activity assessments.     
DMC monitoring will be conducted periodically throughout the study as described in the DMC 
charter. 
 


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4.2 
Study Schematic 
Figure 2. 
Study Diagram for MAD Phase 1b and POC Phase 2 Studies 
 
A = active drug (BOS161721); P = placebo 


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4.3 
Schedule of Assessments 
Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
 
Treatment Period Follow-Up  
Safety  
Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 
to -1 
1 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB test 
(QuantiFERON-TB 
Gold In-Tube)b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (hepatitis B 
and C, HIV-1/2 
combination) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Randomizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
 
Treatment Period Follow-Up  
Safety  
Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 
to -1 
1 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
General  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Injection site reaction 
assessmente 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urine pregnancy test 
(women)g 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Concomitant 
medicationh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
AEs and SAEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA of disease 
activity 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR Damage 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
 
Treatment Period Follow-Up  
Safety  
Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 
to -1 
1 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
Index 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
12-lead ECGi 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry) 
Xj 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Xj 
X 
X 
Coomb’s test directk  
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAl 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbm 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Whole blood RNA 
collection 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xn 
Xn 
Xn 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
 
Treatment Period Follow-Up  
Safety  
Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 
to -1 
1 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PK Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predoseo 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
Xp 
X 
X 
Xp 
 
 
 
 
 
Xp 
X 
X 
X 
X 
X 
Abbreviations: ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; RNA = ribonucleic acid; RNP = ribonucleoprotein; 
SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus 
International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to screening 
or during the screening period must be documented in study records prior to randomization (Day 1). 
c 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
d 
Randomization should occur after patient eligibility has been confirmed by central eligibility review. 
e 
Injection site reaction assessments to be performed predose and at 2 hours postdose. 
f 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 1 at predose and at 1 and 2 hours 
postdose as well as on each of the scheduled outpatient days in the table above.  When the timing of these measurements coincides with a blood collection, 
vital signs should be obtained prior to the time of the blood collection. 
g 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
h 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 1 (randomization day).  See Section 5.6.1 for further details. 
i 
ECG will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled PK 
blood draws. 
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Table 1. 
Schedule of Assessments - Phase 1b - Multiple Ascending Dose  
 
Screena 
Enroll 
 
Treatment Period Follow-Up  
Safety  
Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 
to -1 
1 
7  
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
j 
Clinical laboratory assessments will include a fasting glucose and lipid panel during screening and Week 28. 
k 
When clinically indicated. 
l 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
m 
nAb is assessed if patient is positive for ADA. 
n 
Only dsDNA collected during safety follow-up visits.  
o 
Predose samples occur on study drug administration visit days. 
p 
Postdose samples will be collected at 4, 8, and 24 hours after study drug administration on Days 1, 30, and 180. 
 
 


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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
 
Treatment Period Follow-up  
Safety Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 to -1 
1 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test (women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH and estradiol 
(postmenopausal 
women) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TB test 
(QuantiFERON-TB 
Gold In-Tube)b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-rayb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (Hepatitis 
B and C; HIV-1/2 
combination)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLICC Criteria for 
SLE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool samplec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Randomizationd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
 
Treatment Period Follow-up  
Safety Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 to -1 
1 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
General  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BOS161721 or 
placebo dosing  
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Injection site 
reaction assessmente 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Targeted physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Vital signs (BP, HR, 
and temperature)f 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urine pregnancy test 
(women)g 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Spot urine for 
protein/creatinine 
ratio 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Concomitant 
medicationh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
AEs and SAEs 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
BILAG-2004 Index 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLEDAI-2K 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
PGA 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
ACR-28 joint count 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
CLASI 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
SLICC/ACR 
Damage Index 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
 
Treatment Period Follow-up  
Safety Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 to -1 
1 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
12-lead ECGi 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ count 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Clinical laboratory 
assessments 
(hematology and 
clinical chemistry) 
Xj 
X 
 
 
X 
  
X 
X 
X 
X 
X 
 
 
Xj 
X 
X 
Coomb’s test directk 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Total IgG and IgM  
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
Plasma 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Plasma 
 & 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
Whole blood for 
leukocyte 
immunophenotype 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
ADAl 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
 
 
X 
nAbm 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
pSTAT3n 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Whole blood RNA 
collection 
 
X 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
Xo 
Xo 
Xo 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
 
Treatment Period Follow-up  
Safety Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 to -1 
1 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
CRP 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
PK Labsp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predoseq 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Postdose 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Abbreviations:  ACR = American College of Rheumatology; ADA= anti-drug antibody; AE = adverse event; 
; BILAG = British Isles 
Lupus Assessment Group; BP = blood pressure; C = complement; CD4+ = cluster of differentiation 4; CLASI = Cutaneous Lupus Area and Severity Index; 
CRP = C-reactive protein; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; 
 
; FSH = follicle stimulating hormone; HR = heart rate; HIV = human immunodeficiency virus; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IL-21 = interleukin 21; IV = intravenous; nAb  = neutralizing antibody; PGA = Physician’s Global Assessment; 
PK = pharmacokinetic; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; RNA = ribonucleic acid; RNP = ribonucleoprotein; 
SAE = serious adverse event; SC = subcutaneous; 
; SLEDAI-2K = SLE Disease Activity Index 2000; SLICC = Systemic Lupus 
International Collaborating Clinics; 
; TB = tuberculosis; TDAR = T-cell dependent antigen response. 
a 
Screening assessments will be performed over more than 1 visit. 
b 
If patients have had a TB test and chest x ray within 3 months prior to screening, then these assessments do not need to be repeated during screening.  The 
results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test and a chest x-ray, conducted in the 3 months prior to screening 
or during the screening period must be documented in study records prior to randomization (Day 1). 
c 
Cryptosporidium test is required at screening.  If a patient develops diarrhea during the study a stool sample must be provided to test for ova, parasites, and 
cryptosporidium. 
d 
Randomization should occur after patient eligibility has been confirmed.  The actual randomization procedure can be completed on Day -1 after eligibility 
confirmation or the morning of Day 1 prior to dosing for logistical purposes. 
e 
Injection site reaction assessments to be performed predose and at 2 hours postdose. 
f 
Vital signs will be assessed after the patient has been supine and at rest ≥ 5 minutes.  Vital signs will be assessed on Day 1 at predose and at 1 and 2 hours 
postdose as well as on each of the scheduled outpatient days in the table above.  When the timing of these measurements coincides with a blood collection, 
vital signs should be obtained prior to the time of the blood collection. 
g 
Urine pregnancy test will be collected on WOCBP prior to study drug administration on dosing visits. 
h 
Concomitant use of oral corticosteroids:  A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, however, the daily 
dose must be tapered down to a maximum of 10 mg/day for at least 5 days prior to Day 1 (randomization day).  See Section 5.6.1 for further details. 
i 
ECGs will be performed after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG will be collected before scheduled PK 
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Table 2. 
Schedule of Assessments - Phase 2 Proof of Concept (POC) Study 
 
Screena 
Enroll 
 
Treatment Period Follow-up  
Safety Follow-Up 
Months 
 
 
 
 
1 
1.5 
2 
3 
4 
5 
6 
 
 
7 
8 
9 
Weeks 
 
 
1 
2 
4 
6 
8 
12 
16 
20 
24 
25 
26 
28 
32 
36 
Days 
-28 to -1 
1 
7 
(± 1) 
15 
(± 3) 
30 
(± 3) 
44 
(± 3) 
60 
(± 3) 
90 
(± 3) 
120 
(± 3) 
150 
(± 3) 
180 
(± 3) 
187 
(± 3) 
195 
(± 3) 
210 
(± 3) 
240 
(± 3) 
270 
(± 3) 
Visit Number 
1 
2 
 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
11 
12 
13 
blood draws (Section 7.5).  
j 
Clinical laboratory assessments will include a fasting glucose and lipid panel during screening and Week 28 
k 
When clinically indicated. 
l 
Blood samples for ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be collected from all patients but only 
assayed if the patient had a positive ADA on Day 90. 
m 
nAb is assessed if patient is positive for ADA. 
n 
Predose (trough) samples only. 
o 
Only 
 collected during safety follow-up visits. 
p 
PK samples will only be collected at the investigational sites that will be participating in the PK portion of the study. 
q 
Predose samples occur on study drug administration visit days. 
 
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5 POPULATION 
5.1 
Participant Recruitment 
Advertisements approved by the IRB, and investigator databases, may be used as recruitment 
procedures for adult men and women with moderately to severely active SLE.  
5.2 
Number of Patients 
Approximately 186 male and female patients are planned for enrollment, but may be adjusted 
upward according to the dropout (noncompliance) rate, which will be monitored in a blinded 
fashion in an ongoing basis.  Approximately 30 patients will be randomized for the MAD Phase 
1b study, and approximately 156 patients will be randomized in the POC Phase 2 study.  Note 
that approximately 30 dropouts are assumed.   
5.3 
Patient Screening 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular individual.  Patient eligibility will 
be reviewed and confirmed by the medical monitor or designee prior to randomization.  
Screening assessments (see the Schedule of Assessments [Section 4.3]) for this study must be 
performed between Day -28 and Day -1. 
5.4 
Inclusion Criteria 
Patients who meet the following criteria will be considered eligible to participate in this clinical 
study: 
1. Men and women, ages 18 to 70 years, inclusive; 
2. Patients must be mentally capable of giving consent and there must be evidence of a 
personally signed and dated informed consent document indicating that the patient has been 
informed of all pertinent aspects of the study; 
3. Patients must have SLE as defined by meeting 4 of the Systemic Lupus International 
Collaborating Clinics (SLICC) classification criteria for SLE (with at least 1 clinical and 1 
immunologic criterion or Lupus nephritis as the sole clinical criterion in the presence of 
ANA or anti-dsDNA antibodies), either sequentially or simultaneously. 
4. At screening, patients must have at least 1 of the following: 
a. Elevated antinuclear antibodies (ANA) ≥ 1:80 via immunofluorescent assay at the central 
laboratory;  
b. Positive anti-dsDNA or anti-Smith (Sm) above the normal level as determined by the 
central laboratory; 
c. C3 or C4 below normal as determined by central lab. 


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5. At screening, the SLE Disease Activity Index 2000 (SLEDAI-2K) must be ≥ 6, including 
points from at least 1 of the following clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis  
i. 
Excluding parameters which require central laboratory results:  (hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia) 
ii. 
Points from lupus headache and organic brain syndrome will also be excluded. 
6. On Day 1, the SLEDAI-2K must be ≥ 6, including points from at least 1 of the following 
clinical components: 
a. Arthritis, rash, myositis, mucosal ulcers, pleurisy, pericarditis, and vasculitis. 
i. 
Excluding parameters which require central laboratory results:  (hematuria, pyuria, 
urinary casts, proteinuria, positive anti-dsDNA, decreased complement, 
thrombocytopenia, and leukopenia); 
ii. 
Points from lupus headache and organic brain syndrome are also excluded. 
7. Patients must have at least 1 of the following manifestations of SLE, as defined by the 
BILAG criteria as modified for use in this study, which must be confirmed by the central 
data reviewer: 
a. BILAG A or B score in the mucocutaneous body system; 
b. BILAG A or B score in the musculoskeletal body system due to active polyarthritis 
defined as follows: 
i. 
“BILAG A:” Severe Arthritis, (BILAG item number 41), manifested by observed 
active synovitis in ≥ 2 joints with marked loss of functional range of movements 
and significant impairment of basic activities of daily living that has been present 
on several days cumulatively over the past 4 weeks, including at the time of the 
screening visit.  See APPENDIX 5 for additional detailed specifications. 
• Basic ADLs are defined as the following activities which require 
assistance or assistive devices, (at least 1 must be present and 
documented in source): 
o Ambulation, toileting, grooming- including bathing and dressing; 
feeding oneself, (and not responsive to steroids up to 10 mg/day, 
antimalarials, NSAIDs). 
ii. 
“BILAG B:” Moderate Arthritis, Tendonitis or Tenosynovitis, (BILAG item 
number 42), defined as tendonitis/tenosynovitis, or active synovitis in ≥ 1 joint, 
(observed or throughout history), with some loss of functional range of 
movements which lead to some loss of functional range of motion as manifested 
by effects on instrumental ADLs such as: 


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• Cooking, driving, using the telephone or computer, shopping, cleaning, 
etc, and has been present on several days over the last 4 weeks, and is 
present at the time of the screening visit. 
c. If only one “B” and no “A” score is present in the mucocutaneous body system or in the 
musculoskeletal body system due to arthritis, then at least 1 “B” must be present in the 
other body systems for a total of 2 “B” BILAG body system scores. 
8. Patients must be currently receiving at least 1 of the following: 
a. Administration for a minimum of 12 weeks, and a stable dose for at least 56 days 
(8 weeks prior to signing consent) of the following permitted steroid-sparing agents: 
i. 
Azathioprine (AZA), mycophenolate mofetil or mycophenolic acid, chloroquine, 
hydroxychloroquine, or methotrexate (MTX). 
b. Prednisone (or prednisone-equivalent) cannot exceed 30 mg/day at screening for a patient 
to be eligible and must be stable at a maximum of 10 mg/day for at least 5 days prior to 
Day 1 (randomization) (see APPENDIX 3). 
9. Women of childbearing potential (WOCBP; see Section 5.7 for full information regarding 
WOCBP, definition of menopause, and contraception):  
a. Must have a negative serum pregnancy test at screening.  Urine pregnancy test must be 
negative prior to first dose;  
b. Must not be breastfeeding; 
c. Must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days 
(duration of ovulatory cycle) for a total of 36 weeks after treatment completion; 
10. Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug plus 5 half-lives of 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion. 
11. Patients must demonstrate willingness and ability to comply with the scheduled study visits, 
treatment plans, laboratory tests, and other procedures. 
5.5 
Exclusion Criteria 
Patients presenting with any of the following will not be included in this study: 
1. Drug-induced SLE, rather than “idiopathic” SLE; 
2. Other systemic autoimmune disease (eg, erosive arthritis, rheumatoid arthritis [RA], multiple 
sclerosis [MS], systemic scleroderma, or vasculitis not related to SLE); 
a. RA-Lupus overlap (Rupus), and secondary Sjögren syndrome are allowed. 
3. Any major surgery within 6 weeks of study drug administration, (Day 1), or any elective 
surgery planned during the course of the study; 


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4. Any history or risk for tuberculosis (TB), specifically those with: 
a. Current clinical, radiographic, or laboratory evidence of active TB; 
b. History of active TB; 
c. Latent TB defined as positive QuantiFERON-TB Gold In-Tube (QFT-G) or other 
diagnostic test in the absence of clinical manifestations.  Latent TB is not excluded if the 
patient has documented completion of adequate course of prophylactic treatment with 
regimen recommended by local health authority guideline, or the patient has started 
treatment with isoniazid, or other regimen recommended by local health authority 
guidelines for at least 1 month before Day 1 and continues to receive the prophylactic 
treatment during study until the treatment course is completed. 
5. Active or unstable lupus neuropsychiatric manifestations, including but not limited to any 
condition defined by BILAG A criteria, with the exception of mononeuritis multiplex and 
polyneuropathy, which are allowed; 
6. Severe proliferative lupus nephritis, (WHO Class III, IV), which requires or may require 
induction treatment with cytotoxic agents or high dose CS; 
7. Concomitant illness that, in the opinion of the investigator, is likely to require additional 
systemic glucocorticosteroid therapy during the study, (eg, asthma), is exclusionary; 
a. However, treatment for asthma with inhalational CS therapy is allowed. 
8. Use or planned use of concomitant medication outside of standard of baseline treatment for 
SLE from Day -1 or for any time during the study.  (See Section 5.6 for prohibited 
concomitant medication);  
9. Active and clinically significant infection (bacterial, fungal, viral, or other) within 60 days 
prior to first dose of study drug.  Clinically significant is defined as requiring systemic 
antibiotics or hospitalization; 
10. A history of opportunistic infection, or a history of recurrent or severe disseminated herpes 
zoster or disseminated herpes simplex within the last 3 years; 
11. Chronic viral hepatitis including hepatitis B (HBV) and hepatitis C (HCV), known human 
immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related 
illness; 
12. Cryptosporidium in the stool sample at screening; 
13. White blood cells (WBC) < 1,200/mm3 (1.2 × 109/L) at screening; 
14. Absolute neutrophil count (ANC) < 500/mm3 at screening; 
15. CD4+ count < 500/µL at screening; 
16. Platelets < 50,000/mm3 (50 × 109/L) or < 35,000/ mm3 (35 × 109/L) if related to SLE, at 
screening; 
17. Hemoglobin < 8 g/dL or < 7 g/dL at screening if due to anemia related to SLE; 
18. Proteinuria > 3.0 g/day (3000 mg/day) at screening or equivalent level of proteinuria as 
assessed by protein/creatinine ratio (3 mg/mg or 339 mg/mmol); 


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19. Serum creatinine > 2.0 mg/dL at screening or creatinine clearance (CrCL) < 40 ml/minute 
based on Cockcroft-Gault calculation39:  
GFR = ([1 for male] or [0.85 for female]) × (140 – Age) × BW / (72 × Creatinine) 
20. Serum alanine aminotransferase (ALT) and/or serum aspartate aminotransferase 
(AST) > 2 × ULN at screening, unless explicitly related to lupus based on the investigator’s 
judgment; 
21. Creatinine kinase (CK) > 3.0 × ULN at screening, unless it is related to lupus myositis 
22. Direct bilirubin > 1.5 × ULN at screening (unless related to Gilbert’s syndrome); 
23. Any other laboratory test results that, in the opinion of the Investigator, might place a patient 
at unacceptable risk for participating in this study; 
24. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (eg, IgG protein) or molecules made of components of monoclonal antibodies; 
25. History substance and/or alcohol abuse or dependence within the past 1 year, at the 
investigator’s judgement; 
26. History of cancer within the last 5 years (except for cutaneous basal cell or squamous cell 
cancer, or cervical cancer in situ resolved by excision); 
27. Any other severe acute or chronic medical or psychiatric condition, including recent (within 
the past year) medical conditions (eg, cardiovascular conditions, respiratory illnesses) that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study; 
28. Investigational site staff members directly involved in the conduct of the trial and their 
family members, site staff members otherwise supervised by the investigator, or patients who 
are employees of the sponsor or directly involved in the conduct of the trial; 
29. Currently participating in, or who have participated in other interventional (drug or device) 
clinical study within 30 days or 5 half-lives of baseline, whichever is longer; 
30. Recent (within the past 12 months) or active suicidal ideation or behavior based on patient 
responding “yes” to question 3, 4 or 5 on the Columbia Suicide severity Rating Scale 
(C-SSRS);  
31. Current or pending incarceration;  
32. Current or pending compulsory detainment for treatment of either a psychiatric or physical 
(eg, infectious disease) illness. 
5.6 
Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, 
is considered a concomitant medication.  Patients should stay on stable regimen of other 


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concomitant medications for the treatment of SLE (eg, analgesics, NSAIDs, statins, ACE 
inhibitors/ARBs and other antihypertensive drugs), unless changes in these treatments are 
clinically indicated.  Use of any other drugs for non-SLE conditions, including over-the-counter 
medications and herbal preparations, should remain stable unless change or addition is clinically 
necessary.  Discussion with the medical monitor prior to initiation of new medication is strongly 
recommended.  Any concomitant therapies must be recorded on the eCRF.  Prior and 
concomitant medication use will be recorded for the 30 days prior to screening until the last 
follow-up visit.  In addition, historical treatment for SLE (including immunosuppressant, 
anti-malarial, corticosteroid, and/or biologic agent) will be recorded for the 48 weeks prior to 
screening in the eCRF. 
5.6.1 
Oral Corticosteroid Dose 
Prior to randomization, oral CSs (prednisone or prednisone equivalent), may be used in 
accordance with the investigator’s clinical judgment and best standard of care.  See 
APPENDIX 3 for examples of equivalents. 
A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the study, 
however, the daily dose must be tapered down to a maximum of 10 mg/day for at least 5 days 
prior to Day 1 (randomization day). 
After Day 1 (after initiation of study therapy), no up-titration above 10 mg/day is allowed except 
for up to 1 CS burst for increased disease activity.  
Tapering of steroids during the course of the study will be encouraged and should be evaluated at 
all visits.  
• Once a patient has received the first dose of study drug, prednisone (or prednisone 
equivalent) may be tapered down at the discretion of the investigator; 
o Tapering is allowed after randomization except within 8 weeks of the primary (Week 28) 
and secondary (Week 16) endpoint assessments.  Between Week 8 and Week 16, and 
between Week 20 and Week 28, oral corticosteroid (OCS) doses must be held constant 
otherwise the patient will be declared a non-responder in efficacy assessments. 
A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed during the 
study either between Weeks 1 and 8 or between Weeks 16 and 20, according to the following:   
• An oral CS “burst” between Week 1 and Week 8; (an increase of ≤ 40 mg/day of prednisone 
or equivalent), which must be tapered down to a maximum of 10 mg/day within 2 weeks of 
initiation of the “burst.” 
o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted; 
o The course of the oral CS “burst” is not permitted to extend beyond Week 8. 


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• An oral CS “burst” between Week 16 and Week 20 (an increase of ≤ 20 mg/day prednisone 
or equivalent), which must be tapered down to a maximum of 10 mg/day within 2 weeks of 
initiation of the “burst”. 
o Alternatively, a single IM dose of methylprednisolone (40 mg or equivalent) is permitted. 
Treatment with inhalational CS therapy (eg, for asthma), or by any other route, is allowed.  Other 
concomitant medications for SLE need to be taken at stable doses as per the inclusion criteria 
(Section 5.4). 
5.6.2 
Other Prohibited and/or Restricted Treatments 
Prohibited and/or restricted medications taken prior to study drug administration in the study are 
described below, and washout requirements are provided in APPENDIX 4.  Medications taken 
within 30 days prior to screening must be recorded on the eCRF. 
1. Prior exposure to BOS161721; 
2. Patients who have received treatment with anti-CD20 monoclonal antibodies within 
6 months of screening; recovery of B cells (CD19+) must be documented (record absolute 
number of CD19+ B cells); 
3. Patients who have received treatment with cyclophosphamide within the 1 year prior to 
screening; 
4. Patients who have received treatment with cyclosporine (with exception of ophthalmic use), 
any other calcineurin inhibitor or other immunosuppressive medication not specified in the 
inclusion criteria (oral or topical) within 3 months of screening; 
5. Patients who are currently receiving or are scheduled to receive plasmapheresis or 
lymphapheresis therapy, or have received such therapy within 8 weeks prior to screening; 
6. Patients who have received any live vaccines within 30 days of screening.  Note:  
Furthermore, live vaccines should not be used during the course of the study and within the 
2 months following last dose.  Other inactivated vaccines such as tetanus, etc, may be used 
according to local guidelines during treatment period; 
7. Patients who are scheduled or anticipated to have elective surgery during the course of the 
study; 
8. Initiation of new immunosuppressant or anti-malarial agent is not permitted.  Note:  Dose 
reduction or replacement may be allowed due to intolerability or shortage for patients on a 
stable dose prior to study initiation. 
5.7 
Women of Childbearing Potential 
WOCBP is defined as any woman who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) and is not 
postmenopausal. 
See Section 5.7.2 for detailed information regarding contraceptive requirements for WOCBP. 


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5.7.1 
Determination of Menopause 
Menopause is defined as at least 12 months of amenorrhea in a woman over age 45 in the 
absence of other biological or physiological causes.  Women under the age of 55 years must have 
a documented serum FSH level > 40 mIU/mL at screening to confirm menopause.   
5.7.2 
Contraception 
WOCBP must agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug plus 5 half-lives of study drug BOS161721 plus 30 days (duration of 
ovulatory cycle) for a total of 36 weeks after treatment completion. 
Men who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment with study drug plus 5 half-lives of study drug 
BOS161721 plus 90 days (duration of sperm turnover) for a total of 44 weeks after treatment 
completion. 
Investigators shall counsel WOCBP and men who are sexually active with WOCBP on the 
importance of pregnancy prevention and the implications of an unexpected pregnancy.  
Investigators shall advise WOCBP and men who are sexually active with WOCBP on the use of 
highly effective methods of contraception.  Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly.   
At a minimum, patients must agree to the use of 1 method of highly effective contraception from 
the following: 
• Male condoms with spermicide; 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by patients who 
are WOCBP or a male patient’s WOCBP partner.  Women who are partner of men who are 
patients participating in the study may use hormone-based contraceptives as 1 of the 
acceptable methods of contraception since they will not be receiving study drug. 
• IUDs, such as ParaGard®; 
• Vasectomy; 
• Complete abstinence, defined as complete avoidance of heterosexual intercourse, is an 
acceptable form of contraception.  Women who are abstinent while participating in the study 
must continue to have pregnancy tests.  Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the patient chooses to forego complete 
abstinence. 
Azoospermic men and WOCBP who are continuously not heterosexually active are exempt from 
contraceptive requirements.  However, they must still undergo pregnancy testing. 


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5.8 
Deviation from Inclusion/Exclusion Criteria 
Deviation from the inclusion or exclusion criteria will not be allowed.  If deviation of 
inclusion/exclusion criteria is discovered after randomization, the investigator should contact the 
medical monitor for discussion.  A decision will be made whether to allow a patient continue or 
withdrawal from the study medication.    
See Section 7.8 for additional details.  
5.8.1 
Patient Withdrawal and Replacement 
See Section 6.5 for reasons for removal from the trial.  Withdrawn patients may be replaced 
during the MAD study after discussion between the principal investigator or designee and 
sponsor.   
5.8.2 
Exception for Non-Responders 
Patients will be classified as non-responders if they (1) receive a second rescue medication at any 
time in the study or (2) take rescue medications between Week 8 and Week 16 or between 
Week 20 and Week 28 (as described in Section 5.6.1).  If a patient has been deemed a 
non-responder, they will discontinue from treatment and all End of Treatment assessments will 
be performed.  The patient will then enter the safety follow-up period.  The use of rescue 
medications in the case of non-responders is not to be considered a protocol violation (exclusion 
criteria 8).  Protocol violations will be identified based on blinded data prior to unblinding the 
final analysis dataset. 
 
 


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6 STUDY PROCEDURES 
Refer to the eCRF completion guidelines for data collection requirements and documentation of 
study assessments/procedures. 
6.1 
Screening 
Screening will be the same for both the MAD and POC studies.  Screening for the POC study 
cannot begin until the POC dose decision has been made. 
Screening will take place from Day -28 to Day -1, and assessments may be performed over more 
than 1 visit.  Confirmation that the most current IRB/IEC approved informed consent form (ICF) 
has been signed must occur before any study-specific screening procedures are performed.  
Procedures that are part of standard of care are not considered study-specific procedures and may 
be performed prior to informed consent and used to determine eligibility.   
All screened patients will be assigned a unique screening number.  The screening number will 
include a 3-digit site number and a 4-digit sequential number to identify patients from the time of 
screening.  Only eligible patients who are confirmed by central review as meeting the 
inclusion/exclusion criteria listed in Section 5.4 and Section 5.5 will be enrolled in the study.  
Screened patients who drop out of the clinical study before randomization will be recorded as 
screen failures.  If rescreening occurs, the site will assign a new screening number.   
Specific procedures at the screening visit will include: 
• Medical history documentation;   
• Review of inclusion and exclusion criteria; 
o Patient medical records must contain documentation of SLE diagnosis; 
o C-SSRS.   
• Concomitant medication documentation;   
• Demographics; 
• Full physical examination;  
• Vital signs; 
• Laboratory evaluations: 
o Hematology and clinical chemistry; 
o Serology (Hepatitis B and C; HIV-1/2 combination); 
o TB test 


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o CRP 
o Direct Coomb’s test (if indicated) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype; 
 
; 
o Serum pregnancy test (WOCBP); 
o FSH and estradiol (postmenopausal women) 
o Spot urine for protein/creatinine ratio; 
o Urinalysis. 
o Stool sample  
• 12-lead ECG; 
• SLE-related indices (BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, 
Physician’s Global Assessment (PGA) of disease activity. 
Screening procedures are listed in the Schedule of Assessments (Section 4.3), and details are 
provided in Section 7. 
6.1.1 
Retesting During Screening Period 
A single retesting of laboratory parameters and/or other assessments during the screening period 
is permitted (in addition to any parameters that require a confirmatory value) only if: 
• medically indicated;  
• there is evidence a laboratory sample was mislabeled, inadequately processed, and/or 
deteriorated in transit to the central laboratory. 
Any new result will override the previous result (ie, the most current result prior to 
randomization) and is the value by which study inclusion/exclusion will be assessed, as it 
represents the patient’s most current clinical state.  This will also apply to patients who are being 
rescreened. 
6.2 
Enrollment/Randomization and Day 1 Treatment 
Randomization should occur after patient eligibility for enrollment has been confirmed by the 
central eligibility review.   
The study site will obtain a randomization number when registering the patient in IWRS.  All 
patients will receive BOS161721 or placebo according to the kit number assigned by the IWRS 
randomization scheme.    
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After randomization, procedures include: 
• PROs:  
; 
• C-SSRS;  
• Laboratory evaluations: 
o Hematology and clinical chemistry 
o Direct Coomb’s test (if indicated) 
o CD4+ count, total IgG and IgM levels, plasma 
, plasma 
 and 
, whole blood for leukocyte immunophenotype;  
o ADA;  
o pSTAT3 (predose [trough] samples only in Phase 2);  
o 
;  
o Whole blood RNA collection;  
o 
; 
o See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies; 
o Urine pregnancy test will be collected on WOCBP prior to study drug administration; 
o Spot urine for protein/creatinine ratio; 
o Urinalysis. 
• Concomitant medication documentation;  
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements); 
• Full physical examination; 
• Vital signs (prior to PK blood draw, predose, and at 1 and 2 hours postdose on Day 1); 
• 12-lead ECG (prior to PK blood draw); 
• SLE-related indices (BILAG-2004 Index, SLEDAI-2K , ACR-28 joint count, CLASI, PGA); 
• SLICC/ACR damage index; 
• Study drug administration;  
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o Administration of BOS161721 or placebo will take place on-site, and is discussed in 
Section 8.3. 
• Injection site reaction assessment, predose and 2 hours postdose. 
Procedures on Day 1 are listed in the Schedule of Assessments (Section 4.3), and details are 
provided in Section 7. 
All patients who are enrolled, randomized, and receive study drug, or undergo study-specific 
procedures should reconsent with any updated versions of IRB/IEC approved informed consents 
during study participation as applicable and per institutional guidelines. 
6.3 
Treatment Period/Follow-Up Visits 
See Section 4.3 for allowable windows for each visit.  The following procedures will be 
performed at every study drug administration visit (Weeks 4, 8, 12, 16, 20, and 24) and 
follow-up visits during the treatment period (Weeks 2 and 6):  
• Targeted physical examination; 
• Vital signs (prior to PK blood draw); 
• Concomitant medication documentation; 
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements). 
The following assessments will be performed only at Weeks 4, 8, 12, 16, 20, and 24: 
• PROs:  
; 
• Urine pregnancy tests will be collected on WOCBP prior to study drug administration; 
• Injection site reaction assessments will be performed predose and 2 hours postdose; 
• Direct Coomb’s test (if indicated); 
• Spot urine for protein to creatinine ratio; 
• Urinalysis; 
• 
; 
• Plasma 
; 
• PGA, BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, and the CLASI will be 
completed. 
• In addition the following assessments will be completed: 
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• SLICC/ACR Damage Index will be completed at Week 24 (Visit 10). 
• C-SSRS will be completed at Weeks 12 and 24 (Visits 7 and 10); 
• ECGs will be performed at Weeks 4 and 12 (Visits 4 and 7) prior to PK blood draw. 
• See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively. 
• Hematology and chemistry assessments will be performed at Weeks 4 and 6 (Visits 4 and 5) 
for the MAD study, only, and at Weeks 8, 12, 16, 20, and 24 (Visits 6 through 10) for both 
studies. 
• The CD4+ count and total IgG and IgM levels will be assessed at Weeks 2, 4, 6, 12, and 24 
(Visits 3, 4, 5, 7, and 10). 
• Plasma 
 & 
, ADA, and whole blood for leukocyte immunophenotype 
will be assessed at Weeks 2, 4, 8, 12, and 24 (Visits 3, 4, 6, 7, and 10). 
• pSTAT3 will be assessed at Weeks 4, 6, 8, 12, and 24 (Visits 4, 5, 6, 7, and 10).   
• Whole blood RNA will be collected at Weeks 2, 4, and 12 (Visits 3, 4, and 7). 
• CRP will be measured at Week 12 (Visit 7), and nAb will be assessed if patient is positive 
for ADA at Weeks 12 and 24 (Visits 7 and 10). 
• 
 will be assessed at Week 24 (Visit 10). 
6.4 
Safety Follow-Up Visits 
Safety follow-up visits will take place at Weeks 28, 32, and 36 (Visits 11, 12, and 13).  These 
visits will include the following:  
• PROs:  
; 
• Documentation of AEs and SAEs (see Section 7.2.2.5 on SAE reporting requirements); 
• Injection site reactions; 
• Targeted physical examination; 
• Vital signs (prior to PK blood draw); 
• Spot urine for protein/creatinine ratio and urinalysis; 
• Concomitant medication documentation; 
• BILAG-2004 Index, SLEDAI-2K, ACR-28 joint count, CLASI, and PGA; 
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• Clinical laboratory assessments (hematology and clinical chemistry); 
• Direct Coomb’s test (if indicated); 
• Plasma 
; 
• 
; 
• pSTAT3 (Week 36 only for MAD study); 
• 12-lead ECG (Week 36 only, prior to PK blood draw); 
• CRP (Week 36 only); 
• ADA (Week 36 only); 
• Whole blood RNA collection (Week 36 only); 
• See Table 1 and Table 2 for details of PK sampling in the MAD and POC studies, 
respectively. 
6.5 
Premature Discontinuation 
While patients are encouraged to complete all study evaluations, they may withdraw from the 
study at any time and for any reason.  Every effort will be made to determine why any patient 
withdraws from the study prematurely.  If the patient is unreachable by telephone, a registered 
letter, at the minimum, should be sent to the patient requesting him/her to contact the clinic. 
All patients who withdraw from the study with an ongoing AE or SAE must be followed until 
the end of study or until the event is resolved or deemed stable, respectively.   
If a patient withdraws prematurely after dosing, an end of treatment (EOT) visit should be 
performed (Visit 10) and a last follow-up visit 90 days after dosing should be scheduled 
(Visit 13).  Safety follow-up visit procedures based on the Schedule of Assessments (see 
Section 6.4). 
Patient participation may be terminated prior to completing the study and the reason recorded as 
follows: 
• AE/SAE; 
• Protocol deviation; 
• Lost to follow-up; 
• Patient withdraws consent at their own request; 
• Investigator decision; 
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• Decision by sponsor (other than AE/SAE, protocol deviation, or lost to follow-up). 
Withdrawn patients may be replaced after discussion between the investigator or designee and 
sponsor.   
7 ASSESSMENTS 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the safety 
and wellbeing of the patient.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which he/she has 
taken to ensure that normal processes are adhered to as soon as possible.  All protocol violations 
are entered directly into the eCRFs. 
7.1 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
• General medical history; 
• Documentation of SLE diagnosis; 
• Historical medication therapy for SLE.  
The following demographic information will be recorded:  
• Age; 
• Ethnic origin (Hispanic/Latino or not Hispanic/not Latino); 
• Race (White, American Indian/Alaska Native, Asian, Native Hawaiian or other Pacific 
Islander, Black/African American); 
• Height (without shoes, in cm); 
• Body weight, without shoes (kg);  
• Body mass index (BMI [kg/m2]). 
Other baseline characteristics will be recorded as follows: 
• Concomitant medication documentation (see Section 5.6); 
• Status of child bearing potential and contraception. 


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7.2 
Safety Assessments 
7.2.1 
Laboratory Assessments 
Laboratory tests will be performed at times defined in the Schedule of Assessments 
(Section 4.3).  Patient eligibility will be determined based on these tests at screening.  
Unscheduled clinical labs may be obtained at any time during the study to assess any perceived 
safety concerns. 
A central laboratory will be used (with the exception of urine pregnancy tests and stool analysis) 
to ensure accuracy and consistency in test results.  The central laboratory will transmit all results 
for protocol tests, scheduled and unscheduled, to the clinical data base.  Laboratory/analyte 
results that could unblind the study (ie, biomarker results) will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.  Urinalysis will be performed 
on midstream, clean catch specimens.  Some biomarkers listed above will not be drawn at some 
sites due to geographical logistical challenges.  See the laboratory manual for details. 
 
 


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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
Hemoglobin 
Hematocrit 
RBC count 
RDW 
MCV 
MCH 
MCHC 
Platelet count 
WBC count 
CD4+ count 
Total neutrophils (Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs) 
Reticulocytes (%) 
BUN  
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 (bicarbonate) 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Creatine kinase 
Uric acid 
Albumin 
Total cholesterol 
(fasting) 
LDL-C (fasting) 
HDL-C (fasting) 
Triglycerides (fasting) 
Total protein 
PT/INR 
 
pH 
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Microscopya 
 
Spot urine for protein/creatinine ratio 
FSHb 
Estradiolb 
Urine pregnancy testc 
QuantiFERON®-TB Gold In-Tube test 
(QFT-G)  
Serologyd (Hepatitis B and C; HIV-1/2 
combination) 
Stool samplee 
 
 
 
Additional Testsf   
(potential Hy’s Law) 
 
Immunogenicity, PD and other 
Biomarker Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
Alkaline phosphatase 
(repeat) 
Direct bilirubin 
Indirect bilirubin 
GGT 
 
 
ADA 
nAbg 
pSTAT3 (predose [trough] samples 
only, in Phase 2) 
Total IgG & IgM 
Plasma 
 
Plasma 
 & 
 
Whole blood for leukocyte 
immunophenotype and RNA 
 
Antibodies 
 
 
CRP  
Direct Coomb’s testh 
Abbreviations:  Abs = absolute; ADA = anti-drug antibody; ALT = alanine aminotransferase; 
; 
; AST = aspartate aminotransferase; BUN = blood urea 
nitrogen; C = complement; CD4+ = cluster of differentiation 4; CRP = C-reactive protein; 
dsDNA = double-stranded deoxyribonucleic acid;; FSH = follicle stimulating hormone; 
GGT = gamma-glutamyltransferase; HDL-C = high-density lipoprotein cholesterol; HIV = human 
immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized 
ration; IL-21 = interleukin 21; LDL-C = low-density lipoprotein cholesterol; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = Mean corpuscular volume; nAb = neutralizing 
antibody; pSTAT3 = phosphorylated signal transducer and activator of transcription 3; PT = prothrombin time; 
qual = qualitative; RBC = red blood cell; RDW = RBC distribution width; RNA = ribonucleic acid; 
RNP = ribonucleoprotein; SAE = serious adverse event; SC = subcutaneous; 
 
; TB = tuberculosis.  
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Table 3. 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other Safety Tests 
a. 
On all urine samples.   
b. 
At screening only, in women who are amenorrheic for at least 12 consecutive months and under 55 years old.   
c. 
For WOCBP. 
d. 
Screening only. 
e. 
At screening, and if a patient develops diarrhea during the study a stool sample must be provided to test for ova, 
parasites, and cryptosporidium.   
f. 
Additional testing for potential Hy's Law cases only (See Section 7.2.2.6.3). 
g. 
If patient is positive for ADA. 
h. 
If clinically indicated. 
 
7.2.1.1 
Pregnancy testing 
For WOCBP, a serum pregnancy test will be performed at screening.  Following a negative 
serum pregnancy result at screening, appropriate contraception must be commenced or 
continued and a further negative urine pregnancy test results will then be required at the baseline 
visit before the patient may receive the investigational product.  Urine pregnancy tests will also 
be routinely repeated at study drug administration visits (Visits 2, 4, 6, 7, 8, 9, and 10) prior to 
study drug administration, and additionally whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  In the case of a positive pregnancy test or confirmed 
pregnancy, the patient will be withdrawn from study drug but may remain in the study for safety 
monitoring. 
See Section 7.2.2.7.1 for information on reporting of pregnancies as AEs/SAEs during the study. 
7.2.1.2 
Tuberculosis Screening 
During the screening period, it must be determined and documented that a patient does not have 
evidence of active or latent or inadequately treated TB per the exclusion criteria (Section 5.5).  
The results of TB screening, which includes the QuantiFERON®-TB Gold In-Tube (QFT-G) test 
and a chest x-ray, conducted in the 3 months prior to screening or during the screening period 
must be documented in study records prior to randomization (Day 1). 
7.2.1.2.1 
Mycobacterium Tuberculosis Testing Using QuantiFERON Test40 
QuantiFERON®-TB Gold In-Tube (QFT-G) is an in vitro diagnostic test using a peptide cocktail 
simulating ESAT-6, CFP-10, and TB 7.7 proteins to stimulate cells in heparinized whole blood.  
Detection of INFγ performed by enzyme-linked immunosorbent assay (ELISA) is used to 
identify in vitro responses to these peptide antigens that are associated with Mycobacterium 
tuberculosis infection.  QFT-G is an indirect test for M. tuberculosis infection (including disease) 
and is intended for use in conjunction with risk assessment, radiography and other medical and 
diagnostic evaluations. 
Test results will be reported as positive, negative, or indeterminate.  A negative QFT-G test 
result is required to meet the inclusion criterion.  In the case of an indeterminate result, repeat 
tests should be permitted for the purpose of determining eligibility of patients to enroll in this 


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study.  If a repeat test is indeterminate again, the patient is a screen failure.  The procedure for 
using this test and interpreting the results will be described fully in the laboratory manual, which 
will be provided to investigators. 
7.2.2 
Adverse Events 
7.2.2.1 
Definitions 
An AE is defined as any untoward medical occurrence experienced by a study patient, whether 
or not considered drug related by the principal investigator.   
AEs are unfavorable changes in a general condition, subjective or objective signs or symptoms, 
worsening of pre-existing concomitant disease, and clinically significant abnormality in 
laboratory parameters observed in a patient in the course of a clinical study.   
Non-serious SLE manifestations or abnormal laboratory results related to SLE disease activity 
would not be recorded as AEs unless they meet the definition for SAEs (Section 7.2.2.5). 
7.2.2.2 
Recording of Adverse Events 
AEs should be collected and recorded for each patient from the date of the first dose of study 
drug until the end of their participation in the study, including the safety follow up period.   
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading question such as ‘How have you 
been feeling since you were last asked?’  All AEs and any required remedial action will be 
recorded on the Adverse Events eCRF and Safety Adverse Event Form.  The details of the AE, 
date of AE onset (and time, if known), date of AE outcome (and time, if known), and action 
taken for the AE will be documented together with the principal investigator’s assessment of the 
seriousness of the AE and causal relationship to the study drug and/or the study procedure. 
All AEs should be recorded individually, using diagnostic terms where possible.  If the diagnosis 
is not established, individual symptoms may be reported.  The AEs will subsequently be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).   
7.2.2.3 
Severity of Adverse Events 
Each AE will be assessed by the principal investigator according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03 criteria. 41  
When changes in the severity (grade) of an AE occur more frequently than once a day, the 
maximum severity for the event should be noted for that day.  Any change in severity of signs 
and symptoms over a number of days will be captured by recording a new AE, with the amended 
severity grade and the date (and time, if known) of the change. 
7.2.2.4 
Causality of Adverse Events 
The principal investigator will assess the causal relationship between BOS161721 or placebo and 
the AE.  One of the following categories (Table 4) should be selected based on medical 
judgment, considering the definitions below and all contributing factors. 


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Table 4. 
Causality Definitions 
Related 
A clinical event, including laboratory test abnormality, occurs in a plausible time 
relationship to treatment administration and which concurrent disease or other 
drugs or chemicals cannot explain.  The response to withdrawal of the treatment 
(dechallengea) should be clinically plausible.  The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallengeb 
procedure if necessary. 
Unrelated A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration.  May have negative dechallenge and 
rechallenge information.  Typically explained by extraneous factors 
(eg, concomitant disease, environmental factors, or other drugs or chemicals). 
a 
Dechallenge:  Upon discontinuation of a drug suspected of causing an AE, the symptoms of the AE 
disappear partially or completely, within a reasonable time from drug discontinuation (positive 
dechallenge), or the symptoms continue despite withdrawal of the drug (negative dechallenge).  Note that 
there are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug relatedness 
clearly exists (for example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b 
Rechallenge:  Upon re-administration of a drug suspected of causing an AE in a specific patient in the past, 
the AE recurs upon exposure (positive rechallenge), or the AE does not recur (negative rechallenge). 
An unexpected adverse drug event is any adverse drug event for which the specificity or severity 
is not consistent with the current IP. 
7.2.2.5 
Seriousness of Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life threatening; this means that the patient was at risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe; 
• Requires hospitalization or prolongation in existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Is a congenital anomaly or birth defect; 
• Is another important medical event (see below). 
Important medical events that do not result in death, are not life threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition.  Examples of such events are: 
• Intensive treatment in an emergency room or at home for allergic bronchospasm; 


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• Blood dyscrasias or convulsions that do not result in inpatient hospitalization; 
• Development of drug dependency or drug abuse. 
Hospitalization for elective surgery or routine clinical procedures that are not the result of AE 
(eg, elective surgery for a pre-existing condition that has not worsened) need not be considered 
SAEs.  If anything untoward is reported during the procedure, that occurrence must be reported 
as an AE, either 'serious' or 'nonserious' according to the usual criteria. 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are associated with the 
use of the drug and are serious and unexpected.   
7.2.2.6 
Adverse Events of Special Interest 
AEs of special interest in this study include the following: 
1. Anaphylaxis and serious allergic reactions; 
2. Injection site reaction, including erythema, pain, and induration;  
3. Drug Induced Liver Injury (DILI) assessed following Hy’s Law; 
4. Malignancy; 
5. Opportunistic infections such as disseminated histoplasmosis, cryptococcosis, and 
disseminated tuberculosis;  
6. Cryptosporidiasis.   
7.2.2.6.1 
Anaphylaxis and Serious Allergic Reactions 
Anaphylaxis will be defined according to the National Institute of Allergy and Infectious 
Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.42  In the event of 
anaphylactic reaction or severe/serious hypersensitivity/allergic reaction, the patient must 
discontinue IP and emergency resuscitation measures implemented.  In case of other mild to 
moderate hypersensitivity reaction, depending on the severity, the investigator may manage in 
accordance with the standard-of-care. 
Anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus, or flushing, swollen lips-tongue-uvula) and at 
least 1 of the following: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 


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a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to several 
hours): 
a. Systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from the 
patient’s baseline. 
7.2.2.6.2 
Injection Site Reactions 
Injection site reactions are to be captured and reported as AEs.  These may include injection site 
erythema, pain, and induration.  The investigator should provide a clear description of the 
observed or reported AE including location and severity.  All concomitant treatments used to 
treat injection site reactions should be recorded and captured in the eCRF, together with the AE 
of injection site reactions.   
7.2.2.6.3 
Potential Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver injury 
are considered potential cases of DILI, and as potential Hy’s Law cases, and should always be 
considered important medical events.  If symptoms compatible with DILI precede knowledge of 
serum chemical test abnormalities, liver enzyme measurements should be made immediately, 
regardless of when the next visit or monitoring interval is scheduled.  In some cases, symptoms 
may be an early sign of injury and although typically less sensitive than serum enzyme 
elevations, they may indicate a need for prompt serum testing.  An increase in liver enzymes 
should be confirmed by a repeated test within 48 to 72 hours following the initial test, prior to 
reporting of a potential DILI event.  Patients will continue to have weekly or biweekly liver 
enzyme measurements until resolution or levels return to baseline. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 7.2.2.7.2 for reporting details). 
Potential DILI is defined as: 
1. ALT or AST elevation > 3 × ULN 
AND 
2. Total bilirubin > 2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND 


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3. No other immediately apparent possible causes of Alt or AST elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic. 
The patient should return to the investigational site and be evaluated as soon as possible, include 
laboratory tests, detailed history, and physical assessment.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, CK, total bilirubin, 
direct and indirect bilirubin, GGT, prothrombin time (PT)/International Normalized Ratio (INR), 
and alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and work exposure, should be 
collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary 
tract) may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the results 
of the investigations performed to determine etiology of the abnormal LFTs.  Such potential 
Hy’s Law cases should be reported as SAEs. 
Study drug discontinuation is considered if there is marked serum AST or ALT elevation or 
evidence of functional impairment (as indicated by rising bilirubin or INR, which represent 
substantial liver injury) that is related to study drug.  Discontinuation of treatment should be 
considered if: 
• ALT or AST > 8 × ULN; 
• ALT or AST > 5× ULN for more than 2 weeks; 
Discontinuation of treatment must occur if: 
 
• ALT or AST >3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5); 
• ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
7.2.2.6.4 
Malignancy 
The identification of a malignancy event will be made by the study site and communicated to the 
sponsor or designee.  AEs should be reported as serious per the criteria in Section 7.2.2.5. 
After the first dose of study drug, when there is a decision to biopsy a potentially malignant 
tumor, lymph node, or other tissue, the investigator and/or consultant(s) should contact the 
sponsor clinicians or designee to discuss the issue and any decisions as soon as possible. 


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7.2.2.6.5 
Specific Infections 
Any diagnosis or suggested diagnosis of opportunistic infections such as disseminated 
histoplasmosis, cryptococcosis, shingles, disseminated herpes simplex, or disseminated 
tuberculosis will be recorded as AEs of special interest.   
Cryptosporidiosis is also considered an AE of special interest.  Patients will be evaluated for 
cryptosporidium in the stool at screening, and as clinically indicated (eg, watery diarrhea) during 
the study.  If a patient develops diarrhea during the study a stool sample must be provided to test 
for ova, parasites, and cryptosporidium.   
7.2.2.7 
Reporting of Adverse Events 
AE reporting will be carried out in accordance with applicable local regulations, including 
regulatory agency and IRB reporting requirements.   
Each AE is to be assessed to determine if it meets the criteria for an SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate, and is further 
outlined in Section 7.2.2.7.2. 
7.2.2.7.1 
Reporting of Pregnancy 
As information is available, a pregnancy diagnosed during the study will be reported within 
24 hours to the sponsor via the Pregnancy Notification and Outcome Form, including pregnancy 
in female patients who received study drug and female partners of male study patients who 
received study drug.  The pregnancy should be followed to term and/or outcome and this 
outcome should also be reported to the sponsor via the Pregnancy Notification and Outcome 
Form.  Pregnancy itself is not regarded as an AE or SAE unless there is complication. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and 
the findings are reported). 
If the outcome of the pregnancy meets the criteria for an AE or SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the investigator 
should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
• Spontaneous abortion includes miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as serious 
adverse events when the investigator assesses the neonatal death as related or possibly related 
to exposure to investigational product. 


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7.2.2.7.2 
Reporting of Serious Adverse Events 
The principal investigator is responsible for providing notification to the sponsor of any SAE via 
the Safety Adverse Event Form, whether deemed study drug related or not, that a patient 
experiences during their participation in this study within 24 hours of becoming aware of the 
event. 
If an SAE is fatal or life threatening, notification to the sponsor must be made aware 
immediately, irrespective of the extent of available AE information.  This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports as well as to the 
initial and follow-up reporting of exposure during pregnancy and exposure via breastfeeding 
cases.  In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
The principal investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to the study drug.  All SAEs will be recorded from the time of first dose 
of study drug through the safety follow-up period (up to Week 36).  SAEs occurring after the 
final follow-up visit and coming to the attention of the principal investigator must be reported 
only if there is (in the opinion of the principal investigator) reasonable causal relationship with 
the study drug. 
As a minimum requirement, the initial notification should provide the following information: 
• Study number; 
• Patient number; 
• Details of the SAE (verbatim details are sufficient for immediate notification); 
• Criterion for classification as ‘serious’; 
• Causality assessment (which may be updated in a follow-up report when sufficient 
information is available to make this classification). 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports, etc), with the study patient’s personal identifiers removed.  All relevant information 
obtained by the principal investigator through review of these documents will be recorded and 
submitted to the sponsor within 24 hours of receipt of the information.  If a new Safety Adverse 
Event Form is submitted, then the principal investigator must sign and date the form.  The 
sponsor may also request additional information on the SAE, or clarification of omitted or 
discrepant information from the initial notification, which the principal investigator or an 
authorized delegate should submit to the sponsor within 24 hours of the request as possible.   


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7.2.2.7.3 
Reporting of Adverse Events of Special Interest 
AEs of special interest will be reported to safety immediately or within 24 hours of the site 
becomes aware of the event and recorded as such on the Adverse Events eCRF and Safety 
Adverse Event Form. 
Potential DILI will be reported based on specifications mentioned in Section 7.2.2.6.3.   
Each AE of special interest is to be assessed to determine if it meets the criteria for an SAE.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate, and is further outlined in Section 7.2.2.7.2. 
7.2.2.8 
Follow Up of Adverse Events 
All AEs will be followed up through the safety follow-up visits.  All SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the event has resolved, 
until any abnormal laboratory values have returned to baseline or stabilized at a level acceptable 
to the principal investigator and medical monitor, until there is a satisfactory explanation for the 
changes observed, or until the patient is lost to follow-up.   
See Section 7.2.2.7.1 for details related to follow-up of pregnancy.  See Section 7.2.2.6.3 for 
details related to follow-up of potential DILI.  See Section 7.2.2.6.4 for details related to follow-
up of malignancy. 
7.2.3 
Vital Signs 
Vital signs (blood pressure, heart rate, and body temperature) will be assessed as specified in the 
Schedule of Assessments (Section 4.3).  Vital signs will be assessed on Day 1 at predose and at 
1 and 2 hours postdose, as well as on each of the scheduled visit days during the study.  Supine 
BP and heart rate recordings will be made after the patient has been recumbent and at 
rest ≥ 5 minutes.  When the timing of these measurements coincides with a blood collection, vital 
signs should be obtained prior to the time of the blood collection. 
7.2.4 
12-Lead Electrocardiograms 
ECG will be performed at screening, and Visits 2, 4, and 7, and 13.  ECG recording will initiate 
after the patient has been supine for at least 5 minutes.  On days of PK blood draws, the ECG 
will be collected before scheduled PK blood draws, though timing will be such that PK draws are 
collected on their scheduled times where possible. 
The ECG will include all 12 standard leads and a Lead II rhythm strip on the bottom of the 
tracing.  The ECG will be recorded at a paper speed of 25 mm/second.  The following ECG 
parameters will be collected:  PR interval, QRS interval, RR interval, QT interval, and 
QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
All ECGs must be evaluated by a qualified physician or qualified designee for the presence of 
abnormalities and will be captured electronically and retained for future evaluation if required, 
up to the time of the clinical study report (CSR) completion. 


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7.2.5 
Physical Examinations 
The full physical examination will be completed at screening and Visit 2.  It includes an 
assessment of general appearance and evaluation of head, eyes, ears, nose, mouth, throat, neck, 
thyroid, lymph nodes, and extremities, and dermatologic, respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, neurologic, and psychiatric systems. 
The targeted (limited) physical examination will be completed at Visits 3 through 13.  It includes 
evaluation of patient complaints and SLE disease-related issues, and will exclude the 
genitourinary system. 
7.2.6 
C-SSRS 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening.43 
The C-SSRS evaluation will be performed at screening, Visit 2 (Day 1) and at Visits 7 and 10 
(Weeks 12 and 24, respectively).  Patients with recent (within the past 12 months) or active 
suicidal ideation or behavior based on patient responding “yes” to question 3, 4, or 5 is 
exclusionary at screening will be excluded from the study.  Patients with recent or active suicidal 
ideation or behavior at subsequent study visits will have responses to the C-SSRS reviewed in 
detail to assess patient risk, and appropriate consultative mental health services will be provided. 
7.2.7 
Injection Site Reactions 
Patients will be monitored for local injection site reactions at dosing administration visits, 
Visits 2 (Day 1), Visit 4 (Week 4), and Visits 6 through 10 (Weeks 8, 12, 16, 20, and 24).  
Patients will also be monitored for local injection site reactions at the safety follow-up visits, 
Visits 11, 12, and 13 (Weeks 28, 32, and 36, respectively).  Local injection site reactions will be 
assessed predose and at 2 hours postdose.  Injection site reactions should be managed according 
to the standard of care.  Injection site reactions are to be reported as AEs of special interest (see 
Section 7.2.2.7.3). 
7.2.8 
Immunogenicity 
The serum samples to measure the presence of ADA will be collected as Visits 2, 3, 4, 6, 7, 10, 
and 13 (Week 0, 2, 4, 8, 12, 24, and 36, respectively).  Blood samples (4 mL) to provide 
approximately 1.5 mL of plasma for anti BOS161721 antibody analysis will be collected into 
appropriately labeled tubes containing K2EDTA.  The presence or absence of ADA will be 
determined in the serum samples using validated bioanalytical methods.  Blood samples for 
ADA analysis will be collected up to Day 90 from all patients.  Subsequent ADA samples will be 
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After the first dose, if a patient tests positive in the validated confirmatory ADA assay, the 
sample from this patient will be further analyzed in the neutralizing antibody (nAb) assay. 
7.3 
Efficacy Assessments 
7.3.1 
SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI -2K of 6 or more generally represents moderately to severely active 
disease.44 
The SLEDAI-2K is completed at screening, at Visit 2, Visit 4, and Visits 6 through 13. 
7.3.2 
BILAG 2004 
The BILAG-2004 index is an organ-specific 97-question assessment based on the principle of 
the doctor’s intent to treat.  Only clinical features attributable to SLE disease activity are to be 
recorded and based on the patient’s condition in the last 4 weeks compared with the previous 4 
weeks.  It will be scored as not present (0), improved (1), the same (2), worse (3), or new 
(4).  Disease activity is graded separately for 9 body systems to 5 different grades (A to E) as 
follows: A (“Active”) is very active disease, B (“Beware”) is moderate activity, C 
(“Contentment”) is mild stable disease, D (“Discount”) is inactive now but previously active, and 
E (“Excluded”) indicates the organ was never involved.44  A shift from BILAG-2004 Grade A or 
B to a lower grade indicates a clinically relevant change in disease activity as the BILAG-2004 
grades mirror the decision points for treatment interventions. 
Only investigators that complete BILAG-2004 training will be allowed to perform the 
BILAG-2004 assessments.  Preferably, the same investigator should evaluate the patient at each 
BILAG-2004 assessment from screening to study completion.  The investigator must maintain 
documentation with descriptive details supporting the BILAG-2004 scoring (eg, chart, 
worksheet, clinic notes, and labs) at each visit. 
The BILAG-2004 is completed at screening, Visit 2, 4, and 6 through 13.  See APPENDIX 5 for 
detailed specifications. 
7.3.3 
PGA of Disease Activity 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients”.   
The PGA is completed at screening, Visit 2, 4, and Visits 6 through 13.  When scoring the PGA, 
the assessor should always look back at the score from the previous visit. 


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7.3.4 
Composite Endpoints:  SRI-4, SRI-5, SRI-6, and BICLA Response 
7.3.4.1 
SRI-4 Response 
Patients will be evaluated for SRI-4 scores at Week 28, with evaluation for sustained reduction 
of oral CS (≤ 10 mg/day and ≤ Day 1 dose) between Week 16 and Week 28. 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
1) ≥ 4-point reduction in SLEDAI-2K global score, 2) no new severe disease activity (BILAG A 
organ score) or more than 1 new moderate organ score (BILAG B), and 3) no deterioration from 
baseline in the PGA by ≥ 0.3 points.  The SRI-4 response in patients with moderate to severe 
SLE is associated with broad improvements in clinical and patient-reported outcomes.45  
Each patient, after providing their 28-week SRI-4 response, will be evaluated as either a 
responder or non-responder.   
7.3.4.2 
SRI-5 and SRI-6 Response  
Like the SRI-4, the SRI-5 and SRI-6 are composite indices of SLE disease improvement that 
consists of scores derived from the SLEDAI-2K and the BILAG 2004 Index.  However, the 
SRI-5 and SRI-6 are computed with a minimal three-point or five-point improvement in 
SLEDAI-2K being required, respectively.46 
The SRI-5 and SRI-6 are evaluated for response at Week 24, along with a sustained reduction of 
oral CS (≤ 10 mg/day and ≤ Day 1 dose) between Week 16 and Week 28. 
7.3.4.3 
BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as 1) at least 
1 gradation of improvement in baseline BILAG 2004 scores in all body systems with moderate 
disease activity at entry (eg, all B [moderate disease] scores falling to C [mild], or D [no 
activity]); 2) no new BILAG A or more than 1 new BILAG B scores; 3) no worsening of total 
SLEDAI-2K score from baseline; 4) ≤ 10% deterioration in PGA score and 5) no treatment 
failure.44  It is driven primarily by the BILAG, and has been used in Phase 2 and 3 mAb 
studies.47 
For the endpoints of BICLA response at Week 28, Week 32, and Week 36, patient scores will be 
completed and response determined. 
7.3.5 
 CLASI Response  
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 48  Response is 
defined as 50% improvement from baseline in “A” or “B” scores.  This assessment will be 
applied to all patients as all are required to have cutaneous disease activity. 


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For the secondary efficacy endpoint of CLASI response at Week 28, patient scores on MAD and 
POC studies will be compared with baseline for 50% improvement. 
7.3.6 
ACR-28 Joint Count 
The ACR-28 joint count will evaluate the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded.  The ACR-28 joint count will be 
performed at screening, Visit 2, 4, and 6 through 13. 
7.3.7 
Laboratory Assessments  
Patients will be evaluated for laboratory parameters as specified in the Schedule of Assessments 
(Section 4.3), including:  Fasting glucose and lipid panels, pSTAT3 (predose samples in 
Phase 2), total IgG & IgM, complement:  
, Plasma 
 & 
, whole blood 
for leukocyte immunophenotype and RNA, 
, and antibodies:  (
 
). 
Endpoint analyses will be based on changes from baseline assessments at Week 16 and Week 28. 
7.4 
Other Variables 
7.4.1 
SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.49  It will be performed on Day 1 
(Visit 2), and Day 180 (Visit 10). 
7.4.2 
PROs 
Patients should be encouraged to complete the PROs at the clinic at the beginning of the study 
visit prior to any clinical assessments.  A member of the staff should be available if a patient 
requires further instruction and to review the PRO questionnaires for completeness prior to 
leaving the clinic.  The PROs include the 
 and the 
. 
 
 
   
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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7.5 
Pharmacokinetic Assessments 
During the MAD Phase 1b (all sites) and POC Phase 2 (select sites only) studies, blood samples 
for PK analysis of BOS161721 or placebo concentration will be collected according to Table 1 
and Table 2. 
PK parameters include the following:  
• Cmax, Tmax, AUC, t½, CL, Vd. 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected AEs and/or SAEs and the date and time 
documented in the eCRF.  
Plasma concentrations of BOS161721 will be measured using a validated immunoassay.  The PK 
parameters will be calculated from the plasma concentration-nominal time profiles for the IA2 
and actual time profiles for the final analysis.  The non-compartmental analysis will be 
performed using appropriately validated PK/PD software. 
7.6 
Pharmacodynamic Assessments 
Blood samples for PD parameters (plasma) will be collected at times indicated for each of the 
following parameters: 
• pSTAT3 at Visits 2, 4, 7, 10 (predose samples in POC study), and at Visit 13 (MAD study); 
• Antibodies:  
 at Visits 1, 2, 4, and 6 
through 13; 
• Plasma complement (
) at Visits 1, 2, 4 and 6 through 13. 
• Plasma 
, and 
 at Visits 1 through 4, 6, 7, and 10; 
• Whole blood for leukocyte immunophenotype at Visits 1 through 4, 6, 7, and 10; 
• Whole blood RNA collection at Visits 2 through 4, 7, and 13; 
• IgG and IgM and CD4+ count at Visits 1 through 5, 7, and 10. 
7.7 
Pharmacokinetic/Pharmacodynamic Relationship 
Evidence of any PK/PD relationships will be evaluated between BOS161721 plasma 
concentrations and the available PD endpoints and biomarkers. 
7.8 
Protocol Deviations 
Protocol deviations will be documented during the study.  Per the statistical analysis plan (SAP), 
these will be listed by patient and summarized by deviation category by treatment group. 
CCI
CCI
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CCI


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8 STUDY DRUG MANAGEMENT 
8.1 
Description 
8.1.1 
Formulation  
 
 
   
 
 
 
Additional information regarding dose preparation will be provided in a separate Pharmacy 
Manual. 
8.1.2 
Storage 
All supplies of BOS161721 or placebo must be stored in accordance with the manufacturer’s 
instructions.  BOS161721 or placebo will be stored in a securely locked area, accessible to 
authorized persons only, until needed for dosing. 
Information regarding storage and dose preparation will be provided in a separate Pharmacy 
Manual. 
8.2 
Packaging and Shipment 
Investigational medicinal products will be supplied by Boston Pharmaceuticals, Inc.  
Investigational medicinal products will be packaged and labeled according to applicable local 
and regulatory requirements. 
8.3 
Dose and Administration 
Details of dosing are provided in Section 4.1. 
Each unit dose will be prepared by a qualified staff member.  The vials of investigational product 
(IP) will appear identical and will have a "blinded" label on the vials that will state 
 mg or 
placebo.  When the site goes into the IWRS to request the patient kit(s), the IWRS will assign the 
appropriate number of kits (regardless of assignment to placebo or active treatment) per the dose 
(ie, 
).  If a patient is 
randomized to the placebo arm, they will receive the matching number of kits. 
The designated staff member (or designee under the direction of the designated staff member) 
will dispense BOS161721 or placebo for each patient according to the protocol, randomization 
list, and Pharmacy Manual, if applicable. 
CCI
CCI
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CCI


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After receiving sponsor approval in writing, the investigational site is responsible for returning 
all unused or partially used BOS161721 or placebo to the sponsor or designated third party or for 
preparing BOS161721 or placebo for destruction via incineration. 
Further details are found in a separate Pharmacy Manual. 
8.4 
Accountability 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of BOS161721 or placebo throughout the clinical study.  The drug accountability log 
includes information such as, randomization number, amount dispensed and amount returned to 
the pharmacy (if any).  Products returned to the pharmacy will be stored under the same 
conditions as products not yet dispensed.  The returned products should be marked as ‘returned’ 
and kept separate from the products not yet dispensed. 
All dispensing and accountability records will be available for sponsor review after database lock 
procedures are completed.  During safety monitoring, the drug accountability log will be 
reconciled with the products stored in the pharmacy. 
8.5 
Prohibited Concomitant Therapy 
Prohibited concomitant medications are discussed in Section 5.6 and APPENDIX 4. 
8.6 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the principal 
investigator.  The date and time of dosing will be documented on each dosing day.  Comments 
will be recorded if there are any deviations from the planned dosing procedures. 
 
 


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9 STATISTICS 
There are 2 IAs planned for the study.  The first IA will be conducted at the time of the POC 
decision for dose selection.  The second IA will be performed for futility (see Section 9.3).  
Before the first IA, a SAP will be finalized, providing detailed methods for the analyses outlined 
below.  Any deviations from the planned analyses will be described and justified in the final 
integrated CSR. 
The following standards will be applied for the analysis unless otherwise specified.  Continuous 
data will be summarized by treatment group using descriptive statistics (number, mean, standard 
deviation [SD], minimum, median, and maximum).  Categorical data will be summarized by 
treatment group using frequency tables (number and percentage). 
9.1 
Sample Size 
Sample size in the Phase 1b study is based on operational consideration. 
A summary of the power in the trial for the chosen sample size is provided in Table 5, with 
N = 132 randomized 89:43 to the chosen dose for the POC study and placebo, respectively; this 
includes 12 patients from the MAD study who were in the cohort of the mid or high dose if 
chosen for the POC study. 
Table 5. 
Sample Size 
Type 1 Error 
(1-Sided) 
TRUE Underlying 
Response Rate (%) 
Overall Power 
Minimum OBSERVED Response 
Rates Yielding Statistical 
Significance 
Placebo 
Treatment 
Placebo 
Treatment 
0.025 
40 
60 
0.54 
40 
60 
40 
65 
0.75 
40 
70 
0.9 
0.05 
40 
60 
0.63 
40 
58 
40 
65 
0.81 
40 
70 
0.93 
Total sample size of 156 patients is planned for analysis, but may be adjusted upward according 
to the dropout (noncompliance) rate, which will be monitored in a blinded fashion in an ongoing 
basis.  Note that approximately 36 dropouts are assumed. 
9.2 
Statistical Methods 
9.2.1 
Analysis Populations 
The primary efficacy analysis will be based on the full analysis set (FAS), defined to be all 
patients with at least 1 baseline and post-baseline efficacy evaluation.  A per protocol (PP) 
analysis set may be defined to exclude major protocol violations from the efficacy analysis.  The 
PP Population will include all patients from the FAS except those with major violations to the 
protocol deemed to impact the analysis of the primary endpoint.  These violations will be 


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identified based on blinded data prior to unblinding the final analysis dataset.  Safety analyses 
will be based on all patients who receive test treatment.  Pharmacokinetic analysis will be 
conducted on the PK analysis set (PK), defined as the FAS with sufficient concentration data for 
the calculation of PK parameters.  All analyses will combine data from the MAD and POC 
studies and focus on the active treatment dose chosen for the POC study versus placebo.  The 
0.05 1-sided type 1 error level is included for POC, and the 0.025 1-sided type 1 error level for 
potential use of this trial to support regulatory filing. 
9.2.2 
Demographics and Baseline Characteristics 
Baseline and patient characteristics will be summarized via appropriate summary statistics by 
treatment group and overall, for each phase of the trial.   
9.2.3 
Primary Endpoint(s) 
The proportion of patients who achieve treatment response (measured by SRI-4 at Week 28 
along with a sustained reduction of oral CS) will be analyzed via Cochran-Mantel-Haenszel 
(CMH) analysis.  The primary endpoint will be analyzed on the FAS and if needed the PP 
analysis set.  In addition, missing values will be addressed by employing a last observation 
carried forward (LOCF) analysis and/or other appropriate analytic approaches as a sensitivity 
analysis.  Details will be available in the SAP. 
9.2.4 
Secondary Endpoint(s) 
Binary efficacy endpoints will be assessed via CMH analysis.  Continuous efficacy endpoints 
will be assessed via analysis of covariance (ANCOVA) repeated measures mixed model analysis 
with factors including treatment, time, treatment-by-time interaction, baseline covariate, and 
covariate-by-time interaction.  The secondary efficacy endpoint will be analyzed on the FAS and 
if needed the PP analysis set.  Details will be available in the SAP. 
9.2.5 
Analysis of Safety 
9.2.5.1 
Safety Analysis 
Safety analyses will be performed on the Safety Analysis Set.  AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  Incidences (number and 
percent) of AEs will be presented by treatment group.  Incidences of AEs will also be presented 
by maximum severity and relationship to study medication.  For the MAD study, the placebo 
patients from each cohort will be combined for the summaries.  If there is a clear increase in AE 
rates for placebo patients across the cohorts, the AEs will also be summarized by cohort. 
AEs will be summarized by counts and percentages of patients by treatment group.  Laboratory 
data and vital signs will be summarized by treatment group as summary statistics for value and 
change from baseline at each individual time point.  Summary statistics will include n, arithmetic 
mean, median, arithmetic SD, minimum, and maximum. 
Additional safety parameters will be analyzed descriptively by treatment group.  Descriptive 
statistics (n, mean, standard deviation (SD), median, minimum, maximum) will be calculated by 


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treatment group and time point for continuous variables.  Frequencies and percentages will be 
presented by treatment group for categorical and ordinal variables. 
9.2.5.2 
Data Monitoring Committee 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for anti-IL-21 mAb.  The recommendations made by the DMC 
(ie, dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The DMC will have access to unblinded treatment information during the clinical trial.  To 
prevent inadvertent unblinding of sponsor staff, reports to the DMC will describe each treatment 
group by a coded identifier rather than actual treatment group assignment.  Details regarding 
management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of an anti-IL-21 mAb treatment arm or the entire 
BOS161721 MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  
The recommendation must be supported by the sponsor as indicated in the DMC Charter. 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data 
9.2.6.1 
Analysis of Pharmacokinetic Data 
The PK parameter data will be listed and summarized descriptively in tabular format. 
If data permit, the following analyses will be performed for plasma BOS161721 concentration 
data: 
• A listing of all plasma BOS161721 concentrations by patient at actual times post dose; 
• A descriptive summary of plasma BOS161721 concentrations.  Summary statistics of 
geometric mean, % coefficient of variation, standard deviation, median, minimum, and 
maximum will be tabulated by study days with PK assessments. 
Details will be available in the SAP.   
9.2.6.2 
Analysis of Pharmacodynamic Data 
The PD parameter data will be listed and summarized descriptively in tabular format. 
Binary PD endpoints will be assessed for the FAS population.  Binary PD endpoints will be 
assessed via CMH analysis.  Continuous PD endpoints will be assessed via analysis of 
covariance (ANCOVA) repeated measures mixed model analysis with factors including 
treatment, time, treatment-by-time interaction, baseline covariate, and covariate-by-time 


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interaction.  Normality will be assessed via diagnostic residual plots and Shapiro-Wilk statistic, 
but not as a formal statistical test of normality.  If substantial departures from normality are 
observed, transformation will be used (eg, log and/or rank). 
Details will be available in the SAP. 
9.2.6.3 
Population Pharmacokinetic Analysis or PK/PD Modeling 
Plots of individual patient values for each relevant PD parameter on Y-axis and each relevant PK 
parameter on X-axis will be examined for relationship.  If relationships are revealed by these 
diagnostic plots, PK and PD data from this study may be analyzed using modeling approaches to 
describe the relationship and may also be pooled with data from other studies to investigate any 
association between BOS161721 exposure and biomarkers or significant safety endpoints. 
Details will be available in the SAP.     
9.3 
Interim Analysis and Power 
Two IAs are planned for this study.  The initial IA will be conducted at the time of the POC 
decision for dose selection.  The DMC will review safety and tolerability, and 
PK/PD/biomarkers for dose selection.  Efficacy data will not be reviewed for dose selection so 
there should be no impact on the type 1 error. 
The second IA will be performed for futility.  IA2 is planned to be conducted at Week 16 when 
SRI-4 response is determined for approximately 60 patients (including all patients at the same 
dose level/matching placebo from the MAD study) after completing 3 months of treatment.  The 
purpose of the IA2 is to assess if the trial could stop for an early futility conclusion, or continue.  
Since there is no plan to stop the trial for an early efficacy conclusion, there is no impact on the 
type 1 error.  If that intention changes, then p < 0.0001 is required for an early efficacy 
conclusion at the IA2 in order to not impact the planned type 1 error level. 
Nominal time profiles will be used for calculating PK parameters in the IA2. 
 


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10 ETHICS AND RESPONSIBILITIES 
10.1 Good Clinical Practice 
The procedures set out in this protocol are designed to ensure that the sponsor and the principal 
investigator abide by the principles of the International Council for Harmonisation (ICH) 
guidelines on GCP and the Declaration of Helsinki (Version 2013).  The clinical study also will 
be carried out in the keeping with national and local legal requirements (in accordance with US 
IND regulations [21 CFR 56]). 
10.2 DMC 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) make a dose recommendation for POC portion of the study. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
10.3 Institutional Review Board/Independent Ethics Committee 
Independent Ethics Committees (IEC)/Institutional Review Boards (IRB) must meet the 
guidelines set out by the U.S. Food and Drug Administration (FDA) and conform to local laws 
and customs where appropriate.  Written IRB/IEC approval for the protocol and the signed ICF 
must be obtained and transmitted to Boston Pharmaceuticals or representative before the study 
can be initiated.  The IRB/IEC must be informed of and approve all protocol amendments.  The 
investigator will ensure that this study is conducted in full conformance with all applicable local 
and regional laws and regulations.  The complete text of the World Medical Association 
Declaration of Helsinki is given in APPENDIX 2. 
10.4 Informed Consent 
Before each patient is enrolled in the clinical study, written informed consent will be obtained 
from the patient according to the regulatory and legal requirements of the participating country.  
As part of this procedure, the principal investigator must explain orally and in writing the nature, 
duration, and purpose of the study, and the action of the drug in such a manner that the study 
patient should be informed that he/she is free to withdraw from the study at any time.  He/she 
will receive all information that is required by federal regulations and ICH guidelines.  The 


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principal investigator or designee will provide the sponsor with a copy of the IRB-approved ICF 
prior to the start of the study.   
The informed consent document must be signed and dated; 1 copy will be handed to the patient 
and the principal investigator will retain a copy as part of the clinical study records.  The 
principal investigator will not undertake any investigation specifically required for the clinical 
study until written consent has been obtained.  The terms of the consent and when it was 
obtained must also be documented.   
If the informed consent document is revised, it must be reviewed and approved by the 
responsible IRB/IEC.  Patients currently enrolled may need to sign this revision (based on 
IRB/IEC requirements) and all future subjects enrolled in the clinical study will be required to 
sign this revised ICF. 
10.5 Records Management 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the sponsor.  Data collection processes and procedures will be reviewed and validated 
to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail will be 
maintained of all data changes.  The principal investigator or designee will cooperate with the 
sponsor’s representative(s) for the periodic review of study documents to ensure the accuracy 
and completeness of the data capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data.  This information will be provided to the respective study sites by 
means of electronic or manual queries. 
The principal investigator or designee will prepare and maintain adequate and accurate study 
documents (medical records, ECGs, AE and concomitant medication reporting, raw data 
collection forms, etc.) designed to record all observations and other pertinent data for each 
patient receiving BOS161721 or placebo. 
The principal investigator will allow sponsor representatives, contract designees, authorized 
regulatory authority inspectors, and the IRB to have direct access to all documents pertaining to 
the study. 
Electronic case report forms are required and should be completed for each randomized patient.  
It is the principal investigator’s responsibility to ensure the accuracy, completeness, legibility, 
and timeliness of the data reported on the patients’ eCRF.  Electronic case report forms should be 
completed in a timely fashion to support the study timelines.  Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should document the 
dates and details of study procedures, AEs, and patient status.  The principal investigator or 
designated representative should complete and the principal investigator should verify the source 
documents as the information is collected.  Any outstanding entries must be completed 
immediately after the final examination.  An explanation should be given for all missing data. 
The principal investigator will ensure the accuracy, completeness, and timeliness of the data 
reported to the Sponsor.  Data collection processes and procedures will be reviewed and 


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validated to ensure completeness, accuracy, reliability, and consistency.  A complete audit trail 
will be maintained of all data changes. 
10.6 Source Documentation 
The documents that will form the source data for the clinical study (eg, patient charts, laboratory 
reports) must be defined and documented in the in-house study master file prior to the start of the 
study.  Data on the eCRFs which will be checked against source data during monitoring visits 
must also be defined and documented in the in-house study master file including the percentage 
of each of the source data to be verified and the percentage of patients’ eCRFs to be monitored. 
10.7 Study Files and Record Retention 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of BOS161721.  However, these documents 
should be retained for a longer period if required by the applicable legal requirements. 
 
 


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11 AUDITING AND MONITORING 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and on-site visits.  The study will be routinely 
monitored to ensure compliance with the study protocol and the overall quality of data collected.  
During the on-site visits, the eCRFs will be reviewed for completeness and adherence to the 
protocol.  As part of the data audit, source documents will be made available for review by the 
study monitor.  The study monitor may periodically request review of the investigator study file 
to assure the completeness of documentation in all respects of clinical study conduct.  The study 
monitor will verify that each patient has proper consent documentation from the patient and/or 
patient’s authorized representative for study procedures and for the release of medical records to 
the sponsor, FDA, other regulatory authorities, and the IRB.  The study monitor will also verify 
that assent was obtained for patients not capable of providing informed consent or that 
documentation is provided by the investigator explaining why the patient was unable to provide 
assent.  The investigator or appointed delegate will receive the study monitor during these on-site 
visits and will cooperate in providing the documents for inspection and respond to inquiries.  In 
addition, the investigator will permit inspection of the study files by authorized representatives of 
the regulatory agencies.  On completion of the study, the study monitor will arrange for a final 
review of the study files after which the files should be secured for the appropriate time period. 
Throughout the course of the study, the medical monitor will determine eligibility of all screened 
patients, will address any medical issues that might arise, clarify medical questions, review 
patient safety data (eg, AE/SAE, laboratory, and ECG), and partner with the study team in the 
overall study management.  The study medical monitoring plan will document additional details 
of the study medical oversight and monitoring. 
 


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12 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Boston Pharmaceuticals.  A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, provided the IRB/IEC is 
notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The written 
amendment must be submitted to the IRB/IEC and the investigator must await approval before 
implementing the changes.  Boston Pharmaceuticals will submit protocol amendments to the 
appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the investigator, and/or Boston Pharmaceuticals, the 
amendment to the protocol substantially changes the study design and/or increases the potential 
risk to the patient and/or has an impact on the patient's involvement as a study participant, the 
currently approved written ICF will require similar modification.  In such cases, informed 
consent will be renewed for patients enrolled in the study before continued participation. 
 
 


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13 STUDY REPORT AND PUBLICATIONS 
Boston Pharmaceuticals is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
By signing the protocol, the principal investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  If necessary, the competent authorities will be 
notified of the principal investigator’s name, address, qualifications, and extent of involvement. 
The principal investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted and obtained approval from the sponsor in advance. 
 
 


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14 STUDY DISCONTINUATION  
Both Boston Pharmaceuticals and the principal investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, Boston Pharmaceuticals or 
a specified designee will inform the appropriate regulatory authorities of the termination of the 
study and the reasons for its termination, and the principal investigator will inform the IRB/IEC 
of the same.  In terminating the study Boston Pharmaceuticals and the principal investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. 
 
 


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15 CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Boston Pharmaceuticals, except to the extent necessary to obtain informed 
consent from patients who wish to participate in the trial or to comply with regulatory 
requirements.  However, authorized regulatory officials, IRB/IEC personnel, Boston 
Pharmaceuticals, and its authorized representatives are allowed full access to the records. 
Identification of patients and eCRFs shall be by initials, birthdate, or patient number.  
Documents that identify the patient (eg, the signed informed consent document) must be 
maintained in confidence by the principal investigator.  If required, the patient's full name may 
be made known to an authorized regulatory agency or other authorized official. 
 
 


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7 Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, et al.  Cutting edge:  the 
common gamma-chain is an indispensable subunit of the IL-21 receptor complex.  
J Immunol. 2001;167:1-5. 
8 Habib T, Senadheera S, Weinberg K, Kaushansky K.  The common gamma chain (gamma c) is 
a required signaling component of the IL-21 receptor and supports IL-21-induced cell 
proliferation via JAK3.  Biochemistry. 2002;41:8725-31. 
9 Spolski R, Leonard WJ.  Interleukin-21:  basic biology and implications for cancer and 
autoimmunity.  Annu Rev Immunol. 2008b;26:57-79. 
10 Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, et al.  B-cell-helper neutrophils 
stimulate the diversification and production of immunoglobulin in the marginal zone of 
the spleen.  Nat Immunol. 2011;13(2):170-80. 
11 Costanzo A, Chimenti MS, Botti E, Caruso R, Sarra M, Monteleone G.  IL-21 in the 
pathogenesis and treatment of skin diseases.  J Dermatol Sci.  2010;60(2):61-6. 
12 Avery DT, Bryant VL, Ma CS, de Waal Malefy R, Tangye SG.  IL-21-induced isotype 
switching to IgG and IgA by human naive B cells is differentially regulated by IL-4.  
J Immunol.  2008;181:1767-79. 
13 Rasmussen TK, Andersen T, Bak, RO, Yiu G, Sorensen CM, Stengaard-Pedersen K, et al.  
Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 
production in systemic lupus erythematosus.  Arthritis Research & Therapy 2015;17(154) 
14 Ettinger R, Kuchen S, Lipsky PE.  The role of IL-21 in regulating B-cell function in health 
and disease.  Immunol Rev. 2008;223:60-86. 


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15 Caprioli F, Sarra M, Caruso R, Stolfi C, Fina D, Sica G, et al.  Autocrine regulation of IL-21 
production in human T lymphocytes.  J Immunol.  2008;180(3):1800-7. 
16 Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al.  IL-21 and 
TGF-beta are required for differentiation of human T(H)17 cells.  Nature.  
2008;454(7202):350-2. 
17 Tangye SG, Ma CS, Brink R, Deenick EK.  The good, the bad and the ugly - TFH cells in 
human health and disease.  Nat Rev Immunol. 2013;13(6):412-26. 
18 Fantini MC, Rizzo A, Fina D, Caruso R, Becker C, Neurath MF, et al.  IL-21 regulates 
experimental colitis by modulating the balance between Treg and Th17 cells.  Eur J 
Immunol.  2007;37(11):3155-63. 
19 Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al.  IL-21 
counteracts the regulatory T-cell-mediated suppression of human CD4+ T lymphocytes.  J 
Immunol. 2007;178(2):732-9. 
20 Hippen KL, Bucher C, Schirm DK, Bearl AM, Brender T, Mink KA, et al.  Blocking IL-21 
signaling ameliorates xenogeneic GVHD induced by human lymphocytes.  Blood. 
2012;119(2):619-28. 
21 Davis ID, Skrumsager BK, Cebon J, Nicholaou T, Barlow JW, Moller NP, et al.  An open- 
label, two-arm, phase I trial of recombinant human interleukin-21 in patients with 
metastatic melanoma.  Clin Cancer Res. 2007;13:3630-6. 
22 Frederiksen KS, Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, et al.  
IL-21 induces in vivo immune activation of NK cells and CD8(+) T-cells in patients with 
metastatic melanoma and renal cell carcinoma.  Cancer Immunol Immunother. 
2008;57(10):1439-49. 
23 Karrich JJ, Jachimowski LC, Nagasawa M, Kamp A, Balzarolo M, Wolkers MC, et al.  
IL-21- stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs 
their capacity to induce T-cell proliferation.  Blood. 2013;121(16):3103-11. 
24 Lindner S, Dahlke K, Sontheimer K, Hagn M, Kaltenmeier C, Barth TF, et al.  
Interleukin-21-induced granzyme B-expressing B-cells infiltrate tumors and regulate 
T-cells.  Cancer Res.  2013;73(8):2468-79. 
25 Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al.  Control of matrix 
metalloproteinase production in human intestinal fibroblasts by interleukin 21.  
Gut. 2006;55(12):1774-80. 
26 Nakou M, Papadimitraki ED, Fanouriakis A, Bertsias GK, Choulaki C, Goulidaki N, et al.  
Interleukin-21 is increased in active systemic lupus erythematosus patients and 
contributes to the generation of plasma B-cells.  Clin Exp Rheumatol.  2013;31(2):172-9. 
27 Li Q, Liu Z, Dang E, Jin L, He Z, Yang L, et al.  Follicular helper T-cells (Tfh) and IL-21 
involvement in the pathogenesis of bullous pemphigoid.  PLoS One. 2013;8(7):e68145. 


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28 Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al.  A regulatory effect of IL-21 on 
T follicular helper-like cell and B-cell in rheumatoid arthritis.  Arthritis Res Ther. 
2012;14(6):R255. 
29 Kang KY, Kim HO, Kwok SK, Ju JH, Park KS, Sun DI, et al.  Impact of interleukin-21 in the 
pathogenesis of primary Sjögren’s syndrome:  increased serum levels of interleukin-21 
and its expression in the labial salivary glands.  Arthritis Res Ther. 2011;13(5):R179. 
30 Terrier B, Geri G, Chaara W, Allenbach Y, Rosenzwajg M, Costedoat-Chalumeau N, et al.  
Interleukin-21 modulates Th1 and Th17 responses in gianT-cell arteritis.  Arthritis 
Rheum. 2012a;64(6):2001-11. 
31 Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, et al.  
Interleukin 21 correlates with T-cell and B-cell subset alterations in systemic lupus 
erythematosus.  J Rheumatol. 2012b;39(9):1819-28. 
32 International Conference on Harmonisation.  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals S6 (R1).  2011. 
33 Wang W, Wang EQ, Balthasar JP.  Monoclonal Antibody Pharmacokinetics and 
Pharmacodynamics.  Clin Pharm & Ther 2008; 84(5):548-58. 
34 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
35 Elsaesser H, Sauer K, Brooks DG.  IL-21 is required to control chronic viral infection.  
Science.  2009;324(5934):1569-72 
36 Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, et al.  Loss-of-function 
mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome.  
J Exp Med. 2013;210(3):433-43. 
37 Hunter PR, Nichols G.  Epidemiology and clinical features of Cryptosporidium infection in 
immunocompromised patients.  Clinical microbiology reviews.  2002;15(1):145-54. 
38 Desjardins M, Mazer BD.  B-cell memory and primary immune deficiencies:  interleukin-21 
related defects.  Curr Opin Allergy Clin Immunol. 2013;13(6):639-45. 
39 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31-41. 
40 Guidelines for Using the QuantiFERON®-TB Gold Test for Detecting Mycobacterium 
tuberculosis Infection, US:  
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41 NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, available at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
42 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al.  
Second symposium on the definition and management of anaphylaxis:  summary report – 


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Second National Institute of Allergy and Infectious Diseases/Food Allergy and 
Anaphylaxis Network symposium.  Journal of Allergy and Clinical Immunology 
2006;117:391–7. 
43 Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
44 Castrejon I, Tani C, Jolly M, Huang A, Mosca M.  Indices to assess patients with systemic 
lupus erythematosus in clinical trials, long-term observational studies, and clinical care.  
Clin Exp Rheumatol 2014; 32(85):S85-95. 
45 Furie R, Wang L, Drappa J, Illei G.  Systemic Lupus Erythematosus (SLE) Responder Index 
[SRI(4)] Response Is Associated with Global Benefit in Patients with Moderate to Severe 
SLE [abstract].  Arthritis Rheumatol. 2016; 68 (suppl 10). 
46 Thanou A, Chakravarty E, James JA, Merrill JT. Which outcome measures in SLE clinical 
trials best reflect medical judgment?  Lupus Science & Medicine 2014;1:e000005. 
doi:10.1136/lupus-2013-000005. 
47 Wallace DJ, Kalunian K, Petri MA, Strand V, Houssiau FA, Pike M,et al.  Efficacy and safety 
of epratuzumab in patients with moderate/severe active systemic lupus erythematosus:  
results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, 
multicentre study.  Ann Rheum Dis 2014;73:183-90. 
48 Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S.  The CLASI  (Cutaneous 
Lupus Erythematosus Disease Area and Severity Index):  An Outcome Instrument for 
Cutaneous Lupus Erythematosus.  J Invest Derm. 2005;125(5):889-94. 
49 Stoll T, Seifert B, Isenberg DA.  SLICC/ACR Damage Index is Valid, and Renal and 
Pulmonary Organ Scores are Predictors of Sever Outcome in Patients with Systemic 
Lupus Erythematosus.  Br J Rheumatol.  1996;35:248-54. 
50 
 
. 
CCI


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17 APPENDICES 
APPENDIX 1 
NAMES OF STUDY PERSONNEL 
Sponsor: 
Boston Pharmaceuticals 
55 Cambridge Parkway Suite 401 
Cambridge, MA 02142, USA 
Medical Monitor: 
 
 
 
 
Clinical Research 
Organizations: 
 
 
 
 
 
 
 
Bioanalytical Laboratory: 
 
Central Laboratory: 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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APPENDIX 2 
DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles 
For 
Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The physician’s 
knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my subject will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act only in the subject's interest when providing 
medical care which might have the effect of weakening the physical and mental condition of the 
subject." 
Medical progress is based on research, which ultimately must rest in part on experimentation 
involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic, and therapeutic procedures and the understanding of the etiology and pathogenesis of 
disease.  Even the best-proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility, and 
quality. 


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In current medical practice and in medical research, most prophylactic, diagnostic, and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to reduce 
or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity 
of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any SAEs.  The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration.  
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person.  The responsibility 
for the human subject must always rest with a subject of the research, even though the subject 
has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 


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subject or to others.  This does not preclude the participation of healthy volunteers in medical 
research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed.  Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
subject’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail.  The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal.  After ensuring that the subject has 
understood the information, the physician should then obtain the subject's freely-given informed 
consent, preferably in writing.  If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician who 
is not engaged in the investigation and who is completely independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should not 
be included in research unless the research is necessary to promote the health of the population 
represented and this research cannot instead be performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 


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informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as positive 
results should be published or otherwise publicly available.  Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication.  Reports 
of experimentation not in accordance with the principles laid down in this Declaration should not 
be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic, or therapeutic value.  When medical 
research is combined with medical care, additional standards apply to protect the subjects who 
are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods.  This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic 
method exists. 
At the conclusion of the study, every subject entered into the study should be assured of access to 
the best-proven prophylactic, diagnostic, and therapeutic methods identified by the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the subject-
physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the subject, must be 
free to use unproven or new prophylactic, diagnostic, and therapeutic measures, if in the 
physician’s judgment it offers hope of saving life, re-establishing health, or alleviating suffering.  
Where possible, these measures should be made the object of research, designed to evaluate their 
safety and efficacy.  In all cases, new information should be recorded and, where appropriate, 
published.  The other relevant guidelines of this Declaration should be followed. 
 
 


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APPENDIX 3 
COMMONLY USED CORTICOSTEROID 
EQUIVALENTS 
Medication  
Dose Equivalence 
Prednisone 
20 mg 
Cortisone 
100 mg 
Hydrocortisone 
80 mg 
Prednisolone 
20 mg 
Methylprednisolone 
16 mg 
Triamcinolone 
16 mg 
Budesonide 
4 mg 
Dexamethasone 
3 mg 
Bethamethasone 
2.4 mg 
 
 
 


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APPENDIX 4 
MEDICATION WASHOUT PERIODS  
WASHOUT TIMES OF MEDICATIONS BASED ON 5 HALF-LIVES 
 
Medication 
Discontinuing Prior to Signing Consent 
Abatacept (CTLA4Ig) 
24 weeks 
Alefacept 
12 weeks 
AMG 623 (blisibimod) 
24 weeks 
Anifrolumab 
12 weeks 
Atacicept (TACI-Ig) 
12 weeks 
Belimumab 
48 weeks 
Cyclophosphamide 
24 weeks 
Cyclosporine (except for CSA eye drops) 
4 weeks 
Danazol 
4 weeks 
Dapsone 
4 weeks 
Eculizumab 
12 weeks 
Efalizumab 
12 weeks 
Epratuzumab 
24 weeks 
Intravenous globulin 
4 weeks 
Leflunomide  
8 weeks (4 weeks for washout with cholestyramine) 
Lenalidomide with cholestiramine 
8 weeks 
Lupuzor 
12 weeks 
Memantine 
4 weeks 
Natalizumab 
24 weeks 
Ocrelizumab 
48 weeks (or 24 weeks with recovery of B cell) 
Pimecrolimus 
4 weeks 
Plasmapheresis 
24 weeks 
Retinoids (oral or topical) 
4 weeks 
Rituximab 
48 weeks (or 24 weeks with recovery of B cell) 
Sirolimus 
4 weeks 
Tacrolimus 
4 weeks 
Thalidomide 
8 weeks 
Tocilizumab 
12 weeks 


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APPENDIX 5 
BILAG-2004 (STUDY-SPECIFIC MODIFIED CRITERIA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

SAP_001.pdf: 
 
 
 
 
 
 
 
 
BOS161721-02: A Randomized Double-Blind Phase 1b/2 Combined Staggered 
Multiple Dose Escalation Study of BOS161721 In Systemic Lupus 
Erythematosus (SLE) Patients on a Background of Limited Standard of Care 
 
ClinicalTrials.gov Identifier: NCT03371251  
 
Statistical Analysis Plan, Version 4.0, dated 23-April-2021 
Statistical Analysis Plan, Version 3.0, dated 13-November-2020 
Statistical Analysis Plan, Version 2.0, dated 29-November-2018 
Statistical Analysis Plan, Version 1.0, dated 05-September-2018 
 
 


 
 
Page 1 of 104 
 
 BOS161721-02: A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 
COMBINED STAGGERED MULTIPLE DOSE ESCALATION STUDY OF 
BOS161721 IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS 
ON A BACKGROUND OF LIMITED STANDARD OF CARE 
 
 
Statistical Analysis Plan 
 
 
 
VERSION 4.0 
DATE OF PLAN: 
23Apr2021 
 
 
STUDY DRUG:  
BOS161721 
 
 
PREPARED FOR: 
Boston Pharmaceuticals, Inc. 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 2 of 104 
 
Approval Signature Page: CATO SMS 
 
 
 
 
 
 
Document Author:   
, MS 
Director of Biostatistics 
Date 
 
 
 
 
 
 
Document Reviewer:  
, MS 
Vice President, Biostatistics & 
Note: Reviewed changes from V3.0
 
Date 
 
 
 
 
 
 
 
4/23/2021
4/23/2021
PPD
PPD
PPD
PPD


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 3 of 104 
 
Approval Signature Page: Boston Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
, MD 
Vice President, Clinical Dev
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vice President, Biometrics 
 
Date 
 
 
 
 
4/23/2021
4/23/2021
PPD
PPD
PPD
PPD


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 4 of 104 
 
Contents 
1. 
Introduction ........................................................................................................................... 10 
2. 
Study Objectives and Endpoints ........................................................................................... 11 
2.1. 
Multiple Ascending Dose (MAD) Phase 1b Study ........................................................ 11 
2.2. 
Proof of Concept (POC) Phase 2 Study ......................................................................... 14 
3. 
Study Design ......................................................................................................................... 16 
3.1. 
Study Design and Population ......................................................................................... 16 
3.1.1. 
Multiple Ascending Dose Phase 1b ........................................................................ 17 
3.1.2. 
Proof of Concept Phase 2 ........................................................................................ 18 
3.2. 
Randomization and Blinding .......................................................................................... 19 
3.3. 
Sample Size Considerations ........................................................................................... 19 
3.4. 
Data Monitoring Committee (DMC) .............................................................................. 20 
3.5. 
Interim Analysis (IA) ..................................................................................................... 21 
3.6. 
Timing of Analyses ........................................................................................................ 21 
4. 
Data Analysis Considerations ............................................................................................... 21 
4.1. 
Stratification and Covariates .......................................................................................... 22 
4.2. 
Evaluation of Subgroups ................................................................................................ 22 
4.3. 
Multiple Comparisons and Multiplicity ......................................................................... 23 
5. 
General Data Handling Conventions .................................................................................... 23 
5.1. 
Reference Dates .............................................................................................................. 23 
5.2. 
Study Day and Duration Variables ................................................................................. 24 
5.3. 
Study Time Periods ........................................................................................................ 24 
5.4. 
Baseline, Post-Baseline Changes, and LOCF ................................................................ 25 
5.5. 
Imputation of Partial Dates ............................................................................................ 25 
5.6. 
Multiple Assessments and Visit Windows ..................................................................... 27 
5.7. 
Treatment Group Display ............................................................................................... 27 
5.8. 
Missing Data .................................................................................................................. 27 
6. 
Study Patient Data................................................................................................................. 27 
6.1. 
Analysis Populations/Sets .............................................................................................. 27 
6.2. 
Patient Disposition ......................................................................................................... 28 
6.3. 
Protocol Deviations ........................................................................................................ 28 
6.4. 
Demographic and Baseline Characteristics .................................................................... 29 
6.5. 
Medical History .............................................................................................................. 30 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 5 of 104 
 
6.6. 
Prior and Concomitant Medication and Procedures ....................................................... 31 
6.7. 
Study Drug Exposure and Compliance .......................................................................... 32 
7. 
Efficacy ................................................................................................................................. 33 
7.1. 
Primary Efficacy Endpoint and Analyses ...................................................................... 33 
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 .................................. 33 
7.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 41 
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit ..................................... 41 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit ..................................... 42 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit ..................................... 43 
7.2.4. 
Oral Corticosteroid (CS) Reduction ........................................................................ 43 
7.2.4.1. 
Proportion of Patients with a sustained reduction of oral CS between Day 120 
and Day 210 (MAD) ............................................................................................................. 44 
7.2.4.2. 
Proportion of Patients with a sustained reduction of CS between Day 150 and 
Day 210 (POC) ..................................................................................................................... 45 
7.2.4.3. 
Percent Reduction in CS Administration from Day 0 through Day 210 (POC) . 45 
7.2.5. 
Proportion of new or recurrent BILAG A flare or >1 BILAG B flare through Day 
210 
45 
7.2.6. 
Physician’s Global Assessment (PGA) ................................................................... 46 
7.2.6.1. 
Proportion of Patients with PGA Worsening at Each Visit ................................ 46 
7.2.6.2. 
Results, Changes, and Percentage Change from Baseline in PGA ..................... 46 
7.2.7. 
Proportion of Patients with BICLA Response ........................................................ 47 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) ..................... 48 
7.2.8.1. 
Proportion of Patients with CLASI Response ..................................................... 49 
7.2.8.2. 
Results, Changes, and Percentage Change from Baseline in CLASI .................. 49 
7.2.9. 
Results, Changes, and Percentage Changes from Baseline in Swollen, Tender, and 
Active Joints ACR-28 ........................................................................................................... 50 
7.2.10. 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) .... 51 
7.2.10.1. 
Proportion of Patients with a SLEDAI-2K Response ..................................... 51 
7.2.10.2. 
Results, Changes, and Percentage Change from Baseline in SLEDAI-2K ..... 51 
7.2.11. 
Results, Changes, and Percentage Change from Baseline in SLICC/ACR 
Damage Index ....................................................................................................................... 53 
7.2.12. 
Medication Failure .............................................................................................. 53 
7.2.12.1. 
Proportion of Patients with Medication Failures ............................................. 53 
7.2.12.2. 
Time to Medication Failure (TTMF) ............................................................... 54 
7.2.13. 
Duration of Longest SRI-4 Response.................................................................. 55 


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7.2.14. 
Time to First BILAG A Flare or >1 BILAG B Flare through Day 210 .............. 55 
7.3. 
Exploratory Endpoints and Analyses ............................................................................. 56 
7.3.1. 
 ........................................................................ 57 
8. 
Pharmacokinetics/Pharmacodynamics/ Immunogenicity ..................................................... 57 
8.1. 
Pharmacokinetics ........................................................................................................... 58 
8.2. 
Pharmacodynamics ......................................................................................................... 58 
8.3. 
Immunogenicity ............................................................................................................. 60 
9. 
Quality of Life....................................................................................................................... 66 
9.1. 
.............................................................................................................................. 66 
9.2. 
 ......................................................................................................................... 67 
10. 
Safety ................................................................................................................................. 69 
10.1. 
Adverse Events ......................................................................................................... 69 
10.2. 
Clinical Laboratory Evaluations ............................................................................... 70 
10.3. 
Other Safety Evaluations .......................................................................................... 72 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 72 
10.3.2. 
Vital Signs ................................................................................................................. 73 
10.3.3. 
12-Lead Electrocardiogram (ECG) ........................................................................... 73 
10.3.4. 
Physical Examinations .............................................................................................. 74 
11. 
Changes to the planned analysis ........................................................................................ 74 
12. 
References .......................................................................................................................... 75 
13. 
APPENDICES ................................................................................................................... 77 
13.1. 
COVID-19 Impact and Data Handling ..................................................................... 77 
13.2. 
Physician’s Global Assessment ................................................................................ 78 
13.3. 
SLEDAI-2K Index .................................................................................................... 79 
13.4. 
BILAG 2004 Index ................................................................................................... 81 
13.5. 
ACR-28 Joint Count Assessment.............................................................................. 83 
13.6. 
SLICC/ACR Damage Index ..................................................................................... 84 
13.7. 
CLASI ....................................................................................................................... 85 
13.8. 
................................................................................................................... 86 
13.8.1. 
 ................................................................................................ 86 
13.8.2. 
 ................................................................ 89 
13.9. 
C-SSRS ..................................................................................................................... 91 
13.9.1. 
C-SSRS (Baseline/Screening) ................................................................................... 91 
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13.9.2. 
C-SSRS (Since Last Visit) ........................................................................................ 93 
13.10. 
......................................................................................................................... 95 
13.11. 
CTCAE Grading Details from the Central Laboratory ........................................... 101 
13.12. 
Tables, Listings, and Figures .................................................................................. 103 
13.13. 
Other SAP(s) Describing Analyses not Covered in the SAP .................................. 104 
 
 
 
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ABBREVIATIONS 
ACR 
American College of Rheumatology
ADA 
Anti-drug antibody
AE 
Adverse event
AESI 
Adverse event of special interest
ANA 
Antinuclear antibody
ANCOVA 
Analysis of covariance
ANOVA 
Analysis of variance
APL 
Antiphospholipid
ATC 
Anatomic therapeutic class
AUC 
Area under the curve
BICLA 
BILAG-based Composite Lupus Assessment
BILAG 
British Isles Lupus Assessment Group
BP 
Blood pressure
C3 
Complement C3
C4 
Complement C4
CL 
Systematic clearance
CLASI 
Cutaneous Lupus Area and Severity Index
Cmax 
Maximum plasma concentration
CS 
Corticosteroid
CSR 
Clinical Study Report
C-SSRS 
Columbia Suicide Severity Rating Scale
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation
DLT 
Dose-limiting toxicity
DMC 
Data Monitoring Committee
dsDNA 
Double-stranded deoxyribonucleic acid
ECG  
Electrocardiogram
eCRF 
Electronic case report form
EWB 
Emotional well being
 
FAS 
Full analysis set
FS 
Fatigue subscale
FWB 
Functional well being
HR 
Hazard ratio
IA 
Interim Analysis
IEC 
Independent Ethics Committee
IL-21 
interleukin 21
IM 
Intramuscular
IRB 
Institutional Review Board
ISR 
Injection site reaction
LLN 
Lower limit of normal
LLOQ 
Lower limit of quantification
LOCF 
Last observation carried forward
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LS 
Least squares
MAD 
Multiple Ascending Dose
MCS 
Mental component summary
MedDRA 
Medical Dictionary for Medical Affairs
NAb 
Neutralizing antibody
NCI 
National Cancer Institute
PCS 
Physical component summary
PD 
Pharmacodynamics
PGA 
Physician’s Global Assessment
PK 
Pharmacokinetics
POC 
Proof of concept
PP 
Per protocol set
pSTAT3 
Phosphorylated signal transducer and activator of transcription 3
PT 
Preferred Term
PWB 
Physical well being
Q1 
25th percentile/first quartile
Q3 
75th percentile/third quartile
SAD 
Single ascending dose
SAE 
Serious adverse event
SAP 
Statistical Analysis Plan
SAS 
Statistical analysis system
SC 
Subcutaneously
SD 
Standard deviation
 
SI 
International System of Units
SLE 
Systemic Lupus Erythematosus
SLEDAI-2K 
SLE Disease Activity Index 2000
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
System Organ Class
SRI-4 
SLE Responder Index 4
SRI-5 
SLE Responder Index 5
SRI-6 
SLE Responder Index 6
SS 
Safety analysis set
SSA 
Sjögren syndrome-A (Ro)
SSB 
Sjögren syndrome-B (La)
SWB 
Social/Family well being
t1/2 
Terminal elimination half-life
TEAE 
Treatment emergent adverse event
Tmax 
First time to maximum concentration
TTMF 
Time to medication failure
ULN 
Upper limit of normal
Vd 
Volume of distribution
WHO 
World Health Organization
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1. INTRODUCTION 
 
The Statistical Analysis Plan (SAP) details the planned analyses that will be included in the 
Clinical Study Report (CSR) of study number BOS161721-02: A Randomized Double-Blind 
Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic 
Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care.  
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within Appendix 13.13 of this document.  The author, 
finalization date, signatories, and page numbering of this SAP are independent of those SAPs 
and vice versa. Only the last final versions will be included in the appendix just prior to study 
conclusion. 
 The content of this SAP is based on the protocol Version 7.0 (Amendment 6) dated 
30April2020. 
SAP Revision 
Chronology: 
Date: 
Comments: 
V1.0 
05SEP2018 
Original
V2.0 
29NOV2018 
Modifications due to Protocol Version 4 (Amendment 3) 
 Modified evaluable window for efficacy assessments to be 
inclusive of 35 days since prior assessment. 
 Modified structure of table shells to combine analyses (i.e., 
CLASI total activity and total damage; ACR-28 sum of swelling 
and sum of tenderness; 
 
; biomarker and pharmacodynamic parameters) 
 Modified structure of listing shells 
 
 Clarified Last Observation Carried Forward (LOCF) versus 
observed analyses in the output titles within the shells
V3.0 
13NOV2020 
Modifications due to Protocol Version 7 (Amendment 6) including: 
 Sample size changed based on recent published literature 
 LOCF algorithm updated 
 Modified planned sensitivity analyses based on missing data 
 Added, amended, and removed secondary and exploratory 
endpoints per protocol amdement 6 
 Defined efficacy subgroups 
 Added COVID-19 related data handling details 
 Modified evaluable window for efficacy assessments 
 Modified table, listing, and figure shells in accordance with text 
changes
V4.0 
23APR2021 
Modifications due to pre-lock comments from blinded review of 
draft tables, listing, and figures include: 
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SAP Version and Date: Version 4.0, 23Apr2021 
 
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 Clarifications surrounding duration of longest SRI-4 response 
(LOCF methods and addition of 30 days in the case of missing 
dates) 
 Clarifications provided around LOCF methods for baseline 
disease characteristics used in both the disease characteristics 
summaries and subgroup analyses 
 Handling of biomarker/PD results <LLOQ modified to utilize 
0.5*LLOQ instead of 0 in the analysis 
 BICLA definition clarifications provided 
 Medication failure identification and date determination 
explained as being provided by the sponsor based on the blinded 
review of the prior and concomitant medication eCRF form as 
opposed to utilizing the protocol deviation form. 
 Refinement of the per protocol set  
 Additional corrections of minor typos and clarifications resulting 
from pre-lock review
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Multiple Ascending Dose (MAD) Phase 1b Study 
Objectives 
Endpoints
Primary 
 To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered subcutaneously (SC) in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment, in order to 
estimate the optimal dose. 
Safety Endpoints 
 Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
 Injection site reactions 
 Columbia Suicide Severity Rating Scale 
(C-SSRS) 
 12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
 Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
 Clinical laboratory results and change from 
baseline 
 Physical examinations changes from baseline 
 Anti-drug antibodies (ADAs) 
 Study drug exposure/compliance 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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Objectives 
Endpoints
Secondary 
 To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with moderate to 
severely active SLE. 
Pharmacokinetic (PK) Endpoints 
 BOS161721 concentration by visit and time 
point 
 Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), terminal half-life (t½), systematic 
clearance (CL), volume of distribution (Vd) 
Pharmacodynamic (PD) Endpoints 
 Results and changes (or shifts) from baseline 
to each visit in phosphorylated signal 
transducer and activator of transcription 3 
(pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
 Results and changes (or shifts) from baseline 
in anti-double-stranded DNA (dsDNA), 
antinuclear antibodies (ANA), anti-Sjögren 
syndrome A and B (SSA, SSB), Smith (Sm), 
and antiphospholipid (APL) autoantibodies 
at each visit 
 Results and changes (or shifts) from baseline 
in abrogation of IL-21 gene signature at each 
indicated visit 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints
- 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 See Section 11 
 
 
 
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2.2. Proof of Concept (POC) Phase 2 Study 
Objectives 
Endpoints
Primary 
 To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE SRI-4 
Primary Efficacy Endpoint 
 The proportion of patients with a SRI-4 
response at Day 210 
Secondary 
 To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on clinical indicators of SLE activity, 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care treatment 
Secondary Efficacy Endpoints 
 The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 7.5 mg/day and 
< Day 0 dose) between Day 150 and Day 
210 
- 
new or recurrent BILAG flares 
( ≥ 1 qualifying BILAG A 
or > 1 qualifying BILAG B) through 
Day 210 
- 
PGA worsening 
- 
a BICLA response  
- 
a CLASI response  
- 
medication failures 
 Change and percentage change from baseline 
at each visit in: 
- 
CLASI 
- 
PGA 
- 
Total number of swollen joints, tender 
joints, and active joints (swelling and 
tenderness in the same joint) in the ACR-
28 joint count 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index  
 TTMF 
 Group mean percent reduction in 
corticosteroid administration from baseline 
Day 0 dose through Day 210 in patients 
receiving ≥ 7.5 mg/day prednisone 
equivalent at Day 0


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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Objectives 
Endpoints
 Duration of longest SRI-4 response 
 Time to first BILAG flare (≥ 1 new or 
recurrent BILAG A or > 1 new or recurrent 
BILAG B) relative to baseline through 
Day 210 
Safety 
 To assess safety and tolerability of 
repeat doses of BOS161721 at the 
chosen dose administered SC in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Safety Endpoints 
 Incidence and severity of AEs and SAEs, 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
 Injection site reactions 
 C-SSRS 
 12-lead ECGs parameter results at each visit 
and change from baseline 
 Vital signs (BP, heart rate, and temperature) 
parameter results at each visit and change 
from baseline 
 Clinical laboratory results and change from 
baseline 
 Physical examinations changes from baseline 
 ADAs 
 Study drug exposure/compliance 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 16 of 104 
 
Objectives 
Endpoints
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints will be discussed in the SAP based on their order in  the phase 2 POC portion of the 
study.  The phase 1b MAD endpoints overlap with and will be discussed within the context of 
the phase 2 POC endpoints. 
3. STUDY DESIGN 
3.1. Study Design and Population 
 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of multiple subcutaneous doses of BOS161721 in adult 
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Page 17 of 104 
 
patients with moderately to severely active SLE.  After successfully completing a screening 
phase, eligible patients will be randomized to a specified dose of BOS161721 or placebo.  The 
dosing schedule will be monthly.   
The trial will consist of 2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visit at Days 210, 240, and 270.     
Investigators will assess SLE activity in accordance with accepted evaluation tools (further 
details provided in the SLE Assessment Reference Guide). 
SLE disease activity assessment data will be centrally reviewed by the CRO medical monitor(s), 
independent subject matter expert reviewers/adjudicators and the Sponsor to ensure the scores 
are clinically meaningful, compliant with specific definitions and compatible across various 
disease scoring tools.  The scope of responsibility includes, but is not limited to, review and 
confirmation of BILAG organ system disease grades, BILAG A and B flares,  and clinical 
components of SLEDAI-2Kscore at screening and during the study as well as cross-validation of 
the instruments used in this study to assess disease activity.  Further details on the content, 
processes, procedures and methods of disease activity data reports will be outlined in the 
Medical Data Review Plan and the BILAG-2004 Review Guidelines. 
3.1.1. 
Multiple Ascending Dose Phase 1b  
The MAD portion will consist of 3 cohorts:  
 Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
 Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 single ascending dose (SAD) study (BOS161721-01) in healthy 
patients.  All doses selected for the MAD part of the study are projected not to exceed the mean 
exposure of that achieved at the highest dose in the SAD study. 
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 2 
begins dosing after the Data Monitoring Committee (DMC) evaluation of the safety and 
tolerability data from Cohort 1.  Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 3 begins dosing 
after the DMC evaluation of the safety and tolerability data from Cohorts 1 and 2.  Each cohort 
will continue at their assigned dose level through their respective 6-month treatment periods (See 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
Page 18 of 104 
 
Study Schematic in the study protocol).  If patients discontinue the study in a cohort prior to 
adequate safety follow-up, he/she may be replaced. 
Criteria for dose escalation are further described in the DMC Charter. 
3.1.2. 
Proof of Concept Phase 2  
The dose for the POC portion of the study is 120 mg administered SC monthly (a total of 
7 doses). The rationale for the BOS161721-02 phase 2 POC dose selection was based on 
cumulative safety, tolerability, immunogenicity, PK, and PD data available from an interim 
analysis (IA) performed during the MAD phase 1b portion of the trial.  
The data cut-off for this IA occurred on 
 and included all 6 patients and 
7 doses from Cohort 1 (20 mg), 12 patients and 6 doses from Cohort 2 (60 mg), and 12 patients 
and 4 doses from Cohort 3 (120 mg).  
The safety analysis focused on incidence and severity of all AEs, SAEs, and pre-determined 
adverse events of special interest (AESI). The DMC and designated unblinded Boston 
Pharmaceuticals team met on 
 and did not identify any untoward safety 
signals at any BOS161721 dose levels.  
Because there were no safety, tolerability, or immunogenicity trends observed at the time of the 
IA, the phase 2 POC dose selection was made based on available PK and PD data. pSTAT3 
levels were assessed as the primary PD biomarker of IL-21R signaling levels. This is because IL-
21R signaling, upon IL-21 binding, initially involves phosphorylation of JAK1/JAK3 which 
dissociate from the receptor complex, and phosphorylate STAT3 which translocates to the 
nucleus and drives IL-21-regulated gene expression. 
 
 
The 120 mg dose was communicated to site Investigators participating in the POC phase 2 
portion, and to Institutional Review Boards (IRBs) and the Independent Ethics Committee (IEC).  
For the POC part of the study, approximately 110 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments detailed in the study protocol.   
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
 
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3.2. Randomization and Blinding 
 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an interactive web response system according to a randomization 
list generated by an independent, non-study statistician.  Randomization will be performed 
separately for each study portion and separately for each cohort in the Phase 1b and 2 portions as 
follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
*Approximately 110 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1b MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the IA, ad hoc analyses as needed, and the DMC safety reviews.  The DMC will 
review unblinded data during safety reviews and the IA.  A limited team at Boston 
Pharmaceuticals will review unblinded results from the Phase 1b MAD portion during the IA to 
determine the dose that will be used for the Phase 2 POC portion of the study.  Details regarding 
maintenance of the blinding and content of data reviews will be described in the DMC charter or 
related study documentation.   
3.3. Sample Size Considerations 
 
Sample size in the Phase 1b part of the study is based on operational consideration. 
The sample size in the Phase 2 POC study is based on the primary endpoint, SRI-4 Response at 
Day 210.  Based on efficacy data from a recently completed study with Ustekinumabiii, where 
the primary endpoint was also SRI-4, the sample size in the phase 2 part of the BOS161721-02 
study is set at 96 evaluable patients. In the Ustekinumab study of 102 patients, a statistically 
significant difference in SRI-4 response was shown in favor of Ustekinumab (62% of 
Ustekinumab treated patients achieved SRI-4 response vs. 33% in patients receiving placebo). 
The Ustekinumab phase 2 study is an appropriate comparator to BOS161721-02 because both 
studies share the same primary endpoint of SRI-4 response and BOS161721 and Ustekinumab 
have overlapping mechanisms of action (T follicular helper and Th17 cell biology).  


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Approximately 110 additional patients will be randomized in a 2:1 ratio to BOS161721 versus 
placebo to achieve approximately 96 evaluable patients in the FAS of the phase 2 portion.  This 
assumes 14 patients will discontinue prior to having received treatment or having completed a 
post-baseline efficacy measure.  Enrollment and randomization will be monitored in a blinded 
fashion and may be increased if needed to ensure at least 96 evaluable patients are randomized 
into the FAS (see Section 6.1).    
A total of 96 evaluable patients randomized provides 80% power to detect a treatment difference 
of 29% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance level of 10% 
and using a 2-sided Pearson’s chi-squared test.  This assumes a response rate of 62% for 
BOS161721 and 33% for placebo. 
3.4. Data Monitoring Committee (DMC) 
 
This study will use an external DMC.  The DMC is an independent committee established to 
provide safety oversight and to advise the sponsor regarding actions necessary to protect study 
participants and the scientific integrity of the study. The recommendations made by the DMC 
(i.e., dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in the study protocol. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
 


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3.5. Interim Analysis (IA) 
 
One IA is planned for this study and will be conducted at the time of dose selection for POC. The 
POC dose will be selected based on cumulative available safety, tolerability, PK and PD data 
based on the MAD data.  Since there is no IA during the POC part of the study, there is no 
impact on the type 1 error.   
3.6. Timing of Analyses 
 
The following analyses are planned: 
 An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC portion.   
 The final analysis will be performed when all patients have either completed the POC 
safety follow up or withdrawn from the study.   
 Safety analyses will be performed for DMC reviews throughout the study to evaluate 
accumulating safety data and make dose escalation decisions.  The frequency and details 
of the content and format of the safety review meetings are described in the DMC charter 
and SAP and applicable mock shells. 
4. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.3 or higher. 
All data in the database will be presented in by-patient data listings. 
Unless otherwise stated, all listings will be sorted by study phase, treatment group, patient 
number, and assessment date (and time, if available).  If assessment date is missing, 
chronological visit will be used for sorting. 
Unless stated otherwise, continuous data will be summarized by treatment group based on 
number of patients (n), mean, median, standard deviation (SD), 25th percentile/first quartile (Q1), 
75th percentile/third quartile (Q3), minimum value, and maximum value. 
The geometric % coefficient of variation (CV) is calculated as 100*sqrt(exp(SDlog^2)-1) where 
SDlog is the SD of log-transformed values. 
Unless stated otherwise, categorical data will be summarized by treatment group using n and 
percentage based on the number of non-missing values. 
 The number of missing values will be presented as a separate category with no 
percentage, but only if one or more patients are missing data. 
 Counts of zero will be presented without percentages. 


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 Statistics will be presented in the summary tables based on the following: 
 Minimum and maximum: same number of significant digits as the raw value 
 Mean, median, Q1, and Q3: one additional decimal place to that reported for 
minimum and maximum 
 SD: two additional decimal places than presented for the minimum and maximum  
 Percentages: reported to one decimal place with the exception of 100% which will 
be displayed without decimals. 
 P-values will be reported to four decimal places.  If the value is below 0.0001 it 
will be noted as < 0.0001; if the value above 0.9999 it will be noted as > 0.9999. 
Unless otherwise noted, statistical inference will be based on a 10% significance level (i.e. 90% 
confidence intervals will be produced). 
Statistical testing will be performed on data from the Phase 2 study. 
Numbering for data displays will be based on ICH E3. 
4.1. Stratification and Covariates 
 
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data may be conducted as 
deemed appropriate to evaluate factors for which analyses are not controlled. 
Continuous efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of 
covariance (ANCOVA) when applicable, adjusting for the baseline value. 
Sensitivity analyses of the primary efficacy endpoint may be performed with covariates defined 
based on the subgroups in section 4.2. 
4.2. Evaluation of Subgroups 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The patient will be excluded from subgroup analyses if they are missing the subgroup parameter 
at baseline.  In case of missing data, LOCF methods consistent with the primary efficacy analysis 
described in Section 7.1 will be used for determination of baseline CLASI and SLEDAI.   
4.3. Multiple Comparisons and Multiplicity 
 
The Type 1 error rate will not be adjusted for multiplicity.  
5. GENERAL DATA HANDLING CONVENTIONS 
5.1. Reference Dates 
 
 Screening date is defined as the electronic case report form (eCRF) provided date on 
which a patient was screened for trial entry. 
 Informed consent date is the date the patient signed the informed consent form. 
 Randomization date is defined as the date on which the patient is randomized to study 
treatment. 
 Treatment start date is defined as the date of first dose of study drug. 
 Treatment end date is defined as the date of last dose of study drug. 
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 Age will not be calculated and will come directly from the eCRF.  The eCRF uses the 
informed consent date as its reference date for age calculation. 
 Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date. 
 Efficacy data will use the randomization date as a reference date. 
 Study day will be based on treatment start date as a reference date. 
5.2. Study Day and Duration Variables 
 
Reference date calculations will be defined as follows, assuming non-missing dates:  
 date of interest – reference date + 1 when the date of interest is on or after the reference 
date; 
 otherwise, date of interest – reference date. 
 
If either date is missing or incomplete, reference date calculations will not be performed.  Date 
imputation will be performed as identified in Section 5.5. 
 
Study day will either have a negative value if collected before dosing or a positive value if 
collected on or after the day of drug dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation.  Duration on study is defined as the end of study date –
informed consent date + 1.  Duration of treatment is defined as treatment end date – treatment 
start date + 1, where treatment end date is the date of last dose of study drug. 
Time-to-event endpoints are followed until first event or censoring.  As a result, event time will 
be calculated as: event or censoring date – reference date + 1.  These are further described in 
Section 7. 
When reporting time-to-event data (TTMF and time to BILAG A flare or >1 BILAG B flare) or 
duration outcomes, the results (in days) above will be converted to an appropriate unit.  When 
reporting in months it will be divided by 30.4375; for reporting in weeks it will be divided by 7; 
and for reporting in years it will be divided by 365.25. 
5.3. Study Time Periods 
 
Where applicable, data reporting will be classified by the following study periods for analysis: 
 Pre-treatment is defined as the period prior to a patient’s treatment start date. 
 On-treatment is defined as the period between a patient’s treatment start date and 
treatment end date, inclusive. 
 Post-treatment is defined as the period of time following the on-treatment period. 


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5.4. Baseline, Post-Baseline Changes, and LOCF 
 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
 Baseline will be based on the last non-missing value collected prior to or on the date/time 
of first dose of study drug. 
 Post-baseline values will be those collected after the date/time of first dose of study drug. 
 Change from baseline is defined as: value – baseline value.  
 Percentage change from baseline is defined as: [(value – baseline value) / baseline 
value]*100.  Patients with baseline values of zero are excluded due to division by zero. 
 Most extreme change:  The maximum most extreme change will be the maximum post-
baseline change value; the minimum most extreme change will be the smallest post-
baseline change value. This calculation will consider all assessments collected after the 
first dose of study drug, scheduled or unscheduled. 
 LOCF: 
o Imputation rules for assessments that include multiple components: 
 In case of missing laboratory components, lab values from the most recent 
unscheduled visit <=14 days after the nominal visit will be utilized.  If lab 
values are not available from an unscheduled visit <=14 days after the 
visit, laboratory data will be carried forward from the most recent 
laboratory assessment <=30 (scheduled or unscheduled) days prior to the 
nominal visit. 
 In case of missing non-laboratory components, no imputation will be 
performed.   
o In case of missing the entire score for an assessment, imputation will be based on 
LOCF.  LOCF will only be implemented with the most recent prior visit 
(including unscheduled assessments).  If the most recent prior visit is missing, 
occurred more than 30 days before (current visit date – most recent prior visit date 
> 30), or is not evaluable, LOCF is not implemented.  See Section 7 for further 
details.  Additional details regarding LOCF for components for specific 
assessments are described in Section 7. 
o Observed values do not incorporate any imputations and are presented as 
collected. 
5.5. Imputation of Partial Dates 
 
Adverse Events  
 If the AE start date is completely missing, or if the patient was not treated, no imputation 
will be conducted. 
 If the AE start date is missing day and month, do the following: 
o If the treatment start date is missing or the AE start year does not fall in the same 
year as that of the treatment start date or if the AE record contains information to 


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indicate that the event ended before the treatment start date (e.g. the AE end date 
month and year are earlier than the treatment start date or the full AE end date is 
known and occurs earlier than the treatment start date), then set the AE start 
month and day to January 1st. 
o Otherwise, set the AE start date to the treatment start date.  
 If only the AE start day is missing, do the following: 
o If the study treatment start date is missing or the AE start month and year does not 
fall in the same month and year as that of the treatment start date or if the AE 
contains information to indicate that the event ended before the treatment start 
date, then set the AE start day to the 1st day of the month of the AE start date. 
o Otherwise, set the AE start date to the treatment start date. 
 AE end dates will not be imputed.  
Prior, Concomitant, and Subsequent Medications (Excluding Corticosteroids) 
 The imputation rules for AE start dates will be used for medication start dates. 
 Medication stop dates will be imputed as follows: 
o If the stop date is only missing the day, then the stop day is the last day of the 
month 
o If the stop date is missing both the day and month and the year matches the last 
study date, then the stop month and day is the earlier of the last study date and 
December 31 
o If the stop date is missing both the day and month and the year is earlier than the 
last study date, then the stop month and day is December 31 
o If the stop date is completely missing, no imputation is performed, and the 
medication will be classified as a concomitant medication for patients who were 
treated. 
Corticosteroids 
Due to the criticality of the corticosteroid usage, handling of partial start/stop dates will be 
performed on a case-by-case basis as it will require medical review of the patient records.  Such 
determinations will be made in a blinded fashion prior to database lock and approved by the 
Sponsor. 
Diagnosis Date 
 If the diagnosis date is completely missing, no imputation will be conducted. 
 If the month and day are completely missing but year is present, do the following: 
o Set missing month and day to July 1st 
o If July 1st of the non-missing year is after informed consent date, set month and 
year to January 1st 
 If only the day is missing, set to the 1st of the month 
 


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5.6. Multiple Assessments and Visit Windows 
 
Nominal visits (e.g. those identified by the study eCRF) will be the basis of summarization and 
statistical analysis unless otherwise specified. Unscheduled data may be included in summaries 
of most extreme, baseline, LOCF, and endpoint values; summaries of specific abnormalities any 
time post-baseline; and patient data listings 
5.7. Treatment Group Display 
 
Treatment groups will be displayed with the following columns.  See the mock shells for 
additional details and a visual representation of the treatment group display.  All overall columns 
will be excluded from efficacy outputs. 
 Phase 1b MAD: Cohort 1 BOS 20mg 
 Phase 1b MAD: Cohort 2 BOS 60mg 
 Phase 1b MAD: Cohort 3 BOS 120mg 
 Phase 1b MAD: Placebo 
 Phase 1b MAD: Total BOS (All patients treated with BOS161721, excludes placebo) 
 Phase 2 POC: BOS 120mg 
 Phase 2 POC: Placebo 
 Overall: Total BOS 120mg (All patients treated with BOS161721 120mg in MAD and 
POC) 
 Overall: Total BOS (Patients treated with BOS161721 in MAD and POC, excludes 
placebo) 
 Overall: Total Placebo (Placebo patients in MAD and POC, excludes patients treated 
with BOS161721) 
5.8. Missing Data 
 
Missing data imputation for the efficacy endpoints are discussed in the corresponding efficacy 
sections.  AE, concomitant medication, and corticosteroid date imputations are described in 
Section 5.5.  Missing data and other analysis conventions for noncompartmental analysis of 
pharmacokinetics will follow standard imputation methods, as described in a separate Clinical 
Pharmacology SAP.  Otherwise, missing data will not be imputed. 
6. STUDY PATIENT DATA 
6.1. Analysis Populations/Sets 
 
FAS:  Defined as all patients who receive at least one dose (partial or complete) of study 
treatment and have at least one evaluable post-baseline efficacy evaluation (BILAG, PGA, 


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SLEDAI-2K, CLASI, ACR-28, SLICC/ACR, 
, or 
).  FAS analyses will be 
conducted on the basis of the assigned (randomized) treatment.  The FAS will be used as the 
basis for the primary efficacy analysis. 
Safety Analysis Set (SS): Defined as all patients who receive at least one dose (partial or 
complete) of study treatment and have at least one evaluable post-baseline safety evaluation 
(adverse events, concomitant medications, vital signs, physical examination, ECG, or laboratory 
assessment).  Safety analyses will be conducted on the basis of actual treatment received as 
reported on the eCRF.  The SS will be the basis of all safety reporting. 
Per Protocol Set (PP): Defined as all patients from the FAS except those with major deviations 
to the protocol deemed to impact the analysis of the primary endpoint.  These deviations will be 
identified based on blinded data review prior to study unblinding.  Patients with more than one 
missed dose and patients with both Day 180 and Day 210 efficacy assessments (BILAG, 
SLEDAI-2K, or PGA) missing will be excluded from the PP.  PP analyses will be conducted on 
the basis of the assigned (randomized) treatment.  Additional information on inclusion into this 
population can be found in Section 6.3. 
6.2. Patient Disposition 
 
Disposition data will be summarized for all randomized patients.  The number of patients in each 
analysis set population, the number of patients who discontinued study treatment including 
reasons, and the number of patients who discontinued the study including reasons will be 
summarized.  The number of patients who completed the study, duration on study treatment in 
days and duration on study in days will also be summarized.  Data will be presented overall, by 
study phase, and treatment group. 
A by-patient listing of patient disposition data including reason for discontinuation, if applicable, 
will be presented for all randomized patients.  A by-patient listing of randomization details will 
also be provided for all randomized patients. 
A by-patient listing of inclusion/exclusion criteria and screen failures will be produced for all 
enrolled patients.  Screen failures will otherwise not be included in any analyses. 
6.3. Protocol Deviations 
 
Protocol deviations will be identified and classified as major or minor before database lock and 
unblinding. Major protocol deviations may include but are not limited to: 
 Violation of Inclusion/Exclusion Criteria 
 Use of prohibited therapies 
 Incorrect treatment 
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Major protocol deviations that necessitate exclusion from the efficacy analysis in the PP 
population will be identified prior to database lock and unblinding.  
Protocol deviations will be summarized by any deviation, deviation category, and major/minor 
designation.  Protocol deviations will be summarized overall, by study phase, and treatment 
group for all randomized patients. 
A listing of protocol deviations, including protocol version under which the deviation occurred, 
will be provided for all randomized patients. The protocol deviation listing will also include a 
column to indicate if the deviation resulted in the subject being excluded from the PP set based 
upon blinded clinical review.  A separate listing of COVID-19 related deviations also will be 
provided. 
6.4. Demographic and Baseline Characteristics 
 
Patient demographics and baseline characteristics will be summarized in the SS.  These will 
include age (years), sex (Male / Female), ethnicity (Hispanic or Latino / Not Hispanic or Latino), 
race (American Indian or Alaska Native / Asian / Black or African American / Native Hawaiian 
or Pacific Islander / White / Other), geographic regions (North America / South or Central 
America / Eastern Europe), baseline height (cm), baseline weight (kg), and baseline BMI 
(kg/m2).  Age is reported as collected in the clinical database and will also be categorized as a 
categorical variable (≤45, >45-<65, ≥65) for reporting.  Patient eligibility for central review will 
be summarized.  Childbearing potential and birth control methods for female and male patients 
will be summarized for the DMC meetings and interim analysis only.  Demographics and 
baseline characteristics will be summarized overall, by study phase, and treatment group. 
 
Baseline disease characteristics will also be summarized in the FAS.  The SLEDAI total score, 
PGA, CLASI total activity score, CLASI total damage score, ACR-28 sum of swelling, ACR-28 
sum of tenderness, ACR-28 sum of active joints (swelling and tenderness in the same joint) and 
SLICC/ACR damage index total score will be summarized at baseline.  Frequencies and 
percentages of patients with SLEDAI presence by component, ACR-28 loss of functional range 
interfering with life and ACR-28 impairment of basic activities from inflammation as well as 
BILAG grades by body organ system will be presented.  Frequency and percentage of patients 
with each organ system disease on BILAG SLE history will be summarized.  Frequency and 
percentage of patients with SLICC criteria for SLE will be summarized.  Frequencies and 
percentages of patients with CLASI Activity Score (<8 vs. >=8), SLEDAI-2K (<10 vs. >=10) 
and baseline corticosteroid use (0, <7.5, >= 7.5, <10, >=10 mg/day), will be presented. In case of 
missing data, LOCF methods consistent with the primary efficacy analysis described in Section 
7.1 will be used for baseline disease characteristics summaries.    
 
Frequencies and percentages of patients will also be presented for the following characteristics: 
 
 
Positive anti-ds-DNA 
 Low C3 and/or C4 


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 Positive anti-dsDNA and normal C3 and normal C4 
 Negative anti-dsDNA and low C3 and/or C4 
 Positive anti-dsDNA and low C3 and/or C4 
 Negative anti-dsDNA and normal C3 and normal C4 
 Other 
 
In addition, frequencies and percentages of patients will be presented for the following 
characteristics:  
 
 SLEDAI-2K ≥ 10 and negative** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and positive** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and negative** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and positive** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and positive** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K < 10 and negative** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and negative** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and positive** anti-dsDNA and low C3 and/or C4 
** Positive anti-dsDNA is defined as ≥ 15 IU/mL.  Negative anti-dsDNA is defined as < 15 
IU/mL 
Time from diagnosis to informed consent in years defined as (informed consent date - date of 
diagnosis as recorded on the screening BILAG assessment)/365.35 will be summarized.  Partial 
dates of diagnosis will be handled as defined in section 5.5.  Baseline disease characteristics will 
be summarized overall by study phase and treatment group. 
 
Demographics and baseline characteristics will be listed for all randomized patients.  A separate 
by-patient listing will be created for childbearing potential and birth control for all randomized 
patients. 
 
The following conversions and equations will be used as applicable: 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = weight(kg)/[height(m)2] 
 
6.5. Medical History 
 
The incidence of medical history will be summarized by system organ class (SOC) and preferred 
term (PT) overall, by study phase, and treatment group in the SS.  Patients will be counted once 
per SOC (likewise for PT within SOC). Medical history terms will be coded based on the 
Medical Dictionary for Regulatory Affairs (MedDRA). Medical history will be reported in 


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descending order of overall incidence of SOC and then in descending order of overall incidence 
for PT within the SOC.  
Medical history will be presented in data listings for all randomized patients.  Medical history 
coded terms will be provided, including the SOC and PT.   
The MedDRA version used is defined in the study data management plan. 
6.6. Prior and Concomitant Medication and Procedures 
 
The incidence of medication use will be summarized by World Health Organization (WHO) 
Drug Dictionary anatomic therapeutic class (ATC) Level 2 classification (i.e. therapeutic main 
group) and preferred name. A patient will be counted only once at each level of reporting.  Prior 
medications are those which have been identified to have been discontinued prior to the first 
dose of study medication.  Concomitant medications are those which have been identified to 
have been taken at any point during the period of time between the first dose of study drug and 
last dose of study drug + 90 days, including medications which started prior to first dose of study 
drug that are ongoing at first dose.  Subsequent medications are those which have been started 
after the last dose date + 90 days.  The data management plan specifies the version of WHO 
Drug used. 
Partial dates will be imputed according to Section 5.5 for the determination of prior, 
concomitant, and subsequent medications. 
Concomitant medication use will be summarized and presented overall, by study phase, and 
treatment group in the SS.  
A separate summary will be prepared for corticosteroids.  Corticosteroids will be presented 
overall, by study phase and treatment group in the SS.  The average daily dose of CS (prednisone 
equivalent) at each visit including summary statistics as well as categorical summaries for <5 
mg/day, ≥5 mg/day to ≤10 mg/day, and >10 mg/day and for dosages of interest relevant to Phase 
2, i.e. 0 mg/day, <7.5 mg/day, ≥7.5 mg/day, and for dosages of interest to Phase 1b, i.e.  <10 
mg/day, and ≥10 mg/day will be presented.  Average daily dose is calculated as described in 
Section 7.2.4.  Prednisone equivalence is also provided in the same section. 
All prior and concomitant medication data will be provided together in a by-patient listing 
including the verbatim and preferred drug name and WHO ATC Class (ATC Level 2) for all 
randomized patients.  Past biological, immunosuppressant, antimalarial and corticosteroid SLE 
medication history data will be listed separately for all randomized patients. 
Concomitant procedures will be presented in a data listing for all randomized patients. 
 


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6.7. Study Drug Exposure and Compliance 
 
The total dose administered (mL) and the number of doses received will be summarized as 
continuous variables.  The number and percentage of patients that received any dose and the 
number and percentage of patients who received the total planned dose at each nominal, protocol 
specified, visit (Day 0 / Day 30 / Day 60 / Day 90 / Day 120 / Day 150 / Day 180) will be 
summarized.  The number and percentage of patients who received 1-7 doses (mutually 
exclusive) will also be summarized categorically.  The denominator for the number of patients 
dosed and the number of doses received will be the number of patients in the SS.  The 
denominator for the number of patients who received the total planned dose will be the number 
of patients dosed at the corresponding nominal visit. 
The percent compliance will be summarized descriptively and is defined as 100 * (sum of doses 
received / 7).  Percent compliance will also be calculated categorically as <70%, ≥70% to <85%, 
≥85% to <100%, ≥100%. 
Relative dose intensity will be summarized descriptively and is defined as 100 * (total actual 
dose summed across all visits)/total planned dose summed across all planned visits) per the 
below table. 
Dose Level 
(mg) 
Dose Level 
(mL)* 
Total Planned Dose 
Across All 7 Visits (mL) 
Relative Dose Intensity Calculation 
20 
0.4 
2.8 
(Total actual dose in mL summed 
across all visits / 2.8) X 100 
60 
1.2 
8.4 
(Total actual dose in mL summed 
across all visits / 8.4) X 100 
120 
2.4 
16.8 
(Total actual dose in mL summed 
across all visits / 16.8) X 100 
* Dose Level in mL is based on 50mg/mL administration. 
The duration of exposure in days will also be summarized descriptively and is defined as the last 
dose date – first dose date +1.   
Study drug exposure and compliance will be presented overall, by study phase, and treatment 
group in the SS. 
By-patient listings of BOS161721 and placebo dosing data will be produced for all patients in 
the SS. 


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7. EFFICACY  
7.1. Primary Efficacy Endpoint and Analyses 
 
Safety will be the primary endpoint for the Phase 1b MAD portion of the study and is discussed 
in Section 10.  Efficacy will be evaluated for the Phase 1b MAD portion of the study as an 
exploratory endpoint and details will be included in relation to the Phase 2 POC portion of the 
study within this section.  Efficacy analyses will be presented by study phase and treatment 
group.  
7.1.1. The proportion of patients with a SRI-4 response at Day 210 
 
The primary efficacy endpoint for the POC is the proportion of patients who achieve a SRI-4 
response at Day 210 in the FAS.  
 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K, the BILAG 2004 Index, and the PGA.  SRI-4 response is defined as:  
 
1) ≥ 4-point reduction from baseline in SLEDAI-2K total score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm.   
 
The test for treatment group difference in proportion of patients who achieve a SRI-4 response at 
Day 210 will be based on Pearson’s chi-square test.  The difference in percentages of patients 
who achieve SRI-4 response (BOS161721 vs. Placebo) will be presented with its corresponding 
(Wald) 90% CI.  The number and percentage of SRI-4 responders, along with an exact (Clopper-
Pearson) 90% CI, will be presented by treatment group.  If an expected count for the Pearson 
chi-square test falls below 5, a Fisher’s exact test will be used to assess the treatment difference 
and the CI will be based on an exact method (Santner Snell).  The analyses will be repeated for 
each of the three components contributing to the SRI-4 response.  The primary analysis of the 
primary efficacy endpoint will be performed in the FAS and presented by treatment group. The 
analysis will be repeated in the PP analysis set.  SRI-4 Response at Day 210 will also be repeated 
by all subgroups in Section 4.2 and treatment group for POC Phase 2 only.   
 
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the POC placebo 


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arm, then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 
0.10. 
Evaluability/Non-Responders: 
Medication Failures: Patients who received prohibited medications or undergo unallowable 
corticosteroid (CS) usage will be considered “medication failures” and will be treated as non-
responders at time points on and following the first date of prohibited medication or unallowable 
CS usage for the primary efficacy analysis.  Prohibited medications are detailed in Appendix 4 of 
the study protocol.  Prohibited medications and unallowable CS usage will be recorded as 
protocol deviations in the clinical database.   
A patient is considered to have unallowable CS usage if any of the following is not met: 
 A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the 
study. For patients whose only SLE treatment is steroids, their stable steroid dose must be 
at least 10 mg/day and no more than 30 mg/day for a minimum of 6 weeks at time of 
randomization on Day 0 
 Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to 
Day 0, and be maintained at a constant dose throughout the study duration until the rashes 
resolve. PRN topical steroids are not permitted 
 Once the patient has received the first dose of study drug (Day 0), tapering of oral 
steroids will be highly encouraged and should be continually evaluated during the 
protocol-allowed tapering windows (Day 0 through Day 150) with the target of achieving 
a CS daily dose of < 7.5 mg and < Day 0 dose between Day 150 and Day 210 
 Between Day 150 and Day 210 (i.e., within 60 days of primary endpoint assessments), 
oral CS doses must be held constant 
 CS Burst for SLE-related Indications 
o After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” 
equivalent to ≤ 40 mg/day prednisone for increased SLE disease activity will 
be allowed between Day 0 and Day 120, which must be tapered down to the 
baseline (Day 0) CS dose or lower within 14 days of initiation of the “burst”. 
Any “burst” continuing after Day 120 or occurring after Day 120 is 
considered a protocol deviation.  
o Alternatively, a single intramuscular (IM) dose of methylprednisolone 
( < 40 mg) is permitted during this period. 
 CS Burst for Non-SLE-related Indications 
o A single treatment of oral prednisone equivalent of ≤ 40 mg/day for 14 days is 
permitted for a non-SLE indication, though it must be completed prior to 
Day 120. No long acting steroid injections are permitted.  
o Note: Treatment with inhaled CS are allowed for the treatment of 
non-SLE-related indications only (e.g., for asthma).  
 


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Any other increase from baseline of CS dose or any other systemic use of CS of any kind 
(including intra-articular and intravenous administration) are not permitted from Day 0 through 
Day 210 and will result in the patient being considered a medication failure and will be treated as 
non-responders for the primary efficacy analysis. There is no restriction of CS usage after 
Day 210.  
The determination of medication failures will be reviewed using blinded data and finalized prior 
to unblinding.  Once a patient is determined to be a non-responder, the patient will remain a non-
responder for the remainder of the study. 
Out of Window Assessments:  
 If a patient has an efficacy assessment (i.e. BILAG, SLEDAI-2K, PGA, CLASI, etc.) 
more than 30 days since the previous assessment (current visit – prior visit > 30), the 
corresponding result will not contribute to LOCF analyses. 
 Since the Day 180 nominal visit is assigned as “Day 180/End of Treatment” in the 
clinical database, Day 180 nominal assessments must be >=159 days (180 – 21 day 
sponsor allowed treatment window) since first dose to be considered for “Day 180” 
nominal assessments and also to be considered for LOCF to Day 210 in the case of 
missing Day 210 data for all efficacy analyses.  Note, under protocol amendment 6, 
patients will be allowed to be treated outside of window (after consultation with the 
sponsor) due to the ongoing COVID-19 pandemic. 
 
Early Treatment Withdrawals/Discontinuations:  
For early treatment withdrawal/discontinuation prior to study day 159 (180 days – 21 day 
treatment window), patient will be considered a non-responder after the date of early treatment 
withdrawal/discontinuation assuming the patient was not considered a medication failure prior to 
or on the date of early withdrawal/discontinuation for the primary efficacy analysis.   
 
For early treatment withdrawal/discontinuation on or after study day 159 (180 days – 21 days) 
such that patient has data for nominal visit Day 180 but not for nominal visit Day 210, Day 180 
data will be carried forward to Day 210 for assessment of SRI-4 response. 
 
For early treatment withdrawal/discontinuation on or after study day 159 (180 days – 21 days) 
such that patient does not have data for nominal visit Day 180 and  Day 210, the patient will be 
considered a non-responder on Day 210.  
 
For early treatment withdrawal/discontinuation on Day 210 such that patient has data for 
nominal visit Day 210, the Day 210 data will be used for assessment of SRI-4 response.   
 
 
Missing Data: 
 
 Pre-Treatment: If a patient is missing data during the pre-treatment period for SLEDAI-
2K, PGA, or BILAG, the patient will be excluded from the primary efficacy analysis. 
 


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 Overall SRI-4 Components: Missing data at Day 210 for overall components for 
SLEDAI-2K, BILAG, and PGA will be addressed by employing a LOCF analysis within 
each overall component as described in Section 5.4.  For example, if a patient has data for 
SLEDAI-2K and BILAG at Day 210 but is missing PGA at Day 210, the PGA 
component would employ LOCF as described in Section 5.4. If the overall component is 
missing from Day 180 through Day 210 and the patient is not a medication failure on or 
prior to Day 210 and did not withdraw/discontinue treatment prior to Day 180, the SRI-4 
response at Day 210 will be considered not evaluable.     
 
 Individual Items Contributing to Overall SRI-4 Components: Data collection and 
scoring will be performed in the clinical database for BILAG, SLEDAI-2K, and PGA.  If 
missing individual items contributing to any of the overall components occurs for Day 
210, the overall component will be recalculated per the Table 1.  
Table 1 
SRI-4 Component 
Method for Carrying Forward Individual Items 
Contributing to SRI-4 Component Result/Score 
BILAG Grade 
BILAG Grading is evaluated and entered into the clinical 
database by the medical monitoring team.  Grades are 
adjudicated by independent subject matter experts.  The 
medical monitoring team and the adjudication team will 
utilize BILAG index results to determine BILAG Grades.  
Missing data will be handled by the medical monitoring 
team as follows.  If lab values are missing in the BILAG 
Index at Day 210, lab values from the most recent 
unscheduled visit <=14 days after Day 210 will be utilized 
for determination of the BILAG grade in the applicable 
organ system and entered into the clinical database.  If lab 
values are not available from an unscheduled visit <=14 days 
after Day 210, laboratory data will be carried forward from 
the most recent laboratory assessment (scheduled or 
unscheduled) <=30 days prior to the Day 210 nominal visit 
for determination of BILAG grade.  If the lab components 
for BILAG are missing from Day 210 and no unscheduled 
laboratory assessments occur within 14 days after or 30 days 
prior to the Day 210 assessment, the lab components from 
Day 180 will be utilized if Day 180 occurred within 30 days 
of Day 210.  Otherwise, no individual BILAG Index results 
will be carried forward.  If the BILAG grade for a given 
organ system is missing at Day 210, the grade will be carried 
forward from the Day 180 assessment. If the Day 180 
BILAG grade is also missing, occurred more than 30 days 
before Day 210 (Day 210 visit date – Day 180 visit date > 


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30), or is not evaluable, the Day 210 grade will be 
considered not evaluable.
SLEDAI-2K 
If lab values are missing at Day 210, lab values will be 
imputed based on the below hierarchy of determination: 
(1) If any unscheduled laboratory assessments occurred 
<=14 days after the Day 210 visit, the laboratory 
values at the most recent unscheduled laboratory 
assessment will be used for the determination of 
missing laboratory SLEDAI-2K criteria.  For 
example, if platelet count is missing at Day 210 and 
an unscheduled laboratory assessment occurs 10 days 
after the Day 210 visit date, the platelet count from 
the unscheduled laboratory assessment would be used 
to determine if the patient had thrombocytopenia at 
Day 210 for SLEDAI-2K. 
(2) Else if #1 does not occur or lab values are not 
available at the unscheduled visit noted in #1, the 
laboratory data will be carried forward from the most 
recent laboratory assessment (scheduled or 
unscheduled) <=30 days prior to the Day 210 
nominal visit to make the SLEDAI-2K 
determination.  For example, if a patient is missing 
thrombocytopenia and leukopenia SLEDAI-2K 
components at Day 210, they have an unscheduled 
lab assessment 10 days earlier with platelet counts 
populated and WBC not populated, and they have a 
Day 180 assessment within 30 days of the Day 210 
visit with both platelets and WBC present, the 
platelet value from the unscheduled visit would be 
carried forward to the Day 210 for thrombocytopenia 
component designation and the WBC value would be 
carried forward from the Day 180 assessment to Day 
210 for the Leukopenia component designation.   
(3) If the lab components for SLEDAI-2K are missing 
from Day 210 and no unscheduled laboratory 
assessments occur within 14 days after or 30 days 
prior to the Day 210 assessment, the lab components 
from Day 180 will be carried forward, if available 
and if Day 180 occurred within 30 days of Day 210.   
 
Otherwise, no non-lab individual SLEDAI-2K components 
will be carried forward.  If non-lab individual components 
are missing at Day 210, the entire SLEDAI-2K score from 
Day 180 will be carried forward.  If Day 180 is missing, 
occurred more than 30 days before Day 210, or is not 


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evaluable, LOCF is not implemented and the Day 210 score 
will be considered not evaluable. In the case of missing  
SLEDAI-2K lab components at Day 210, where any 
SLEDAI-2K lab component is carried forward (or back) per 
above, the SLEDAI-2K total score will be recalculated 
outside of the clinical database as the sum of: 
(1) All of the non-missing weights for each descriptor at 
Day 210 
(2) All individual lab component weights carried forward 
from the Day 180 visit or unscheduled visit, as 
applicable. 
If any components are still missing at Day 210 after carrying 
forward available lab components, the Day 210 SLEDAI-2K 
score will not be recalculated and will be considered not 
evaluable. 
Note: Clinical input may be obtained prior to database lock 
and unblinding to make a final determination of SLEDAI-2K 
criteria in the case of carrying forward (or back) individual 
lab component scores.
PGA 
Individual components are not applicable for PGA and will 
not be carried forward.  Total PGA VAS measurement will 
be carried forward from the Day 180 visit in the case of 
missing PGA measurement at Day 210. If total PGA score is 
also missing from Day 180, occurred more than 30 days 
before Day 210, or is not evaluable, LOCF is not 
implemented and the Day 210 visit will be considered not 
evaluable. 
Table 2 summarizes the primary analysis and details several sensitivity analyses which may be 
performed: 
 
Table 2 
Analysis 
Analysis 
Population
Criteria 
Primary Analysis 
LOCF for missing data, 
Medication 
Failures=Non-Responder 
FAS 
The primary analysis of the primary efficacy endpoint will be 
performed based on LOCF methods for missing data.  
 
(1) Medication failures are considered non-responders on and 
after the date of medication failure 
(2) Early withdrawals/discontinuations prior to study day 159 
will be considered non-responders after the date of early 
withdrawal/discontinuation 


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a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered a non-responder on and after the date of 
medication failure.  
b. In case of early withdrawal/discontinuation after 
study day 159 but before Day 210 such that patient 
has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 
data will be carried forward to Day 210. 
(3) Patients with missing Day 180 and Day 210 data without 
prior medication failure and without early 
withdrawal/discontinuation prior to study day 159 are 
considered not evaluable and are excluded from analysis 
Sensitivity Analysis 1: 
Observed (no LOCF for 
missing data), 
Medication 
Failures=Non-Responder 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on purely observed data.  No LOCF imputations 
will be performed for missing data. 
Additional criteria are as follows: 
(1) Medication failures are considered non-responders on and 
after the date of medication failure 
(2) Early withdrawals/discontinuations prior to Day 210 will 
be considered non-responders after the date of early 
withdrawal/discontinuation 
a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered a non-responder on and after the date of 
medication failure.  
(3) Patients with missing Day 210 data without prior 
medication failure and without early 
withdrawal/discontinuation prior to Day 210 are 
considered not evaluable and are excluded from the 
sensitivity analysis 
If lab component scores are carried forward from Day 180 to Day 
210 in order to assign a Day 210 grade in the primary analysis, the 
Day 210 assessment will be considered not evaluable for this 
sensitivity analysis.
Sensitivity Analysis 2: 
LOCF for missing data, 
Exclude Medication 
Failures 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on LOCF methods for missing data detailed for 
the primary efficacy analysis. 
Additional/modified criteria are as follows: 
(1) Medication failures are considered not evaluable and are 
excluded from the sensitivity analysis on and after the date 
of medication failure


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(2) Early withdrawals/discontinuations prior to study day 159 
will be considered not evaluable and will be excluded from 
analysis after the date of early withdrawal/discontinuation 
a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered not evaluable and excluded on and after 
the date of medication failure.  
b. In case of early withdrawal/discontinuation after 
study day 159 but before Day 210 such that patient 
has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 
data will be carried forward to Day 210. 
(3) Patients with missing Day 180 and Day 210 data are 
considered not evaluable and are excluded from the 
sensitivity analysis
Sensitivity Analysis 3: 
Observed (no LOCF for 
missing data), Exclude 
Medication Failures 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on purely observed data.  No LOCF imputations 
will be performed for missing data. 
Additional criteria are as follows: 
(1) Medication failures are considered not evaluable and are 
excluded from the sensitivity analysis on and after the date 
of medication failure 
(2) Early withdrawals/discontinuations prior to Day 210 will 
be considered not evaluable and are excluded from the 
sensitivity analysis after the date of early 
withdrawal/discontinuation 
a. 
If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered not evaluable and excluded on and after 
the date of medication failure. 
(3) Patients with missing Day 210 data are considered not 
evaluable and are excluded from the sensitivity analysis 
If lab component scores are carried forward from Day 180 to Day 
210 in order to assign a Day 210 grade in the primary analysis, the 
Day 210 assessment will be considered not evaluable for this 
sensitivity analysis.
Sensitivity Analysis 4: 
LOCF for missing data, 
Medication 
Failures=Non-
Responder, Logistic 
Regression 
FAS 
 
  
 
CCI


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Additional sensitivity analyses may be performed to consider the effect of missing data. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
A summary of disposition of SRI-4 response per the primary analysis at day 210 will be 
presented by study phase and treatment group in the FAS and PP.  Sensitivity analysis 2 (LOCF, 
Exclude Medication Failures) will also be performed for disposition of SRI-4 response at day 
210.  These summaries will include the number of SRI-4 responders and the number of SRI-4 
non-responders with a breakdown of reasons for non-response (early withdrawal, medication 
failure, <4-point reduction from baseline in SLEDAI-2K total score, new BILAG 1A/2B, and 
PGA worsening).  Denominators for percentages will be the number of patients eligible for SRI-
4 response analysis (patients not deemed not evaluable) defined as those with data for PGA, 
SLEDAI-2K and BILAG at Day 210 (whether or not due to LOCF, FAS analysis). 
 
A listing of SRI Response data at Days 30, 60, 90, 120, 150, 180 and 210 will be presented in the 
FAS.  A listing of SRI-4 Response at Day 210 (Primary and Sensitivity Analyses) will also be 
presented in the FAS.  A listing of patients with medication failures, early 
withdrawals/discontinuations and those excluded from the primary efficacy analysis will also be 
provided for all randomized patients. 
 
7.2. Secondary Efficacy Endpoints and Analyses 
 
PK and PD measures are the secondary endpoints for the Phase 1b MAD part of the study and 
exploratory endpoints for the POC part of the study. Those analyses are described in Section 8.   
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit 
The primary analysis methods described in Section 7.1.1 and Table 2 will be repeated for each 
nominal visit and will be presented by study phase and treatment group in the FAS.  Other 
analyses described in Section 7.1.1 may also be performed.  The 3 components will not be 
summarized separately by visit.  In case of missing data, LOCF methods will be implemented as 
described in section 5.4 and Table 1.  LOCF will only be implemented with the most recent prior 
nominal visit.  If the most recent prior nominal visit is missing, occurred more than 30 days 
before, or is not evaluable, LOCF is not implemented.  For example, if Day 30 SLEDAI 
assessment is complete but Day 60 and Day 90 SLEDAI assessments are missing, Day 60 will 
implement LOCF from Day 30 assuming Day 30 is within 30 days of Day 60 and Day 60 
SLEDAI will be included in the analysis but Day 90 will not carry forward from Day 60 and thus 
Day 90 will be considered not evaluable and will be excluded from the analysis.  Similarly, if 
Day 150 assessments are complete but Day 180 and Day 210 are missing, Day 180 will 
implement LOCF from Day 150 assuming Day 150 is within 30 days of Day 180 and will be 
included in the analysis but Day 210 will not carry forward from Day 180, will be considered not 
evaluable, and will be excluded from the analysis.   


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If a patient is a medication failure, the patient is considered to be a non-responder at timepoints 
on or after the first date of prohibited medication/unallowable CS usage. 
If a patient discontinues/withdraws early, the patient will be considered a non-responder after the 
date of discontinuation/withdrawal (unless the patient had a prior medication failure in which 
case the patient is considered a non-responder on and after the date of medication failure). 
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-4 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
A graphical display of SRI-4 response by study phase, treatment group, and visit in the FAS will 
be presented. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit 
The SRI-5 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K, the BILAG 2004 Index and the PGA.  Response based on the SRI-5 is defined 
by:  
1) ≥ 5-point reduction from baseline in SLEDAI-2K total score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The primary analysis described in Section 7.1.1 and Table 2 will be repeated for each nominal 
visit as described in Section 7.2.1 based on the SRI-5 response definition and will be presented 
by study phase and treatment group in the FAS.  The 3 components will not be summarized 
separately by visit for SRI-5 response. Other analyses described in Section 7.1.1 may also be 
performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-5 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 


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7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit 
The SRI-6 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K,  the BILAG 2004 Index and the PGA.  Response based on the SRI-6 is defined 
by:  
1) ≥ 6-point reduction from baseline in SLEDAI-2K total score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The primary analysis described in Section 7.1.1 and Table 2 will be repeated for each nominal 
visit as described in Section 7.2.1 based on the SRI-6 response definition and will be presented 
by study phase and treatment group in the FAS.  The 3 components will not be summarized 
separately by visit for SRI-6 response. Other analyses described in Section 7.1.1 may also be 
performed.  
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-6 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.4. 
Oral Corticosteroid (CS) Reduction 
The average daily CS dose will be presented over time starting with Day 0 as baseline.  Oral CS 
usage for all visits will be based on the average daily dose, defined as the sum of the 
corticosteroid doses taken each day from the date of the previous visit to the day before the date 
of the current visit (converted to prednisone equivalent dose) / the duration between the two 
visits.  For example, the average daily dose at Day 0 (Baseline) is the sum of daily doses of CS 
from the screening visit to the day prior to Day 0 divided by the duration between the screening 
visit to the day prior to Day 0, inclusive. Similarly, the average daily dose at Day 30 is the sum 
of daily doses of CS from Day 0 to the day prior to Day 30 divided by the duration between Day 
0 to the day prior to Day 30, inclusive.  Partial dates for CS use will be imputed based on details 
in Section 5.5.  Oral CS will be converted to prednisone dose equivalence for analysis of 
reduction of oral CS use.  Common prednisone dose equivalents are provided in Table 3. 
 
 


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Table 3 
Medication 
Prednisone Dose Equivalence 
Prednisone 
1 mg
Cortisone 
5 mg
Hydrocortisone 
4 mg
Deflazacort 
1.2 mg
Meprednisone 
1 mg
Prednisolone 
1 mg
Methylprednisolone 
0.8 mg
Methylprednisolone Acetate 
0.8 mg
Triamcinolone 
0.8 mg
Triamcinolone Acetonide 
0.8 mg
Budesonide 
0.25 mg
Dexamethasone 
0.16 mg
Bethamethasone 
0.16 mg
 
7.2.4.1. Proportion of Patients with a sustained reduction of oral CS between Day 
120 and Day 210 (MAD) 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 10 mg/day prednisone equivalent and < Day 0 dose, between Day 120 and Day 210 determined 
based on actual daily CS usage on and in between the nominal visit dates will be summarized for 
MAD Phase 1b by treatment group in the FAS.  To qualify as sustained reduction, the actual 
daily CS usage needs to meet the definition above every day between nominal visit dates for Day 
120 and Day 210 inclusive.  LOCF and imputation for missing values will not be performed.  
Otherwise, statistical methods described in Section 7.1.1 will be implemented.  Patients who 
withdraw prior to Day 210 or are designated as a medication failure on or prior to Day 210 or 
miss the Day 120 and/or the day 210 visit will not be considered to have sustained reduction in 
CS.  Denominators for percentages are the number of patients taking oral CS at baseline.  


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7.2.4.2. Proportion of Patients with a sustained reduction of CS between Day 150 
and Day 210 (POC) 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 7.5 mg/day prednisone equivalent and < Day 0 dose, between Day 150 and Day 210 
determined based on actual daily CS usage on and in between the nominal visit dates will be 
summarized for POC Phase 2 by treatment group in the FAS.  To qualify as sustained reduction, 
the actual daily CS usage needs to meet the definition above every day between nominal visit 
dates for Day 150 and Day 210 inclusive.  LOCF and imputation for missing values will not be 
performed.  Otherwise, statistical methods described in Section 7.1.1 will be implemented.  
Patients who withdraw prior to Day 210 or are designated as a medication failure on or prior to 
Day 210 or miss the Day 150 and/or Day 210 visit will not be considered to have sustained 
reduction in CS.  Denominators for percentages are the number of patients taking oral CS at 
baseline.  
 
7.2.4.3. Percent Reduction in CS Administration from Day 0 through Day 210 
(POC) 
The percent reduction in CS administration from Day 0 through Day 210 determined based on 
the average daily CS usage will be summarized for POC Phase 2 by treatment group and visit.  
Average daily dose will be calculated for nominal visits as defined in Section 7.2.4.  This will be 
performed for patients in the FAS who received ≥ 7.5 mg/day prednisone equivalent at Day 0.  
Patients considered medication failures will be excluded from the percent reduction analysis at 
timepoints on and after the first date of medication failure. 
 
 
7.2.5. Proportion of new or recurrent BILAG A flare or >1 BILAG B flare through 
Day 210 
The proportion of patients with a new or recurrent BILAG A flare or >1 BILAG B flares through 
Day 210 will be summarized by study phase and treatment group in the FAS.  Statistical methods 
described in Section 7.1.1 will be implemented.  BILAG flares will be adjudicated, recorded in 
the clinical database, and summarized as recorded in the clinical database.  Flare assessments 
will be performed on BILAG grades whether or not designation of a BILAG grade required 
carrying component data forward by the assessor.  However, no LOCF methods will be 
implemented with respect to flare data itself.  When discrepancies between the two-reviewers 
occurs, the adjudicated flare determination will be used for analyses.  The proportion of new or 
recurrent BILAG A flare or >1 BILAG B flare will be summarized overall and by nominal visit.  
The denominator for percentages of patients with a new or recurrent flare will be patients in the 
FAS with a post-baseline BILAG assessment at the given visit.  
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 


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Results as recorded in the clinical database will be presented in separate data listings for BILAG 
SLE history, BILAG-2004 index, and BILAG grading for all randomized patients. 
 
7.2.6. 
Physician’s Global Assessment (PGA) 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients.”   
7.2.6.1. Proportion of Patients with PGA Worsening at Each Visit 
The proportion of patients with PGA worsening, defined as an increase of ≥30mm from baseline, 
will be summarized by study phase and treatment group in the FAS overall (at any post-baseline 
nominal visit) and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented.  In case of missing data, LOCF methods will be implemented as described in 
section 5.4 and Table 1 and in Section 7.2.1 for the “at each visit” analyses.   
The analyses described in Section 7.1.1 and Table 2 (Primary Analysis methods) will be repeated 
for each nominal visit as described in Section 7.2.1 based on the PGA worsening definition and 
will be presented by study phase and treatment group in the FAS.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline PGA assessment (overall analysis) or with evaluable PGA assessment (whether or not 
imputed via LOCF depending on the analysis) at a given visit (nominal visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.6.2. Results, Changes, and Percentage Change from Baseline in PGA 
The analysis of PGA will be performed separately using an ANCOVA model with change or 
percentage change from baseline to each nominal visit as the dependent variable, treatment group 
as the factor, and the corresponding baseline PGA result as a covariate.  The p-value for the 
difference between the BOS161721 and placebo groups at each nominal visit is based on the F-
test. 
Descriptive statistics for PGA will be summarized separately at baseline and each visit.  Change 
and percentage change from baseline will be summarized at each post-baseline visit.  The least 
squares (LS) mean estimate, its standard error and 90% CI will be tabulated by treatment group 
and for the difference between treatment groups (BOS161721 versus placebo) for change and 
percentage change at each visit.  In case of missing data, LOCF methods will be implemented as 
described in Section 5.4 and Table 1 and in Section 7.2.1.   
Two separate approaches will be taken based on handling for medication failures and treatment 
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Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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Approach 1:  Corresponding to Primary Analysis Methods (Medication Failure LOCF): If a 
patient is a medication failure, the most recent assessment prior to the medication failure date 
will be carried forward to all subsequent assessments.  In the case of patients who 
withdraw/discontinue early without prior medication failure, the most recent data on or prior to 
withdrawal/discontinuation will be carried forward to all subsequent assessments.  In case of 
early withdrawal/discontinuation after Day 180 but before Day 210 such that patient has Day 180 
data but is lacking Day 210 data in a patient without medication failure, the Day 180 data will be 
carried forward to Day 210. 
Approach 2:  Corresponding to Sensitivity Analysis 2 Methods (Exclude Medication Failure): If 
a patient is a medication failure, all assessments on and after medication failure date will be 
considered not evaluable and will be excluded.  In the case of patients who withdraw/discontinue 
early without prior medication failure, all assessments after the early withdrawal date will be 
considered not evaluable and will be excluded.  In case of early withdrawal/discontinuation after 
Day 180 but before Day 210 such that patient has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 data will be carried forward to Day 210.  
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
PGA observed results will be presented in a data listing for all randomized patients. 
 
7.2.7. 
Proportion of Patients with BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as:  
1) at least 1 gradation of improvement in baseline BILAG 2004 scores in all body systems with 
all A [severe disease] scores falling to B [moderate], C [mild] or D [no activity] OR all B 
[moderate disease] scores falling to C [mild] or D [no activity]) 
 
AND 
2) no new BILAG A or more than 1 new BILAG B scores 
AND 
3) no worsening of total SLEDAI-2K score from baseline 
AND 
4) ≤ 10% deterioration in PGA score 
AND 
5) no medication failure. 


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Statistical methods described in Section 7.1.1 will be implemented.  In case of missing data, 
LOCF methods will be implemented as described in section 5.4 and Table 1 and in Section 7.2.1 
for the “at each visit” analysis.  The primary analysis and sensitivity analysis 2 (LOCF for 
missing data, Exclude Medication Failures) methods described in Section 7.1.1 and Table 2 will 
be repeated overall and as described in Section 7.2.1 for Days 210, 240, and 270 based on the 
BICLA response definition and will be presented by study phase and treatment group in the FAS.  
Other analyses described in Section 7.1.1 may also be performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline BICLA assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) (overall analysis) or at a 
given visit (nominal visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 
The total activity score will be calculated by summing the scores on the left side of the form 
(erythema, scale/hypertrophy, mucous membrane, alopecia – recent hair loss and alopecia 
clinically not obviously scarred). 
The total damage score will be calculated by: 
(1) Sum the responses for “Dyspigmentation” in all anatomical locations 
(2) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts at least 12 months”, then multiply the sum in #1 by 2. 
(3) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts less than 12 months”, then the sum in #1 will not change. 
(4) If the sum in #1 is 0 and a response for “Report duration of dyspigmentation after active 
lesions have resolved” is missing, then the sum in #1 will not change. 
(5) Determine the Dyspigmentation Score based on the results from 2, 3, or 4. 
(6) Sum the remaining scores on the right side of the form (scarring/atrophy/panniculitis, 
alopecia - scarring of the scalp judged clinically). 
(7) Sum the scores from #5 and #6 to obtain the total damage score. 
If any individual scores which contribute to the total activity score or the total damage score are 
missing, the total score in question will not be calculated.  If total activity score or total damage 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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score are missing at a visit, LOCF methods will be implemented as described in Section 5.4 and 
Section 7.2.1 for the “at each visit” analyses.  
The mean and SD of the change from baseline in CLASI total activity and total damage scores 
will be presented graphically over time by study phase and treatment group. 
7.2.8.1. Proportion of Patients with CLASI Response 
CLASI response is defined as 50% improvement from baseline in CLASI.  A CLASI-A response 
applies to “A” (total activity) and a CLASI-B response applies to “B” (total damage) score.  
Statistical methods described in Section 7.1.1 will be implemented. In case of missing data, 
LOCF methods will be implemented as described in Section 5.4 and 7.2.1 for the “at each visit” 
analysis. Individual components of the CLASI will not be carried forward; however, the total 
activity score or total damage score may be carried forward from the most recent prior visit.  If 
the most recent prior visit is missing, occurred more than 30 days before (current visit date – 
most recent prior visit date > 30), or is not evaluable, LOCF is not implemented. The primary 
analysis methods (LOCF for missing data, medication failure=non-responder) as described in 
Section 7.1.1 and Table 2 will be performed at each visit based on the CLASI response definition 
and will be presented by study phase and treatment group in the FAS.  
 
 
The analysis will also be repeated in line with Sensitivity Analysis 2 (LOCF for missing data, 
exclude medication failures) in Section 7.1.1. 
Other analyses described in Section 7.1.1 may also be performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline CLASI assessment (whether observed or imputed via LOCF depending on the analysis) 
at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
7.2.8.2. Results, Changes, and Percentage Change from Baseline in CLASI 
The analysis of CLASI total activity score and CLASI total damage score will be performed 
separately using an ANCOVA model with change or percentage change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the corresponding 
baseline CLASI score as a covariate.  The p-value for the difference between the BOS161721 
and placebo groups at each nominal visit is based on the F-test. 
Descriptive statistics for the activity score and damage score will be summarized separately at 
baseline and each visit.  Change and percentage change from baseline will be summarized at 
each post-baseline visit.  The LS Mean estimate, its standard error and 90% CI will be tabulated 
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by treatment group and for the difference between treatment groups (BOS161721 versus 
placebo) for change and percentage change at each visit.  Statistical methods described in 
Section 7.1.1 will be implemented.  In case of missing data, LOCF methods will be implemented 
as described in Section 5.4 and Section 7.2.1 for the “at each visit” analyses. Individual 
components of the CLASI will not be carried forward; however, the total activity score or total 
damage score may be carried forward from the most recent prior visit.  If the most recent prior 
visit is missing, occurred more than 30 days before (current visit date – most recent prior visit 
date > 30), or is not evaluable, LOCF is not implemented. The analyses will be performed in line 
with the two approaches outlined in Section 7.2.6.2. 
 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
CLASI observed results will be presented in data listings for all randomized patients. 
7.2.9. Results, Changes, and Percentage Changes from Baseline in Swollen, 
Tender, and Active Joints ACR-28 
The ACR-28 joint count evaluates the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet, hip and ankle are excluded.  The sum of active 
joints is also evaluated and is defined as the total number of joints with swelling and tenderness 
in the same joint. The joint sums for tender and swollen joints are recorded in the database. The 
sum of active joints will be derived. 
The analysis of ACR-28 Swollen and Tender Joints for the sum of tenderness (left and right), the 
sum of swelling (left and right), and sum of active joints (left and right) will be performed 
separately using an ANCOVA model with change and percentage change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the baseline ACR-28 
score as a covariate.  The p-value for the difference between the BOS161721 and placebo groups 
at each nominal visit is based on the F-test.   
Descriptive statistics for the tenderness, swelling, and derived active joint sums will be 
summarized separately at baseline and each visit.  Change and percentage change from baseline 
will be summarized at each post-baseline visit.  The LS Mean estimate, its standard error and 
90% CI will be tabulated by treatment group and for the difference between treatment groups 
(BOS161721 versus placebo) for change and percentage change at each visit. 
Statistical methods described in Section 7.1.1 will be implemented.  In case of missing data, 
LOCF methods will be implemented as described in Section 5.4 and in Section 7.2.1 for the “at 
each visit” analyses. Individual components of ACR-28 will not be carried forward; however, the 
total ACR-28 score may be carried forward from the most recent prior visit.  If the most recent 
prior visit is missing, occurred more than 30 days before (current visit date – most recent prior 
visit date > 30), or is not evaluable, LOCF is not implemented. The analyses will be performed in 
line with the two approaches outlined in Section 7.2.6.1. 
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The mean and SD of the change from baseline in ACR-28 sum of tenderness, sum of swelling, 
and sum of active joints based on primary analysis methods will be presented graphically over 
time by study phase and treatment group. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
Swollen, tender, and active joints ACR-28 observed results will be presented in data listings for 
all randomized patients. 
7.2.10. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-
2K) 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI 2K of 6 or more generally represents moderately to severely active 
disease. 
7.2.10.1. Proportion of Patients with a SLEDAI-2K Response 
The proportion of patients with a SLEDAI-2K response, defined as ≥ 4-point reduction from 
baseline in SLEDAI-2K total score, will be summarized by study phase and treatment group in 
the FAS overall and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented.  In case of missing data, LOCF methods will be implemented as described in 
section 5.4 and Table 1 and in Section 7.2.1 for the “at each visit” analyses.   
The analyses described in Section 7.1.1 and Table 2 (Primary Analysis methods and Sensitivity 
Analysis 2 methods) will be repeated for each nominal visit as described in Section 7.2.1 based 
on the SLEDAI-2K response definition and will be presented by study phase and treatment group 
in the FAS. 
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SLEDAI-2K assessment (overall analysis) or with evaluable SLEDAI-2K assessment 
(whether observed or imputed via LOCF depending on the analysis) at a given visit (nominal 
visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.10.2. Results, Changes, and Percentage Change from Baseline in SLEDAI-2K 
The analysis of SLEDAI-2K will be performed using an ANCOVA model with change and 
percent change from baseline to each nominal visit as the dependent variable, treatment group as 
the factor, and the baseline SLEDAI-2K score as a covariate.  The SLEDAI-2K total score is 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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calculated and provided in the clinical database.  In case of missing data, SLEDAI-2K will be re-
calculated outside the clinical database after application of imputation rules.  
Descriptive statistics for the SLEDAI-2K total score will be summarized separately at baseline 
and each visit.  Change and percentage change from baseline will be summarized at each post-
baseline visit.  The LS mean estimate, its standard error and 90% CI will be tabulated by 
treatment group and for the difference between treatment groups (BOS161721 versus placebo) 
for change and percentage change at each visit. The p-value for the difference between the 
BOS161721 and placebo groups at each nominal visit is based on the F-test. 
Statistical methods described in Section 7.1.1 will be implemented,.  In case of missing data, 
LOCF methods will be implemented as described in section 5.4 and Table 1 and in Section 7.2.1 
for the “at each visit” analyses. The analyses will be performed in line with the two approaches 
outlined in Section 7.2.6.1. 
Approach 1 corresponding to the primary analysis methods (LOCF for missing data, medication 
failure LOCF) will be repeated for subgroups 
 as defined 
below:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.2.11. 
Results, Changes, and Percentage Change from Baseline in SLICC/ACR 
Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.  It will be performed on Days 0 
and 180. 
The analysis of SLICC/ACR Damage Index total score will be performed using an ANCOVA 
model with change and percentage change from baseline to Day 180 as the dependent variable, 
treatment group as the factor, and the baseline SLICC/ACR Damage Index total score as a 
covariate.  The SLICC/ACR Damage Index total score is calculated and provided in the clinical 
database.  A missing total SLICC/ACR Damage Index score will not be imputed.  Observed 
results will be presented for the change and percentage change from baseline analysis.  The p-
value for the difference between the BOS161721 and placebo groups at each nominal visit is 
based on the F-test.   
Descriptive statistics for the SLICC/ACR Damage Index total score will be summarized 
separately at baseline and Day 180.  Change and percentage change from baseline will be 
summarized at Day 180.  The LS Mean estimate, its standard error and 90% CI will be tabulated 
by treatment group and for the difference between treatment groups (BOS161721 versus 
placebo) for change and percentage change at Day 180. 
In case of medication failure or early withdrawal/discontinuation prior to Day 180, the Day 180 
assessment will be considered not evaluable and will not contribute to the analysis at that visit.   
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Observed SLICC/ACR Damage Index data will be presented in a by-patient listing for all 
randomized patients.  SLICC Criteria for SLE at screening will also be presented in a by-patient 
listing for all randomized patients. 
7.2.12. 
Medication Failure 
7.2.12.1. Proportion of Patients with Medication Failures 
Patients who received prohibited medications or had unallowable CS usage as described in 
Section 4.6 of the study protocol will be considered “medication failures” and will be treated as 
non-responders at time points on and following the first date of prohibited medication or 
unallowable CS usage for the primary efficacy analysis and selected sensitivity and secondary 
efficacy analyses.  The determination of medication failures and medication failure dates will be 
reviewed using blinded data and finalized prior to unblinding.   


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The number and proportion of patients with medication failures will be summarized by study 
phase and treatment group in the FAS overall and by visit.  A patient will be counted as a 
medication failure at each visit occurring on and after the date in which a patient is considered a 
medication failure.  Statistical methods described in Section 7.1.1 will be implemented for 
observed data only.  LOCF and missing data imputation will not be performed. 
The denominator is the number of patients in FAS (overall analysis) and the number of patients 
with non-missing visit data (for the by visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.12.2. Time to Medication Failure (TTMF) 
Medication failure is defined in Section 4.6 of the study protocol and discussed in Section 7.1.1. 
TTMF will be computed as the event date (as described below) – randomization date + 1. 
Kaplan-Meier methods will be used to estimate TTMF for each treatment group.  Estimates of 
median TTMF will be provided along with 90% confidence intervals.  Q1 and Q3 will also be 
tabulated. Comparisons between treatment groups will use the two-sided log-rank test.  In 
addition, hazard ratio (HR) estimates with 90% CIs will be calculated from a Cox proportional 
hazards regression analysis that includes treatment as a factor.  Censoring rules are defined as in 
Table 4. 
Table 4 
Situation 
Date of Event or Censoring 
Outcome 
Patient is designated a medication failure 
(received prohibited meds or unallowable 
CS burst) 
Date of first dose of 
medication leading to 
medication failure 
designation.  These dates will 
be identified by the sponsor 
based on the prior and 
concomitant medication eCRF 
form. 
Event 
Patient withdraws from study (no medication 
failure) 
Censored at date of 
withdrawal 
Censored 
Patient completes the study (no medication 
failure) 
Censored at last study visit 
Censored 
Patient dies during study (no medication 
failure) 
Censored at the date of death 
Censored 
 


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Kaplan-Meier curves of TTMF will be plotted over time. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to medication failure data will be provided in a by-patient listing in the full analysis set. 
7.2.13. 
Duration of Longest SRI-4 Response 
Duration of longest SRI-4 response will be computed for patients who have been identified as a 
responder at least once based on criteria defined in Section 7.1.1 utilizing LOCF methods 
consistent with the primary efficacy analysis.  The duration of longest response will be defined 
as the longest period a patient meets the SRI-4 responder criteria at consecutive visits.  This will 
be computed as the date of last consecutive SRI-4 response – date of first consecutive response + 
1.  If the last consecutive response is based on LOCF methods and the last consecutive response 
does not have a date, duration of longest SRI-4 Response will be computed as the (date of last 
non-missing consecutive SRI-4 response + 30) – date of first consecutive response + 1. 
The duration of longest SRI-4 response will be analyzed using an analysis of variance (ANOVA) 
model with treatment group as the effect.  The p-value for the difference between the 
BOS161721 and placebo group is based on the F-test. 
The mean, SD, median, minimum, maximum, Q3, Q4, LS Mean estimate, its standard error and 
90% CI will be tabulated by treatment group and for the difference between treatment groups 
(BOS161721 versus placebo). 
If a patient has missed a visit between two scheduled visits with a response at both, the patient 
will be counted as having a response at the missed visit unless otherwise specified.   
Duration of longest SRI-4 response will be displayed in the SRI response listing. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
7.2.14. 
Time to First BILAG A Flare or >1 BILAG B Flare through Day 210 
Time to first BILAG A Flare or >1 BILAG B Flare will be computed as the event date (as 
described below) – randomization date + 1.  If a patient is designated as a medication failure 
prior to or on their day 210 visit, they will be considered as having a BILAG flare (event) as of 
the date of first dose of the medication leading to the medication failure designation due to 
prohibited medication or unallowable CS burst.  
Time to first BILAG A Flare or >1 BILAG B Flare will be analyzed with Kaplan-Meier methods 
described for TTMF and censoring as described in Table 5.  Kaplan-Meier curves will be plotted 
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Table 5 
Situation 
Date of Event or Censoring 
Outcome 
Patient has a BILAG A Flare or >1 BILAG 
B Flare (Noted as BILAG 1A/2B Flare) 
prior to or on their Day 210 visit 
Date of first BILAG 1A/2B 
Flare 
Event 
Patient is designated a medication failure 
(received prohibited meds or unallowable 
CS burst) prior to or on their Day 210 visit  
 
Date of first dose of 
medication leading to 
medication failure 
designation.  These dates will 
be obtained from date of the 
medication failure identified 
by the sponsor based on the 
prior and concomitant 
medication eCRF form. 
Event 
Patient withdraws from study (no BILAG 
1A/2B Flare, no medication failure) prior to 
or on their Day 210 visit 
Censored at date of last non-
missing BILAG flare 
assessment (prior to or on 
withdrawal) through Day 210 
Censored 
Patient completes the study (no BILAG 
1A/2B Flare, no medication failure) 
Censored at date of last non-
missing BILAG flare 
assessment through Day 210 
Censored 
Patient dies during study (no BILAG 1A/2B 
Flare, no medication failure) prior to or on 
their Day 210 visit 
Censored at the day of death 
Censored 
An event will be counted once in a patient who is a medication failure and also experiences a 
BILAG flare.  Date of event will be the date of the earlier of the two reasons.   
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to first BILAG A Flare or >1 BILAG B Flare data will be provided in a by-patient listing 
in the full analysis set. 
7.3. Exploratory Endpoints and Analyses 
Efficacy will be evaluated for the Phase 1b MAD portion of the study as an exploratory 
endpoints and details are noted throughout sections 7.1 and 7.2.  Exploratory endpoints and 
analyses may be included in relation to the Phase 2 POC part of the study as described within 
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7.3.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
8. PHARMACOKINETICS/PHARMACODYNAMICS/ 
IMMUNOGENICITY  
 
Pharmacokinetics, pharmacodynamics, and immunogenicity are secondary endpoints for the 
Phase 1b MAD study and exploratory endpoints for the Phase 2 POC study.   
PD results reported as less than the lower limit of quantification (LLOQ) will be counted as 
0.5*LLOQ to calculate summary linear statistics and will be reported as <LLOQ in listings.  All 
observed Immunogenicity and PD data, as provided by an external vendor, will be presented in 
by-patient listings. 
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within an Appendix of this document.  The author, 
finalization date, signatories, and page numbering of this SAP are independent of those SAPs 
and vice versa. Only the last final versions will be included in the appendix just prior to study 
conclusion. 
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8.1. Pharmacokinetics 
BOS161721 PK concentration and parameter analyses will performed by a separate PK vendor 
and described under a separate SAP. 
8.2. Pharmacodynamics 
Descriptive statistics for the observed results of the following PD endpoints/results will be 
summarized separately at baseline and each visit.  Change from baseline and percentage change 
from baseline will be summarized at each post-baseline visit.  In cases where both numeric and 
qualitative results are provided, the summaries will be based on the numeric results.  In cases 
where only qualitative results are provided and results given only as titers, shifts will be 
summarized.  Graphical presentations of mean and SD of the change from baseline over time 
will also be presented for the parameters in table 6. 
Table 6 
PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Clinical PD Biomarkers  
 MAD and POC 
NA (all) 
C-Reactive Protein 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Other Biomarkers 
Phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3) 
MAD only 
% pSTAT3+ Lymphocytes –Stimulated; 
Ratio MEF (Stimulated / Unstimulated) 
Leukocyte immunophenotype 
(B and NK Cells) 
MAD only 
CD19+% of CD45+ Lymphocytes; 
IgD+C27-% of CD19+; 
IgD+CD27-CD38++CD24++% of 
CD19+; 
IgD-CD27-% of CD19+; 
IgD+CD27+% of CD19+; 
IgD-CD27+% of CD19+; 
IgD-CD27+CD38++CD138-% of 
CD19+; 
IgD-CD27+CD38++CD138+% of 
CD19+; 
CD56+% OF CD45+ Lymphocytes
Leukocyte  immunophenotype 
(T-Cells) 
MAD only 
CD4+CD8-% of CD3+; 
CXCR5+% of CD4+CD8-; 
PD-1+% of CD4+CD8-; 
ICOS+% of CD4+CD8-; 
CD25+CD127-% of CD4+CD8-; 
CXCR5+% of CD25+CD127-; 
PD-1+% of CD25+CD127-; 
ICOS+% of CD25+CD127-; 
CD8+CD4-% of CD3+ 
 
MAD only 
 
 
 
 
 
 
 
 
 
  
MAD and POC 
 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
 
MAD 
NA (all) – Listing only  
 
MAD and POC 
NA (all) – Listing only (including fold 
change)  
 
 
 
 
 
Additional PD results may be plotted over time by treatment group and visit. 
8.3. Immunogenicity 
Immunogenicity data as collected on the eCRF will be provided in by-patient data listings 
including neutralizing antibodies (NAb) and ADA for all relevant timepoints.  
All serum ADA samples that are confirmed positive in the ADA assay will be analyzed for the 
presence of NAb.   
The proportion of patients with positive or negative ADA will be summarized by study phase, 
treatment group, and overall, at baseline (pre-dose), and post-baseline in the FAS.  The 
frequency and percentage of patients with transient positive and persistent positive ADA will 
also be included in the summary.  If warranted based on data,  treatment-emergent transient 
positive and treatment-emergent persistent positive ADA will be summarized.  The frequency 
and percentage of patients with confirmed positive, treatment-emergent confirmed positive, and 
negative ADA at each post-baseline timepoint will also be summarized.  ADA designations and 
denominators are defined in table 7. 
Table 7 
Timepoint 
ADA 
Designations 
Definition 
Denominator/Evaluable 
Patients 
Baseline (Day 0 Pre-
Dose) 
Positive 
Confirmed positive ADA at 
baseline 
Number of patients with a 
baseline and at least one 
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Negative 
Negative ADA at baseline 
post-baseline ADA 
assessment  
 
Post-Baseline 
Positive 
Confirmed positive ADA at any 
time after baseline 
Number of patients with at 
least one post-baseline 
ADA assessment 
Negative 
Negative ADA at all times after 
baseline 
Transient 
Positiveiv 
(1) Last ADA sampling timepoint 
is negative 
AND 2a OR 2b: 
(2a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
and last ADA negative sample is at 
least 16 weeks apart from the 
previous confirmed positive 
sample. 
OR 
(2b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) and last 
ADA negative sample is at least 16 
weeks apart from the previous 
confirmed positive sample. 
Persistent 
Positiveiv 
1 OR 2 OR 3: 
(1) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) 
OR 


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(2) Confirmed positive ADA at the 
last post-baseline assessment 
OR 
(3) Negative ADA at the last post-
baseline assessment and a prior 
confirmed positive ADA sample 
occurred less than 16 weeks before 
the last post-baseline negative ADA 
sample 
 Treatment-Emergent 
Positive 
A post-baseline confirmed positive 
result exists with a titer >=4 times 
greater than the baseline titer 
OR 
Any post-baseline confirmed 
positive result after a negative 
baseline result 
Note: The number of treatment-
emergent transient positive and 
treatment-emergent persistent 
positive ADA will sum to the total 
positive treatment-emergent ADA 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Number of patients with at 
least one post-baseline 
ADA assessment 
Transient 
Positiveiv 
Scenario 1: 
(1) Negative ADA at baseline  
AND 
(2) Last ADA sampling timepoint 
is negative 
 AND (3a OR 3b): 
(3a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
and last ADA negative sample is at 


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least 16 weeks apart from the 
previous confirmed positive 
sample. 
OR 
(3b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) and last 
ADA negative sample is at least 16 
weeks apart from the previous 
confirmed positive sample. 
Scenario 2: 
(1) Confirmed positive ADA at 
baseline  
AND 
(2) Last ADA sampling timepoint 
is negative or is the same as 
baseline ADA levels 
 AND (3a OR 3b): 
(3a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
and the titer at the post-baseline 
timepoint is >=4 times greater than 
the baseline titer 
OR 
(3b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) and the 
titers at each of the two or more 
post-baseline confirmed positive 


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timepoints are >=4 times greater 
than the baseline titer 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Persistent 
Positiveiv 
Scenario 1: 
(1) Negative ADA at baseline  
AND (2 OR 3 OR 4): 
(2) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) 
OR 
(3) Confirmed positive ADA at the 
last post-baseline assessment 
OR 
(4) Negative ADA at the last post-
baseline assessment and a prior 
confirmed positive ADA sample 
occurred less than 16 weeks before 
the last post-baseline negative ADA 
sample 
Scenario 2: 
(1) Confirmed positive ADA at 
baseline  
AND (2 OR 3 OR 4): 
(2) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) and the 


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titers at each of the two or more 
post-baseline confirmed positive 
timepoints are >=4 times greater 
than the baseline titer 
OR 
(3) Confirmed positive ADA at the 
last post-baseline assessment and 
the titer at the last post-baseline 
timepoint is >=4 times greater than 
the baseline titer 
OR 
(4) Negative/similar to baseline 
ADA at the last post-baseline 
assessment and a prior 
confirmed positive ADA 
sample occurred less than 16 
weeks before the last post-
baseline negative/similar to 
baseline ADA sample and the 
titer of the confirmed positive 
ADA is >=4 times greater than 
the baseline titer 
 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Post-baseline at each 
timepoint 
Positive 
Confirmed Positive ADA at the 
post-baseline timepoint 
Number of patients with 
ADA assessment at 
baseline and at the post-
baseline timepoint 
Treatment-
Emergent  
Scenario 1: 
(1) Negative ADA at baseline 
(2) Confirmed positive ADA at 
the post-baseline timepoint 
Scenario 2: 
(1) Confirmed positive ADA at 
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(2) Confirmed positive ADA at 
the post-baseline timepoint 
and the titer at the of the 
confirmed positive ADA is 
>=4 times greater than the 
baseline titer 
Negative 
Negative ADA at the post-baseline 
timepoint 
Overall 
Positive 
A patient with positive baseline 
(pre-dose) ADA or positive post-
baseline ADA 
 
Number of patients with a 
baseline or post-baseline 
ADA assessment 
Negative 
A patient with negative baseline 
(pre-dose) ADA and negative post-
baseline ADA at all time points 
 
The frequency and percentages of positive and negative neutralizing antibodies will be 
summarized in the FAS overall and at each relevant post-baseline timepoint (i.e., Day 15, Day 
30, Day 60, Day 90, Day 180, Day 270). The denominators will be the number of patients with 
non-missing NAb data overall and at each timepoint, respectively. 
The adverse event overview table from section 10.1 will be repeated by post-baseline positive 
and negative ADA as defined in table 7 in the safety analysis set.  Additional adverse event 
analyses may be performed by post-baseline transient positive and persistent positive. 
9. QUALITY OF LIFE  
9.1. 
 
 
 
 
 
 
 
 
 
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9.2. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. SAFETY  
 
All safety analysis reporting will be based on the Safety Analysis Set.  Unless otherwise noted, 
all safety analyses will be presented overall, by study phase, and treatment group. 
10.1. Adverse Events 
AEs will be collected and recorded for each patient from the date of the first dose of study drug 
until the end of their participation in the study, including the safety follow up period.  Severity of 
adverse events will be graded by the investigator according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  AEs will also 
be assessed for relationship to study drug, and seriousness.  Adverse events will be marked as 
AESIs, dose-limiting toxicities (DLTs), or injection site reactions (ISRs), where applicable.  AEs 
will be considered treatment-emergent adverse events (TEAEs) if they started any time after first 
dose or if the year, month and day of start date were missing.  Any missing severity assessments 
will be assumed to be Grade 3, missing relationship assessments will be assumed to be related, 
and missing seriousness assessments will be assumed as serious. 
An overview of TEAEs will be produced, including counts and percentages of patients with any 
incidences of TEAE, TEAEs related to study treatment, SAEs, SAEs related to study treatment, 
any CTCAE grade 2 or higher TEAEs, any CTCAE grade 2 or higher TEAEs related to study 
treatment, any CTCAE grade 3 TEAEs, any CTCAE grade 3 or higher TEAEs related to study 
treatment, any CTCAE grade 4 TEAEs, any CTCAE grade 4 or higher TEAEs related to study 
treatment, TEAEs leading to study treatment discontinuation, treatment related TEAEs leading to 
study treatment discontinuation, TEAEs of special interest, related TEAEs of special interest, 
DLTs, related DLTs, TEAEs resulting in death, related TEAEs resulting in death, and injection 
site reactions.  The maximum CTCAE grade (Grades 1-5) will also be included on the summary 
table. 
Adverse events will be coded based on the MedDRA. Patients will be counted once per SOC 
(and likewise for PT within SOC). TEAEs will be summarized by SOC and PT in descending 
order of overall incidence of SOC (and PT within SOC).  The MedDRA version used is defined 
in the study data management plan. 
Summaries of adverse events by SOC and PT will include the following types:  
 TEAEs; 
 TEAEs related to study treatment;  
 SAEs; 
 Related Serious TEAEs; 
 CTCAE Grade 3 or higher TEAEs; 
 CTCAE Grade 3 or higher TEAEs related to study treatment; 
 TEAEs leading to treatment discontinuation; and 
 Dose-Limiting Toxicities 
 TEAEs of Special Interest 


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A summary of TEAEs by SOC, PT, and maximum CTCAE grade will also be prepared.  For 
these summaries, TEAEs will be sorted for each patient by SOC/PT and CTCAE grade; patients 
will be counted once within a SOC/PT based on their maximum CTCAE grade.  Missing 
CTCAE grade will be counted as grade 3 and will also be presented in a ‘Missing’ row for 
completeness. 
A summary of TEAEs by PT and maximum CTCAE grade will also be prepared with sections 
for any TEAE and TEAEs related to study treatment.  For these summaries, patients will be 
counted once within a PT based on their maximum CTCAE grade.  Missing CTCAE grade will 
be counted as grade 3.  An additional summary of TEAEs by PT and maximum CTCAE grade 
will summarized for all TEAEs and TEAEs related to treatment for PTs with at least one patient 
experiencing a CTCAE grade 3 or higher and PTs where 10% or more of patients experience a 
CTCAE grade 1 or 2 for that PT.  The summary will be sorted by the total incidence of the PT in 
the any TEAE section.   
A comprehensive listing of all AEs will be provided in a by-patient data listing for the safety 
analysis set. In addition, the following listings will be provided for the safety analysis set:  
 TEAEs related to study treatment;  
 SAEs;  
 TEAEs leading to treatment discontinuation; and 
 AESIs 
 CTCAE Grade 3 or Higher TEAEs 
10.2. Clinical Laboratory Evaluations 
Laboratory tests will be performed at times defined in the protocol Schedule of Assessments.  
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI).  The following laboratory evaluations will be reported in data summaries, 
with asterisks indicating those that will be graded using NCI CTCAE.  Grading will be 
performed by the Central Lab for relevant laboratory parameters based on the details provided in 
Appendix 13.11 .  If a grade is not present in the central lab database for a graded lab parameter, 
the grade will be analyzed as grade 0. 
Hematology: Hemoglobin*, Hematocrit, RBC count, RDW, MCV, MCH, MCHC, Platelet 
count*, WBC count*, CD4+ count*, Total neutrophils (Abs)*, Eosinophils (Abs), Monocytes 
(Abs), Basophils (Abs), Lymphocytes (Abs)* 
 
Clinical chemistry: Alanine Aminotransferase*, Albumin*, Alkaline Phosphatase*, Aspartate 
Aminotransferase*, Bicarbonate, Bilirubin*, Blood urea nitrogen, C Reactive Protein, Calcium, 
Chloride, Creatine Kinase*, Creatinine*, Glucose (fasting)*, Glucose (random)*, Potassium*, 
Protein, Sodium*, Uric acid*, eGFR (Cockcroft-Gault)*, eGFR (MDRD)*, Total cholesterol 
(fasting)*, LDL-C (fasting), HDL-C (fasting), Triglycerides (fasting)*, Gamma Glutamyl 
Transferase (GGT)*.  Per protocol, GGT is collected in cases of potential drug-induced liver 
injury. 


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Coagulation: Prothrombin Intl. Normalized Ratio*, Prothrombin Time 
Urinalysis: pH, Glucose (qual), Protein (qual)*, Blood (qual)*, Ketones (qual), Nitrites (qual), 
Leukocyte esterase (qual), Urobilinogen (qual), Urine bilirubin (qual), Microscopy 
 
Observed values, changes, and percentage changes from baseline for hematology, clinical 
chemistry, and coagulation laboratory evaluations will be summarized at each visit and most 
extreme change.  Endpoint analyses will be based on changes from baseline assessments at Days 
120 and 210. 
The number and percent of patients with a CTCAE toxicity grade of 3 or higher will be tabulated 
by laboratory evaluation with defined CTCAE grading at each visit for hematology, clinical 
chemistry, coagulation, and urinalysis (protein only).  Patients with missing values post-baseline 
will be excluded from the summary. The denominator for percentages will be the number of 
patients with a post-baseline assessment for the laboratory parameter in question at that visit. 
Hematology, clinical chemistry, coagulation, and urinalysis (protein only) shift tables displaying 
the shift from baseline to the worst value of CTCAE grade will be presented based on the most 
extreme change as it relates to the relevant CTCAE definition. CTCAE relating to “high/hyper” 
conditions will depend on the maximum post-baseline value while CTCAE “low/hypo” will be 
reported based on the minimum post-baseline value.  Separate shift tables will be prepared for 
parameters with bi-directional toxicity grading.  Lab parameters which are optional, such as 
gamma glutamyl transferase, will not be included in the shift tables. 
Hematology and clinical chemistry laboratory data which is not graded will also be summarized 
in shift tables of baseline to each visit based on range categories of low (below lower limit of 
normal [LLN], normal, and high [above upper limit of normal [ULN]]). 
Urinalysis laboratory data (excluding protein) will also be summarized in a shift table of baseline 
to each visit based on range categories of low (below lower limit of normal [LLN]), normal, 
abnormal, and high (above upper limit of normal [ULN]). 
Selected hematology and clinical chemistry laboratory results will be plotted over time for 
treatment group for MAD phase 1b portion of the study in the safety analysis set.  The mean and 
SD of the change from baseline for selected hematology and clinical chemistry laboratory results 
will be plotted over time for the POC Phase 2 portion of the study in the safety analysis set. 
All laboratory parameters as well as a summary of central laboratory tests and chest x-ray will be 
provided in patient data listings for all randomized patients.  By patient listings of clinical 
chemistry and hematology data will be presented in the safety analysis set for the DMC and 
interim analysis only. 


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10.3. Other Safety Evaluations 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening. i   The C-SSRS evaluation will be performed as specified in the protocol 
Schedule of Assessments. 
The C-SSRS has 11 binary (yes/no) outcomes corresponding to five categories of suicidal 
ideation, five categories of suicidal behavior, and the category of self-injurious behavior without 
suicidal intent: 
Suicidal ideation is present if there is a “yes” response to any of the 5 suicidal ideation category 
questions. Suicidal behavior is present if there is a “yes” response to any of the 5 suicidal 
behavior category questions.  Suicidal ideation or behavior is present if there is a “yes” response 
to any of the 10 suicidal or ideation or behavior category questions. 
The number and percentage of patients with any post-baseline occurrence of the following 
ideations and behaviors will be presented overall, by study phase and treatment group: 
 Suicidal ideation (overall and by individual question),  
 Suicidal behavior (overall and by individual question),  
 Suicidal ideation or behavior,  
 
A similar tabulation of the occurrence of any of the above ideations and behaviors at baseline or 
as part of their lifetime history/past 12-month history (collected at the screening visit) will be 
presented overall, by study phase, and treatment group. 
 
A shift table displaying the shift from worst pre-treatment category to the worst post-baseline 
category will be presented overall, by study phase, and treatment group.  Best to worst C-SSRS 
category is defined in the following order: no suicidal ideation or behavior, suicidal ideation, and 
suicidal behavior.  The worst post-baseline shift is calculated based on all post-baseline visits, 
including unscheduled visits.  Worst pre-treatment will include all C-SSRS assessments prior to 
first dose date/time (screening or baseline).  The denominator will be the number of patients with 
at least one non-missing baseline and post-baseline C-SSRS assessment. 
Missing data will not be imputed. 


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All C-SSRS individual items will be presented in data listings for screening and post-screening 
(since last visit), separately.  A separate listing will be presented for patients with suicidal 
ideation, suicidal behavior, or non-suicidal self-injurious behavior for all randomized patients. 
10.3.2. 
Vital Signs 
Vital signs include: heart rate (beats/min); temperature (oC); systolic and diastolic blood pressure 
(mmHg).  Observed values, changes, and percentage changes from baseline for vital signs will 
be summarized at each visit and time point, as well as for most extreme change overall, by study 
phase, and treatment group.  
All vital signs data will be presented in patient data listings for all randomized patients. 
10.3.3. 
12-Lead Electrocardiogram (ECG) 
ECG will be assessed as specified in the protocol Schedule of Assessments.  The following ECG 
parameters will be collected:  PR interval (msec), QRS interval (msec), RR interval (msec), QT 
interval (msec), and QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
(msec).  ECG parameters and ECG evaluation will come directly from the database and will not 
be calculated during analysis.   
Observed values, changes, and percentage changes from baseline for ECG parameters will be 
summarized at each visit, as well as for most extreme change overall, by study phase, and 
treatment group.  
The number and percent of patients with the following parameters at any post-baseline visit and 
at each visit will be summarized:  
 Abnormal, not clinically significant ECGs 
 Abnormal, clinically significant ECGs 
 
The number and percent of patients with each ECG evaluation result will be summarized by 
visit.  The worst ECG evaluation at any post-baseline visit will also be summarized in the order 
of: Normal, Abnormal, not clinically significant, Abnormal, clinically significant. 
For the summary of incidence at any post-baseline visit, the denominators for percentages will 
include patients with one or more non-missing value at any post-baseline visit.  For the by-visit 
summaries, the denominators for percentages will include patients with a non-missing value at 
that visit.  
Investigator reported ECG result shifts from baseline to each visit and worst case post-baseline 
will be summarized.  Worst case post-baseline will be based on the most abnormal observed 
value on or after the randomization date. 


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All ECG data will be presented in a by patient data listing for all randomized patients.  A 
separate by patient listing for patients with abnormal, clinically significant 12-lead ECGs will 
also be provided in the safety analysis set for DMC meetings and the interim analysis only. 
10.3.4. 
Physical Examinations 
Targeted physical examination data and full physical examination data will be presented in 
patient data listings.  A separate by patient listing for patients with abnormal, clinically 
significant physical examination findings will also be provided in the safety analysis set for 
DMC meetings and the interim analysis only. 
11. CHANGES TO THE PLANNED ANALYSIS 
 
The following changes were made to the planned analyses: 
 Time to SRI-4 Response was originally a planned endpoint for the MAD and POC portions of 
the study.  This was removed from the POC portion of the study upon Protocol Amendment 6 
(30Apr2020); however, the endpoint was inadvertently maintained in the protocol for the 
MAD portion of the study.  This analysis will not be performed for any study part. 
 Rules for applying LOCF were vague within the protocol and were further detailed in this 
SAP.  See Section 7 for further details. 
 The PP was clarified to include additional criteria beyond the protocol description.  The PP 
will exclude patients with more than one missed dose and missing both Day 180 and Day 210 
efficacy assessments (BILAG, SLEDAI-2K, or PGA).   
 Cytokine, chemokine and genotyping data were originally planned to be part of the MAD and 
POC portion of the study; however, data for these parameters is only available for the MAD 
portion of the study. 
 The definition of the CLASI response in the protocol is vague as the protocol defines the 
CLASI response as 50% improvement from baseline in “A” (total activity) or “B” (total 
damage) scores.  The SAP further calrifies the CLASI response as 50% improvement from 
baseline in CLASI and distinguishes a CLASI-A response from a CLASI-B response.


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12. REFERENCES 
 
i. Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
ii.
 
 
 
iii. Van Vollenhoven RF, Hahn BH, Tsokos GC, et al. Efficacy and safety of ustekinumab, an 
IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a 
multicentre, double-blind, phase 2, randomised, controlled study. Lancet. 
2018;392(10155):1330-1339. 
iv. Shankar G, et al.  Assessment and Reporting of the Clinical Immunogenicity of Therapeutic 
Proteins and Peptides – Harmonized Terminology and Tactical Recommendations.  AAPS 
Journal, 2014; 16(4):663. 
v. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study 
reports questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
vi. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf. Accessed 13 Jan 2016. 
vii. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9
_Guideline.pdf . Accessed 15 June 2016. 
viii. FDA Guidance for Industry Systemic Lupus Erythematosus – Developing Medical Products 
for Treatment. 2010. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm072063.pdf.  Accessed 23February2018. 
ix. Committee for Medicinal Products for Human use (CHMP).  EMA Guideline on clinical 
investigation of medicinal products for the treatment of systemic lupus erythematosus and lupus 
nephritis. 2015.  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500
184889.pdf. Accessed 04March2018. 
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x. 
 
xi. Nilsson M, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K.  
Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide. V2 2013.  
https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-Clinical-
Trials-1.pdf.  Accessed 18May2018. 
xii. 
 
 
  
 
xiii. 
 
  
. 
xiv. 
 
. 
 
 
 
 
 
 
 
 
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13. APPENDICES 
 
13.1. COVID-19 Impact and Data Handling 
 
The COVID-19 Pandemic resulted in contingency plans for BOS161721-02. 
 Safety Oversight: In case a patient cannot return to the study site for the 
scheduled visit, the site staff will contact the patient remotely for safety follow up, for 
example, via telephone or video conferencing.  The analysis of safety data will include all 
collected data regardless of remote data collection. 
 
 Central Laboratory: In the case of courier issues that will prevent the 
protocol-required laboratory specimens to be sent to the study core laboratory, 
the site should have the safety laboratory specimens (Hematology, 
Chemistry, and Urinalysis) sent to their local laboratory for analysis and review 
by the study physician.  The local laboratory data will not be entered into the clinical 
database or analyzed/presented in data summaries. 
 
 Investigational Product Dosing: In cases when dosing cannot be performed 
during the protocol-designated windows, the Investigator should discuss each 
case with the Sponsor to determine whether it is a missed visit or whether the 
dosing can be performed outside protocol windows (as a protocol deviation). A 
minimum of 2 weeks must be maintained between consecutive doses. Patients 
who miss more than 2 doses of the study drug (whether consecutive or not) will 
be discontinued from the study and will undergo assessments as outlined in 
Section 5.5 of the study protocol (Premature Discontinuation).  A sensitivity analysis of 
SRI-4 response using LOCF for missing data and/or observed case data may be 
performed to assess the impact of patients that did not follow the original protocol dosing 
schedule. 
An addendum to this SAP will be developed that documents all additional data handling 
techniques employed to manage COVID impacted data, if needed, prior to database lock and 
unblinding.  
 
 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 4.0, 23Apr2021 
 
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13.2. Physician’s Global Assessment 
 
 
 


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13.3. SLEDAI-2K Index 
 
 
 


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13.4. BILAG 2004 Index 
 


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13.5. ACR-28 Joint Count Assessment 
 


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13.6. SLICC/ACR Damage Index 
 


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13.7. CLASI 


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13.8. 
 
 
 
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13.9. C-SSRS 
13.9.1.  C-SSRS (Baseline/Screening) 
 


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13.9.2. C-SSRS (Since Last Visit) 
 
 
 


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13.11. CTCAE Grading Details from the Central Laboratory 
 


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13.12. Tables, Listings, and Figures 
 
Table, listing, and figure shells will be provided in a separate living mock shell document. 
 
 


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13.13. Other SAP(s) Describing Analyses not Covered in the SAP 
 
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within this Appendix. 


 
 
Page 1 of 104 
 
 BOS161721-02: A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 
COMBINED STAGGERED MULTIPLE DOSE ESCALATION STUDY OF 
BOS161721 IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS 
ON A BACKGROUND OF LIMITED STANDARD OF CARE 
 
 
Statistical Analysis Plan 
 
 
 
VERSION 3.0 
DATE OF PLAN: 
13Nov2020 
 
 
STUDY DRUG:  
BOS161721 
 
 
PREPARED FOR: 
Boston Pharmaceuticals, Inc. 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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Approval Signature Page: Array Biostatistics, LLC 
 
 
 
 
 
 
 
Document Author:   
, MS 
Director of Biostatistics 
 
Date 
 
 
 
 
 
 
Document Reviewer:  
, PhD 
Vice President, Biostatistical Consulting
 
Date 
 
 
 
 
 
 
 
PPD
PPD


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SAP Version and Date: Version 3.0, 13Nov2020 
 
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Approval Signature Page: Boston Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
Clinical Operations Lead 
 
Date 
 
 
 
 
 
 
 
 
 
, MD 
Vice President, Clinical Development
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sr. Director, Biostatistics 
 
Date 
 
 
 
 
PPD
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SAP Version and Date: Version 3.0, 13Nov2020 
 
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Contents 
1. 
Introduction ........................................................................................................................... 10 
2. 
Study Objectives and Endpoints ........................................................................................... 11 
2.1. 
Multiple Ascending Dose (MAD) Phase 1b Study ........................................................ 11 
2.2. 
Proof of Concept (POC) Phase 2 Study ......................................................................... 14 
3. 
Study Design ......................................................................................................................... 16 
3.1. 
Study Design and Population ......................................................................................... 16 
3.1.1. 
Multiple Ascending Dose Phase 1b ........................................................................ 17 
3.1.2. 
Proof of Concept Phase 2 ........................................................................................ 18 
3.2. 
Randomization and Blinding .......................................................................................... 19 
3.3. 
Sample Size Considerations ........................................................................................... 20 
3.4. 
Data Monitoring Committee (DMC) .............................................................................. 20 
3.5. 
Interim Analysis (IA) ..................................................................................................... 21 
3.6. 
Timing of Analyses ........................................................................................................ 21 
4. 
Data Analysis Considerations ............................................................................................... 22 
4.1. 
Stratification and Covariates .......................................................................................... 23 
4.2. 
Evaluation of Subgroups ................................................................................................ 23 
4.3. 
Multiple Comparisons and Multiplicity ......................................................................... 24 
5. 
General Data Handling Conventions .................................................................................... 24 
5.1. 
Reference Dates .............................................................................................................. 24 
5.2. 
Study Day and Duration Variables ................................................................................. 24 
5.3. 
Study Time Periods ........................................................................................................ 25 
5.4. 
Baseline, Post-Baseline Changes, and LOCF ................................................................ 25 
5.5. 
Imputation of Partial Dates ............................................................................................ 26 
5.6. 
Multiple Assessments and Visit Windows ..................................................................... 27 
5.7. 
Treatment Group Display ............................................................................................... 27 
5.8. 
Missing Data .................................................................................................................. 28 
6. 
Study Patient Data................................................................................................................. 28 
6.1. 
Analysis Populations/Sets .............................................................................................. 28 
6.2. 
Patient Disposition ......................................................................................................... 29 
6.3. 
Protocol Deviations ........................................................................................................ 29 
6.4. 
Demographic and Baseline Characteristics .................................................................... 30 
6.5. 
Medical History .............................................................................................................. 31 


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6.6. 
Prior and Concomitant Medication and Procedures ....................................................... 31 
6.7. 
Study Drug Exposure and Compliance .......................................................................... 32 
7. 
Efficacy ................................................................................................................................. 33 
7.1. 
Primary Efficacy Endpoint and Analyses ...................................................................... 33 
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 .................................. 33 
7.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 41 
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit ..................................... 42 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit ..................................... 42 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit ..................................... 43 
7.2.4. 
Oral Corticosteroid (CS) Reduction ........................................................................ 44 
7.2.4.1. 
Proportion of Patients with a sustained reduction of oral CS between Day 120 
and Day 210 (MAD) ............................................................................................................. 44 
7.2.4.2. 
Proportion of Patients with a sustained reduction of CS between Day 150 and 
Day 210 (POC) ..................................................................................................................... 45 
7.2.4.3. 
Percent Reduction in CS Administration from Day 0 through Day 210 (POC) . 45 
7.2.5. 
Proportion of new or recurrent BILAG A flare or >1 BILAG B flare through Day 
210 
45 
7.2.6. 
Physician’s Global Assessment (PGA) ................................................................... 46 
7.2.6.1. 
Proportion of Patients with PGA Worsening at Each Visit ................................ 46 
7.2.6.2. 
Results, Changes, and Percentage Change from Baseline in PGA ..................... 46 
7.2.7. 
Proportion of Patients with BICLA Response ........................................................ 47 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) ..................... 48 
7.2.8.1. 
Proportion of Patients with CLASI Response ..................................................... 49 
7.2.8.2. 
Results, Changes, and Percentage Change from Baseline in CLASI .................. 49 
7.2.9. 
Results, Changes, and Percentage Changes from Baseline in Swollen, Tender, and 
Active Joints ACR-28 ........................................................................................................... 50 
7.2.10. 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) .... 51 
7.2.10.1. 
Proportion of Patients with a SLEDAI-2K Response ..................................... 51 
7.2.10.2. 
Results, Changes, and Percentage Change from Baseline in SLEDAI-2K ..... 51 
7.2.11. 
Results, Changes, and Percentage Change from Baseline in SLICC/ACR 
Damage Index ....................................................................................................................... 52 
7.2.12. 
Medication Failure .............................................................................................. 53 
7.2.12.1. 
Proportion of Patients with Medication Failures ............................................. 53 
7.2.12.2. 
Time to Medication Failure (TTMF) ............................................................... 54 
7.2.13. 
Duration of Longest SRI-4 Response.................................................................. 55 


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7.2.14. 
Time to First BILAG A Flare or >1 BILAG B Flare through Day 210 .............. 55 
7.3. 
Exploratory Endpoints and Analyses ............................................................................. 56 
7.3.1. 
 ........................................................................ 56 
8. 
Pharmacokinetics/Pharmacodynamics/ Immunogenicity ..................................................... 57 
8.1. 
Pharmacokinetics ........................................................................................................... 57 
8.2. 
Pharmacodynamics ......................................................................................................... 58 
8.3. 
Immunogenicity ............................................................................................................. 60 
9. 
Quality of Life....................................................................................................................... 66 
9.1. 
 .............................................................................................................................. 66 
9.2. 
 ......................................................................................................................... 67 
10. 
Safety ................................................................................................................................. 68 
10.1. 
Adverse Events ......................................................................................................... 68 
10.2. 
Clinical Laboratory Evaluations ............................................................................... 70 
10.3. 
Other Safety Evaluations .......................................................................................... 71 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 71 
10.3.2. 
Vital Signs ................................................................................................................. 72 
10.3.3. 
12-Lead Electrocardiogram (ECG) ........................................................................... 72 
10.3.4. 
Physical Examinations .............................................................................................. 73 
11. 
Changes to the planned analysis ........................................................................................ 73 
12. 
References .......................................................................................................................... 75 
13. 
APPENDICES ................................................................................................................... 77 
13.1. 
COVID-19 Impact and Data Handling ..................................................................... 77 
13.2. 
Physician’s Global Assessment ................................................................................ 78 
13.3. 
SLEDAI-2K Index .................................................................................................... 79 
13.4. 
BILAG 2004 Index ................................................................................................... 81 
13.5. 
ACR-28 Joint Count Assessment.............................................................................. 83 
13.6. 
SLICC/ACR Damage Index ..................................................................................... 84 
13.7. 
CLASI ....................................................................................................................... 85 
13.8. 
 ................................................................................................................... 86 
13.8.1. 
 ................................................................................................ 86 
13.8.2. 
 ................................................................ 89 
13.9. 
C-SSRS ..................................................................................................................... 91 
13.9.1. 
C-SSRS (Baseline/Screening) ................................................................................... 91 
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13.9.2. 
C-SSRS (Since Last Visit) ........................................................................................ 93 
13.10. 
 ......................................................................................................................... 95 
13.11. 
CTCAE Grading Details from the Central Laboratory ........................................... 101 
13.12. 
Table of Contents for Tables, Listings, and Figures ............................................... 103 
13.13. 
Other SAP(s) Describing Analyses not Covered in the SAP .................................. 104 
 
 
 
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ABBREVIATIONS 
ACR 
American College of Rheumatology
ADA 
Anti-drug antibody
AE 
Adverse event
AESI 
Adverse event of special interest
ANA 
Antinuclear antibody
ANCOVA 
Analysis of covariance
ANOVA 
Analysis of variance
APL 
Antiphospholipid
ATC 
Anatomic therapeutic class
AUC 
Area under the curve
BICLA 
BILAG-based Composite Lupus Assessment
BILAG 
British Isles Lupus Assessment Group
BP 
Blood pressure
C3 
Complement C3
C4 
Complement C4
CL 
Systematic clearance
CLASI 
Cutaneous Lupus Area and Severity Index
Cmax 
Maximum plasma concentration
CS 
Corticosteroid
CSR 
Clinical Study Report
C-SSRS 
Columbia Suicide Severity Rating Scale
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation
DLT 
Dose-limiting toxicity
DMC 
Data Monitoring Committee
dsDNA 
Double-stranded deoxyribonucleic acid
ECG  
Electrocardiogram
eCRF 
Electronic case report form
EWB 
Emotional well being
 
FAS 
Full analysis set
FS 
Fatigue subscale
FWB 
Functional well being
HR 
Hazard ratio
IA 
Interim Analysis
IEC 
Independent Ethics Committee
IL-21 
interleukin 21
IM 
Intramuscular
IRB 
Institutional Review Board
ISR 
Injection site reaction
LLN 
Lower limit of normal
LLOQ 
Lower limit of quantification
LOCF 
Last observation carried forward
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LS 
Least squares
MAD 
Multiple Ascending Dose
MCS 
Mental component summary
MedDRA 
Medical Dictionary for Medical Affairs
NAb 
Neutralizing antibody
NCI 
National Cancer Institute
PCS 
Physical component summary
PD 
Pharmacodynamics
PGA 
Physician’s Global Assessment
PK 
Pharmacokinetics
POC 
Proof of concept
PP 
Per protocol set
pSTAT3 
Phosphorylated signal transducer and activator of transcription 3
PT 
Preferred Term
PWB 
Physical well being
Q1 
25th percentile/first quartile
Q3 
75th percentile/third quartile
SAD 
Single ascending dose
SAE 
Serious adverse event
SAP 
Statistical Analysis Plan
SAS 
Statistical analysis system
SC 
Subcutaneously
SD 
Standard deviation
 
SI 
International System of Units
SLE 
Systemic Lupus Erythematosus
SLEDAI-2K 
SLE Disease Activity Index 2000
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
System Organ Class
SRI-4 
SLE Responder Index 4
SRI-5 
SLE Responder Index 5
SRI-6 
SLE Responder Index 6
SS 
Safety analysis set
SSA 
Sjögren syndrome-A (Ro)
SSB 
Sjögren syndrome-B (La)
SWB 
Social/Family well being
t1/2 
Terminal elimination half-life
TEAE 
Treatment emergent adverse event
Tmax 
First time to maximum concentration
TTMF 
Time to medication failure
ULN 
Upper limit of normal
Vd 
Volume of distribution
WHO 
World Health Organization
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Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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1. INTRODUCTION 
 
The Statistical Analysis Plan (SAP) details the planned analyses that will be included in the 
Clinical Study Report (CSR) of study number BOS161721-02: A Randomized Double-Blind 
Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic 
Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care.  
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within Appendix 13.13 of this document.  The author, 
finalization date, signatories, and page numbering of this SAP are independent of those SAPs 
and vice versa. Only the last final versions will be included in the appendix just prior to study 
conclusion. 
 The content of this SAP is based on the protocol Version 7.0 (Amendment 6) dated 
30April2020. 
SAP Revision 
Chronology: 
Date: 
Comments: 
V1.0 
05SEP2018 
Original
V2.0 
29NOV2018 
Modifications due to Protocol Version 4 (Amendment 3) 
 Modified evaluable window for efficacy assessments to be 
inclusive of 35 days since prior assessment. 
 Modified structure of table shells to combine analyses (i.e., 
CLASI total activity and total damage; ACR-28 sum of 
swelling and sum of tenderness;
 
 biomarker and 
pharmacodynamic parameters) 
 Modified structure of listing shells
 
 
 Clarified Last Observation Carried Forward (LOCF) versus 
observed analyses in the output titles within the shells
V3.0 
13NOV2020 
Modifications due to Protocol Version 7 (Amendment 6) 
including: 
 Sample size changed based on recent published literature 
 LOCF algorithm updated 
 Modified planned sensitivity analyses based on missing data 
 Added, amended, and removed secondary and exploratory 
endpoints per protocol amdement 6 
 Defined efficacy subgroups 
 Added COVID-19 related data handling details 
 Modified evaluable window for efficacy assessments 
 Modified table, listing, and figure shells in accordance with 
text changes
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Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Multiple Ascending Dose (MAD) Phase 1b Study 
Objectives 
Endpoints
Primary 
 To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered subcutaneously (SC) in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment, in order to 
estimate the optimal dose. 
Safety Endpoints 
 Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
 Injection site reactions 
 Columbia Suicide Severity Rating Scale 
(C-SSRS) 
 12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
 Vital signs (blood pressure [BP], heart rate, 
and temperature) parameter results at each 
visit and change from baseline 
 Clinical laboratory results and change from 
baseline 
 Physical examinations changes from baseline 
 Anti-drug antibodies (ADAs) 
 Study drug exposure/compliance 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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Objectives 
Endpoints
Secondary 
 To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and PD 
effects in patients with moderate to 
severely active SLE. 
Pharmacokinetic (PK) Endpoints 
 BOS161721 concentration by visit and time 
point 
 Maximum observed concentration (Cmax), 
first time to maximum concentration (Tmax), 
area under the concentration-time curve 
(AUC), terminal half-life (t½), systematic 
clearance (CL), volume of distribution (Vd) 
Pharmacodynamic (PD) Endpoints 
 Results and changes (or shifts) from baseline 
to each visit in phosphorylated signal 
transducer and activator of transcription 3 
(pSTAT3), C3 and C4 levels, and leukocyte 
immunophenotype 
 Results and changes (or shifts) from baseline 
in anti-double-stranded DNA (dsDNA), 
antinuclear antibodies (ANA), anti-Sjögren 
syndrome A and B (SSA, SSB), Smith (Sm), 
and antiphospholipid (APL) autoantibodies 
at each visit 
 Results and changes (or shifts) from baseline 
in abrogation of IL-21 gene signature at each 
indicated visit 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints
- 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 See Section 11 
 
 
 
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2.2. Proof of Concept (POC) Phase 2 Study 
Objectives 
Endpoints
Primary 
 To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE SRI-4 
Primary Efficacy Endpoint 
 The proportion of patients with a SRI-4 
response at Day 210 
Secondary 
 To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on clinical indicators of SLE activity, 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care treatment 
Secondary Efficacy Endpoints 
 The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 7.5 mg/day and 
< Day 0 dose) between Day 150 and Day 
210 
- 
new or recurrent BILAG flares 
( ≥ 1 qualifying BILAG A 
or > 1 qualifying BILAG B) through 
Day 210 
- 
PGA worsening 
- 
a BICLA response  
- 
a CLASI response  
- 
medication failures 
 Change and percentage change from baseline 
at each visit in: 
- 
CLASI 
- 
PGA 
- 
Total number of swollen joints, tender 
joints, and active joints (swelling and 
tenderness in the same joint) in the ACR-
28 joint count 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index  
 TTMF 
 Group mean percent reduction in 
corticosteroid administration from baseline 
Day 0 dose through Day 210 in patients 
receiving ≥ 7.5 mg/day prednisone 
equivalent at Day 0


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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Objectives 
Endpoints
 Duration of longest SRI-4 response 
 Time to first BILAG flare (≥ 1 new or 
recurrent BILAG A or > 1 new or recurrent 
BILAG B) relative to baseline through 
Day 210 
Safety 
 To assess safety and tolerability of 
repeat doses of BOS161721 at the 
chosen dose administered SC in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Safety Endpoints 
 Incidence and severity of AEs and SAEs, 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
 Injection site reactions 
 C-SSRS 
 12-lead ECGs parameter results at each visit 
and change from baseline 
 Vital signs (BP, heart rate, and temperature) 
parameter results at each visit and change 
from baseline 
 Clinical laboratory results and change from 
baseline 
 Physical examinations changes from baseline 
 ADAs 
 Study drug exposure/compliance 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 3.0, 13Nov2020 
 
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Objectives 
Endpoints
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Endpoints will be discussed in the SAP based on their order in  the phase 2 POC portion of the 
study.  The phase 1b MAD endpoints overlap with and will be discussed within the context of 
the phase 2 POC endpoints. 
3. STUDY DESIGN 
3.1. Study Design and Population 
 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and PK of multiple subcutaneous doses of BOS161721 in adult 
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patients with moderately to severely active SLE.  After successfully completing a screening 
phase, eligible patients will be randomized to a specified dose of BOS161721 or placebo.  The 
dosing schedule will be monthly.   
The trial will consist of 2 double-blinded portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety follow-up visit at Days 210, 240, and 270.     
Investigators will assess SLE activity in accordance with accepted evaluation tools (further 
details provided in the SLE Assessment Reference Guide). 
SLE disease activity assessment data will be centrally reviewed by the CRO medical monitor(s), 
independent subject matter expert reviewers/adjudicators and the Sponsor to ensure the scores 
are clinically meaningful, compliant with specific definitions and compatible across various 
disease scoring tools.  The scope of responsibility includes, but is not limited to, review and 
confirmation of BILAG organ system disease grades, BILAG A and B flares,  and clinical 
components of SLEDAI-2Kscore at screening and during the study as well as cross-validation of 
the instruments used in this study to assess disease activity.  Further details on the content, 
processes, procedures and methods of disease activity data reports will be outlined in the 
Medical Data Review Plan and the BILAG-2004 Review Guidelines. 
3.1.1. 
Multiple Ascending Dose Phase 1b  
The MAD portion will consist of 3 cohorts:  
 Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
 Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 single ascending dose (SAD) study (BOS161721-01) in healthy 
patients.  All doses selected for the MAD part of the study are projected not to exceed the mean 
exposure of that achieved at the highest dose in the SAD study. 
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 2 
begins dosing after the Data Monitoring Committee (DMC) evaluation of the safety and 
tolerability data from Cohort 1.  Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 3 begins dosing 
after the DMC evaluation of the safety and tolerability data from Cohorts 1 and 2.  Each cohort 
will continue at their assigned dose level through their respective 6-month treatment periods (See 


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Study Schematic in the study protocol).  If patients discontinue the study in a cohort prior to 
adequate safety follow-up, he/she may be replaced. 
Criteria for dose escalation are further described in the DMC Charter. 
3.1.2. 
Proof of Concept Phase 2  
The dose for the POC portion of the study is 120 mg administered SC monthly (a total of 
7 doses). The rationale for the BOS161721-02 phase 2 POC dose selection was based on 
cumulative safety, tolerability, immunogenicity, PK, and PD data available from an interim 
analysis (IA) performed during the MAD phase 1b portion of the trial.  
The data cut-off for this IA occurred on 
 and included all 6 patients and 
7 doses from Cohort 1 (20 mg), 12 patients and 6 doses from Cohort 2 (60 mg), and 12 patients 
and 4 doses from Cohort 3 (120 mg).  
The safety analysis focused on incidence and severity of all AEs, SAEs, and pre-determined 
adverse events of special interest (AESI). The DMC and designated unblinded Boston 
Pharmaceuticals team met on 
 and did not identify any untoward safety 
signals at any BOS161721 dose levels.  
Because there were no safety, tolerability, or immunogenicity trends observed at the time of the 
IA, the phase 2 POC dose selection was made based on available PK and PD data. pSTAT3 
levels were assessed as the primary PD biomarker of IL-21R signaling levels. This is because IL-
21R signaling, upon IL-21 binding, initially involves phosphorylation of JAK1/JAK3 which 
dissociate from the receptor complex, and phosphorylate STAT3 which translocates to the 
nucleus and drives IL-21-regulated gene expression. 
 
 
The 120 mg dose was communicated to site Investigators participating in the POC phase 2 
portion, and to Institutional Review Boards (IRBs) and the Independent Ethics Committee (IEC).  
For the POC part of the study, approximately 110 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments detailed in the study protocol.   
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
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Study Diagram for MAD Phase 1b and POC Phase 2 
 
A = active drug (BOS161721); P = placebo 
3.2. Randomization and Blinding 
 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an interactive web response system according to a randomization 
list generated by an independent, non-study statistician.  Randomization will be performed 
separately for each study portion and separately for each cohort in the Phase 1b and 2 portions as 
follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
*Approximately 110 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
 


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Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1b MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the IA, ad hoc analyses as needed, and the DMC safety reviews.  The DMC will 
review unblinded data during safety reviews and the IA.  A limited team at Boston 
Pharmaceuticals will review unblinded results from the Phase 1b MAD portion during the IA to 
determine the dose that will be used for the Phase 2 POC portion of the study.  Details regarding 
maintenance of the blinding and content of data reviews will be described in the DMC charter or 
related study documentation.   
3.3. Sample Size Considerations 
 
Sample size in the Phase 1b part of the study is based on operational consideration. 
The sample size in the Phase 2 POC study is based on the primary endpoint, SRI-4 Response at 
Day 210.  Based on efficacy data from a recently completed study with Ustekinumabiii, where 
the primary endpoint was also SRI-4, the sample size in the phase 2 part of the BOS161721-02 
study is set at 96 evaluable patients. In the Ustekinumab study of 102 patients, a statistically 
significant difference in SRI-4 response was shown in favor of Ustekinumab (62% of 
Ustekinumab treated patients achieved SRI-4 response vs. 33% in patients receiving placebo). 
The Ustekinumab phase 2 study is an appropriate comparator to BOS161721-02 because both 
studies share the same primary endpoint of SRI-4 response and BOS161721 and Ustekinumab 
have overlapping mechanisms of action (T follicular helper and Th17 cell biology).  
Approximately 110 additional patients will be randomized in a 2:1 ratio to BOS161721 versus 
placebo to achieve approximately 96 evaluable patients in the FAS of the phase 2 portion.  This 
assumes 14 patients will discontinue prior to having received treatment or having completed a 
post-baseline efficacy measure.  Enrollment and randomization will be monitored in a blinded 
fashion and may be increased if needed to ensure at least 96 evaluable patients are randomized 
into the FAS (see Section 6.1).    
A total of 96 evaluable patients randomized provides 80% power to detect a treatment difference 
of 29% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance level of 10% 
and using a 2-sided Pearson’s chi-squared test.  This assumes a response rate of 62% for 
BOS161721 and 33% for placebo. 
3.4. Data Monitoring Committee (DMC) 
 
This study will use an external DMC.  The DMC is an independent committee established to 
provide safety oversight and to advise the sponsor regarding actions necessary to protect study 
participants and the scientific integrity of the study. The recommendations made by the DMC 


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(i.e., dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in the study protocol. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
3.5. Interim Analysis (IA) 
 
One IA is planned for this study and will be conducted at the time of dose selection for POC. The 
POC dose will be selected based on cumulative available safety, tolerability, PK and PD data 
based on the MAD data.  Since there is no IA during the POC part of the study, there is no 
impact on the type 1 error.   
3.6. Timing of Analyses 
 
The following analyses are planned: 
 An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC portion.   
 The final analysis will be performed when all patients have either completed the POC 
safety follow up or withdrawn from the study.   
 Safety analyses will be performed for DMC reviews throughout the study to evaluate 
accumulating safety data and make dose escalation decisions.  The frequency and details 
of the content and format of the safety review meetings are described in the DMC charter 
and SAP and applicable mock shells. 


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4. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.3 or higher. 
All data in the database will be presented in by-patient data listings. 
Unless otherwise stated, all listings will be sorted by study phase, treatment group, patient 
number, and assessment date (and time, if available).  If assessment date is missing, 
chronological visit will be used for sorting. 
Unless stated otherwise, continuous data will be summarized by treatment group based on 
number of patients (n), mean, median, standard deviation (SD), 25th percentile/first quartile (Q1), 
75th percentile/third quartile (Q3), minimum value, and maximum value. 
The geometric % coefficient of variation (CV) is calculated as 100*sqrt(exp(SDlog^2)-1) where 
SDlog is the SD of log-transformed values. 
Unless stated otherwise, categorical data will be summarized by treatment group using n and 
percentage based on the number of non-missing values. 
 The number of missing values will be presented as a separate category with no 
percentage, but only if one or more patients are missing data. 
 Counts of zero will be presented without percentages. 
 Statistics will be presented in the summary tables based on the following: 
 Minimum and maximum: same number of significant digits as the raw value 
 Mean, median, Q1, and Q3: one additional decimal place to that reported for 
minimum and maximum 
 SD: two additional decimal places than presented for the minimum and maximum  
 Percentages: reported to one decimal place with the exception of 100% which will 
be displayed without decimals. 
 P-values will be reported to four decimal places.  If the value is below 0.0001 it 
will be noted as < 0.0001; if the value above 0.9999 it will be noted as > 0.9999. 
Unless otherwise noted, statistical inference will be based on a 10% significance level (i.e. 90% 
confidence intervals will be produced). 
Statistical testing will be performed on data from the Phase 2 study. 
Numbering for data displays will be based on ICH E3. 
 


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4.1. Stratification and Covariates 
 
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data may be conducted as 
deemed appropriate to evaluate factors for which analyses are not controlled. 
Continuous efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of 
covariance (ANCOVA) when applicable, adjusting for the baseline value. 
Sensitivity analyses of the primary efficacy endpoint may be performed with covariates defined 
based on the subgroups in section 4.2. 
4.2. Evaluation of Subgroups 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The patient will be excluded from subgroup analyses if they are missing the subgroup parameter 
at baseline. 
4.3. Multiple Comparisons and Multiplicity 
 
The Type 1 error rate will not be adjusted for multiplicity.  
5. GENERAL DATA HANDLING CONVENTIONS 
5.1. Reference Dates 
 
 Screening date is defined as the electronic case report form (eCRF) provided date on 
which a patient was screened for trial entry. 
 Informed consent date is the date the patient signed the informed consent form. 
 Randomization date is defined as the date on which the patient is randomized to study 
treatment. 
 Treatment start date is defined as the date of first dose of study drug. 
 Treatment end date is defined as the date of last dose of study drug. 
 Age will not be calculated and will come directly from the eCRF.  The eCRF uses the 
informed consent date as its reference date for age calculation. 
 Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date. 
 Efficacy data will use the randomization date as a reference date. 
 Study day will be based on treatment start date as a reference date. 
5.2. Study Day and Duration Variables 
 
Reference date calculations will be defined as follows, assuming non-missing dates:  
 date of interest – reference date + 1 when the date of interest is on or after the reference 
date; 
 otherwise, date of interest – reference date. 
 
If either date is missing or incomplete, reference date calculations will not be performed.  Date 
imputation will be performed as identified in Section 5.5. 
 
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Study day will either have a negative value if collected before dosing or a positive value if 
collected on or after the day of drug dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation.  Duration on study is defined as the end of study date –
informed consent date + 1.  Duration of treatment is defined as treatment end date – treatment 
start date + 1, where treatment end date is the date of last dose of study drug. 
Time-to-event endpoints are followed until first event or censoring.  As a result, event time will 
be calculated as: event or censoring date – reference date + 1.  These are further described in 
Section 7. 
When reporting time-to-event data (TTMF and time to BILAG A flare or >1 BILAG B flare) or 
duration outcomes, the results (in days) above will be converted to an appropriate unit.  When 
reporting in months it will be divided by 30.4375; for reporting in weeks it will be divided by 7; 
and for reporting in years it will be divided by 365.25. 
5.3. Study Time Periods 
 
Where applicable, data reporting will be classified by the following study periods for analysis: 
 Pre-treatment is defined as the period prior to a patient’s treatment start date. 
 On-treatment is defined as the period between a patient’s treatment start date and 
treatment end date, inclusive. 
 Post-treatment is defined as the period of time following the on-treatment period. 
5.4. Baseline, Post-Baseline Changes, and LOCF 
 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
 Baseline will be based on the last non-missing value collected prior to or on the date/time 
of first dose of study drug. 
 Post-baseline values will be those collected after the date/time of first dose of study drug. 
 Change from baseline is defined as: value – baseline value.  
 Percentage change from baseline is defined as: [(value – baseline value) / baseline 
value]*100.  Patients with baseline values of zero are excluded due to division by zero. 
 Most extreme change:  The maximum most extreme change will be the maximum post-
baseline change value; the minimum most extreme change will be the smallest post-
baseline change value. This calculation will consider all assessments collected after the 
first dose of study drug, scheduled or unscheduled. 
 LOCF: 
o Imputation rules for assessments that include multiple components: 


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 In case of missing laboratory components, lab values from the most recent 
unscheduled visit <=14 days after the nominal visit will be utilized.  If lab 
values are not available from an unscheduled visit <=14 days after the 
visit, laboratory data will be carried forward from the most recent 
laboratory assessment <=30 (scheduled or unscheduled) days prior to the 
nominal visit. 
 In case of missing non-laboratory components, no imputation will be 
performed.   
o In case of missing the entire score for an assessment, imputation will be based on 
LOCF.  LOCF will only be implemented with the most recent prior visit 
(including unscheduled assessments).  If the most recent prior visit is missing, 
occurred more than 30 days before (current visit date – most recent prior visit date 
> 30), or is not evaluable, LOCF is not implemented.  See Section 7 for further 
details.  Additional details regarding LOCF for components for specific 
assessments are described in Section 7. 
o Observed values do not incorporate any imputations and are presented as 
collected. 
5.5. Imputation of Partial Dates 
 
Adverse Events  
 If the AE start date is completely missing, or if the patient was not treated, no imputation 
will be conducted. 
 If the AE start date is missing day and month, do the following: 
o If the treatment start date is missing or the AE start year does not fall in the same 
year as that of the treatment start date or if the AE record contains information to 
indicate that the event ended before the treatment start date (e.g. the AE end date 
month and year are earlier than the treatment start date or the full AE end date is 
known and occurs earlier than the treatment start date), then set the AE start 
month and day to January 1st. 
o Otherwise, set the AE start date to the treatment start date.  
 If only the AE start day is missing, do the following: 
o If the study treatment start date is missing or the AE start month and year does not 
fall in the same month and year as that of the treatment start date or if the AE 
contains information to indicate that the event ended before the treatment start 
date, then set the AE start day to the 1st day of the month of the AE start date. 
o Otherwise, set the AE start date to the treatment start date. 
 AE end dates will not be imputed.  
Prior, Concomitant, and Subsequent Medications (Excluding Corticosteroids) 
 The imputation rules for AE start dates will be used for medication start dates. 
 Medication stop dates will be imputed as follows: 


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o If the stop date is only missing the day, then the stop day is the last day of the 
month 
o If the stop date is missing both the day and month and the year matches the last 
study date, then the stop month and day is the earlier of the last study date and 
December 31 
o If the stop date is missing both the day and month and the year is earlier than the 
last study date, then the stop month and day is December 31 
o If the stop date is completely missing, no imputation is performed, and the 
medication will be classified as a concomitant medication for patients who were 
treated. 
Corticosteroids 
Due to the criticality of the corticosteroid usage, handling of partial start/stop dates will be 
performed on a case-by-case basis as it will require medical review of the patient records.  Such 
determinations will be made in a blinded fashion prior to database lock and approved by the 
Sponsor. 
Diagnosis Date 
 If the diagnosis date is completely missing, no imputation will be conducted. 
 If the month and day are completely missing but year is present, do the following: 
o Set missing month and day to July 1st 
o If July 1st of the non-missing year is after informed consent date, set month and 
year to January 1st 
 If only the day is missing, set to the 1st of the month 
 
5.6. Multiple Assessments and Visit Windows 
 
Nominal visits (e.g. those identified by the study eCRF) will be the basis of summarization and 
statistical analysis unless otherwise specified. Unscheduled data may be included in summaries 
of most extreme, baseline, LOCF, and endpoint values; summaries of specific abnormalities any 
time post-baseline; and patient data listings 
5.7. Treatment Group Display 
 
Treatment groups will be displayed with the following columns.  See the mock shells for 
additional details and a visual representation of the treatment group display.  All overall columns 
will be excluded from efficacy outputs. 
 Phase 1b MAD: Cohort 1 BOS 20mg 
 Phase 1b MAD: Cohort 2 BOS 60mg 
 Phase 1b MAD: Cohort 3 BOS 120mg 


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 Phase 1b MAD: Placebo 
 Phase 1b MAD: Total BOS (All patients treated with BOS161721, excludes placebo) 
 Phase 2 POC: BOS 120mg 
 Phase 2 POC: Placebo 
 Overall: Total BOS 120mg (All patients treated with BOS161721 120mg in MAD and 
POC) 
 Overall: Total BOS (Patients treated with BOS161721 in MAD and POC, excludes 
placebo) 
 Overall: Total Placebo (Placebo patients in MAD and POC, excludes patients treated 
with BOS161721) 
5.8. Missing Data 
 
Missing data imputation for the efficacy endpoints are discussed in the corresponding efficacy 
sections.  AE, concomitant medication, and corticosteroid date imputations are described in 
Section 5.5.  Missing data and other analysis conventions for noncompartmental analysis of 
pharmacokinetics will follow standard imputation methods, as described in a separate Clinical 
Pharmacology SAP.  Otherwise, missing data will not be imputed. 
6. STUDY PATIENT DATA 
6.1. Analysis Populations/Sets 
 
FAS:  Defined as all patients who receive at least one dose (partial or complete) of study 
treatment and have at least one evaluable post-baseline efficacy evaluation (BILAG, PGA, 
SLEDAI-2K, CLASI, ACR-28, SLICC/ACR, 
, or 
).  FAS analyses will be 
conducted on the basis of the assigned (randomized) treatment.  The FAS will be used as the 
basis for the primary efficacy analysis. 
Safety Analysis Set (SS): Defined as all patients who receive at least one dose (partial or 
complete) of study treatment and have at least one evaluable post-baseline safety evaluation 
(adverse events, concomitant medications, vital signs, physical examination, ECG, or laboratory 
assessment).  Safety analyses will be conducted on the basis of actual treatment received as 
reported on the eCRF.  The SS will be the basis of all safety reporting. 
Per Protocol Set (PP): Defined as all patients from the FAS except those with major deviations 
to the protocol deemed to impact the analysis of the primary endpoint.  These deviations will be 
identified based on blinded data review prior to study unblinding.  Patients with more than one 
missed dose will be excluded from the PP.  PP analyses will be conducted on the basis of the 
assigned (randomized) treatment.  Additional information on inclusion into this population can 
be found in Section 6.3. 
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Pharmacokinetic Analysis Set (PK): Defined as all patients in the FAS with sufficient data for 
the calculation of PK parameters. This analysis population will not be used for analyses 
corresponding to this SAP.   
6.2. Patient Disposition 
 
Disposition data will be summarized for all randomized patients.  The number of patients in each 
analysis set population, the number of patients who discontinued study treatment including 
reasons, and the number of patients who discontinued the study including reasons will be 
summarized.  The number of patients who completed the study, duration on study treatment in 
days and duration on study in days will also be summarized.  Data will be presented overall, by 
study phase, and treatment group. 
A by-patient listing of patient disposition data including reason for discontinuation, if applicable, 
will be presented for all randomized patients.  A by-patient listing of randomization details will 
also be provided for all randomized patients. 
A by-patient listing of inclusion/exclusion criteria and screen failures will be produced for all 
enrolled patients.  Screen failures will otherwise not be included in any analyses. 
6.3. Protocol Deviations 
 
Protocol deviations will be identified and classified as major or minor before database lock and 
unblinding. Major protocol deviations may include but are not limited to: 
 Violation of Inclusion/Exclusion Criteria 
 Use of prohibited therapies 
 Incorrect treatment 
Major protocol deviations that necessitate exclusion from the efficacy analysis in the PP 
population will be identified prior to database lock and unblinding.  
Protocol deviations will be summarized by any deviation, deviation category, and major/minor 
designation.  Protocol deviations will be summarized overall, by study phase, and treatment 
group for all randomized patients. 
A listing of protocol deviations, including protocol version under which the deviation occurred, 
will be provided for all randomized patients. A separate listing of COVID-19 related deviations 
also will be provided. 
 
 


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6.4. Demographic and Baseline Characteristics 
 
Patient demographics and baseline characteristics will be summarized in the SS.  These will 
include age (years), sex (Male / Female), ethnicity (Hispanic or Latino / Not Hispanic or Latino), 
race (American Indian or Alaska Native / Asian / Black or African American / Native Hawaiian 
or Pacific Islander / White / Other), geographic regions (North America / South or Central 
America / Eastern Europe), baseline height (cm), baseline weight (kg), and baseline BMI 
(kg/m2).  Age is reported as collected in the clinical database and will also be categorized as a 
categorical variable (≤45, >45-<65, ≥65) for reporting.  Patient eligibility for central review will 
be summarized.  Childbearing potential and birth control methods for female and male patients 
will be summarized for the DMC meetings and interim analysis only.  Demographics and 
baseline characteristics will be summarized overall, by study phase, and treatment group. 
 
Baseline disease characteristics will also be summarized in the FAS.  The SLEDAI total score, 
PGA, CLASI total activity score, CLASI total damage score, ACR-28 sum of swelling, ACR-28 
sum of tenderness, ACR-28 sum of active joints (swelling and tenderness in the same joint) and 
SLICC/ACR damage index total score will be summarized at baseline.  Frequencies and 
percentages of patients with SLEDAI presence by component, ACR-28 loss of functional range 
interfering with life and ACR-28 impairment of basic activities from inflammation as well as 
BILAG grades by body organ system will be presented.  Frequency and percentage of patients 
with each organ system disease on BILAG SLE history will be summarized.  Frequency and 
percentage of patients with SLICC criteria for SLE will be summarized.  Frequencies and 
percentages of patients with CLASI Activity Score (<8 vs. >=8), SLEDAI-2K (<10 vs. >=10) 
and baseline corticosteroid use (0, <7.5, >= 7.5, <10, >=10 mg/day), will be presented.   
 
Frequencies and percentages of patients will also be presented for the following characteristics: 
 
 
Positive anti-ds-DNA 
 Low C3 and/or C4 
 Positive anti-dsDNA and normal C3 and normal C4 
 Negative anti-dsDNA and low C3 and/or C4 
 Positive anti-dsDNA and low C3 and/or C4 
 Negative anti-dsDNA and normal C3 and normal C4 
 Other 
 
In addition, frequencies and percentages of patients will be presented for the following 
characteristics:  
 
 SLEDAI-2K ≥ 10 and negative** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and positive** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and negative** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and positive** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and positive** anti-dsDNA and normal C3 and normal C4 


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 SLEDAI-2K < 10 and negative** anti-dsDNA and low C3 and/or C4 
 SLEDAI-2K < 10 and negative** anti-dsDNA and normal C3 and normal C4 
 SLEDAI-2K ≥ 10 and positive** anti-dsDNA and low C3 and/or C4 
** Positive anti-dsDNA is defined as ≥ 15 IU/mL.  Negative anti-dsDNA is defined as < 15 
IU/mL 
Time from diagnosis to informed consent in years defined as (informed consent date - date of 
diagnosis as recorded on the screening BILAG assessment)/365.35 will be summarized.  Partial 
dates of diagnosis will be handled as defined in section 5.5.  Baseline disease characteristics will 
be summarized overall by study phase and treatment group. 
 
Demographics and baseline characteristics will be listed for all randomized patients.  A separate 
by-patient listing will be created for childbearing potential and birth control for all randomized 
patients. 
 
The following conversions and equations will be used as applicable: 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = weight(kg)/[height(m)2] 
 
6.5. Medical History 
 
The incidence of medical history will be summarized by system organ class (SOC) and preferred 
term (PT) overall, by study phase, and treatment group in the SS.  Patients will be counted once 
per SOC (likewise for PT within SOC). Medical history terms will be coded based on the 
Medical Dictionary for Regulatory Affairs (MedDRA). Medical history will be reported in 
descending order of overall incidence of SOC and then in descending order of overall incidence 
for PT within the SOC.  
Medical history will be presented in data listings for all randomized patients.  Medical history 
coded terms will be provided, including the SOC and PT.   
The MedDRA version used is defined in the study data management plan. 
6.6. Prior and Concomitant Medication and Procedures 
 
The incidence of medication use will be summarized by World Health Organization (WHO) 
Drug Dictionary anatomic therapeutic class (ATC) Level 2 classification (i.e. therapeutic main 
group) and preferred name. A patient will be counted only once at each level of reporting.  Prior 
medications are those which have been identified to have been discontinued prior to the first 
dose of study medication.  Concomitant medications are those which have been identified to 
have been taken at any point during the period of time between the first dose of study drug and 


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last dose of study drug + 90 days, including medications which started prior to first dose of study 
drug that are ongoing at first dose.  Subsequent medications are those which have been started 
after the last dose date + 90 days.  The data management plan specifies the version of WHO 
Drug used. 
Partial dates will be imputed according to Section 5.5 for the determination of prior, 
concomitant, and subsequent medications. 
Concomitant medication use will be summarized and presented overall, by study phase, and 
treatment group in the SS.  
A separate summary will be prepared for corticosteroids.  Corticosteroids will be presented 
overall, by study phase and treatment group in the SS.  The average daily dose of CS (prednisone 
equivalent) at each visit including summary statistics as well as categorical summaries for <5 
mg/day, ≥5 mg/day to ≤10 mg/day, and >10 mg/day will be presented.  Average daily dose is 
calculated as described in Section 7.2.4.  Prednisone equivalence is also provided in the same 
section. 
All prior and concomitant medication data will be provided together in a by-patient listing 
including the verbatim and preferred drug name and WHO ATC Class (ATC Level 2) for all 
randomized patients.  Past biological, immunosuppressant, antimalarial and corticosteroid SLE 
medication history data will be listed separately for all randomized patients. 
Concomitant procedures will be presented in a data listing for all randomized patients. 
6.7. Study Drug Exposure and Compliance 
 
The total dose administered (mL) and the number of doses received will be summarized as 
continuous variables.  The number and percentage of patients that received any dose and the 
number and percentage of patients who received the total planned dose at each nominal, protocol 
specified, visit (Day 0 / Day 30 / Day 60 / Day 90 / Day 120 / Day 150 / Day 180) will be 
summarized.  The number and percentage of patients who received 1-7 doses (mutually 
exclusive) will also be summarized categorically.  The denominator for the number of patients 
dosed and the number of doses received will be the number of patients in the SS.  The 
denominator for the number of patients who received the total planned dose will be the number 
of patients dosed at the corresponding nominal visit. 
The percent compliance will be summarized descriptively and is defined as 100 * (sum of doses 
received / 7).  Percent compliance will also be calculated categorically as <70%, ≥70% to <85%, 
≥85% to <100%, ≥100%. 
Relative dose intensity will be summarized descriptively and is defined as 100 * (total actual 
dose summed across all visits)/total planned dose summed across all planned visits) per the 
below table. 


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Dose Level 
(mg) 
Dose Level 
(mL)* 
Total Planned Dose 
Across All 7 Visits (mL) 
Relative Dose Intensity Calculation 
20 
0.4 
2.8 
(Total actual dose in mL summed 
across all visits / 2.8) X 100 
60 
1.2 
8.4 
(Total actual dose in mL summed 
across all visits / 8.4) X 100 
120 
2.4 
16.8 
(Total actual dose in mL summed 
across all visits / 16.8) X 100 
* Dose Level in mL is based on 50mg/mL administration. 
The duration of exposure in days will also be summarized descriptively and is defined as the last 
dose date – first dose date +1.   
Study drug exposure and compliance will be presented overall, by study phase, and treatment 
group in the SS. 
By-patient listings of BOS161721 and placebo dosing data will be produced for all patients in 
the SS. 
7. EFFICACY  
7.1. Primary Efficacy Endpoint and Analyses 
 
Safety will be the primary endpoint for the Phase 1b MAD portion of the study and is discussed 
in Section 10.  Efficacy will be evaluated for the Phase 1b MAD portion of the study as an 
exploratory endpoint and details will be included in relation to the Phase 2 POC portion of the 
study within this section.  Efficacy analyses will be presented by study phase and treatment 
group.  
7.1.1. The proportion of patients with a SRI-4 response at Day 210 
 
The primary efficacy endpoint for the POC is the proportion of patients who achieve a SRI-4 
response at Day 210 in the FAS.  
 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K, the BILAG 2004 Index, and the PGA.  SRI-4 response is defined as:  
 
1) ≥ 4-point reduction from baseline in SLEDAI-2K total score  
 
AND 


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2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm.   
 
The test for treatment group difference in proportion of patients who achieve a SRI-4 response at 
Day 210 will be based on Pearson’s chi-square test.  The difference in percentages of patients 
who achieve SRI-4 response (BOS161721 vs. Placebo) will be presented with its corresponding 
(Wald) 90% CI.  The number and percentage of SRI-4 responders, along with an exact (Clopper-
Pearson) 90% CI, will be presented by treatment group.  If an expected count for the Pearson 
chi-square test falls below 5, a Fisher’s exact test will be used to assess the treatment difference 
and the CI will be based on an exact method (Santner Snell).  The analyses will be repeated for 
each of the three components contributing to the SRI-4 response.  The primary analysis of the 
primary efficacy endpoint will be performed in the FAS and presented by treatment group. The 
analysis will be repeated in the PP analysis set.  SRI-4 Response at Day 210 will also be repeated 
by all subgroups in Section 4.2 and treatment group for POC Phase 2 only.   
 
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the POC placebo 
arm, then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 
0.10. 
Evaluability/Non-Responders: 
Medication Failures: Patients who received prohibited medications or undergo unallowable 
corticosteroid (CS) usage will be considered “medication failures” and will be treated as non-
responders at time points on and following the first date of prohibited medication or unallowable 
CS usage for the primary efficacy analysis.  Prohibited medications are detailed in Appendix 4 of 
the study protocol.  Prohibited medications and unallowable CS usage will be recorded as 
protocol deviations in the clinical database.   
A patient is considered to have unallowable CS usage if any of the following is not met: 
 A maximum daily dose of 30 mg/day of oral CS will be acceptable for eligibility for the 
study. For patients whose only SLE treatment is steroids, their stable steroid dose must be 
at least 10 mg/day and no more than 30 mg/day for a minimum of 6 weeks at time of 
randomization on Day 0 
 Topical steroids may be used, but the dose must be stable for at least 6 weeks prior to 
Day 0, and be maintained at a constant dose throughout the study duration until the rashes 
resolve. PRN topical steroids are not permitted 
 Once the patient has received the first dose of study drug (Day 0), tapering of oral 
steroids will be highly encouraged and should be continually evaluated during the 


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protocol-allowed tapering windows (Day 0 through Day 150) with the target of achieving 
a CS daily dose of < 7.5 mg and < Day 0 dose between Day 150 and Day 210 
 Between Day 150 and Day 210 (i.e., within 60 days of primary endpoint assessments), 
oral CS doses must be held constant 
 CS Burst for SLE-related Indications 
o After Day 0 (first dose of study drug), a maximum of 1 oral CS “burst” 
equivalent to ≤ 40 mg/day prednisone for increased SLE disease activity will 
be allowed between Day 0 and Day 120, which must be tapered down to the 
baseline (Day 0) CS dose or lower within 14 days of initiation of the “burst”. 
Any “burst” continuing after Day 120 or occurring after Day 120 is 
considered a protocol deviation.  
o Alternatively, a single intramuscular (IM) dose of methylprednisolone 
( < 40 mg) is permitted during this period. 
 CS Burst for Non-SLE-related Indications 
o A single treatment of oral prednisone equivalent of ≤ 40 mg/day for 14 days is 
permitted for a non-SLE indication, though it must be completed prior to 
Day 120. No long acting steroid injections are permitted.  
o Note: Treatment with inhaled CS are allowed for the treatment of 
non-SLE-related indications only (e.g., for asthma).  
 
Any other increase from baseline of CS dose or any other systemic use of CS of any kind 
(including intra-articular and intravenous administration) are not permitted from Day 0 through 
Day 210 and will result in the patient being considered a medication failure and will be treated as 
non-responders for the primary efficacy analysis. There is no restriction of CS usage after 
Day 210.  
The determination of medication failures will be reviewed using blinded data and finalized prior 
to unblinding.  Once a patient is determined to be a non-responder, the patient will remain a non-
responder for the remainder of the study. 
Out of Window Assessments:  
 If a patient has an efficacy assessment (i.e. BILAG, SLEDAI-2K, PGA, CLASI, etc.) 
more than 30 days since the previous assessment (current visit – prior visit > 30), the 
corresponding result will not contribute to LOCF analyses. 
 Since the Day 180 nominal visit is assigned as “Day 180/End of Treatment” in the 
clinical database, Day 180 nominal assessments must be >=159 days (180 – 21 day 
protocol allowed treatment window) since first dose to be considered for “Day 180” 
nominal assessments and also to be considered for LOCF to Day 210 in the case of 
missing Day 210 data for all efficacy analyses. 
 
Early Treatment Withdrawals/Discontinuations:  
For early treatment withdrawal/discontinuation prior to study day 159 (180 days – 21 day 
treatment window), patient will be considered a non-responder after the date of early treatment 


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withdrawal/discontinuation assuming the patient was not considered a medication failure prior to 
or on the date of early withdrawal/discontinuation for the primary efficacy analysis.   
 
For early treatment withdrawal/discontinuation on or after study day 159 (180 days – 21 days) 
such that patient has data for nominal visit Day 180 but not for nominal visit Day 210, Day 180 
data will be carried forward to Day 210 for assessment of SRI-4 response. 
 
For early treatment withdrawal/discontinuation on or after study day 159 (180 days – 21 days) 
such that patient does not have data for nominal visit Day 180 and  Day 210, the patient will be 
considered a non-responder on Day 210.  
 
For early treatment withdrawal/discontinuation on Day 210 such that patient has data for 
nominal visit Day 210, the Day 210 data will be used for assessment of SRI-4 response.   
 
 
Missing Data: 
 
 Pre-Treatment: If a patient is missing data during the pre-treatment period for SLEDAI-
2K, PGA, or BILAG, the patient will be excluded from the primary efficacy analysis. 
 
 Overall SRI-4 Components: Missing data at Day 210 for overall components for 
SLEDAI-2K, BILAG, and PGA will be addressed by employing a LOCF analysis within 
each overall component as described in Section 5.4.  For example, if a patient has data for 
SLEDAI-2K and BILAG at Day 210 but is missing PGA at Day 210, the PGA 
component would employ LOCF as described in Section 5.4. If the overall component is 
missing from Day 180 through Day 210 and the patient is not a medication failure on or 
prior to Day 210 and did not withdraw/discontinue treatment prior to Day 180, the SRI-4 
response at Day 210 will be considered not evaluable.     
 
 Individual Items Contributing to Overall SRI-4 Components: Data collection and 
scoring will be performed in the clinical database for BILAG, SLEDAI-2K, and PGA.  If 
missing individual items contributing to any of the overall components occurs for Day 
210, the overall component will be recalculated per the Table 1.  
Table 1 
SRI-4 Component 
Method for Carrying Forward Individual Items 
Contributing to SRI-4 Component Result/Score 
BILAG Grade 
BILAG Grading is evaluated and entered into the clinical 
database by the medical monitoring team.  Grades are 
adjudicated by independent subject matter experts.  The 
medical monitoring team and the adjudication team will 
utilize BILAG index results to determine BILAG Grades.  
Missing data will be handled by the medical monitoring 
team as follows.  If lab values are missing in the BILAG 


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Index at Day 210, lab values from the most recent 
unscheduled visit <=14 days after Day 210 will be utilized 
for determination of the BILAG grade in the applicable 
organ system and entered into the clinical database.  If lab 
values are not available from an unscheduled visit <=14 days 
after Day 210, laboratory data will be carried forward from 
the most recent laboratory assessment (scheduled or 
unscheduled) <=30 days prior to the Day 210 nominal visit 
for determination of BILAG grade.  If the lab components 
for BILAG are missing from Day 210 and no unscheduled 
laboratory assessments occur within 14 days after or 30 days 
prior to the Day 210 assessment, the lab components from 
Day 180 will be utilized if Day 180 occurred within 30 days 
of Day 210.  Otherwise, no individual BILAG Index results 
will be carried forward.  If the BILAG grade for a given 
organ system is missing at Day 210, the grade will be carried 
forward from the Day 180 assessment. If the Day 180 
BILAG grade is also missing, occurred more than 30 days 
before Day 210 (Day 210 visit date – Day 180 visit date > 
30), or is not evaluable, the Day 210 grade will be 
considered not evaluable.
SLEDAI-2K 
If lab values are missing at Day 210, lab values will be 
imputed based on the below hierarchy of determination: 
(1) If any unscheduled laboratory assessments occurred 
<=14 days after the Day 210 visit, the laboratory 
values at the most recent unscheduled laboratory 
assessment will be used for the determination of 
missing laboratory SLEDAI-2K criteria.  For 
example, if platelet count is missing at Day 210 and 
an unscheduled laboratory assessment occurs 10 days 
after the Day 210 visit date, the platelet count from 
the unscheduled laboratory assessment would be used 
to determine if the patient had thrombocytopenia at 
Day 210 for SLEDAI-2K. 
(2) Else if #1 does not occur or lab values are not 
available at the unscheduled visit noted in #1, the 
laboratory data will be carried forward from the most 
recent laboratory assessment (scheduled or 
unscheduled) <=30 days prior to the Day 210 
nominal visit to make the SLEDAI-2K 
determination.  For example, if a patient is missing 
thrombocytopenia and leukopenia SLEDAI-2K 
components at Day 210, they have an unscheduled 
lab assessment 10 days earlier with platelet counts 
populated and WBC not populated, and they have a 


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Day 180 assessment within 30 days of the Day 210 
visit with both platelets and WBC present, the 
platelet value from the unscheduled visit would be 
carried forward to the Day 210 for thrombocytopenia 
component designation and the WBC value would be 
carried forward from the Day 180 assessment to Day 
210 for the Leukopenia component designation.   
(3) If the lab components for SLEDAI-2K are missing 
from Day 210 and no unscheduled laboratory 
assessments occur within 14 days after or 30 days 
prior to the Day 210 assessment, the lab components 
from Day 180 will be carried forward, if available 
and if Day 180 occurred within 30 days of Day 210.   
 
Otherwise, no non-lab individual SLEDAI-2K components 
will be carried forward.  If non-lab individual components 
are missing at Day 210, the entire SLEDAI-2K score from 
Day 180 will be carried forward.  If Day 180 is missing, 
occurred more than 30 days before Day 210, or is not 
evaluable, LOCF is not implemented and the Day 210 score 
will be considered not evaluable. In the case of missing  
SLEDAI-2K lab components at Day 210, where any 
SLEDAI-2K lab component is carried forward (or back) per 
above, the SLEDAI-2K total score will be recalculated 
outside of the clinical database as the sum of: 
(1) All of the non-missing weights for each descriptor at 
Day 210 
(2) All individual lab component weights carried forward 
from the Day 180 visit or unscheduled visit, as 
applicable. 
If any components are still missing at Day 210 after carrying 
forward available lab components, the Day 210 SLEDAI-2K 
score will not be recalculated and will be considered not 
evaluable. 
Note: Clinical input may be obtained prior to database lock 
and unblinding to make a final determination of SLEDAI-2K 
criteria in the case of carrying forward (or back) individual 
lab component scores.
PGA 
Individual components are not applicable for PGA and will 
not be carried forward.  Total PGA VAS measurement will 
be carried forward from the Day 180 visit in the case of 
missing PGA measurement at Day 210. If total PGA score is 
also missing from Day 180, occurred more than 30 days 
before Day 210, or is not evaluable, LOCF is not 


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implemented and the Day 210 visit will be considered not 
evaluable. 
Table 2 summarizes the primary analysis and details several sensitivity analyses which may be 
performed: 
 
Table 2 
Analysis 
Analysis 
Population
Criteria 
Primary Analysis 
LOCF for missing data, 
Medication 
Failures=Non-Responder 
FAS 
The primary analysis of the primary efficacy endpoint will be 
performed based on LOCF methods for missing data.  
 
(1) Medication failures are considered non-responders on and 
after the date of medication failure 
(2) Early withdrawals/discontinuations prior to study day 159 
will be considered non-responders after the date of early 
withdrawal/discontinuation 
a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered a non-responder on and after the date of 
medication failure.  
b. In case of early withdrawal/discontinuation after 
study day 159 but before Day 210 such that patient 
has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 
data will be carried forward to Day 210. 
(3) Patients with missing Day 180 and Day 210 data without 
prior medication failure and without early 
withdrawal/discontinuation prior to study day 159 are 
considered not evaluable and are excluded from analysis 
Sensitivity Analysis 1: 
Observed (no LOCF for 
missing data), 
Medication 
Failures=Non-Responder 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on purely observed data.  No LOCF imputations 
will be performed for missing data. 
Additional criteria are as follows: 
(1) Medication failures are considered non-responders on and 
after the date of medication failure 
(2) Early withdrawals/discontinuations prior to Day 210 will 
be considered non-responders after the date of early 
withdrawal/discontinuation 
a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 


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considered a non-responder on and after the date of 
medication failure.  
(3) Patients with missing Day 210 data without prior 
medication failure and without early 
withdrawal/discontinuation prior to Day 210 are 
considered not evaluable and are excluded from the 
sensitivity analysis 
If lab component scores are carried forward from Day 180 to Day 
210 in order to assign a Day 210 grade in the primary analysis, the 
Day 210 assessment will be considered not evaluable for this 
sensitivity analysis.
Sensitivity Analysis 2: 
LOCF for missing data, 
Exclude Medication 
Failures 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on LOCF methods for missing data detailed for 
the primary efficacy analysis. 
Additional/modified criteria are as follows: 
(1) Medication failures are considered not evaluable and are 
excluded from the sensitivity analysis on and after the date 
of medication failure 
(2) Early withdrawals/discontinuations prior to study day 159 
will be considered not evaluable and will be excluded from 
analysis after the date of early withdrawal/discontinuation 
a. If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered not evaluable and excluded on and after 
the date of medication failure.  
b. In case of early withdrawal/discontinuation after 
study day 159 but before Day 210 such that patient 
has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 
data will be carried forward to Day 210. 
(3) Patients with missing Day 180 and Day 210 data are 
considered not evaluable and are excluded from the 
sensitivity analysis
Sensitivity Analysis 3: 
Observed (no LOCF for 
missing data), Exclude 
Medication Failures 
FAS 
A sensitivity analysis of the primary efficacy endpoint may be 
performed based on purely observed data.  No LOCF imputations 
will be performed for missing data. 
Additional criteria are as follows: 
(1) Medication failures are considered not evaluable and are 
excluded from the sensitivity analysis on and after the date 
of medication failure 
(2) Early withdrawals/discontinuations prior to Day 210 will 
be considered not evaluable and are excluded from the 
sensitivity analysis after the date of early 
withdrawal/discontinuation 


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a. 
If patient is a medication failure prior to 
withdrawal/discontinuation, patient will be 
considered not evaluable and excluded on and after 
the date of medication failure. 
(3) Patients with missing Day 210 data are considered not 
evaluable and are excluded from the sensitivity analysis 
If lab component scores are carried forward from Day 180 to Day 
210 in order to assign a Day 210 grade in the primary analysis, the 
Day 210 assessment will be considered not evaluable for this 
sensitivity analysis.
Sensitivity Analysis 4: 
LOCF for missing data, 
Medication 
Failures=Non-
Responder, Logistic 
Regression 
FAS 
 
  
 
 
Additional sensitivity analyses may be performed to consider the effect of missing data. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
A summary of disposition of SRI-4 response per the primary analysis at day 210 will be 
presented by study phase and treatment group in the FAS and PP.  Sensitivity analysis 2 (LOCF, 
Exclude Medication Failures) will also be performed for disposition of SRI-4 response at day 
210.  These summaries will include the number of SRI-4 responders and the number of SRI-4 
non-responders with a breakdown of reasons for non-response (early withdrawal, medication 
failure, <4-point reduction from baseline in SLEDAI-2K total score, new BILAG 1A/2B, and 
PGA worsening).  Denominators for percentages will be the number of patients eligible for SRI-
4 response analysis (patients not deemed not evaluable) defined as those with data for PGA, 
SLEDAI-2K and BILAG at Day 210 (whether or not due to LOCF, FAS analysis). 
 
A listing of SRI Response data at Days 30, 60, 90, 120, 150, 180 and 210 will be presented in the 
FAS.  A listing of SRI-4 Response at Day 210 (Primary and Sensitivity Analyses) will also be 
presented in the FAS.  A listing of patients with medication failures, early 
withdrawals/discontinuations and those excluded from the primary efficacy analysis will also be 
provided for all randomized patients. 
 
7.2. Secondary Efficacy Endpoints and Analyses 
 
PK and PD measures are the secondary endpoints for the Phase 1b MAD part of the study and 
exploratory endpoints for the POC part of the study. Those analyses are described in Section 8.   
CCI


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7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit 
The primary analysis methods described in Section 7.1.1 and Table 2 will be repeated for each 
nominal visit and will be presented by study phase and treatment group in the FAS.  Other 
analyses described in Section 7.1.1 may also be performed.  The 3 components will not be 
summarized separately by visit.  In case of missing data, LOCF methods will be implemented as 
described in section 5.4 and Table 1.  LOCF will only be implemented with the most recent prior 
nominal visit.  If the most recent prior nominal visit is missing, occurred more than 30 days 
before, or is not evaluable, LOCF is not implemented.  For example, if Day 30 SLEDAI 
assessment is complete but Day 60 and Day 90 SLEDAI assessments are missing, Day 60 will 
implement LOCF from Day 30 assuming Day 30 is within 30 days of Day 60 and Day 60 
SLEDAI will be included in the analysis but Day 90 will not carry forward from Day 60 and thus 
Day 90 will be considered not evaluable and will be excluded from the analysis.  Similarly, if 
Day 150 assessments are complete but Day 180 and Day 210 are missing, Day 180 will 
implement LOCF from Day 150 assuming Day 150 is within 30 days of Day 180 and will be 
included in the analysis but Day 210 will not carry forward from Day 180, will be considered not 
evaluable, and will be excluded from the analysis.   
If a patient is a medication failure, the patient is considered to be a non-responder at timepoints 
on or after the first date of prohibited medication/unallowable CS usage. 
If a patient discontinues/withdraws early, the patient will be considered a non-responder after the 
date of discontinuation/withdrawal (unless the patient had a prior medication failure in which 
case the patient is considered a non-responder on and after the date of medication failure). 
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-4 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
A graphical display of SRI-4 response by study phase, treatment group, and visit in the FAS will 
be presented. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit 
The SRI-5 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K, the BILAG 2004 Index and the PGA.  Response based on the SRI-5 is defined 
by:  
1) ≥ 5-point reduction from baseline in SLEDAI-2K total score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 


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AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The primary analysis described in Section 7.1.1 and Table 2 will be repeated for each nominal 
visit as described in Section 7.2.1 based on the SRI-5 response definition and will be presented 
by study phase and treatment group in the FAS.  The 3 components will not be summarized 
separately by visit for SRI-5 response. Other analyses described in Section 7.1.1 may also be 
performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-5 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit 
The SRI-6 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K,  the BILAG 2004 Index and the PGA.  Response based on the SRI-6 is defined 
by:  
1) ≥ 6-point reduction from baseline in SLEDAI-2K total score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The primary analysis described in Section 7.1.1 and Table 2 will be repeated for each nominal 
visit as described in Section 7.2.1 based on the SRI-6 response definition and will be presented 
by study phase and treatment group in the FAS.  The 3 components will not be summarized 
separately by visit for SRI-6 response. Other analyses described in Section 7.1.1 may also be 
performed.  
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SRI-6 assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 


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7.2.4. 
Oral Corticosteroid (CS) Reduction 
The average daily CS dose will be presented over time starting with Day 0 as baseline.  Oral CS 
usage for all visits will be based on the average daily dose, defined as the sum of the 
corticosteroid doses taken each day from the date of the previous visit to the day before the date 
of the current visit (converted to prednisone equivalent dose) / the duration between the two 
visits.  For example, the average daily dose at Day 0 (Baseline) is the sum of daily doses of CS 
from the screening visit to the day prior to Day 0 divided by the duration between the screening 
visit to the day prior to Day 0, inclusive. Similarly, the average daily dose at Day 30 is the sum 
of daily doses of CS from Day 0 to the day prior to Day 30 divided by the duration between Day 
0 to the day prior to Day 30, inclusive.  Partial dates for CS use will be imputed based on details 
in Section 5.5.  Oral CS will be converted to prednisone dose equivalence for analysis of 
reduction of oral CS use.  Common prednisone dose equivalents are provided in Table 3. 
Table 3 
Medication 
Prednisone Dose Equivalence 
Prednisone 
1 mg 
Cortisone 
5 mg 
Hydrocortisone 
4 mg 
Prednisolone 
1 mg 
Methylprednisolone 
0.8 mg 
Triamcinolone 
0.8 mg 
Budesonide 
0.25 mg 
Dexamethasone 
0.16 mg 
Bethamethasone 
0.16 mg 
 
7.2.4.1. Proportion of Patients with a sustained reduction of oral CS between Day 
120 and Day 210 (MAD) 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 10 mg/day prednisone equivalent and < Day 0 dose, between Day 120 and Day 210 determined 
based on actual daily CS usage on and in between the nominal visit dates will be summarized for 
MAD Phase 1b by treatment group in the FAS.  To qualify as sustained reduction, the actual 
daily CS usage needs to meet the definition above every day between nominal visit dates for Day 
120 and Day 210 inclusive.  LOCF and imputation for missing values will not be performed.  
Otherwise, statistical methods described in Section 7.1.1 will be implemented.  Patients who 
withdraw prior to Day 210 or are designated as a medication failure on or prior to Day 210 or 
miss the Day 120 and/or the day 210 visit will not be considered to have sustained reduction in 
CS.  Denominators for percentages are the number of patients taking oral CS at baseline.  
 


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7.2.4.2. Proportion of Patients with a sustained reduction of CS between Day 150 
and Day 210 (POC) 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 7.5 mg/day prednisone equivalent and < Day 0 dose, between Day 150 and Day 210 
determined based on actual daily CS usage on and in between the nominal visit dates will be 
summarized for POC Phase 2 by treatment group in the FAS.  To qualify as sustained reduction, 
the actual daily CS usage needs to meet the definition above every day between nominal visit 
dates for Day 150 and Day 210 inclusive.  LOCF and imputation for missing values will not be 
performed.  Otherwise, statistical methods described in Section 7.1.1 will be implemented.  
Patients who withdraw prior to Day 210 or are designated as a medication failure on or prior to 
Day 210 or miss the Day 150 and/or Day 210 visit will not be considered to have sustained 
reduction in CS.  Denominators for percentages are the number of patients taking oral CS at 
baseline.  
 
7.2.4.3. Percent Reduction in CS Administration from Day 0 through Day 210 
(POC) 
The percent reduction in CS administration from Day 0 through Day 210 determined based on 
the average daily CS usage will be summarized for POC Phase 2 by treatment group and visit.  
Average daily dose will be calculated for nominal visits as defined in Section 7.2.4.  This will be 
performed for patients in the FAS who received ≥ 7.5 mg/day prednisone equivalent at Day 0.  
Patients considered medication failures will be excluded from the percent reduction analysis at 
timepoints on and after the first date of medication failure. 
 
 
7.2.5. Proportion of new or recurrent BILAG A flare or >1 BILAG B flare through 
Day 210 
The proportion of patients with a new or recurrent BILAG A flare or >1 BILAG B flares through 
Day 210 will be summarized by study phase and treatment group in the FAS.  Statistical methods 
described in Section 7.1.1 will be implemented.  BILAG flares will be adjudicated, recorded in 
the clinical database, and summarized as recorded in the clinical database.  No LOCF methods 
will be implemented.  When discrepancies between the two-reviewers occurs, the adjudicated 
flare determination will be used for analyses.  The proportion of new or recurrent BILAG A flare 
or >1 BILAG B flare will be summarized overall and by nominal visit.  The denominator for 
percentages of patients with a new or recurrent flare will be patients in the FAS with a post-
baseline BILAG assessment at the given visit.  
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
Results as recorded in the clinical database will be presented in separate data listings for BILAG 
SLE history, BILAG-2004 index, and BILAG grading for all randomized patients. 
 


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7.2.6. 
Physician’s Global Assessment (PGA) 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients.”   
7.2.6.1. Proportion of Patients with PGA Worsening at Each Visit 
The proportion of patients with PGA worsening, defined as an increase of >30mm from baseline, 
will be summarized by study phase and treatment group in the FAS overall (at any post-baseline 
nominal visit) and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented.  In case of missing data, LOCF methods will be implemented as described in 
section 5.4 and Table 1 and in Section 7.2.1 for the “at each visit” analyses.   
The analyses described in Section 7.1.1 and Table 2 (Primary Analysis methods) will be repeated 
for each nominal visit as described in Section 7.2.1 based on the PGA worsening definition and 
will be presented by study phase and treatment group in the FAS.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline PGA assessment (overall analysis) or with evaluable PGA assessment (whether or not 
imputed via LOCF depending on the analysis) at a given visit (nominal visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.6.2. Results, Changes, and Percentage Change from Baseline in PGA 
The analysis of PGA will be performed separately using an ANCOVA model with change or 
percentage change from baseline to each nominal visit as the dependent variable, treatment group 
as the factor, and the corresponding baseline PGA result as a covariate.  The p-value for the 
difference between the BOS161721 and placebo groups at each nominal visit is based on the F-
test. 
Descriptive statistics for PGA will be summarized separately at baseline and each visit.  Change 
and percentage change from baseline will be summarized at each post-baseline visit.  The least 
squares (LS) mean estimate, its standard error and 90% CI will be tabulated by treatment group 
and for the difference between treatment groups (BOS161721 versus placebo) for change and 
percentage change at each visit.  In case of missing data, LOCF methods will be implemented as 
described in Section 5.4 and Table 1 and in Section 7.2.1.   
Two separate approaches will be taken based on handling for medication failures and treatment 
withdrawals: 
Approach 1:  Corresponding to Primary Analysis Methods (Medication Failure LOCF): If a 
patient is a medication failure, the most recent assessment prior to the medication failure date 
will be carried forward to all subsequent assessments.  In the case of patients who 


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withdraw/discontinue early without prior medication failure, the most recent data on or prior to 
withdrawal/discontinuation will be carried forward to all subsequent assessments.  In case of 
early withdrawal/discontinuation after Day 180 but before Day 210 such that patient has Day 180 
data but is lacking Day 210 data in a patient without medication failure, the Day 180 data will be 
carried forward to Day 210. 
Approach 2:  Corresponding to Sensitivity Analysis 2 Methods (Exclude Medication Failure): If 
a patient is a medication failure, all assessments on and after medication failure date will be 
considered not evaluable and will be excluded.  In the case of patients who withdraw/discontinue 
early without prior medication failure, all assessments after the early withdrawal date will be 
considered not evaluable and will be excluded.  In case of early withdrawal/discontinuation after 
Day 180 but before Day 210 such that patient has Day 180 data but is lacking Day 210 data in a 
patient without medication failure, the Day 180 data will be carried forward to Day 210.  
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
PGA observed results will be presented in a data listing for all randomized patients. 
 
7.2.7. 
Proportion of Patients with BICLA Response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as:  
1) at least 1 gradation of improvement in baseline BILAG 2004 scores in all body systems with 
moderate disease activity at entry (e.g., all A [severe disese] score falling to B [moderate], C 
[mild] or D [no activity] or all B [moderate disease] scores falling to C [mild], or D [no activity]) 
AND 
2) no new BILAG A or more than 1 new BILAG B scores 
AND 
3) no worsening of total SLEDAI-2K score from baseline 
AND 
4) ≤ 10% deterioration in PGA score 
AND 
5) no medication failure. 
Statistical methods described in Section 7.1.1 will be implemented.  In case of missing data, 
LOCF methods will be implemented as described in section 5.4 and Table 1 and in Section 7.2.1 
for the “at each visit” analysis.  The primary analysis and sensitivity analysis 2 (LOCF for 


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missing data, Exclude Medication Failures) methods described in Section 7.1.1 and Table 2 will 
be repeated overall and as described in Section 7.2.1 for Days 210, 240, and 270 based on the 
BICLA response definition and will be presented by study phase and treatment group in the FAS.  
Other analyses described in Section 7.1.1 may also be performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline BICLA assessment defined as those with data for PGA, SLEDAI-2K and BILAG 
(whether observed or imputed via LOCF depending on the analysis) (overall analysis) or at a 
given visit (nominal visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 
The total activity score will be calculated by summing the scores on the left side of the form 
(erythema, scale/hypertrophy, mucous membrane, alopecia – recent hair loss and alopecia 
clinically not obviously scarred). 
The total damage score will be calculated by: 
(1) Sum the responses for “Dyspigmentation” in all anatomical locations 
(2) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts at least 12 months”, then multiply the sum in #1 by 2. 
(3) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts less than 12 months”, then the sum in #1 will not change. 
(4) If the sum in #1 is 0 and a response for “Report duration of dyspigmentation after active 
lesions have resolved” is missing, then the sum in #1 will not change. 
(5) Determine the Dyspigmentation Score based on the results from 2, 3, or 4. 
(6) Sum the remaining scores on the right side of the form (scarring/atrophy/panniculitis, 
alopecia - scarring of the scalp judged clinically). 
(7) Sum the scores from #5 and #6 to obtain the total damage score. 
If any individual scores which contribute to the total activity score or the total damage score are 
missing, the total score in question will not be calculated.  If total activity score or total damage 
score are missing at a visit, LOCF methods will be implemented as described in Section 5.4 and 
Section 7.2.1 for the “at each visit” analyses.  


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The mean and SD of the change from baseline in CLASI total activity and total damage scores 
will be presented graphically over time by study phase and treatment group. 
7.2.8.1. Proportion of Patients with CLASI Response 
CLASI response is defined as 50% improvement from baseline in CLASI.  A CLASI-A response 
applies to “A” (total activity) and a CLASI-B response applies to “B” (total damage) score.  
Statistical methods described in Section 7.1.1 will be implemented. In case of missing data, 
LOCF methods will be implemented as described in Section 5.4 and 7.2.1 for the “at each visit” 
analysis. Individual components of the CLASI will not be carried forward; however, the total 
activity score or total damage score may be carried forward from the most recent prior visit.  If 
the most recent prior visit is missing, occurred more than 30 days before (current visit date – 
most recent prior visit date > 30), or is not evaluable, LOCF is not implemented. The primary 
analysis methods (LOCF for missing data, medication failure=non-responder) as described in 
Section 7.1.1 and Table 2 will be performed at each visit based on the CLASI response definition 
and will be presented by study phase and treatment group in the FAS.  
 
 
The analysis will also be repeated in line with Sensitivity Analysis 2 (LOCF for missing data, 
exclude medication failures) in Section 7.1.1. 
Other analyses described in Section 7.1.1 may also be performed.   
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline CLASI assessment (whether observed or imputed via LOCF depending on the analysis) 
at a given visit.   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
7.2.8.2. Results, Changes, and Percentage Change from Baseline in CLASI 
The analysis of CLASI total activity score and CLASI total damage score will be performed 
separately using an ANCOVA model with change or percentage change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the corresponding 
baseline CLASI score as a covariate.  The p-value for the difference between the BOS161721 
and placebo groups at each nominal visit is based on the F-test. 
Descriptive statistics for the activity score and damage score will be summarized separately at 
baseline and each visit.  Change and percentage change from baseline will be summarized at 
each post-baseline visit.  The LS Mean estimate, its standard error and 90% CI will be tabulated 
by treatment group and for the difference between treatment groups (BOS161721 versus 
placebo) for change and percentage change at each visit.  Statistical methods described in 
Section 7.1.1 will be implemented.  In case of missing data, LOCF methods will be implemented 
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as described in Section 5.4 and Section 7.2.1 for the “at each visit” analyses. Individual 
components of the CLASI will not be carried forward; however, the total activity score or total 
damage score may be carried forward from the most recent prior visit.  If the most recent prior 
visit is missing, occurred more than 30 days before (current visit date – most recent prior visit 
date > 30), or is not evaluable, LOCF is not implemented. The analyses will be performed in line 
with the two approaches outlined in Section 7.2.6.2. 
 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
CLASI observed results will be presented in data listings for all randomized patients. 
7.2.9. Results, Changes, and Percentage Changes from Baseline in Swollen, 
Tender, and Active Joints ACR-28 
The ACR-28 joint count evaluates the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded.  The sum of active joints is also 
evaluated and is defined as the total number of joints with swelling and tenderness in the same 
joint. The joint sums for tender and swollen joints are recorded in the database. The sum of 
active joints will be derived. 
The analysis of ACR-28 Swollen and Tender Joints for the sum of tenderness (left and right), the 
sum of swelling (left and right), and sum of active joints (left and right) will be performed 
separately using an ANCOVA model with change and percentage change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the baseline ACR-28 
score as a covariate.  The p-value for the difference between the BOS161721 and placebo groups 
at each nominal visit is based on the F-test.   
Descriptive statistics for the tenderness, swelling, and derived active joint sums will be 
summarized separately at baseline and each visit.  Change and percentage change from baseline 
will be summarized at each post-baseline visit.  The LS Mean estimate, its standard error and 
90% CI will be tabulated by treatment group and for the difference between treatment groups 
(BOS161721 versus placebo) for change and percentage change at each visit. 
Statistical methods described in Section 7.1.1 will be implemented.  In case of missing data, 
LOCF methods will be implemented as described in Section 5.4 and in Section 7.2.1 for the “at 
each visit” analyses. Individual components of ACR-28 will not be carried forward; however, the 
total ACR-28 score may be carried forward from the most recent prior visit.  If the most recent 
prior visit is missing, occurred more than 30 days before (current visit date – most recent prior 
visit date > 30), or is not evaluable, LOCF is not implemented. The analyses will be performed in 
line with the two approaches outlined in Section 7.2.6.1. 
The mean and SD of the change from baseline in ACR-28 sum of tenderness, sum of swelling, 
and sum of active joints based on primary analysis methods will be presented graphically over 
time by study phase and treatment group. 
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Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
Swollen, tender, and active joints ACR-28 observed results will be presented in data listings for 
all randomized patients. 
7.2.10. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-
2K) 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI 2K of 6 or more generally represents moderately to severely active 
disease. 
7.2.10.1. Proportion of Patients with a SLEDAI-2K Response 
The proportion of patients with a SLEDAI-2K response, defined as ≥ 4-point reduction from 
baseline in SLEDAI-2K total score, will be summarized by study phase and treatment group in 
the FAS overall and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented.  In case of missing data, LOCF methods will be implemented as described in 
section 5.4 and Table 1 and in Section 7.2.1 for the “at each visit” analyses.   
The analyses described in Section 7.1.1 and Table 2 (Primary Analysis methods and Sensitivity 
Analysis 2 methods) will be repeated for each nominal visit as described in Section 7.2.1 based 
on the SLEDAI-2K response definition and will be presented by study phase and treatment group 
in the FAS. 
The denominators for analyses will be the number of patients in the FAS with an evaluable post-
baseline SLEDAI-2K assessment (overall analysis) or with evaluable SLEDAI-2K assessment 
(whether observed or imputed via LOCF depending on the analysis) at a given visit (nominal 
visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.10.2. Results, Changes, and Percentage Change from Baseline in SLEDAI-2K 
The analysis of SLEDAI-2K will be performed using an ANCOVA model with change and 
percent change from baseline to each nominal visit as the dependent variable, treatment group as 
the factor, and the baseline SLEDAI-2K score as a covariate.  The SLEDAI-2K total score is 
calculated and provided in the clinical database.  In case of missing data, SLEDAI-2K will be re-
calculated outside the clinical database after application of imputation rules.  
Descriptive statistics for the SLEDAI-2K total score will be summarized separately at baseline 
and each visit.  Change and percentage change from baseline will be summarized at each post-


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baseline visit.  The LS mean estimate, its standard error and 90% CI will be tabulated by 
treatment group and for the difference between treatment groups (BOS161721 versus placebo) 
for change and percentage change at each visit. The p-value for the difference between the 
BOS161721 and placebo groups at each nominal visit is based on the F-test. 
Statistical methods described in Section 7.1.1 will be implemented,.  In case of missing data, 
LOCF methods will be implemented as described in section 5.4 and Table 1 and in Section 7.2.1 
for the “at each visit” analyses. The analyses will be performed in line with the two approaches 
outlined in Section 7.2.6.1. 
Approach 1 corresponding to the primary analysis methods (LOCF for missing data, medication 
failure = non-responder) will be repeated for subgroups 
 as 
defined below:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.11. 
Results, Changes, and Percentage Change from Baseline in SLICC/ACR 
Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
CCI
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demonstrated content, face, criterion, and discriminant validity.  It will be performed on Days 0 
and 180. 
The analysis of SLICC/ACR Damage Index total score will be performed using an ANCOVA 
model with change and percentage change from baseline to Day 180 as the dependent variable, 
treatment group as the factor, and the baseline SLICC/ACR Damage Index total score as a 
covariate.  The SLICC/ACR Damage Index total score is calculated and provided in the clinical 
database.  A missing total SLICC/ACR Damage Index score will not be imputed.  Observed 
results will be presented for the change and percentage change from baseline analysis.  The p-
value for the difference between the BOS161721 and placebo groups at each nominal visit is 
based on the F-test.   
Descriptive statistics for the SLICC/ACR Damage Index total score will be summarized 
separately at baseline and Day 180.  Change and percentage change from baseline will be 
summarized at Day 180.  The LS Mean estimate, its standard error and 90% CI will be tabulated 
by treatment group and for the difference between treatment groups (BOS161721 versus 
placebo) for change and percentage change at Day 180. 
In case of medication failure or early withdrawal/discontinuation prior to Day 180, the Day 180 
assessment will be considered not evaluable and will not contribute to the analysis at that visit.   
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Observed SLICC/ACR Damage Index data will be presented in a by-patient listing for all 
randomized patients.  SLICC Criteria for SLE at screening will also be presented in a by-patient 
listing for all randomized patients. 
7.2.12. 
Medication Failure 
7.2.12.1. Proportion of Patients with Medication Failures 
Patients who received prohibited medications or had unallowable CS usage as described in 
Section 4.6 of the study protocol will be considered “medication failures” and will be treated as 
non-responders at time points on and following the first date of prohibited medication or 
unallowable CS usage for the primary efficacy analysis and selected sensitivity and secondary 
efficacy analyses.  The determination of medication failures and medication failure dates will be 
reviewed using blinded data and finalized prior to unblinding.   
The number and proportion of patients with medication failures will be summarized by study 
phase and treatment group in the FAS overall and by visit.  A patient will be counted as a 
medication failure at each visit occurring on and after the date in which a patient is considered a 
medication failure.  Statistical methods described in Section 7.1.1 will be implemented for 
observed data only.  LOCF and missing data imputation will not be performed. 


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The denominator is the number of patients in FAS (overall analysis) and the number of patients 
with non-missing visit data (for the by visit analysis).   
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.12.2. Time to Medication Failure (TTMF) 
Medication failure is defined in Section 4.6 of the study protocol and discussed in Section 7.1.1. 
TTMF will be computed as the event date (as described below) – randomization date + 1. 
Kaplan-Meier methods will be used to estimate TTMF for each treatment group.  Estimates of 
median TTMF will be provided along with 90% confidence intervals.  Q1 and Q3 will also be 
tabulated. Comparisons between treatment groups will use the two-sided log-rank test.  In 
addition, hazard ratio (HR) estimates with 90% CIs will be calculated from a Cox proportional 
hazards regression analysis that includes treatment as a factor.  Censoring rules are defined as in 
Table 4. 
Table 4 
Situation 
Date of Event or Censoring 
Outcome 
Patient is designated a medication failure 
(received prohibited meds or unallowable 
CS burst) 
Date of first dose of 
medication leading to 
medication failure 
designation.  These dates will 
be obtained from the date of 
deviation on the protocol 
deviation eCRF form. 
Event 
Patient withdraws from study (no medication 
failure) 
Censored at date of 
withdrawal 
Censored 
Patient completes the study (no medication 
failure) 
Censored at last study visit 
Censored 
Patient dies during study (no medication 
failure) 
Censored at the date of death 
Censored 
 
Kaplan-Meier curves of TTMF will be plotted over time. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to medication failure data will be provided in a by-patient listing in the full analysis set. 


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7.2.13. 
Duration of Longest SRI-4 Response 
Duration of longest SRI-4 response will be computed for patients who have been identified as a 
responder at least once based on criteria defined in Section 7.1.1.  The duration of longest 
response will be defined as the longest period a patient meets the SRI-4 responder criteria at 
consecutive visits.  This will be computed as the date of last consecutive SRI-4 response – date 
of first consecutive response + 1. 
The duration of longest SRI-4 response will be analyzed using an analysis of variance (ANOVA) 
model with treatment group as the effect.  The p-value for the difference between the 
BOS161721 and placebo group is based on the F-test. 
The mean, SD, median, minimum, maximum, Q3, Q4, LS Mean estimate, its standard error and 
90% CI will be tabulated by treatment group and for the difference between treatment groups 
(BOS161721 versus placebo). 
If a patient has missed a visit between two scheduled visits with a response at both, the patient 
will be counted as having a response at the missed visit unless otherwise specified.   
Duration of longest SRI-4 response will be displayed in the SRI response listing. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
7.2.14. 
Time to First BILAG A Flare or >1 BILAG B Flare through Day 210 
Time to first BILAG A Flare or >1 BILAG B Flare will be computed as the event date (as 
described below) – randomization date + 1.  If a patient is designated as a medication failure 
prior to or on their day 210 visit, they will be considered as having a BILAG flare (event) as of 
the date of first dose of the medication leading to the medication failure designation due to 
prohibited medication or unallowable CS burst.  
Time to first BILAG A Flare or >1 BILAG B Flare will be analyzed with Kaplan-Meier methods 
described for TTMF and censoring as described in Table 5.  Kaplan-Meier curves will be plotted 
over time. 
Table 5 
Situation 
Date of Event or Censoring 
Outcome 
Patient has a BILAG A Flare or >1 BILAG 
B Flare (Noted as BILAG 1A/2B Flare) 
prior to or on their Day 210 visit 
Date of first BILAG 1A/2B 
Flare 
Event 


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Patient is designated a medication failure 
(received prohibited meds or unallowable 
CS burst) prior to or on their Day 210 visit  
 
Date of first dose of 
medication leading to 
medication failure 
designation.  These dates will 
be obtained from the date of 
deviation on the protocol 
deviation eCRF form. 
Event 
Patient withdraws from study (no BILAG 
1A/2B Flare, no medication failure) prior to 
or on their Day 210 visit 
Censored at date of last non-
missing BILAG flare 
assessment (prior to or on 
withdrawal) through Day 210 
Censored 
Patient completes the study (no BILAG 
1A/2B Flare, no medication failure) 
Censored at date of last non-
missing BILAG flare 
assessment through Day 210 
Censored 
Patient dies during study (no BILAG 1A/2B 
Flare, no medication failure) prior to or on 
their Day 210 visit 
Censored at the day of death 
Censored 
An event will be counted once in a patient who is a medication failure and also experiences a 
BILAG flare.  Date of event will be the date of the earlier of the two reasons.   
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to first BILAG A Flare or >1 BILAG B Flare data will be provided in a by-patient listing 
in the full analysis set. 
7.3. Exploratory Endpoints and Analyses 
Efficacy will be evaluated for the Phase 1b MAD portion of the study as an exploratory 
endpoints and details are noted throughout sections 7.1 and 7.2.  Exploratory endpoints and 
analyses may be included in relation to the Phase 2 POC part of the study as described within 
this section. 
7.3.1. 
 
 
 
 
 
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8. PHARMACOKINETICS/PHARMACODYNAMICS/ 
IMMUNOGENICITY  
 
Pharmacokinetics, pharmacodynamics, and immunogenicity are secondary endpoints for the 
Phase 1b MAD study and exploratory endpoints for the Phase 2 POC study.   
PD results reported as less than the lower limit of quantification (LLOQ) will be counted as 0 to 
calculate summary linear statistics and will be reported as <LLOQ in listings.  All observed 
Immunogenicity and PD data, as provided by an external vendor, will be presented in by-patient 
listings. 
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within an Appendix of this document.  The author, 
finalization date, signatories, and page numbering of this SAP are independent of those SAPs 
and vice versa. Only the last final versions will be included in the appendix just prior to study 
conclusion. 
8.1. Pharmacokinetics 
BOS161721 PK concentration and parameter analyses will performed by a separate PK vendor 
and described under a separate SAP. 
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8.2. Pharmacodynamics 
Descriptive statistics for the observed results of the following PD endpoints/results will be 
summarized separately at baseline and each visit.  Change from baseline and percentage change 
from baseline will be summarized at each post-baseline visit.  In cases where both numeric and 
qualitative results are provided, the summaries will be based on the numeric results.  In cases 
where only qualitative results are provided and results given only as titers, shifts will be 
summarized.  Graphical presentations of mean and SD of the change from baseline over time 
will also be presented for the parameters in table 6. 
Table 6 
PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Clinical PD Biomarkers  
 MAD and POC 
NA (all) 
C-Reactive Protein 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
Other Biomarkers 
Phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3) 
MAD only 
% pSTAT3+ Lymphocytes –Stimulated; 
Ratio MEF (Stimulated / Unstimulated) 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Leukocyte immunophenotype 
(B and NK Cells) 
MAD only 
CD19+% of CD45+ Lymphocytes; 
IgD+C27-% of CD19+; 
IgD+CD27-CD38++CD24++% of 
CD19+; 
IgD-CD27-% of CD19+; 
IgD+CD27+% of CD19+; 
IgD-CD27+% of CD19+; 
IgD-CD27+CD38++CD138-% of 
CD19+; 
IgD-CD27+CD38++CD138+% of 
CD19+; 
CD56+% OF CD45+ Lymphocytes
Leukocyte  immunophenotype 
(T-Cells) 
MAD only 
CD4+CD8-% of CD3+; 
CXCR5+% of CD4+CD8-; 
PD-1+% of CD4+CD8-; 
ICOS+% of CD4+CD8-; 
CD25+CD127-% of CD4+CD8-; 
CXCR5+% of CD25+CD127-; 
PD-1+% of CD25+CD127-; 
ICOS+% of CD25+CD127-; 
CD8+CD4-% of CD3+ 
 
MAD only 
 
 
 
 
 
 
 
 
 
  
MAD and POC 
 
 
 
MAD and POC 
Analyses planned for available 
 
data will be described 
in a separate SAP to be included in the 
appendix of this SAP. 
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Additional PD results may be plotted over time by treatment group and visit. 
8.3. Immunogenicity 
Immunogenicity data as collected on the eCRF will be provided in by-patient data listings 
including neutralizing antibodies (NAb) and ADA for all relevant timepoints.  
All serum ADA samples that are confirmed positive in the ADA assay will be analyzed for the 
presence of NAb.   
The proportion of patients with positive or negative ADA will be summarized by study phase, 
treatment group, and overall, at baseline (pre-dose), and post-baseline in the FAS.  The 
frequency and percentage of patients with transient positive and persistent positive ADA will 
also be included in the summary.  If warranted based on data,  treatment-emergent transient 
positive and treatment-emergent persistent positive ADA will be summarized.  The frequency 
and percentage of patients with confirmed positive, treatment-emergent confirmed positive, and 
negative ADA at each post-baseline timepoint will also be summarized.  ADA designations and 
denominators are defined in table 7. 
Table 7 
Timepoint 
ADA 
Designations 
Definition 
Denominator/Evaluable 
Patients 
Baseline (Day 0 Pre-
Dose) 
Positive 
Confirmed positive ADA at 
baseline 
Number of patients with a 
baseline and at least one 
post-baseline ADA 
assessment  
 
Negative 
Negative ADA at baseline 
Post-Baseline 
Positive 
Confirmed positive ADA at any 
time after baseline 
Number of patients with at 
least one post-baseline 
ADA assessment 
Negative 
Negative ADA at all times after 
baseline 
Transient 
Positiveiv 
(1) Last ADA sampling timepoint 
is negative 
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AND 2a OR 2b: 
(2a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
OR 
(2b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) 
Persistent 
Positiveiv 
1 OR 2 OR 3: 
(1) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) 
OR 
(2) Confirmed positive ADA at the 
last post-baseline assessment 
OR 
(3) Negative ADA at the last post-
baseline assessment and a prior 
confirmed positive ADA sample 
occurred less than 16 weeks before 
the last post-baseline negative ADA 
sample 
 Treatment-Emergent 
Positive 
A post-baseline confirmed positive 
result exists with a titer >=4 times 
greater than the baseline titer 
OR 
Number of patients with at 
least one post-baseline 
ADA assessment 


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Any post-baseline confirmed 
positive result after a negative 
baseline result 
Note: The number of treatment-
emergent transient positive and 
treatment-emergent persistent 
positive ADA will sum to the total 
positive treatment-emergent ADA 
 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Transient 
Positiveiv 
Scenario 1: 
(1) Negative ADA at baseline  
AND 
(2) Last ADA sampling timepoint 
is negative 
 AND (3a OR 3b): 
(3a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
OR 
(3b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) 
Scenario 2: 
(1) Confirmed positive ADA at 
baseline  
AND 


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(2) Last ADA sampling timepoint 
is negative or is the same as 
baseline ADA levels 
 AND (3a OR 3b): 
(3a) Only one post-baseline 
confirmed positive ADA (excluding 
the last sampling timepoint) exists 
and the titer at the post-baseline 
timepoint is >=4 times greater than 
the baseline titer 
OR 
(3b) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are less than 16 
weeks apart (irrespective of any 
negative ADA in between) and the 
titers at each of the two or more 
post-baseline confirmed positive 
timepoints are >=4 times greater 
than the baseline titer 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Persistent 
Positiveiv 
Scenario 1: 
(1) Negative ADA at baseline  
AND (2 OR 3 OR 4): 
(2) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) 
OR 


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(3) Confirmed positive ADA at the 
last post-baseline assessment 
OR 
(4) Negative ADA at the last post-
baseline assessment and a prior 
confirmed positive ADA sample 
occurred less than 16 weeks before 
the last post-baseline negative ADA 
sample 
Scenario 2: 
(1) Confirmed positive ADA at 
baseline  
AND (2 OR 3 OR 4): 
(2) Two or more post-baseline 
confirmed positive ADA where the 
first and last ADA confirmed 
positive samples are more than 16 
weeks apart (irrespective of any 
negative ADA in between) and the 
titers at each of the two or more 
post-baseline confirmed positive 
timepoints are >=4 times greater 
than the baseline titer 
OR 
(3) Confirmed positive ADA at the 
last post-baseline assessment and 
the titer at the last post-baseline 
timepoint is >=4 times greater than 
the baseline titer 
OR 
(4) Negative/similar to baseline 
ADA at the last post-baseline 
assessment and a prior 
confirmed positive ADA 
sample occurred less than 16 
weeks before the last post-


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baseline negative/similar to 
baseline ADA sample and the 
titer of the confirmed positive 
ADA is >=4 times greater than 
the baseline titer 
 
Note: If baseline ADA data is 
missing, the baseline value is 
treated as negative for this analyses 
Post-baseline at each 
timepoint 
Positive 
Confirmed Positive ADA at the 
post-baseline timepoint 
Number of patients with 
ADA assessment at 
baseline and at the post-
baseline timepoint 
Treatment-
Emergent  
Scenario 1: 
(1) Negative ADA at baseline 
(2) Confirmed positive ADA at 
the post-baseline timepoint 
Scenario 2: 
(1) Confirmed positive ADA at 
baseline 
(2) Confirmed positive ADA at 
the post-baseline timepoint 
and the titer at the of the 
confirmed positive ADA is 
>=4 times greater than the 
baseline titer 
Negative 
Negative ADA at the post-baseline 
timepoint 
Overall 
Positive 
A patient with positive baseline 
(pre-dose) ADA or positive post-
baseline ADA 
 
Number of patients with a 
baseline or post-baseline 
ADA assessment 
Negative 
A patient with negative baseline 
(pre-dose) ADA and negative post-
baseline ADA at all time points 
 


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The frequency and percentages of positive and negative neutralizing antibodies will be 
summarized in the FAS overall and at each relevant post-baseline timepoint (i.e., Day 15, Day 
30, Day 60, Day 90, Day 180, Day 270). The denominators will be the number of patients with 
non-missing NAb data overall and at each timepoint, respectively. 
The adverse event overview table from section 10.1 will be repeated by post-baseline positive 
and negative ADA as defined in table 7 in the safety analysis set.  Additional adverse event 
analyses may be performed by post-baseline transient positive and persistent positive. 
 
9. QUALITY OF LIFE  
9.1. 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
 
 
 
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9.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. SAFETY  
 
All safety analysis reporting will be based on the Safety Analysis Set.  Unless otherwise noted, 
all safety analyses will be presented overall, by study phase, and treatment group. 
10.1. Adverse Events 
AEs will be collected and recorded for each patient from the date of the first dose of study drug 
until the end of their participation in the study, including the safety follow up period.  Severity of 
adverse events will be graded by the investigator according to National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  AEs will also 
be assessed for relationship to study drug, and seriousness.  Adverse events will be marked as 
AESIs, dose-limiting toxicities (DLTs), or injection site reactions (ISRs), where applicable.  AEs 
will be considered treatment-emergent adverse events (TEAEs) if they started any time after first 
dose or if the year, month and day of start date were missing.  Any missing severity assessments 
will be assumed to be Grade 3, missing relationship assessments will be assumed to be related, 
and missing seriousness assessments will be assumed as serious. 
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An overview of TEAEs will be produced, including counts and percentages of patients with any 
incidences of TEAE, TEAEs related to study treatment, SAEs, SAEs related to study treatment, 
any CTCAE grade 2 or higher TEAEs, any CTCAE grade 2 or higher TEAEs related to study 
treatment, any CTCAE grade 3 TEAEs, any CTCAE grade 3 or higher TEAEs related to study 
treatment, any CTCAE grade 4 TEAEs, any CTCAE grade 4 or higher TEAEs related to study 
treatment, TEAEs leading to study treatment discontinuation, treatment related TEAEs leading to 
study treatment discontinuation, TEAEs of special interest, related TEAEs of special interest, 
DLTs, related DLTs, TEAEs resulting in death, related TEAEs resulting in death, and injection 
site reactions.  The maximum CTCAE grade (Grades 1-5) will also be included on the summary 
table. 
Adverse events will be coded based on the MedDRA. Patients will be counted once per SOC 
(and likewise for PT within SOC). TEAEs will be summarized by SOC and PT in descending 
order of overall incidence of SOC (and PT within SOC).  The MedDRA version used is defined 
in the study data management plan. 
Summaries of adverse events by SOC and PT will include the following types:  
 TEAEs; 
 TEAEs related to study treatment;  
 SAEs; 
 Related Serious TEAEs; 
 CTCAE Grade 3 or higher TEAEs; 
 CTCAE Grade 3 or higher TEAEs related to study treatment; 
 TEAEs leading to treatment discontinuation; and 
 Dose-Limiting Toxicities 
 TEAEs of Special Interest 
A summary of TEAEs by SOC, PT, and maximum CTCAE grade will also be prepared.  For 
these summaries, TEAEs will be sorted for each patient by SOC/PT and CTCAE grade; patients 
will be counted once within a SOC/PT based on their maximum CTCAE grade.  Missing 
CTCAE grade will be counted as grade 3 and will also be presented in a ‘Missing’ row for 
completeness. 
A summary of TEAEs by PT and maximum CTCAE grade will also be prepared with sections 
for any TEAE and TEAEs related to study treatment.  For these summaries, patients will be 
counted once within a PT based on their maximum CTCAE grade.  Missing CTCAE grade will 
be counted as grade 3.  An additional summary of TEAEs by PT and maximum CTCAE grade 
will summarized for all TEAEs and TEAEs related to treatment for PTs with at least one patient 
experiencing a CTCAE grade 3 or higher and PTs where 10% or more of patients experience a 
CTCAE grade 1 or 2 for that PT.  The summary will be sorted by the total incidence of the PT in 
the any TEAE section.   
A comprehensive listing of all AEs will be provided in a by-patient data listing for the safety 
analysis set. In addition, the following listings will be provided for the safety analysis set:  


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 TEAEs related to study treatment;  
 SAEs;  
 TEAEs leading to treatment discontinuation; and 
 AESIs 
 CTCAE Grade 3 or Higher TEAEs 
10.2. Clinical Laboratory Evaluations 
Laboratory tests will be performed at times defined in the protocol Schedule of Assessments.  
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI).  The following laboratory evaluations will be reported in data summaries, 
with asterisks indicating those that will be graded using NCI CTCAE.  Grading will be 
performed by the Central Lab for relevant laboratory parameters based on the details provided in 
Appendix 13.11 .  If a grade is not present in the central lab database for a graded lab parameter, 
the grade will be analyzed as grade 0. 
Hematology: Hemoglobin*, Hematocrit, RBC count, RDW, MCV, MCH, MCHC, Platelet 
count*, WBC count*, CD4+ count*, Total neutrophils (Abs)*, Eosinophils (Abs), Monocytes 
(Abs), Basophils (Abs), Lymphocytes (Abs)* 
 
Clinical chemistry: Alanine Aminotransferase*, Albumin*, Alkaline Phosphatase*, Aspartate 
Aminotransferase*, Bicarbonate, Bilirubin*, Blood urea nitrogen, C Reactive Protein, Calcium, 
Chloride, Creatine Kinase*, Creatinine*, Glucose (fasting)*, Glucose (random)*, Potassium*, 
Protein, Sodium*, Uric acid*, eGFR (Cockcroft-Gault)*, eGFR (MDRD)*, Total cholesterol 
(fasting)*, LDL-C (fasting), HDL-C (fasting), Triglycerides (fasting)*, Gamma Glutamyl 
Transferase*. 
 
Coagulation: Prothrombin Intl. Normalized Ratio*, Activated Partial Thromboplastin Time* 
Urinalysis: pH, Glucose (qual), Protein (qual)*, Blood (qual)*, Ketones (qual), Nitrites (qual), 
Leukocyte esterase (qual), Urobilinogen (qual), Urine bilirubin (qual), Microscopy 
 
Observed values, changes, and percentage changes from baseline for hematology, clinical 
chemistry, and coagulation laboratory evaluations will be summarized at each visit and most 
extreme change.  Endpoint analyses will be based on changes from baseline assessments at Days 
120 and 210. 
The number and percent of patients with a CTCAE toxicity grade of 3 or higher will be tabulated 
by laboratory evaluation with defined CTCAE grading at each visit for hematology, clinical 
chemistry, coagulation, and urinalysis (protein only).  Patients with missing values post-baseline 
will be excluded from the summary. The denominator for percentages will be the number of 
patients with a post-baseline assessment for the laboratory parameter in question at that visit. 
Hematology, clinical chemistry, coagulation, and urinalysis (protein only) shift tables displaying 
the shift from baseline to the worst value of CTCAE grade will be presented based on the most 


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extreme change as it relates to the relevant CTCAE definition. CTCAE relating to “high/hyper” 
conditions will depend on the maximum post-baseline value while CTCAE “low/hypo” will be 
reported based on the minimum post-baseline value.  Separate shift tables will be prepared for 
parameters with bi-directional toxicity grading.  Lab parameters which are optional, such as 
gamma glutamyl transferase, will not be included in the shift tables. 
Hematology and clinical chemistry laboratory data which is not graded will also be summarized 
in shift tables of baseline to each visit and most extreme change based on range categories of low 
(below lower limit of normal [LLN], normal, and high [above upper limit of normal [ULN]]). 
Urinalysis laboratory data (excluding protein) will also be summarized in a shift table of baseline 
to each visit based on range categories of low (below lower limit of normal [LLN]), normal, 
abnormal, and high (above upper limit of normal [ULN]). 
Selected hematology and clinical chemistry laboratory results will be plotted over time for 
treatment group for MAD phase 1b portion of the study in the safety analysis set.  The mean and 
SD of the change from baseline for selected hematology and clinical chemistry laboratory results 
will be plotted over time for the POC Phase 2 portion of the study in the safety analysis set. 
All laboratory parameters as well as a summary of central laboratory tests and chest x-ray will be 
provided in patient data listings for all randomized patients.  By patient listings of clinical 
chemistry and hematology data will be presented in the safety analysis set for the DMC and 
interim analysis only. 
10.3. Other Safety Evaluations 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening. i   The C-SSRS evaluation will be performed as specified in the protocol 
Schedule of Assessments. 
The C-SSRS has 11 binary (yes/no) outcomes corresponding to five categories of suicidal 
ideation, five categories of suicidal behavior, and the category of self-injurious behavior without 
suicidal intent: 
Suicidal ideation is present if there is a “yes” response to any of the 5 suicidal ideation category 
questions. Suicidal behavior is present if there is a “yes” response to any of the 5 suicidal 
behavior category questions.  Suicidal ideation or behavior is present if there is a “yes” response 
to any of the 10 suicidal or ideation or behavior category questions. 


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The number and percentage of patients with any post-baseline occurrence of the following 
ideations and behaviors will be presented overall, by study phase and treatment group: 
 Suicidal ideation (overall and by individual question),  
 Suicidal behavior (overall and by individual question),  
 Suicidal ideation or behavior,  
 
A similar tabulation of the occurrence of any of the above ideations and behaviors at baseline or 
as part of their lifetime history/past 12-month history (collected at the screening visit) will be 
presented overall, by study phase, and treatment group. 
 
A shift table displaying the shift from worst pre-treatment category to the worst post-baseline 
category will be presented overall, by study phase, and treatment group.  Best to worst C-SSRS 
category is defined in the following order: no suicidal ideation or behavior, suicidal ideation, and 
suicidal behavior.  The worst post-baseline shift is calculated based on all post-baseline visits, 
including unscheduled visits.  Worst pre-treatment will include all C-SSRS assessments prior to 
first dose date/time (screening or baseline).  The denominator will be the number of patients with 
at least one non-missing baseline and post-baseline C-SSRS assessment. 
Missing data will not be imputed. 
All C-SSRS individual items will be presented in data listings for screening and post-screening 
(since last visit), separately.  A separate listing will be presented for patients with suicidal 
ideation, suicidal behavior, or non-suicidal self-injurious behavior for all randomized patients. 
10.3.2. 
Vital Signs 
Vital signs include: heart rate (beats/min); temperature (oC); systolic and diastolic blood pressure 
(mmHg).  Observed values, changes, and percentage changes from baseline for vital signs will 
be summarized at each visit and time point, as well as for most extreme change overall, by study 
phase, and treatment group.  
All vital signs data will be presented in patient data listings for all randomized patients. 
10.3.3. 
12-Lead Electrocardiogram (ECG) 
ECG will be assessed as specified in the protocol Schedule of Assessments.  The following ECG 
parameters will be collected:  PR interval (msec), QRS interval (msec), RR interval (msec), QT 
interval (msec), and QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
(msec).  ECG parameters and ECG evaluation will come directly from the database and will not 
be calculated during analysis.   
Observed values, changes, and percentage changes from baseline for ECG parameters will be 
summarized at each visit, as well as for most extreme change overall, by study phase, and 
treatment group.  


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The number and percent of patients with the following parameters at any post-baseline visit and 
at each visit will be summarized:  
 Abnormal, not clinically significant ECGs 
 Abnormal, clinically significant ECGs 
 
The number and percent of patients with each ECG evaluation result will be summarized by 
visit.  The worst ECG evaluation at any post-baseline visit will also be summarized in the order 
of: Normal, Abnormal, not clinically significant, Abnormal, clinically significant. 
For the summary of incidence at any post-baseline visit, the denominators for percentages will 
include patients with one or more non-missing value at any post-baseline visit.  For the by-visit 
summaries, the denominators for percentages will include patients with a non-missing value at 
that visit.  
Investigator reported ECG result shifts from baseline to each visit and worst case post-baseline 
will be summarized.  Worst case post-baseline will be based on the most abnormal observed 
value on or after the randomization date. 
All ECG data will be presented in a by patient data listing for all randomized patients.  A 
separate by patient listing for patients with abnormal, clinically significant 12-lead ECGs will 
also be provided in the safety analysis set for DMC meetings and the interim analysis only. 
10.3.4. 
Physical Examinations 
Targeted physical examination data and full physical examination data will be presented in 
patient data listings.  A separate by patient listing for patients with abnormal, clinically 
significant physical examination findings will also be provided in the safety analysis set for 
DMC meetings and the interim analysis only. 
11. CHANGES TO THE PLANNED ANALYSIS 
 
The following changes were made to the planned analyses: 
 Time to SRI-4 Response was originally a planned endpoint for the MAD and POC portions of 
the study.  This was removed from the POC portion of the study upon Protocol Amendment 6 
(30Apr2020); however, the endpoint was inadvertently maintained in the protocol for the 
MAD portion of the study.  This analysis will not be performed for any study part. 
 Rules for applying LOCF were vague within the protocol and were further detailed in this 
SAP.  See Section 7 for further details. 
 The PP was clarified to include additional criteria beyond the protocol description.  The PP 
will exclude patients with more than one missed dose.   


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 Cytokine, chemokine and genotyping data were originally planned to be part of the MAD and 
POC portion of the study; however, data for these parameters is only available for the MAD 
portion of the study. 
 The definition of the CLASI response in the protocol is vague as the protocol defines the 
CLASI response as 50% improvement from baseline in “A” (total activity) or “B” (total 
damage) scores.  The SAP further calrifies the CLASI response as 50% improvement from 
baseline in CLASI and distinguishes a CLASI-A response from a CLASI-B response.


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12. REFERENCES 
 
i. Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
ii.
 
 
 
iii. Van Vollenhoven RF, Hahn BH, Tsokos GC, et al. Efficacy and safety of ustekinumab, an 
IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a 
multicentre, double-blind, phase 2, randomised, controlled study. Lancet. 
2018;392(10155):1330-1339. 
iv. Shankar G, et al.  Assessment and Reporting of the Clinical Immunogenicity of Therapeutic 
Proteins and Peptides – Harmonized Terminology and Tactical Recommendations.  AAPS 
Journal, 2014; 16(4):663. 
v. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study 
reports questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
vi. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf. Accessed 13 Jan 2016. 
vii. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9
_Guideline.pdf . Accessed 15 June 2016. 
viii. FDA Guidance for Industry Systemic Lupus Erythematosus – Developing Medical Products 
for Treatment. 2010. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm072063.pdf.  Accessed 23February2018. 
ix. Committee for Medicinal Products for Human use (CHMP).  EMA Guideline on clinical 
investigation of medicinal products for the treatment of systemic lupus erythematosus and lupus 
nephritis. 2015.  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500
184889.pdf. Accessed 04March2018. 
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x. 
 
xi. Nilsson M, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K.  
Columbia-Suicide Severity Rating Scale Scoring and Data Analysis Guide. V2 2013.  
https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-Clinical-
Trials-1.pdf.  Accessed 18May2018. 
xii. 
 
 
  
 
xiii. 
 
  
 
xiv. 
 
 
 
 
 
 
 
 
 
 
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13. APPENDICES 
 
13.1. COVID-19 Impact and Data Handling 
 
The COVID-19 Pandemic resulted in contingency plans for BOS161721-02. 
 Safety Oversight: In case a patient cannot return to the study site for the 
scheduled visit, the site staff will contact the patient remotely for safety follow up, for 
example, via telephone or video conferencing.  The analysis of safety data will include all 
collected data regardless of remote data collection. 
 
 Central Laboratory: In the case of courier issues that will prevent the 
protocol-required laboratory specimens to be sent to the study core laboratory, 
the site should have the safety laboratory specimens (Hematology, 
Chemistry, and Urinalysis) sent to their local laboratory for analysis and review 
by the study physician.  The local laboratory data will not be entered into the clinical 
database or analyzed/presented in data summaries. 
 
 Investigational Product Dosing: In cases when dosing cannot be performed 
during the protocol-designated windows, the Investigator should discuss each 
case with the Sponsor to determine whether it is a missed visit or whether the 
dosing can be performed outside protocol windows (as a protocol deviation). A 
minimum of 2 weeks must be maintained between consecutive doses. Patients 
who miss more than 2 doses of the study drug (whether consecutive or not) will 
be discontinued from the study and will undergo assessments as outlined in 
Section 5.5 of the study protocol (Premature Discontinuation).  A sensitivity analysis of 
SRI-4 response using LOCF for missing data and/or observed case data may be 
performed to assess the impact of patients that did not follow the original protocol dosing 
schedule. 
An addendum to this SAP will be developed that documents all additional data handling 
techniques employed to manage COVID impacted data, if needed, prior to database lock and 
unblinding.  
 
 


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13.2. Physician’s Global Assessment 
 
 
 


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13.3. SLEDAI-2K Index 
 
 
 


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13.4. BILAG 2004 Index 
 


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13.5. ACR-28 Joint Count Assessment 
 


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13.6. SLICC/ACR Damage Index 
 


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13.7. CLASI 


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13.8. 
 
13.8.1. 
 
 
 
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13.9. C-SSRS 
13.9.1.  C-SSRS (Baseline/Screening) 
 


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13.9.2. C-SSRS (Since Last Visit) 
 
 
 


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13.10. 
 
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13.11. CTCAE Grading Details from the Central Laboratory 
 


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13.12. Table of Contents for Tables, Listings, and Figures 
 
The table of contents for tables, listings, and figures will be provided in a corresponding mock 
shell document. 
 
 


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13.13. Other SAP(s) Describing Analyses not Covered in the SAP 
 
SAPs describing analyses (pharmacokinetics [PK], PK/pharmacodynamics[PD], etc.) not 
covered within this SAP will be included within this Appendix. 


 
 
Page 1 of 58 
 
BOS161721-02: A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 
COMBINED STAGGERED MULTIPLE DOSE ESCALATION STUDY OF 
BOS161721 IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS 
ON A BACKGROUND OF LIMITED STANDARD OF CARE 
 
 
Statistical Analysis Plan 
 
 
 
VERSION 2.0 
DATE OF PLAN: 
29Nov2018 
 
 
STUDY DRUG:  
BOS161721 
 
 
PREPARED FOR: 
Boston Pharmaceuticals, Inc. 


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Approval Signature Page: Array Biostatistics, LLC 
 
 
 
 
 
 
 
Document Author:   
, MS 
Senior Biostatistician 
 
Date 
 
 
 
 
 
 
Document Reviewer:  
, MS 
Vice President, Biostatistics & Statistical Programming 
 
Date 
 
 
 
 
 
 
 
PPD
PPD


PPD
PPD
PPD
PPD


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Contents 
1. 
Introduction ............................................................................................................................. 9 
2. 
Study Objectives and Endpoints ............................................................................................. 9 
2.1. 
Multiple Ascending Dose (MAD) Phase 1b Study .......................................................... 9 
2.2. 
Proof of Concept (POC) Phase 2 Study ......................................................................... 11 
3. 
Study Design ......................................................................................................................... 13 
3.1. 
Study Design and Population ......................................................................................... 13 
3.1.1. 
Multiple Ascending Dose Phase 1b ........................................................................ 14 
3.1.2. 
Proof of Concept Phase 2 ........................................................................................ 15 
3.2. 
Randomization and Blinding .......................................................................................... 16 
3.3. 
Sample Size Considerations ........................................................................................... 16 
3.4. 
Data Monitoring Committee (DMC).............................................................................. 17 
3.5. 
Interim Analysis (IA) ..................................................................................................... 17 
3.6. 
Timing of Analyses ........................................................................................................ 18 
4. 
Data Analysis Considerations ............................................................................................... 18 
4.1. 
Stratification and Covariates .......................................................................................... 19 
4.2. 
Evaluation of Subgroups ................................................................................................ 19 
4.3. 
Multiple Comparisons and Multiplicity ......................................................................... 19 
5. 
General Data Handling Conventions .................................................................................... 19 
5.1. 
Assigned and Actual Treatment ..................................................................................... 19 
5.2. 
Reference Dates.............................................................................................................. 20 
5.3. 
Study Day and Duration Variables................................................................................. 20 
5.4. 
Study Time Periods ........................................................................................................ 21 
5.5. 
Baseline, Post-Baseline Changes, and Last Observation Carried Forward (LOCF) ...... 21 
5.6. 
Imputation of Partial Dates ............................................................................................ 21 
5.7. 
Multiple Assessments and Visit Windows ..................................................................... 22 
5.8. 
Treatment Group Display ............................................................................................... 22 
5.9. 
Missing Data .................................................................................................................. 23 
6. 
Study Patient Data................................................................................................................. 23 
6.1. 
Analysis Populations/Sets .............................................................................................. 23 
6.2. 
Patient Disposition ......................................................................................................... 24 
6.3. 
Protocol Deviations ........................................................................................................ 24 


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6.4. 
Demographic and Baseline Characteristics .................................................................... 24 
6.5. 
Medical History .............................................................................................................. 25 
6.6. 
Prior and Concomitant Medication and Procedures ....................................................... 25 
6.7. 
Study Drug Exposure and Compliance .......................................................................... 26 
7. 
Efficacy ................................................................................................................................. 26 
7.1. 
Primary Efficacy Endpoint and Analyses ...................................................................... 26 
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 .................................. 26 
7.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 30 
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit ..................................... 30 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit ..................................... 30 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit ..................................... 31 
7.2.4. 
Proportion of Patients with a sustained reduction of oral corticosteroid (CS) 
between Day 120 and Day 210 ............................................................................................. 31 
7.2.5. 
Proportion of new BILAG A flare or >1 BILAG B flare relative to baseline through 
Day 210 32 
7.2.6. 
Proportion of patients with PGA worsening ........................................................... 32 
7.2.7. 
Proportion of patients with BICLA response.......................................................... 32 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) ..................... 33 
7.2.8.1. 
Proportion of patients with CLASI response ...................................................... 34 
7.2.8.2. 
Results and Changes from Baseline in CLASI ................................................... 34 
7.2.9. 
Results and Changes from Baseline in Swollen and Tender Joints ACR-28 ......... 35 
7.2.10. 
Results and Changes from Baseline in SLEDAI-2K .......................................... 35 
7.2.11. 
Results and Changes from Baseline in SLICC/ACR Damage Index .................. 36 
7.2.12. 
Medication Failure .............................................................................................. 37 
7.2.12.1. 
Proportion of patients with medication failures .............................................. 37 
7.2.12.2. 
Time to Medication Failure (TTMF) ............................................................... 37 
7.2.13. 
Duration of Longest SRI-4 Response ................................................................. 38 
7.2.14. 
Time to First SRI-4 Response ............................................................................. 39 
7.2.15. 
Time to First BILAG A Flare or >1 BILAG B Flare Compared to Baseline 
through Day 210 ................................................................................................................... 40 
8. 
Pharmacokinetics/Pharmacodynamics .................................................................................. 41 
8.1. 
Pharmacokinetics ........................................................................................................... 41 
8.2. 
Pharmacodynamics......................................................................................................... 41 
9. 
Quality of Life....................................................................................................................... 43 


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9.1. 
 .............................................................................................................................. 43 
9.2. 
 ......................................................................................................................... 44 
10. 
Safety ................................................................................................................................. 45 
10.1. 
Adverse Events ......................................................................................................... 45 
10.2. 
Clinical Laboratory Evaluations ............................................................................... 47 
10.3. 
Other Safety Evaluations .......................................................................................... 48 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 48 
10.3.2. 
Vital Signs ................................................................................................................. 49 
10.3.3. 
12-Lead Electrocardiogram (ECG) ........................................................................... 49 
10.3.4. 
Physical Examinations .............................................................................................. 50 
10.3.5. 
Anti-Drug Antibodies (ADAs) ................................................................................. 50 
11. 
Changes to the planned analysis ........................................................................................ 50 
12. 
References .......................................................................................................................... 51 
13. 
APPENDICES ................................................................................................................... 53 
13.1. 
 ................................................................ 54 
13.2. 
CTCAE Grading Details from the Central Laboratory ............................................. 56 
13.3. 
Table of Contents for Tables, Listings, and Figures ................................................. 58 
 
 
 
 
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ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANA 
Antinuclear antibody 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APL 
Antiphospholipid 
AUC 
Area under the curve 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
Blood pressure 
C3 
Complement C3 
C4 
Complement C4 
CL 
Systematic clearance 
CLASI 
Cutaneous Lupus Area and Severity Index 
Cmax 
Maximum plasma concentration 
CPAP 
Clinical Pharmacology Analysis Plan 
CS 
Corticosteroid 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
dsDNA 
Double-stranded deoxyribonucleic acid 
ECG  
Electrocardiogram 
 
 
FAS 
Full analysis set 
HR 
Hazard ratio 
IA 
Interim Analysis 
IEC 
Independent Ethics Committee 
IL-21 
interleukin 21 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IWRS 
Interactive web response system  
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Medical Affairs 
nAb 
Neutralizing antibody 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
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PGA 
Physician’s Global Assessment 
PK 
Pharmacokinetics 
POC 
Proof of concept 
PP 
Per protocol set 
pSTAT3 
Phosphorylated signal transducer and activator of transcription 3 
PT 
Preferred Term 
SAD 
Single ascending dose 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SC 
Subcutaneously 
 
 
SLE 
Systemic Lupus Erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
System Organ Class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS 
Safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
t1/2 
Terminal elimination half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
First time to maximum concentration 
TTMF 
Time to medication failure 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
WHO 
World Health Organization 
 
 
 
 
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1. INTRODUCTION 
 
The statistical analysis plan (SAP) details the planned analyses that will be included in the 
Clinical Study Report (CSR) of study number BOS161721-02: A Randomized Double-Blind 
Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic 
Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care.  The content 
of this SAP is based on the protocol Version 4.0 (Amendment 3) dated 27July2018. 
Revision Chronology: 
 
 
V1.0 
05SEP2018 
Original 
 
 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Multiple Ascending Dose (MAD) Phase 1b Study 
Objectives 
Endpoints 
Primary 
• To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered subcutaneously (SC) in 
adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment, in order to estimate the 
optimal dose. 
Safety Endpoints 
• Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• Injection site reactions 
• Columbia Suicide Severity Rating Scale 
(C-SSRS) 
• 12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• Vital signs (blood pressure [BP], heart 
rate, and temperature) parameter results at 
each visit and change from baseline 
• Clinical laboratory results and change 
from baseline 
• Physical examinations changes from 
baseline 
• Anti-drug antibodies (ADAs) 
• Study drug exposure/compliance 


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Secondary 
• To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and 
PD effects in patients with mild to 
moderate SLE. 
Pharmacokinetic (PK) Endpoints 
• BOS161721 concentration by visit and 
time point 
• Maximum observed concentration (Cmax), 
first time to maximum concentration 
(Tmax), area under the concentration-time 
curve (AUC), t½, systematic clearance 
(CL), volume of distribution (Vd) 
Pharmacodynamic (PD) Endpoints 
• Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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- 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
• 
 
 
Note:
 
2.2. Proof of Concept (POC) Phase 2 Study 
Objectives 
Endpoints 
Primary 
• To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE Responder Index 4 
(SRI-4) 
Primary Efficacy Endpoint 
• The proportion of patients with a SRI-4 
response at Day 210 
 
 
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Secondary 
• To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on clinical indicators of SLE activity, 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care treatment 
Secondary Efficacy Endpoints 
• The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B 
flares relative to baseline through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• Time to medication failure 
• Duration of longest SRI-4 response 
• Time to first SRI-4 response 
• Time to BILAG A flare or > 1 BILAG B 
flare compared to baseline through 
Day 210 
Safety 
• To assess safety and tolerability of 
repeat doses of BOS161721 (20, 60, 
and 120 mg) administered SC in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Safety Endpoints 
• Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• Injection site reactions 
• C-SSRS 
• 12-lead ECGs parameter results at each 
visit and change from baseline 
• Vital signs (blood pressure [BP], heart 
rate, and temperature) parameter results at 
each visit and change from baseline 


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• Clinical laboratory results and change 
from baseline 
• Physical examinations changes from 
baseline 
• ADAs 
• Study drug exposure/compliance 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
• 
 
 
The order in which the endpoints for this trial will be discussed in subsequent sections is based 
on the phase 2 POC portion of the study.  The phase 1b MAD endpoints will also be discussed 
within the context of the phase 2 POC portion of the study but will appear out of the specified 
order in the above table in an effort to maintain common concepts across both phases in one 
location within the SAP. 
3. STUDY DESIGN 
3.1. Study Design and Population 
 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and pharmacokinetics (PK) of subcutaneously (SC) doses of 
BOS161721 in adult patients with moderately to severely active SLE.  After successfully 
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completing a screening phase, eligible patients will be randomized to a specified dose of 
BOS161721 or placebo.  The dosing schedule will be monthly.   
The trial will consist of 2 double blinded- portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety/efficacy  follow-up visit at Days 210, and safety follow up visits at Days 
240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” British 
Isles Lupus Assessment Group (BILAG) system organ disease, confirmation of clinical 
components of the SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening and 
during the study, and cross validation- of the instruments used in this study to assess the disease 
activity.  Further details on the content and methods of data reports by the medical monitor and 
sponsor will be outlined in the Medical Data Review Plan along with the processes and 
procedures that will be followed. 
3.1.1. 
Multiple Ascending Dose Phase 1b  
The MAD portion will consist of 3 cohorts:  
• Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 single ascending dose (SAD) study (BOS161721-01) in healthy 
subjects.  All doses selected for the MAD part of the study are projected not to exceed the mean 
exposure of that achieved in the SAD study. 
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 2 
begins dosing (after the data monitoring committee (DMC) evaluation of the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 3 begins dosing 
after the DMC evaluation of the safety and tolerability data from Cohorts 1 and 2.  Each cohort 
will continue at their assigned dose level through their respective 6-month treatment periods (See 
Study Schematic in the study protocol).  If patients discontinue the study in a cohort prior to 
adequate safety follow-up, he/she may be replaced. 


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Criteria for dose escalation are further described in the DMC Charter. 
3.1.2. 
Proof of Concept Phase 2  
The optimal dose is chosen based on MAD Phase 1b safety, tolerability, immunogenicity, and 
PK and PD data.  The dose will be communicated by a letter to site investigators participating in 
the POC Phase 2 portion, and to the Institutional Review Board / Independent Ethics Committee 
(IRB/IEC). 
For the POC part of the study, approximately 156 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments detailed in the study protocol.  Dose 
selection will be based on the DMC and sponsor’s assessment of safety, tolerability, 
immunogenicity, and PK and PD data from the MAD portion of 30 patients treated with 
BOS161721/placebo. 
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
Study Diagram for MAD Phase 1b and POC Phase 2 
Day 0
24 week treatment phase
Dose 1
Dose TBD N=104 
Placebo N=52
Low Dose (20 mg) N=6 (5A, 1P) 
Monthly visits 
Medium Dose (60 mg) N=12 (9A, 3P) 
Dose 3
2 month
6 patients complete dose 2:  dose escalate Cohort 2 if safe
Dose 1
Dose 2
1 month
High Dose (120 mg) N=12  (9A, 3P)
Dose 1
Dose 3 + 30 days: 
•
Phase 2 POC dose determined
•
Continue dosing Cohort 3 if safe
Follow up 
Dose 6
5 month
Dose 7
6 month
Dose 7
6 month
Dose 7
6 month
Screening
Week -4
8 patients complete dose 2:
•
Dose escalate Cohort 3 if safe
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Day 0
Day 0
Multiple Ascending Dose (MAD)
Phase 1b 
Proof of Concept (POC)
Phase 2 
Dose Evaluation
Phase
Follow up
90 days
90 days
Follow up 
90 days
Follow up 
90 days
Dose 1
Day 1
Dose 3
2 month
Dose 6
5 month
Dose 7
6 month
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Dose 3
2 month
A = active drug (BOS161721); P = placebo 
 


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3.2. Randomization and Blinding 
 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
portion and separately for each cohort in the Phase 1b and 2 portions as follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1 MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the interim analysis (IA) and the DMC safety reviews.  The DMC will review 
unblinded data during safety reviews and the IA.  A limited team at Boston Pharmaceuticals will 
review unblinded results from the Phase 1b MAD portion during the IA to determine the dose 
that will be used for the Phase 2 POC portion of the study.  Details regarding maintenance of the 
blinding and content of data reviews will be described in the DMC charter or related study 
documentation.   
3.3. Sample Size Considerations 
 
Sample size in the Phase 1b MAD part of the study is based on operational consideration. 
The sample size in the Phase 2 POC study is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable patients in the FAS.  This assumes 
24 patients will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 patients are randomized into the FAS.    
A total of 132 patients randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 


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from most recent non-missing result and patients are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
3.4. Data Monitoring Committee (DMC) 
 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in the study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC 
(i.e., dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in the study protocol. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
3.5. Interim Analysis (IA) 
 
One interim analysis is planned for this study and will be conducted at the time of the POC 
decision for dose selection.  The POC dose will be selected based on the MAD data.  Since there 
is no IA during the POC part of the study, there is no impact on the type 1 error.   
Interim analysis outputs will be a subset of those to be performed for the final analysis. 


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3.6. Timing of Analyses 
 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC portion.   
• The final analysis will be performed when all patients have either completed the POC 
safety follow up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
content and format of the safety review meetings are described in the DMC charter and 
SAP/mock shells. 
4. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.3 or higher. 
All data in the database will be presented in by-patient data listings. 
Unless otherwise stated, all listings will be sorted by study phase, treatment group, patient 
number, and assessment date (and time, if available).  If assessment date is missing, 
chronological visit will be used for sorting. 
Unless stated otherwise, continuous data will be summarized by treatment group based on 
number of patients (n), mean, median, standard deviation (SD), 25th percentile/first quartile (Q1), 
75th percentile/third quartile (Q3), minimum value, and maximum value. 
The geometric % coefficient of variation is calculated as 100*sqrt(exp(SDlog^2)-1) where SDlog 
is standard deviation of log-transformed values. 
Unless stated otherwise, categorical data will be summarized by treatment group using n and 
percentage based on the number of non-missing values. 
• The number of missing values will be presented as a separate category with no 
percentage, but only if one or more patients are missing data. 
• Counts of zero will be presented without percentages. 
 Statistics will be presented in the summary tables based on the following: 
• Minimum and Maximum: same number of significant digits as the raw value 
• Mean, Median, Q1, and Q3: one additional decimal place to that reported for 
Minimum and Maximum 
• SD: two additional decimal places than presented for the Minimum and 
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• Percentages: reported to one decimal place with the exception of 100% which will 
be displayed without decimals. 
• P-values will be reported to four decimal places.  If the value is below 0.0001 it 
will be noted as < 0.0001; if the value above 0.9999 it will be noted as > 0.9999. 
Unless otherwise noted, statistical inference will be based on a 10% significance level (i.e. 90% 
confidence intervals will be produced). 
Statistical testing will be performed on data from the Phase 2 study only. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of duration of treatment. 
Numbering for data displays will be based on ICH E3. 
4.1. Stratification and Covariates 
 
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data may be conducted as 
deemed appropriate to evaluate factors for which analyses are not controlled. 
Continuous efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of 
covariance (ANCOVA) when applicable, adjusting for the baseline value. 
4.2. Evaluation of Subgroups 
 
There are no formal plans for examining subgroups. 
4.3. Multiple Comparisons and Multiplicity 
 
The Type 1 error rate will not be adjusted for multiplicity.  
5. GENERAL DATA HANDLING CONVENTIONS 
5.1. Assigned and Actual Treatment 
 
Patients are assigned to a study treatment and cohort based on the study schematic in Section 3.    
Full analysis set (FAS) and per protocol (PP) analyses will be conducted on the basis of the 
randomized (assigned) treatment.  Safety analyses will be conducted on the basis of the actual 
treatment received based on the exposure data collected in the case report form (CRF). 


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5.2. Reference Dates 
 
• Screening date is defined as the CRF provided date on which a patient was screened for 
trial entry. 
• Randomization date is defined as the date on which the patient is randomized to study 
treatment. 
• Treatment start date is defined as the date of first dose of study drug. 
• Treatment end date is defined as the date of last dose of study drug. 
• Age will not be calculated and will come directly from the CRF.  The CRF uses the 
informed consent date as its reference date for age calculation. 
• Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date. 
• Efficacy data will use the randomization date as a reference date. 
• Study day will be based on treatment start date as a reference date. 
5.3. Study Day and Duration Variables 
 
Reference date calculations will be defined as follows, assuming non-missing dates:  
• date of interest – reference date + 1 when the date of interest is on or after the reference 
date; 
• otherwise, date of interest – reference date. 
 
If either date is missing or incomplete, reference date calculations will not be performed.  Date 
imputation will be performed as identified in Section 5.6. 
 
Study day will either have a negative value if collected before dosing or a positive value if 
collected on or after the day of drug dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation.  Duration on study is defined as the end of study date –
randomization date + 1.  Duration of treatment is defined as treatment end date – treatment start 
date + 1, where treatment end date is the date of last dose of study drug. 
Time-to-event endpoints are followed until first event or censoring.  As a result, event time will 
be calculated as: event or censoring date – reference date + 1.  These are further described in 
Section 7. 
When reporting time-to-event data (Time to Medication Failure, Time to first SRI-4 Response, 
Time to BILAG A Flare or >1 BILAG B flare) or duration outcomes, the results (in days) above 
will be converted to an appropriate unit.  When reporting in months it will be divided by 
30.4375; for reporting in weeks it will be divided by 7; and for reporting in years it will be 
divided by 365.25. 


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5.4. Study Time Periods 
 
Where applicable, data reporting will be classified by the following study periods for analysis: 
• Pre-treatment is defined as the period prior to a patient’s treatment start date. 
• On-treatment is defined as the period between a patient’s treatment start date and 
treatment end date, inclusive. 
• Post-treatment is defined as the period of time following the on-treatment period. 
5.5. Baseline, Post-Baseline Changes, and Last Observation Carried Forward 
(LOCF) 
 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
• Baseline will be based on the last non-missing value collected prior to or on the treatment 
start date (and time, if applicable). 
• Post-baseline values will be those collected after the date/time of first dose of study drug. 
• Change from baseline is defined as: value – baseline value.  
• Most extreme change:  The maximum most extreme change will be the maximum post-
baseline value; the minimum most extreme change will be the smallest post-baseline 
value. This calculation will consider all assessments collected after the first dose of study 
drug, scheduled or unscheduled. 
LOCF will be based on the last non-missing value collected.  This calculation will consider all 
assessments, scheduled or unscheduled, including baseline.  If a patient withdraws from the 
study, their most recent non-missing assessment prior to withdraw will be carried forward.  
Additional details regarding LOCF for specific endpoints are provided in Section 7. 
Observed values do not incorporate any imputations and are presented as collected. 
5.6. Imputation of Partial Dates 
 
Adverse Events  
• If the AE start date is completely missing, or if the patient was not treated, no imputation 
will be conducted. 
• If the AE start date is missing day and month, do the following: 
o If the treatment start date is missing or the AE start year does not fall in the same 
year as that of the treatment start date or if the AE record contains information to 
indicate that the event ended before the treatment start date (e.g. the AE end date 
month and year are earlier than the treatment start date or the full AE end date is 


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known and occurs earlier than the treatment start date), then set the AE start 
month and day to January 1st. 
o Otherwise, set the AE start date to the treatment start date.  
• If only the AE start day is missing, do the following: 
o If the study treatment start date is missing or the AE start month and year does not 
fall in the same month/year as that of the treatment start date or if the AE contains 
information to indicate that the event ended before the treatment start date, then 
set the AE start month and day to the 1st day of the month of the treatment start 
date. 
o Otherwise, set the AE start date to the treatment start date. 
• AE end dates will not be imputed.  
Prior, Concomitant, and Subsequent Medications 
• The imputation rules for AE start dates will be used for medication start dates. 
• Medication stop dates will be imputed as follows: 
o If the stop date is only missing the day, then the stop day is the last day of the 
month 
o If the stop date is missing both the day and month and the year matches the last 
study date, then the stop month and day is the earlier of the last study date and 
December 31 
o If the stop date is missing both the day and month and the year is earlier than the 
last study date, then the stop month and day is December 31 
o If the stop date is completely missing, no imputation is performed, and the 
medication will be classified as a concomitant medication for subjects who were 
treated unless the medication began after the end of study treatment. 
5.7. Multiple Assessments and Visit Windows 
 
Nominal visits (e.g. those identified by the study CRF) will be the basis of summarization and 
statistical analysis; no visit date windowing will be conducted. Unscheduled data may be 
included in summaries of most extreme, baseline, and endpoint values; summaries of specific 
abnormalities any time post-baseline; and patient data listings 
5.8. Treatment Group Display 
 
Treatment groups will be displayed with the following columns.  See the mock shells for 
additional details and a visual representation of the treatment group display. 
• Phase 1b MAD: Cohort 1 BOS 20mg 
• Phase 1b MAD: Cohort 2 BOS 60mg 
• Phase 1b MAD: Cohort 3 BOS 120mg 
• Phase 1b MAD: Placebo 


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• Phase 1b MAD: Total BOS (All patients treated with BOS161721, excludes placebo) 
• Phase 2 POC: BOS <dose> where <dose> is the value determined during the IA 
• Phase 2 POC: Placebo 
• Overall: Total BOS <dose>mg where <dose> is the common dose between the Phase 1b 
MAD and Phase 2 POC portions of the study (to be determined during the IA).  If a 
common dose is not determined, this column will be omitted. 
• Overall: Total BOS (Patients treated with BOS161721 in MAD and POC, excludes 
placebo) 
• Overall: Total Placebo (Placebo patients in MAD and POC, excludes patients treated 
with BOS161721) 
5.9. Missing Data 
 
Missing data imputation for the efficacy endpoints are discussed in the corresponding efficacy 
sections.  AE and concomitant medication date imputations are described in Section 5.6.  
Missing data for noncompartmental analysis of pharmacokinetics will follow standard 
imputation methods, as described in a separate Clinical Pharmacology Analysis Plan (CPAP).  
Otherwise, missing data will not be imputed. 
6. STUDY PATIENT DATA 
6.1. Analysis Populations/Sets 
 
Full Analysis Set (FAS):  Defined as all patients who receive at least one dose of study treatment 
and have at least one evaluable post-baseline efficacy evaluation (BILAG, PGA, SLEDAI-2K, 
CLASI, ACR-28, SLICC/ACR, 
, or 
).  FAS analyses will be conducted on the 
basis of the randomized treatment.  The FAS will be used as the basis for the primary efficacy 
analysis. 
Safety Analysis Set (SS): Defined as all patients who receive at least one dose of study 
treatment.  Safety analyses will be conducted on the basis of actual treatment received.  The SS 
will be the basis of all safety reporting. 
Per Protocol Set (PP): Defined to exclude major protocol violations from the efficacy analysis.  
The PP will include all patients from the FAS except those with major violations to the protocol 
deemed to impact the analysis of the primary endpoint.  These violations will be identified based 
on blinded data prior to study unblinding.  PP analyses will be conducted on the basis of the 
randomized treatment.  Additional information on inclusion into this population can be found in 
Section 6.3. 
Pharmacokinetic Analysis Set (PK): Defined as the FAS patients who received at least one dose 
of BOS161721 with sufficient concentration data for the calculation of at least one PK 
parameter. 
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6.2. Patient Disposition 
 
Disposition data will be summarized for all randomized patients.  The number of patients in each 
analysis population, the number of patients who discontinued study treatment including reasons, 
and the number of patients who discontinued the study including reasons will be summarized.  
The number of patients who completed the study will also be summarized.  Data will be 
presented by study phase and treatment group. 
A by-patient listing of patient disposition data including reason for discontinuation, if applicable, 
will be presented for all randomized patients.  A by-patient listing of randomization details will 
also be provided for all randomized patients. 
A by-patient listing of inclusion/exclusion criteria and screen failures will be produced for all 
enrolled patients.  Screen failures will otherwise not be included in any analyses. 
6.3. Protocol Deviations 
 
Protocol deviations will be identified and classified as major violations before database lock and 
unblinding. Major protocol deviations may include but are not limited to: 
• Violation of Inclusion/Exclusion Criteria 
• Use of prohibited therapies 
• Incorrect treatment 
Protocol deviations will be summarized by protocol version, deviation category, and 
major/minor designation.  Protocol deviations will be summarized by study phase and treatment 
group for all randomized patients. 
A listing of protocol deviations will be provided for all randomized patients. 
6.4. Demographic and Baseline Characteristics 
 
Patient demographics and baseline characteristics will be summarized in the SS.  These will 
include age (years), gender (Male / Female), ethnicity (Hispanic or Latino / Not Hispanic or 
Latino), race (American Indian or Alaska Native / Asian / Black or African American / Native 
Hawaiian or Pacific Islander / White / Other), baseline height (cm), baseline weight (kg), and 
baseline BMI (kg/m2).  Age is reported as collected in the clinical database and will also be 
categorized as a categorical variable (≤45, >45-<65, ≥65) for reporting.  Patient eligibility for 
central review will be summarized.  Childbearing potential and birth control methods for female 
and male patients will be summarized for the DMC meetings and interim analysis only.  
Demographics and baseline characteristics will be summarized by study phase and treatment 
group. 
 


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Demographics and baseline characteristics will be listed for all randomized patients.  A separate 
by-patient listing will be created for childbearing potential and birth control for all randomized 
patients. 
 
The following conversions and equations will be used as applicable: 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = weight(kg)/[height(m)2] 
 
6.5. Medical History 
 
Medical history will be presented in data listings for all randomized patients.  Medical history 
coded terms will be provided, including the system organ class and preferred term.  The data 
management plan specifies the version of MedDRA used for medical history coding. 
6.6. Prior and Concomitant Medication and Procedures 
 
The incidence of medication use will be summarized by WHO Drug Dictionary anatomic 
therapeutic class (ATC) Level 2 classification (i.e. therapeutic main group) and preferred name. 
A patient will be counted only once at each level of reporting.  Prior medications are those which 
have been identified to have been discontinued prior to the first dose of study medication.  
Concomitant medications are those which have been identified to have been taken at any point 
during the period of time between the first and last dose of study medication, including 
medications which started prior to first dose of study medication but are ongoing at first dose.  
Subsequent medications are those which have been started after the last dose date.  The data 
management plan specifies the version of WHO Drug used. 
Partial dates will be imputed according to Section 5.6 for the determination of prior, 
concomitant, and subsequent medications. 
Concomitant medication use will be summarized and presented by study phase and treatment 
group in the SS.  
All prior and concomitant medication data will be provided together in a by-patient listing 
including the verbatim and preferred drug name and WHO ATC Class (ATC Level 2) for all 
randomized patients.  Past biological, immunosuppressant, antimalarial and corticosteroid SLE 
medication history data will be listed separately for all randomized patients. 
Concomitant procedures will be presented in a data listing for all randomized patients. 
 


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6.7. Study Drug Exposure and Compliance 
 
The total dose administered (mL) and the number of doses received will be summarized as 
continuous variables.  The number and percentage of patients dosed and the number of patients 
who received the total planned dose at each nominal, protocol specified, visit (Day 0 / Day 30 / 
Day 60 / Day 90 / Day 120 / Day 150 / Day 180) will be summarized.  The denominator for the 
number of patients dosed will be the number of patients in the SS.  The denominator for the 
number of patients who received the total planned dose will be the number of patients dosed at 
the corresponding nominal visit. 
The percent compliance will be calculated descriptively and is defined as 100 * (total actual dose 
summed across all visits)/total planned dose summed across all visits). 
The duration of exposure in days will also be summarized descriptively and is defined as the last 
dose date – first dose date +1.   
Study drug exposure and compliance will be presented by study phase and treatment group in the 
SS. 
By-patient listings of BOS161721 and placebo dosing data will be produced for all patients in 
the SS. 
7. EFFICACY  
7.1. Primary Efficacy Endpoint and Analyses 
 
Safety is the primary endpoint for the Phase 1b MAD portion of the study and is discussed 
in Section 9.  Efficacy will be evaluated for the Phase 1b MAD portion of the study as an 
exploratory endpoint and details will be included in relation to the Phase 2 POC portion of the 
study within this section.  
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 
 
The primary efficacy endpoint is the proportion of patients who achieve a SRI-4 response at Day 
210.  
 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
 
1) ≥ 4-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 


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2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm.   
 
The proportion of patients who achieve a SRI-4 response at Day 210 will be presented and 
assessed using Pearson’s chi-square test.  The number of SRI-4 responders, treatment difference 
versus placebo, odds ratio, and 90% confidence interval will be displayed.  The 90% confidence 
interval will be calculated with Wilson (score) confidence limits for the binomial proportion by 
treatment group.  If any of the expected cell counts are less than 5, Fisher’s exact test will be 
used and exact confidence intervals will be constructed.  The analyses will be repeated for each 
of the three components contributing to the SRI-4 response.  The primary analysis of the primary 
efficacy endpoint will be performed in the FAS and presented by treatment group. The analysis 
will be repeated in the PP analysis set.   
 
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 0.10. 
Evaluability/Non-Responders: 
Patients who received prohibited medications or unallowable corticosteroid (CS) usage will be 
considered “medication failures” and will be treated as non-responders for the primary efficacy 
analysis.  Prohibited medications are detailed in Appendix 4 of the study protocol.  Prohibited 
medications and unallowable CS usage will be recorded as protocol deviations in the clinical 
database.   
A patient is considered to have unallowable CS usage if any of the following is not met: 
• After Day 0 (after initiation of study therapy), no up-titration above 10 mg/day is allowed 
except for up to 1 CS burst for increased disease activity.  
• Tapering is allowed after randomization except within 60 days of the primary (Day 210) 
and secondary (Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant. 
• A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed 
during the study between Day 0 and Day 60, according to the following:   
o An oral CS “burst” between Day 0 and Day 60; (an increase of ≤ 40 mg/day of 
prednisone or equivalent), which must be tapered down to a maximum of 
10 mg/day within 2 weeks of initiation of the “burst” 


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o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o The course of the oral CS “burst” is not permitted to extend beyond Day 60 
Patients who received an allowable CS burst but having missing data at Day 210 will be 
considered a medication failure and will be treated as non-responders for the primary efficacy 
analysis.  The determination of medication failures will be reviewed using blinded data and 
finalized prior to unblinding.  Once a patient is determined to be a non-responder, they will not 
be considered for response at a later visit. 
 
If a patient has a BILAG, SLEDAI-2K, or PGA assessment outside of a 30 day +/-4 day window 
since the previous assessment (0-25 or >=35 days since the prior assessment), the corresponding 
result will be considered not evaluable and will be excluded from all analyses.  The excluded 
result will not contribute to LOCF analyses.  In these cases, the individual assessment (i.e. 
BILAG, SLEDAI-2K, or PGA) will be considered as if it was missed and analyses will be 
handled per the below details. 
 
Missing Data: 
 
• If a patient is missing data during the pre-treatment period for SLEDAI-2K, PGA, or 
BILAG, the patient will be excluded from the primary efficacy analysis. 
 
• Missing data at Day 210 for overall components for SLEDAI-2K, BILAG, and PGA will 
be addressed by employing a last observation carried forward (LOCF) analysis within 
each overall component as described in Section 5.5.  For example, if a patient has data for 
SLEDAI-2K and BILAG at Day 210 but is missing PGA at Day 210, the PGA 
component would employ LOCF.  Data collection and scoring will be performed in the 
clinical database for BILAG, SLEDAI-2K, and PGA.  As such, missing individual items 
contributing to any of the overall components will not be imputed/carried forward.   
 
• Missing data for visits other than Day 210 will be handled in the same way as Day 210. 
 
• If one or more consecutive visits are missed, LOCF analyses will be carried forward from 
the most recent prior assessment.  For example, if the Day 150, Day 180 and Day 210 
assessments are all missed but the Day 120 assessment was performed, the Day 120 
assessment would be carried forward to Days 150, 180, and 210 for analysis. 
 
Several sensitivity analyses will be performed: 
Analysis 
Criteria 
Sensitivity Analysis 1 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (including LOCF methods) for patients in the full analysis 
set excluding patients with: 


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(1) Positive anti-drug antibodies at baseline through Day 210.   
AND 
(2) Confirmed nAb at Day 90 and Day 180 OR missing Day 90 and 
missing Day 180 nAb OR missing Day 90 nAb and confirmed nAb at 
Day 180. 
 
Missing ADA and missing nAb results will be handled with a LOCF 
approach as discussed in Section 5.5.  Additional analyses exploring 
impact of baseline factors such as baseline disease severity, race, and 
other characteristics may be performed. 
Sensitivity Analysis 2 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (including LOCF methods) for patients in the full analysis 
set; however, if a patient has a BILAG, SLEDAI-2K, or PGA 
assessment outside of a 30 day +/-4 day window since the previous 
assessment (0-25 or >=35 days since the prior assessment), the 
corresponding result will be considered evaluable and will be 
included in the analysis and will contribute to LOCF. 
Sensitivity Analysis 3 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (excluding LOCF methods) to consider the effect of 
missing data by excluding patients with either or both of the 
following criteria: 
(1) Missing assessments at Day 210 (patients with a missed 
assessment of any of BILAG, SLEDAI-2K, or PGA at Day 210 
would be excluded). 
AND/OR 
(2) Patients with any Day 210 assessment which occurred outside  of 
the 30 day +/- 4 day window (patients with an out of window 
assessment of any of BILAG, SLEDAI-2K, or PGA at Day 210 
would be excluded). 
 
Additional sensitivity analyses may be performed to consider the effect of missing data. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
A summary of disposition of SRI-4 response at day 210 will be presented by study phase and 
treatment group in the FAS and PP.  Sensitivity analysis 1 will also be performed for disposition 
of SRI-4 response at day 210.  These summaries will include the number of SRI-4 responders 
and the number of SRI-4 non-responders with a breakdown of reasons for non-response (early 
withdrawal, medication failure, <4-point reduction from baseline in SLEDAI-2K global score, 
new BILAG 1A/2B, and PGA worsening).  Denominators for percentages will be the number of 
patients eligible for SRI-4 response analysis. 
 


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A listing of SRI Response data at Day 150, Day 180, and Day 210 will be presented in the FAS.  
A listing of patients excluded from the efficacy analysis will also be provided for all randomized 
patients. 
 
7.2. Secondary Efficacy Endpoints and Analyses 
Pharmacokinetics and pharmacodynamics are the secondary endpoints for the Phase 1b MAD 
part of the study and are described in Section 8.  Efficacy will be evaluated for the Phase 1b 
MAD part of the study as an exploratory endpoint and details will be included in relation to the 
Phase 2 POC part of the study within this section.  
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit 
The analyses described in Section 7.1.1, including sensitivity analyses allowing out of window 
assessment results (Sensitivity Analysis 2) and excluding patients with missing or out of window 
assessments (Sensitivity Analysis 3), will be repeated for each nominal visit and will be 
presented by study phase and treatment group in the FAS.  The 3 components will not be 
summarized separately by visit. 
A graphical display of SRI-4 response by study phase, treatment group, and visit in the FAS will 
be presented. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit 
The SRI-5 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-5 is defined by:  
1) ≥ 5-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The analyses described in Section 7.1.1, including sensitivity analyses excluding patients with 
missing or out of window assessments (Sensitivity Analysis 3), will be repeated for each nominal 
visit based on the SRI-5 response definition and will be presented by study phase and treatment 
group in the FAS.  The 3 components will not be summarized separately by visit for SRI-5 
response. 


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Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit 
The SRI-6 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-6 is defined by:  
1) ≥ 6-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The analyses described in Section 7.1.1, including sensitivity analyses excluding patients with 
missing or out of window assessments (Sensitivity Analysis 3), will be repeated for each nominal 
visit based on the SRI-6 response definition and will be presented by study phase and treatment 
group in the FAS.  The 3 components will not be summarized separately by visit for SRI-6 
response. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.4. 
Proportion of Patients with a sustained reduction of oral corticosteroid 
(CS) between Day 120 and Day 210 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 10 mg/day and ≤ Day 0 dose, between Day 120 and Day 210 will be summarized by study 
phase and treatment group in the FAS.  LOCF and imputation for missing values will not be 
performed.  Otherwise, statistical methods described in Section 7.1.1 will be implemented.   
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 


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7.2.5. 
Proportion of new BILAG A flare or >1 BILAG B flare relative to 
baseline through Day 210 
The proportion of new BILAG A flare or >1 BILAG B flare relative to baseline through Day 210 
will be summarized by study phase and treatment group in the FAS.  Statistical methods 
described in Section 7.1.1 will be implemented, including LOCF methods within a body system.  
The analyses will also be repeated in observed data only (no LOCF).  A BILAG A flare is 
defined as a new A score in at least one body system when compared to baseline.  A BILAG B 
flare is defined as a new B score in at least two body systems at the same assessment when 
compared to baseline.  BILAG grading is collected at each protocol specified visit as an 
assessment of “the past 4 weeks”.  As such, the BILAG grade will be compared to baseline and 
the most recent prior assessment, as appropriate, to determine a new flare.  The proportion of 
new BILAG A flare or >1 BILAG B flare relative to baseline will be summarized overall and by 
nominal visit. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
Observed results will be presented in separate data listings for BILAG SLE history, BILAG-
2004 index, and BILAG grading for all randomized patients. 
 
7.2.6. 
Proportion of patients with PGA worsening 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients.”  The proportion of patients with PGA worsening, defined as an 
increase of >30mm from baseline, will be summarized by study phase and treatment group in the 
FAS overall and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented, including LOCF methods.  The analyses will also be repeated in observed data 
only (no LOCF). 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
PGA observed results will be presented in a data listing for all randomized patients. 
 
7.2.7. 
Proportion of patients with BICLA response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as:  
1) at least 1 gradation of improvement in baseline BILAG 2004 scores in all body systems with 
moderate disease activity at entry (e.g., all B [moderate disease] scores falling to C [mild], or D 
[no activity]) 
AND 


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2) no new BILAG A or more than 1 new BILAG B scores 
AND 
3) no worsening of total SLEDAI-2K score from baseline 
AND 
4) ≤ 10% deterioration in PGA score 
AND 
5) no medication failure. 
LOCF and imputation for missing values will not be performed.  Otherwise, statistical methods 
described in Section 7.1.1 will be implemented. The analyses will be repeated overall and for 
each nominal visit based on the BICLA response definition and will be presented by study phase 
and treatment group in the FAS. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 
The total activity score will be calculated by summing the scores on the left side of the form 
(erythema, scale/hypertrophy, mucous membrane, alopecia – recent hair loss and clinically not 
obviously scarred). 
The total damage score will be calculated by: 
(1) Sum the responses for “Dyspigmentation” in all anatomical locations 
(2) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts at least 12 months”, then multiply the sum in #1 by 2. 
(3) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts less than 12 months”, then the sum in #1 will not change. 
(4) If the sum in #1 is 0 and a response for “Report duration of dyspigmentation after active 
lesions have resolved” is missing, then the sum in #1 will not change. 
(5) Determine the Dyspigmentation Score based on the results from 2, 3, or 4. 
(6) Sum the remaining scores on the right side of the form (scarring/atrophy/panniculitis, 
alopecia - scarring of the scalp judged clinically). 


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(7) Sum the scores from #5 and #6 to obtain the total damage score. 
If the total activity score or total damage score cannot be calculated, the total activity score or 
total damage score will be imputed using the LOCF method described in Section 5.5.  If one of 
the total scores can be calculated and the other cannot, LOCF will be implemented for only the 
total score which cannot be calculated.  If any individual scores which contribute to the total 
activity score or the total damage score, the total score in question will not be calculated and 
LOCF methods for total score will be implemented.  LOCF methods will be implemented for 
CLASI response analyses only.   
A sensitivity analysis for CLASI response will also be performed in the FAS excluding patients 
with missing CLASI results within a visit.  If one or both of the total activity score or total 
damage score are missing at a visit, the patient will not be included in the response analysis at 
that visit.  LOCF methods will not be implemented for the sensitivity analysis. 
The mean and standard deviation of the change from baseline in CLASI total activity and total 
damage scores will be presented graphically over time by study phase and treatment group. 
7.2.8.1. Proportion of patients with CLASI response 
CLASI response is defined as 50% improvement from baseline in “A” (total activity) or “B” 
(total damage) scores.  This assessment will be applied to all patients as all are required to have 
cutaneous disease activity. 
The analyses described in Section 7.1.1 will be repeated overall and for each nominal visit based 
on the CLASI response definition and will be presented by study phase and treatment group in 
the FAS. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
7.2.8.2. Results and Changes from Baseline in CLASI 
The analysis of CLASI total activity score and CLASI total damage score will be performed 
separately using an analysis of covariance (ANCOVA) model with change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the corresponding 
baseline CLASI score as a covariate.  The p-value for the difference between the BOS161721 
and placebo groups at each nominal visit is based on the F-test. 
Descriptive statistics for the activity score and damage score will be summarized separately at 
baseline and each visit.  Change from baseline will be summarized at each post-baseline visit.  
The LS Mean estimate, its standard error and 90% CI will be tabulated by treatment group and 
for the difference between treatment groups (BOS161721 versus placebo) for change at each 
visit.  Missing CLASI results will not be imputed.  Observed results only will be presented for 
the change from baseline analysis. 
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CLASI observed results will be presented in data listings for all randomized patients. 
7.2.9. 
Results and Changes from Baseline in Swollen and Tender Joints ACR-
28 
The ACR-28 joint count evaluates the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 
The analysis of Swollen and Tender Joints ACR-28 for the sum of tenderness (left and right) and 
the sum of swelling (left and right) will be performed separately using an analysis of covariance 
(ANCOVA) model with change from baseline to each nominal visit as the dependent variable, 
treatment group as the factor, and the baseline ACR-28 score as a covariate.  The derived sum 
for tenderness and swelling is calculated and provided in the clinical database.  A missing total 
sum of swelling or sum of tenderness will not be imputed.  Observed results only will be 
presented for the change from baseline analysis.  The p-value for the difference between the 
BOS161721 and placebo groups at each nominal visit is based on the F-test.   
Descriptive statistics for the tenderness and swelling derived sums will be summarized separately 
at baseline and each visit.  Change from baseline will be summarized at each post-baseline visit.  
The LS Mean estimate, its standard error and 90% CI will be tabulated by treatment group and 
for the difference between treatment groups (BOS161721 versus placebo) for change at each 
visit. 
The mean and standard deviation of the change from baseline in ACR-28 sum of tenderness and 
sum of swelling will be presented graphically over time by study phase and treatment group. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
Swollen and Tender Joints ACR-28 observed results will be presented in data listings for all 
randomized patients. 
7.2.10. 
Results and Changes from Baseline in SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI-2K of 6 or more generally represents moderately to severely active 
disease. 
The analysis of SLEDAI-2K will be performed using an analysis of covariance (ANCOVA) 
model with change from baseline to each nominal visit as the dependent variable, treatment 
group as the factor, and the baseline SLEDAI-2K score as a covariate.  The SLEDAI-2K total 
score is calculated and provided in the clinical database.  A missing total SLEDAI-2K score will 
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The p-value for the difference between the BOS161721 and placebo groups at each nominal visit 
is based on the F-test.   
Descriptive statistics for the SLEDAI-2K total score will be summarized separately at baseline 
and each visit.  Change from baseline will be summarized at each post-baseline visit.  The LS 
Mean estimate, its standard error and 90% CI will be tabulated by treatment group and for the 
difference between treatment groups (BOS161721 versus placebo) for change at each visit. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
The mean and standard deviation of the change from baseline in observed SLEDAI-2K total 
score will be presented graphically over time by study phase and treatment group. 
SLEDAI-2K observed results will be presented in a data listing for all randomized patients. 
7.2.11. 
Results and Changes from Baseline in SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.  It will be performed on Days 0 
and 180. 
The analysis of SLICC/ACR Damage Index total score will be performed using an analysis of 
covariance (ANCOVA) model with change from baseline to each nominal visit as the dependent 
variable, treatment group as the factor, and the baseline SLICC/ACR Damage Index total score 
as a covariate.  The SLICC/ACR Damage Index total score is calculated and provided in the 
clinical database.  A missing total SLICC/ACR Damage Index score will not be imputed.  
Observed results only will be presented for the change from baseline analysis.  The p-value for 
the difference between the BOS161721 and placebo groups at each nominal visit is based on the 
F-test.   
Descriptive statistics for the SLICC/ACR Damage Index total score will be summarized 
separately at baseline and each visit.  Change from baseline will be summarized at each post-
baseline visit.  The LS Mean estimate, its standard error and 90% CI will be tabulated by 
treatment group and for the difference between treatment groups (BOS161721 versus placebo) 
for change at each visit. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Observed SLICC/ACR Damage Index data will be presented in a by-patient listing for all 
randomized patients.  SLICC Criteria for SLE at screening will also be presented in a by-patient 
listing for all randomized patients. 


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7.2.12. 
Medication Failure 
7.2.12.1. Proportion of patients with medication failures 
Patients who received prohibited medications or unallowable CS usage as described in Section 
4.6 of the study protocol will be considered “medication failures” and will be treated as non-
responders for the primary efficacy analysis and selected sensitivity and secondary efficacy 
analyses.  Patients who received an allowable CS burst but having missing data at Day 210 will 
considered a medication failure.  The determination of medication failures will be reviewed 
using blinded data and finalized prior to unblinding.   
The proportion of patients with medication failures will be summarized by study phase and 
treatment group in the FAS overall and by visit.  A patient will be counted as a medication 
failure at each visit occurring on or after the date in which a patient is considered a medication 
failure.  Statistical methods described in Section 7.1.1 will be implemented for observed data 
only.  LOCF and missing data imputation will not be performed. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.12.2. Time to Medication Failure (TTMF) 
Medication failure is defined in Section 4.6 of the study protocol and discussed in Section 7.1.1. 
Time to medication failure will be computed as the event date (as described below) – 
randomization date + 1. 
The date of medication failure will be reviewed by Boston Pharmaceuticals and agreed upon 
prior to database lock and unblinding. 
Kaplan-Meier methods will be used to estimate TTMF for each treatment group.  Estimates of 
median TTMF will be provided along with 90% confidence intervals.  Q1 and Q3 will also be 
tabulated. Comparisons between treatment groups will use the one-sided log-rank test.  In 
addition, hazard ratio (HR) estimates with 90% CIs will be calculated from a Cox proportional 
hazards regression analysis that includes treatment as a factor.  Censoring rules are defined as 
follows. 
 


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Situation 
Date of Event or Censoring 
Outcome 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Event 
Patient withdraws from study (no medication 
failure) 
Censored at date of withdrawal Censored 
Patient completes the study (no medication 
failure) 
Censored at last study visit 
Censored 
Patient dies during study (no medication 
failure) 
Censored at the date of death 
Censored 
 
Kaplan-Meier curves of TTMF will be plotted over time. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to medication failure data will be provided in a by-patient listing in the full analysis set. 
7.2.13. 
Duration of Longest SRI-4 Response 
Duration of longest SRI-4 response will be computed for patients who have been identified as a 
responder at least once based on criteria defined in Section 7.1.1.  The duration of longest 
response will be defined as the longest period a patient meets the SRI-4 responder criteria at 
consecutive visits.  This will be computed as the date of last consecutive SRI-4 response – date 
of first consecutive response + 1. 
The duration of longest SRI-4 response will be analyzed using an analysis of variance (ANOVA) 
model with treatment group as the effect.  The p-value for the difference between the 
BOS161721 and placebo group is based on the F-test. 
The mean, standard deviation, median, minimum, maximum, Q3, Q4, LS Mean estimate, its 
standard error and 90% CI will be tabulated by treatment group and for the difference between 
treatment groups (BOS161721 versus placebo). 
If a patient has missed a visit between two scheduled visits with a response at both, the patient 
will be counted as having a response at the missed visit.   


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Duration of longest SRI-4 response will be displayed in the SRI response listing. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
7.2.14. 
Time to First SRI-4 Response 
SRI-4 response is defined in Section 7.1.1.  Time to first SRI-4 response will be computed as the 
event date (as described below) – randomization date + 1. 
Time to first SRI-4 response will be analyzed with Kaplan-Meier methods described for TTMF 
and censoring as described below.  Kaplan-Meier curves will be plotted over time. 
Situation 
Date of Event or Censoring 
Outcome 
Patient has SRI-4 Response (prior to 
medication failure, withdrawal, or death) 
First date where a patient has 
been documented to have 
achieved a SRI-4 responder 
designation 
Event 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) prior to SRI-4 response/non-responder 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Censored 
Patient withdraws from study (no SRI-4 
response, no medication failure) 
Censored at date of last visit 
with non-missing SRI-4 
assessments (BILAG, 
SLEDAI-2K, and PGA) prior 
to withdrawal 
Censored 
Patient completes the study (no SRI-4 
Response, no medication failure) 
Censored at date of last visit 
with non-missing SRI-4 
assessments (BILAG, 
SLEDAI-2K, and PGA) 
Censored 
Patient dies during study (no SRI-4 response, 
no medication failure) 
Censored at the date of death 
Censored 
 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
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Time to first SRI-4 response data will be provided in a by-patient listing in the full analysis set. 
7.2.15. 
Time to First BILAG A Flare or >1 BILAG B Flare Compared to 
Baseline through Day 210 
Time to first BILAG A Flare or >1 BILAG B Flare will be will be computed as the event date (as 
described below) – randomization date + 1.  If a patient is designated as a medication failure 
prior to or on their day 210 visit, they will be considered as having a BILAG flare (event) as of 
the date of first dose of the medication leading to the medication failure designation due to 
prohibited medication or unallowable CS burst. 
Time to first BILAG A Flare or >1 BILAG B Flare will be analyzed with Kaplan-Meier methods 
described for TTMF and censoring as described below.  Kaplan-Meier curves will be plotted 
over time. 
Situation 
Date of Event or Censoring 
Outcome 
Patient has a BILAG A Flare or >1 BILAG B 
Flare compared to baseline (Noted as BILAG 
1A/2B Flare) prior to or on their day 210 visit 
Date of first BILAG 1A/2B 
Flare 
Event 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) prior to or on their day 210 visit 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Censored 
Patient withdraws from study (no BILAG 
1A/2B Flare, no medication failure) prior to or 
on their day 210 visit 
Censored at date of last non-
missing BILAG assessment 
(prior to withdrawal) through 
day 210 
Censored 
Patient completes the study (no BILAG 
1A/2B Flare, no medication failure) 
Censored at date of last non-
missing BILAG assessment 
through day 210 
Censored 
Patient dies during study (no BILAG 1A/2B 
Flare, no medication failure) prior to or on 
their day 210 visit 
Censored at the day of death 
Censored 
 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
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Time to first BILAG A Flare or >1 BILAG B Flare data will be provided in a by-patient listing 
in the full analysis set. 
8. PHARMACOKINETICS/PHARMACODYNAMICS  
 
Pharmacokinetics and pharmacodynamics are secondary endpoints for the Phase 1b MAD study 
and exploratory endpoints for the Phase 2 POC study.   
PK concentrations and PD results reported as less than the lower limit of quantification (LLOQ) 
will be counted as 0 to calculate summary linear statistics, 0.5*LLOQ for geometric statistics, 
and will be reported as <LLOQ in listings. 
PK blood sampling as collected on the CRF will be provided in by-patient data listings.  All 
observed PK concentrations and PD data will also be presented in by-patient listings, including 
, nAb, and ADA.  PK parameters, as provided by Human Predictions, LLC, 
will be displayed in by-patient data listings. 
Additional details surrounding the PK and PD analysis, modeling, and evidence of PK/PD 
relationships will be provided in a separate CPAP. 
8.1. Pharmacokinetics 
BOS161721 PK concentrations will be summarized and listed in the PK set by study phase, 
treatment group, visit, and timepoint.  Summary statistics will include the geometric mean, 
geometric standard deviation, geometric % coefficient of variation, n, mean, standard deviation, 
median, minimum, and maximum.  BOS161721 concentrations will be plotted over time by 
treatment group and visit. 
PK parameters for the PK analysis set will be calculated by Human Predictions, LLC and will be 
provided to Array Biostatistics to prepare outputs for the MAD Phase 1b.  Details surrounding 
the PK parameter calculations will be provided in a separate CPAP.  Summary statistics will be 
presented for Cmax, Tmax, AUC, t½, CL, and Vd and will include the same statistics as PK 
concentrations except Tmax which will include n, median, minimum, and maximum, only.   
8.2. Pharmacodynamics 
Descriptive statistics for the observed results of the following PD endpoints/results will be 
summarized separately at baseline and each visit.  Change from baseline will be summarized at 
each post-baseline visit.  In cases where both numeric and qualitative results are provided, the 
summaries will be based on the numeric results.  Graphical presentations of mean and standard 
deviation of the change from baseline over time will also be presented for the below parameters. 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3) 
MAD only 
% pSTAT3+ Lymphocytes –Stimulated; 
Ratio MEF (Stimulated / Unstimulated) 
 MAD and POC 
NA (all) 
Leukocyte immunophenotype 
(B and NK Cells) 
MAD and POC 
CD19+% of CD45+ Lymphocytes; 
IgD+C27-% of CD19+; 
IgD+CD27-CD38++CD24++% of 
CD19+; 
IgD-CD27-% of CD19+; 
IgD+CD27+% of CD19+; 
IgD-CD27+% of CD19+; 
IgD-CD27+CD38++CD138-% of 
CD19+; 
IgD-CD27+CD38++CD138+% of 
CD19+; 
CD56+% OF CD45+ Lymphocytes 
Leukocyte  imunophenotype 
(T-Cells) 
MAD and POC 
CD4+CD8-% of CD3+; 
CXCR5+% of CD4+CD8-; 
PD-1+% of CD4+CD8-; 
ICOS+% of CD4+CD8-; 
CD25+CD127-% of CD4+CD8-; 
CXCR5+% of CD25+CD127-; 
PD-1+% of CD25+CD127-; 
ICOS+% of CD25+CD127-; 
CD8+CD4-% of CD3+ 
 
MAD and POC 
 
 
 
 
 
 
 
 
 
 
 
 
MAD and POC 
NA (all) 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
MAD and POC 
All parameters for ‘average target CP’ 
values 
 
 
Additional immunogenicity and PD results may be plotted over time by treatment group and 
visit. 
9. QUALITY OF LIFE  
 
9.1. 
 
 
 
 
 
 
 
 
 
 
 
   
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9.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. SAFETY  
 
All safety analysis reporting will be based on the Safety Analysis Set. 
10.1. Adverse Events 
Adverse events (AEs) will be collected and recorded for each patient from the date of the first 
dose of study drug until the end of their participation in the study, including the safety follow up 
period.  Severity of adverse events will be graded according to National Cancer Institute 
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Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  AEs will also 
be assessed for relationship to study drug, and seriousness.  Adverse events will be marked as 
adverse events of special interest (AESIs), dose-limiting toxicities (DLTs), or injection site 
reactions (ISRs), where applicable.  AEs will be considered treatment-emergent adverse events 
(TEAEs) if they started any time after first dose or if the start date was missing.  Any missing 
severity assessments will be assumed to be Grade 3, missing relationship assessments will be 
assumed to be related, and missing seriousness assessments will be assumed as serious. 
An overview of TEAEs will be produced, including counts and percentages of patients with any 
incidences of TEAE, TEAEs related to study treatment, Serious adverse events (SAEs), SAEs 
related to study treatment, CTCAE grade 2 or higher TEAEs, CTCAE grade 2 or higher TEAEs 
related to study treatment, CTCAE grade 3 TEAEs, CTCAE grade 3 or higher TEAEs related to 
study treatment, CTCAE grade 4 TEAEs, CTCAE grade 4 or higher TEAEs related to study 
treatment, TEAEs leading to study treatment discontinuation, Related TEAEs leading to study 
treatment discontinuation, TEAEs of special interest, Dose-limiting toxicities, TEAEs resulting 
in death, and injection site reactions. 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs 
(MedDRA) for reporting by system organ class (SOC) and preferred term (PT) in descending 
order of overall incidence.  The MedDRA version used is defined in the study data management 
plan. 
Summaries of adverse events by SOC and PT will include the following types:  
• TEAEs; 
• TEAEs related to study treatment;  
• SAEs; 
• CTCAE Grade 3 or higher TEAEs related to study treatment; 
• TEAEs leading to treatment discontinuation; and 
• Dose-Limiting Toxicities 
• TEAEs of Special Interest 
A summary of TEAEs by SOC, PT, and maximum CTCAE grade will also be prepared.  For 
these summaries, TEAEs will be sorted for each patient by SOC/PT and CTCAE grade; patients 
will be counted once within a SOC/PT based on their maximum CTCAE grade.  Missing 
CTCAE grade will be counted in a missing row.   
A summary of TEAEs by PT and maximum CTCAE grade will also be prepared with sections 
for any TEAE and related TEAEs.  For these summaries, patients will be counted once within a 
PT based on their maximum CTCAE grade.  Missing CTCAE grade will be counted as grade 3.  
Preferred terms will be included if at least one patient has a CTCAE grade 3 or higher for the PT.  
PTs will also be included if 10% or more of patients experience a CTCAE grade 1 or 2 TEAE.  
The summary will be sorted by the total incidence of the PT in the any TEAE section.   
A comprehensive listing of all AEs will be provided in a by-patient data listing for the safety 
analysis set. In addition, the following listings will be provided for the safety analysis set:  


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• TEAEs related to study treatment;  
• SAEs;  
• TEAEs leading to treatment discontinuation; and 
• Adverse Events of Special Interest 
10.2. Clinical Laboratory Evaluations 
Laboratory tests will be performed at times defined in the protocol Schedule of Assessments.  
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI).  The following laboratory evaluations will be reported in data summaries, 
with asterisks indicating those that will be graded using CTCAE.  Grading will be performed by 
the Central Lab based on the details provided in Appendix 13.2 for relevant laboratory 
parameters.  If a grade is not present in the central lab database for a graded lab parameter, the 
grade will be analyzed as grade 0. 
Hematology: Hemoglobin*, Hematocrit, RBC count, RDW, MCV, MCH, MCHC, Platelet 
count*, WBC count*, CD4+ count*, Total neutrophils (Abs)*, Eosinophils (Abs), Monocytes 
(Abs), Basophils (Abs), Lymphocytes (Abs)* 
 
Clinical chemistry: Alanine Aminotransferase*, Albumin*, Alkaline Phosphatase*, Aspartate 
Aminotransferase*, Bicarbonate, Bilirubin*, Blood urea nitrogen, C Reactive Protein, Calcium, 
Chloride, Creatine Kinase*, Creatinine*, Glucose (fasting)*, Glucose (random)*, Potassium*, 
Protein, Sodium*, Uric acid*, eGFR (Cockcroft-Gault)*, eGFR (MDRD)*, Total cholesterol 
(fasting)*, LDL-C (fasting), HDL-C (fasting), Triglycerides (fasting)*, Gamma Glutamyl 
Transferase*. 
 
Coagulation: Prothrombin Intl. Normalized Ratio*, Activated Partial Thromboplastin Time* 
Urinalysis: pH, Glucose (qual), Protein (qual)*, Blood (qual)*, Ketones, Nitrites, Leukocyte 
esterase, Urobilinogen, Urine bilirubin, Microscopy 
 
Observed values and changes from baseline for hematology, clinical chemistry, and coagulation 
laboratory evaluations will be summarized at each visit and most extreme change.  Endpoint 
analyses will be based on changes from baseline assessments at Days 120 and 210. 
The number and percent of patients with a NCI-CTCAE toxicity grade of 3 or higher will be 
tabulated by laboratory evaluation with defined NCI-CTCAE grading at each visit for 
hematology, clinical chemistry, and coagulation.  Patients with missing values post-baseline will 
be excluded from the summary. The denominator for percentages will be the number of patients 
with at least one post-baseline assessment for the laboratory parameter in question. 
Hematology, clinical chemistry, and coagulation shift tables displaying the shift from baseline to 
the worst value of NCI-CTCAE grade will be presented based on the most extreme change as it 
relates to the relevant NCI-CTCAE definition. NCI-CTCAE relating to “high/hyper” conditions 
will depend on the maximum post-baseline value while NCI-CTCAE “low/hypo” will be 


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reported based on the minimum post-baseline value.  Separate shift tables will be prepared for 
parameters with bi-directional toxicity grading.  Lab parameters which are optional, such as 
gamma glutamyl transferase, will not be included in the shift tables. 
Hematology and clinical chemistry laboratory data which is not graded will also be summarized 
in shift tables of baseline to each visit and most extreme change based on range categories of low 
(below lower limit of normal [LLN], normal, and high [above upper limit of normal [ULN]]). 
Selected hematology and clinical chemistry laboratory results will be plotted over time for 
treatment group for MAD phase 1b portion of the study in the safety analysis set.  The mean and 
standard deviation of the change from baseline for selected hematology and clinical chemistry 
laboratory results will be plotted over time for the POC Phase 2 portion of the study in the safety 
analysis set. 
All laboratory parameters as well as a summary of central laboratory tests and chest x-ray will be 
provided in patient data listings for all randomized patients.  By patient listings of clinical 
chemistry and hematology data will be presented in the safety analysis set for the DMC and 
interim analysis only. 
10.3. Other Safety Evaluations 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening. i   The C-SSRS evaluation will be performed as specified in the protocol 
Schedule of Assessments. 
The C-SSRS has 11 binary (yes/no) outcomes corresponding to five categories of suicidal 
ideation, five categories of suicidal behavior, and the category of self-injurious behavior without 
suicidal intent: 
Suicidal ideation is present if there is a “yes” response to any of the 5 suicidal ideation category 
questions. Suicidal behavior is present if there is a “yes” response to any of the 5 suicidal 
behavior category questions.  Suicidal ideation or behavior is present if there is a “yes” response 
to any of the 10 suicidal or ideation or behavior category questions. 
The number and percentage of patients with any post-baseline occurrence of the following 
ideations and behaviors will be presented by study phase and treatment group: 
• Suicidal ideation (overall and by individual question),  
• Suicidal behavior (overall and by individual question),  


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• Suicidal ideation or behavior,  
 
A similar tabulation of the occurrence of any of the above ideations and behaviors at baseline or 
as part of their lifetime history/past 12-month history (collected at the screening visit) will be 
presented by study phase and treatment group. 
 
A shift table displaying the shift from worst pre-treatment category to the worst post-baseline 
category will be presented by study phase and treatment group.  Best to worst C-SSRS category 
is defined in the following order: no suicidal ideation or behavior, suicidal ideation, and suicidal 
behavior.  The worst post-baseline shift is calculated based on all post-baseline visits, including 
unscheduled visits.  Worst pre-treatment will include all C-SSRS assessments prior to first dose 
date/time (screening or baseline).  The denominator will be the number of patients with at least 
one non-missing baseline and post-baseline C-SSRS assessment. 
Missing data will not be imputed. 
All C-SSRS individual items will be presented in data listings for screening and post-screening 
(since last visit), separately.  A separate listing will be presented for patients with suicidal 
ideation, suicidal behavior, or non-suicidal self-injurious behavior for all randomized patients. 
10.3.2. 
Vital Signs 
Vital signs include: heart rate (beats/min); temperature (oC); systolic and diastolic blood pressure 
(mmHg); and weight (kg).  Observed values and changes from baseline for vital signs will be 
summarized at each visit and time point, as well as for most extreme change by study phase and 
treatment group.  
All vital signs data will be presented in patient data listings for all randomized patients. 
10.3.3. 
12-Lead Electrocardiogram (ECG) 
ECG will be assessed as specified in the protocol Schedule of Assessments.  The following ECG 
parameters will be collected:  PR interval (msec), QRS interval (msec), RR interval (msec), QT 
interval (msec), and QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
(msec).  ECG parameters and ECG evaluation will come directly from the database and will not 
be calculated during analysis.   
Observed values and changes from baseline for ECG parameters will be summarized at each 
visit, as well as for most extreme change by study phase and treatment group.  
The number and percent of patients with the following parameters at any post-baseline visit and 
at each visit will be summarized:  
• Abnormal, not clinically significant ECGs 
• Abnormal, clinically significant ECGs 


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The number and percent of patients with each ECG evaluation result will be summarized by 
visit.  The worst ECG evaluation at any post-baseline visit will also be summarized in the order 
of: Normal, Abnormal, not clinically significant, Abnormal, clinically significant. 
For the summary of incidence at any post-baseline visit, the denominators for percentages will 
include patients with one or more non-missing value at any post-baseline visit.  For the by-visit 
summaries, the denominators for percentages will include patients with a non-missing value at 
that visit.  
Investigator reported ECG result shifts from baseline to each visit and worst case post-baseline 
will be summarized.  Worst case post-baseline will be based on the most abnormal observed 
value on or after the randomization date. 
All ECG data will be presented in a by patient data listing for all randomized patients.  A 
separate by patient listing for patients with abnormal, clinically significant 12-lead ECGs will 
also be provided in the safety analysis set for DMC meetings and the interim analysis only. 
10.3.4. 
Physical Examinations 
Targeted physical examination data and full physical examination data will be presented in 
patient data listings.  A separate by patient listing for patients with abnormal, clinically 
significant physical examination findings will also be provided in the safety analysis set for 
DMC meetings and the interim analysis only. 
10.3.5. 
Anti-Drug Antibodies (ADAs) 
The serum samples to measure the presence of ADA will be collected as specified in the protocol 
Schedule of Assessments.  ADAs will be summarized and listed according to details provided in 
Section 8. 
 
11. CHANGES TO THE PLANNED ANALYSIS 
 
No changes have been made to the planned analysis. 
 
 
 
 


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12. REFERENCES 
 
i Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
 
 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study 
reports questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 
1995. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3
_Guideline.pdf. Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 
1998. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Ste
p4/E9_Guideline.pdf . Accessed 15 June 2016. 
FDA Guidance for Industry Systemic Lupus Erythematosus – Developing Medical Products for 
Treatment. 
2010. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm072063.pdf.  Accessed 23February2018. 
Committee for Medicinal Products for Human use (CHMP).  EMA Guideline on clinical 
investigation of medicinal products for the treatment of systemic lupus erythematosus and lupus 
nephritis. 
2015.  http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/
WC500184889.pdf. Accessed 04March2018. 
 
Nilsson M, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K.  Columbia-
Suicide Severity Rating Scale Scoring and Data Analysis Guide. V2 
2013.  https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-
Clinical-Trials-1.pdf.  Accessed 18May2018. 
 
 
  
 
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13. APPENDICES 
 


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13.2. CTCAE Grading Details from the Central Laboratory 
 


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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 2.0, 29Nov2018 
 
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13.3. Table of Contents for Tables, Listings, and Figures 
 
The table of contents for tables, listings, and figures will be provided in a corresponding mock 
shell document. 
 


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BOS161721-02: A RANDOMIZED DOUBLE-BLIND PHASE 1b/2 
COMBINED STAGGERED MULTIPLE DOSE ESCALATION STUDY OF 
BOS161721 IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATIENTS 
ON A BACKGROUND OF LIMITED STANDARD OF CARE 
Statistical Analysis Plan 
VERSION 1.0 
DATE OF PLAN: 
05Sep2018 
STUDY DRUG:
BOS161721 
PREPARED FOR: 
Boston Pharmaceuticals, Inc. 


Sponsor: Boston Pharmaceuticals, Inc.
Protocol Number: BOS I 61 721-02
SAP Version and Date: Version I .0, 05Sep20l B
Approval Signature Page: Array Biostatistics, LLC
Docirment Author:
, MS
Senior Biostatistician
 
, MS
Vice President, Biostatistics & Statistical programming
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PPD
PPD
PPD
PPD
PPD
PPD


PPD
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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Contents 
1. 
Introduction ............................................................................................................................. 9 
2. 
Study Objectives and Endpoints ............................................................................................. 9 
2.1. 
Multiple Ascending Dose (MAD) Phase 1b Study .......................................................... 9 
2.2. 
Proof of Concept (POC) Phase 2 Study ......................................................................... 11 
3. 
Study Design ......................................................................................................................... 13 
3.1. 
Study Design and Population ......................................................................................... 13 
3.1.1. 
Multiple Ascending Dose Phase 1b ........................................................................ 14 
3.1.2. 
Proof of Concept Phase 2 ........................................................................................ 15 
3.2. 
Randomization and Blinding .......................................................................................... 16 
3.3. 
Sample Size Considerations ........................................................................................... 16 
3.4. 
Data Monitoring Committee (DMC).............................................................................. 17 
3.5. 
Interim Analysis (IA) ..................................................................................................... 17 
3.6. 
Timing of Analyses ........................................................................................................ 18 
4. 
Data Analysis Considerations ............................................................................................... 18 
4.1. 
Stratification and Covariates .......................................................................................... 19 
4.2. 
Evaluation of Subgroups ................................................................................................ 19 
4.3. 
Multiple Comparisons and Multiplicity ......................................................................... 19 
5. 
General Data Handling Conventions .................................................................................... 19 
5.1. 
Assigned and Actual Treatment ..................................................................................... 19 
5.2. 
Reference Dates.............................................................................................................. 20 
5.3. 
Study Day and Duration Variables................................................................................. 20 
5.4. 
Study Time Periods ........................................................................................................ 21 
5.5. 
Baseline, Post-Baseline Changes, and Last Observation Carried Forward (LOCF) ...... 21 
5.6. 
Imputation of Partial Dates ............................................................................................ 21 
5.7. 
Multiple Assessments and Visit Windows ..................................................................... 22 
5.8. 
Treatment Group Display ............................................................................................... 22 
5.9. 
Missing Data .................................................................................................................. 23 
6. 
Study Patient Data................................................................................................................. 23 
6.1. 
Analysis Populations/Sets .............................................................................................. 23 
6.2. 
Patient Disposition ......................................................................................................... 24 
6.3. 
Protocol Deviations ........................................................................................................ 24 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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6.4. 
Demographic and Baseline Characteristics .................................................................... 24 
6.5. 
Medical History .............................................................................................................. 25 
6.6. 
Prior and Concomitant Medication and Procedures ....................................................... 25 
6.7. 
Study Drug Exposure and Compliance .......................................................................... 26 
7. 
Efficacy ................................................................................................................................. 26 
7.1. 
Primary Efficacy Endpoint and Analyses ...................................................................... 26 
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 .................................. 26 
7.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 30 
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit ..................................... 30 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit ..................................... 30 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit ..................................... 31 
7.2.4. 
Proportion of Patients with a sustained reduction of oral corticosteroid (CS) 
between Day 120 and Day 210 ............................................................................................. 31 
7.2.5. 
Proportion of new BILAG A flare or >1 BILAG B flare relative to baseline through 
Day 210 32 
7.2.6. 
Proportion of patients with PGA worsening ........................................................... 32 
7.2.7. 
Proportion of patients with BICLA response.......................................................... 32 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) ..................... 33 
7.2.8.1. 
Proportion of patients with CLASI response ...................................................... 34 
7.2.8.2. 
Results and Changes from Baseline in CLASI ................................................... 34 
7.2.9. 
Results and Changes from Baseline in Swollen and Tender Joints ACR-28 ......... 35 
7.2.10. 
Results and Changes from Baseline in SLEDAI-2K .......................................... 35 
7.2.11. 
Results and Changes from Baseline in SLICC/ACR Damage Index .................. 36 
7.2.12. 
Medication Failure .............................................................................................. 37 
7.2.12.1. 
Proportion of patients with medication failures .............................................. 37 
7.2.12.2. 
Time to Medication Failure (TTMF) ............................................................... 37 
7.2.13. 
Duration of Longest SRI-4 Response ................................................................. 38 
7.2.14. 
Time to First SRI-4 Response ............................................................................. 39 
7.2.15. 
Time to First BILAG A Flare or >1 BILAG B Flare Compared to Baseline 
through Day 210 ................................................................................................................... 40 
8. 
Pharmacokinetics/Pharmacodynamics .................................................................................. 41 
8.1. 
Pharmacokinetics ........................................................................................................... 41 
8.2. 
Pharmacodynamics......................................................................................................... 41 
9. 
Quality of Life....................................................................................................................... 43 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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9.1. 
 .............................................................................................................................. 43 
9.2. 
 ......................................................................................................................... 44 
10. 
Safety ................................................................................................................................. 45 
10.1. 
Adverse Events ......................................................................................................... 45 
10.2. 
Clinical Laboratory Evaluations ............................................................................... 47 
10.3. 
Other Safety Evaluations .......................................................................................... 48 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 48 
10.3.2. 
Vital Signs ................................................................................................................. 49 
10.3.3. 
12-Lead Electrocardiogram (ECG) ........................................................................... 49 
10.3.4. 
Physical Examinations .............................................................................................. 50 
10.3.5. 
Anti-Drug Antibodies (ADAs) ................................................................................. 50 
11. 
Changes to the planned analysis ........................................................................................ 50 
12. 
References .......................................................................................................................... 51 
13. 
APPENDICES ................................................................................................................... 53 
13.1. 
 ................................................................ 54 
13.2. 
CTCAE Grading Details from the Central Laboratory ............................................. 56 
13.3. 
Table of Contents for Tables, Listings, and Figures ................................................. 58 
 
 
 
 
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Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANA 
Antinuclear antibody 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APL 
Antiphospholipid 
AUC 
Area under the curve 
BICLA 
BILAG-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
BP 
Blood pressure 
C3 
Complement C3 
C4 
Complement C4 
CL 
Systematic clearance 
CLASI 
Cutaneous Lupus Area and Severity Index 
Cmax 
Maximum plasma concentration 
CPAP 
Clinical Pharmacology Analysis Plan 
CS 
Corticosteroid 
CSR 
Clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
dsDNA 
Double-stranded deoxyribonucleic acid 
ECG  
Electrocardiogram 
 
 
FAS 
Full analysis set 
HR 
Hazard ratio 
IA 
Interim Analysis 
IEC 
Independent Ethics Committee 
IL-21 
interleukin 21 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IWRS 
Interactive web response system  
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Medical Affairs 
nAb 
Neutralizing antibody 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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PGA 
Physician’s Global Assessment 
PK 
Pharmacokinetics 
POC 
Proof of concept 
PP 
Per protocol set 
pSTAT3 
Phosphorylated signal transducer and activator of transcription 3 
PT 
Preferred Term 
SAD 
Single ascending dose 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SC 
Subcutaneously 
 
 
SLE 
Systemic Lupus Erythematosus 
SLEDAI-2K 
SLE Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 
Sm 
Smith 
SOC 
System Organ Class 
SRI-4 
SLE Responder Index 4 
SRI-5 
SLE Responder Index 5 
SRI-6 
SLE Responder Index 6 
SS 
Safety analysis set 
SSA 
Sjögren syndrome-A (Ro) 
SSB 
Sjögren syndrome-B (La) 
t1/2 
Terminal elimination half-life 
TEAE 
Treatment emergent adverse event 
Tmax 
First time to maximum concentration 
TTMF 
Time to medication failure 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
WHO 
World Health Organization 
 
 
 
 
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Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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1. INTRODUCTION 
 
The statistical analysis plan (SAP) details the planned analyses that will be included in the 
Clinical Study Report (CSR) of study number BOS161721-02: A Randomized Double-Blind 
Phase 1b/2 Combined Staggered Multiple Dose Escalation Study of BOS161721 in Systemic 
Lupus Erythematosus (SLE) Patients on a Background of Limited Standard of Care.  The content 
of this SAP is based on the protocol Version 4.0 (Amendment 3) dated 27July2018. 
Revision Chronology: 
 
 
V1.0 
05SEP2018 
Original 
 
 
 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Multiple Ascending Dose (MAD) Phase 1b Study 
Objectives 
Endpoints 
Primary 
• To assess safety, tolerability, and 
immunogenicity of repeat doses of 
BOS161721 (20, 60, and 120 mg) 
administered subcutaneously (SC) in 
adult patients with moderately to 
severely active SLE on limited 
background standard of care 
treatment, in order to estimate the 
optimal dose. 
Safety Endpoints 
• Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• Injection site reactions 
• Columbia Suicide Severity Rating Scale 
(C-SSRS) 
• 12-lead electrocardiograms (ECGs) 
parameter results at each visit and change 
from baseline 
• Vital signs (blood pressure [BP], heart 
rate, and temperature) parameter results at 
each visit and change from baseline 
• Clinical laboratory results and change 
from baseline 
• Physical examinations changes from 
baseline 
• Anti-drug antibodies (ADAs) 
• Study drug exposure/compliance 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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Secondary 
• To characterize the PK of BOS161721 
and select the optimal dose of 
BOS161721 based on safety, PK, and 
PD effects in patients with mild to 
moderate SLE. 
Pharmacokinetic (PK) Endpoints 
• BOS161721 concentration by visit and 
time point 
• Maximum observed concentration (Cmax), 
first time to maximum concentration 
(Tmax), area under the concentration-time 
curve (AUC), t½, systematic clearance 
(CL), volume of distribution (Vd) 
Pharmacodynamic (PD) Endpoints 
• Results and changes (or shifts) from 
baseline to each visit in phosphorylated 
signal transducer and activator of 
transcription 3 (pSTAT3), C3 and C4 
levels, and leukocyte immunophenotype 
• Results and changes (or shifts) from 
baseline in anti-double-stranded DNA 
(dsDNA), antinuclear antibodies (ANA), 
anti-Sjögren syndrome A and B (SSA, 
SSB), Smith (Sm), and antiphospholipid 
(APL) autoantibodies at each visit 
• Results and changes (or shifts) from 
baseline in abrogation of IL-21 gene 
signature at each indicated visit 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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- 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
 
• 
 
 
Note:
 
2.2. Proof of Concept (POC) Phase 2 Study 
Objectives 
Endpoints 
Primary 
• To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on the SLE Responder Index 4 
(SRI-4) 
Primary Efficacy Endpoint 
• The proportion of patients with a SRI-4 
response at Day 210 
 
 
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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Secondary 
• To demonstrate a superior effect of 
BOS161721 at the chosen dose 
compared with placebo for response 
on clinical indicators of SLE activity, 
in adult patients with moderately to 
severely active SLE on limited 
background standard of care treatment 
Secondary Efficacy Endpoints 
• The proportion of patients with: 
- 
SRI-4 response at each visit 
- 
SRI-5 and SRI-6 response at each visit 
- 
a sustained reduction of oral 
corticosteroid (CS) (≤ 10 mg/day and 
≤ Day 0 dose) between Day 120 and 
Day 210 
- 
new BILAG A flare or > 1 BILAG B 
flares relative to baseline through 
Day 210 
- 
PGA worsening 
- 
a BICLA response 
- 
a CLASI response 
- 
medication failures 
• Results and changes from baseline in: 
- 
CLASI 
- 
swollen and tender joints ACR-28 
- 
SLEDAI-2K 
- 
SLICC/ACR damage index 
• Time to medication failure 
• Duration of longest SRI-4 response 
• Time to first SRI-4 response 
• Time to BILAG A flare or > 1 BILAG B 
flare compared to baseline through 
Day 210 
Safety 
• To assess safety and tolerability of 
repeat doses of BOS161721 (20, 60, 
and 120 mg) administered SC in adult 
patients with moderately to severely 
active SLE on limited background 
standard of care treatment 
Safety Endpoints 
• Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
related AEs, AEs leading to study drug 
discontinuation, AEs by severity and 
relatedness 
• Injection site reactions 
• C-SSRS 
• 12-lead ECGs parameter results at each 
visit and change from baseline 
• Vital signs (blood pressure [BP], heart 
rate, and temperature) parameter results at 
each visit and change from baseline 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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• Clinical laboratory results and change 
from baseline 
• Physical examinations changes from 
baseline 
• ADAs 
• Study drug exposure/compliance 
Exploratory 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
• 
 
• 
 
 
The order in which the endpoints for this trial will be discussed in subsequent sections is based 
on the phase 2 POC portion of the study.  The phase 1b MAD endpoints will also be discussed 
within the context of the phase 2 POC portion of the study but will appear out of the specified 
order in the above table in an effort to maintain common concepts across both phases in one 
location within the SAP. 
3. STUDY DESIGN 
3.1. Study Design and Population 
 
This is a Phase 1b/2 combined, randomized, multicenter, double-blind, placebo-controlled trial to 
study the clinical efficacy, safety, and pharmacokinetics (PK) of subcutaneously (SC) doses of 
BOS161721 in adult patients with moderately to severely active SLE.  After successfully 
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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completing a screening phase, eligible patients will be randomized to a specified dose of 
BOS161721 or placebo.  The dosing schedule will be monthly.   
The trial will consist of 2 double blinded- portions:  MAD Phase 1b and POC Phase 2.  Patients 
may receive a total of 7 SC monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 
180, followed by safety/efficacy  follow-up visit at Days 210, and safety follow up visits at Days 
240, and 270.     
SLE disease activity assessment data will be centrally reviewed by medical monitor and sponsor 
to ensure the scores are clinically meaningful and compliant with specific definition.  The scope 
of responsibility includes, but is not limited to, review and confirmation of “A” and “B” British 
Isles Lupus Assessment Group (BILAG) system organ disease, confirmation of clinical 
components of the SLE Disease Activity Index 2000 (SLEDAI-2K) score at screening and 
during the study, and cross validation- of the instruments used in this study to assess the disease 
activity.  Further details on the content and methods of data reports by the medical monitor and 
sponsor will be outlined in the Medical Data Review Plan along with the processes and 
procedures that will be followed. 
3.1.1. 
Multiple Ascending Dose Phase 1b  
The MAD portion will consist of 3 cohorts:  
• Cohort 1 (20 mg SC) will include 6 patients 
o 5 patients will receive BOS161721 (active group) and 1 patient will receive placebo 
(placebo group) 
• Cohorts 2 (60 mg SC) and 3 (120 mg SC) will include 12 patients each 
o 9 patients in the active group and 3 in the placebo group 
Doses selected for each of the 3 cohorts is based on a 90-day safety, tolerability, PK and PD data 
review from the Phase 1 single ascending dose (SAD) study (BOS161721-01) in healthy 
subjects.  All doses selected for the MAD part of the study are projected not to exceed the mean 
exposure of that achieved in the SAD study. 
The MAD portion of the study design is staggered, where after the 6 patients in Cohort 1 have 
received 2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 2 
begins dosing (after the data monitoring committee (DMC) evaluation of the safety and 
tolerability data from Cohort 1).  Similarly, after 8 of the 12 patients in Cohort 2 have received 
2 doses and have completed 2 weeks of follow up- after the second dose, Cohort 3 begins dosing 
after the DMC evaluation of the safety and tolerability data from Cohorts 1 and 2.  Each cohort 
will continue at their assigned dose level through their respective 6-month treatment periods (See 
Study Schematic in the study protocol).  If patients discontinue the study in a cohort prior to 
adequate safety follow-up, he/she may be replaced. 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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Criteria for dose escalation are further described in the DMC Charter. 
3.1.2. 
Proof of Concept Phase 2  
The optimal dose is chosen based on MAD Phase 1b safety, tolerability, immunogenicity, and 
PK and PD data.  The dose will be communicated by a letter to site investigators participating in 
the POC Phase 2 portion, and to the Institutional Review Board / Independent Ethics Committee 
(IRB/IEC). 
For the POC part of the study, approximately 156 additional patients will be randomized to 
active or placebo groups in a 2:1 ratio.   
As in the MAD part of the study, each patient in the POC portion may receive a total of 7 SC 
monthly doses of study drug on Days 0, 30, 60, 90, 120, 150, and 180.  Assessments will be 
completed according to the Schedule of Assessments detailed in the study protocol.  Dose 
selection will be based on the DMC and sponsor’s assessment of safety, tolerability, 
immunogenicity, and PK and PD data from the MAD portion of 30 patients treated with 
BOS161721/placebo. 
DMC safety reviews will be conducted periodically throughout the study as described in the 
DMC charter. 
Study Diagram for MAD Phase 1b and POC Phase 2 
Day 0
24 week treatment phase
Dose 1
Dose TBD N=104 
Placebo N=52
Low Dose (20 mg) N=6 (5A, 1P) 
Monthly visits 
Medium Dose (60 mg) N=12 (9A, 3P) 
Dose 3
2 month
6 patients complete dose 2:  dose escalate Cohort 2 if safe
Dose 1
Dose 2
1 month
High Dose (120 mg) N=12  (9A, 3P)
Dose 1
Dose 3 + 30 days: 
•
Phase 2 POC dose determined
•
Continue dosing Cohort 3 if safe
Follow up 
Dose 6
5 month
Dose 7
6 month
Dose 7
6 month
Dose 7
6 month
Screening
Week -4
8 patients complete dose 2:
•
Dose escalate Cohort 3 if safe
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Day 0
Day 0
Multiple Ascending Dose (MAD)
Phase 1b 
Proof of Concept (POC)
Phase 2 
Dose Evaluation
Phase
Follow up
90 days
90 days
Follow up 
90 days
Follow up 
90 days
Dose 1
Day 1
Dose 3
2 month
Dose 6
5 month
Dose 7
6 month
Dose 2
1 month
Dose 4
3 month
Dose 5
4 month
Dose 3
2 month
A = active drug (BOS161721); P = placebo 
 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
Page 16 of 58 
 
3.2. Randomization and Blinding 
 
This is a randomized, double-blind study.   
Patients meeting all inclusion and exclusion criteria will be centrally randomized to either 
placebo or BOS161721 using an IWRS according to a randomization list generated by an 
independent, non-study statistician.  Randomization will be performed separately for each study 
portion and separately for each cohort in the Phase 1b and 2 portions as follows: 
Phase/Cohort 
Number of Patients 
Randomization Ratio BOS161721:Placebo 
Phase 1b/Cohort 1 
6 
5:1 
Phase 1b/Cohort 2 
12 
3:1 
Phase 1b/Cohort 3 
12 
3:1 
Phase 2 
156* 
2:1 
*Additional patients may be enrolled to ensure sufficient numbers of patients are in the full analysis set (FAS). 
Eligible patients will be assigned to the study portion which is active at time of enrollment.  
Similarly, patients in the Phase 1 MAD will be assigned to the cohort which is active.  Each 
patient will be assigned a unique randomization number which will not be reused.   
All patients, investigators, and study team participants will be blinded to treatment assignment.  
An independent biostatistician not otherwise involved on the study will be unblinded and prepare 
materials for the interim analysis (IA) and the DMC safety reviews.  The DMC will review 
unblinded data during safety reviews and the IA.  A limited team at Boston Pharmaceuticals will 
review unblinded results from the Phase 1b MAD portion during the IA to determine the dose 
that will be used for the Phase 2 POC portion of the study.  Details regarding maintenance of the 
blinding and content of data reviews will be described in the DMC charter or related study 
documentation.   
3.3. Sample Size Considerations 
 
Sample size in the Phase 1b MAD part of the study is based on operational consideration. 
The sample size in the Phase 2 POC study is based on the primary endpoint, SRI-4 Response at 
Day 210.  Approximately 156 additional patients will be randomized in a 2:1 ratio to 
BOS161721 versus placebo to achieve 132 evaluable patients in the FAS.  This assumes 
24 patients will drop prior to having received treatment and an evaluable post-baseline efficacy 
measure.  Enrollment and randomization will be monitored in a blinded fashion and increased if 
needed to ensure at least 132 patients are randomized into the FAS.    
A total of 132 patients randomized provides more than 80% power to detect a treatment 
difference of 25% in SRI-4 response rates at Day 210, based on a targeted 2-sided significance 
level of 10% and using a 2-sided Pearson’s chi-squared test.  This assumes a response rate of 
65% for BOS161721 and 40% for placebo, where missing data at Day 210 is carried forward 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
Page 17 of 58 
 
from most recent non-missing result and patients are treated as a non-responder if a prohibited 
medication defined as a medication failure occurs. 
3.4. Data Monitoring Committee (DMC) 
 
This study will use an external DMC.  The DMC is an independent committee established to 
provide oversight of safety considerations in the study and to provide advice to the sponsor 
regarding actions the committee deems necessary for the continuing protection of enrolled 
patients and those yet to be recruited to the trial as well as for the continuing validity and 
scientific merit of the study results.  The DMC is charged with assessing such actions in light of 
an acceptable benefit/risk profile for BOS161721.  The recommendations made by the DMC 
(i.e., dose escalation, etc.) will be forwarded to the sponsor for final decision.  The sponsor will 
forward such decisions, which may include summaries of safety data which are not endpoints, to 
regulatory authorities, as appropriate. 
The sponsor will appoint a DMC for the periodic review of available study data.  The DMC is an 
independent group of experts that advises the sponsor and the study investigators.  The members 
of the DMC serve in an individual capacity and provide their expertise and recommendations.  
The primary responsibilities of the DMC are to (1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct, and progress, (2) make 
recommendations to the sponsor concerning the continuation, modification, or termination of the 
study and (3) suggest dose for POC portion of the study as described in the study protocol. 
The DMC considers study-specific data as well as relevant background knowledge about the 
disease, test agent, or patient population under study.  The DMC is responsible for defining its 
deliberative processes, including event triggers that would call for an unscheduled review, 
stopping guidelines, unmasking (unblinding), and voting procedures prior to initiating any data 
review.  The DMC is also responsible for maintaining the confidentiality of its internal 
discussions and activities as well as the contents of reports provided to it. 
The DMC will have access to unblinded treatment information during the clinical trial.  Details 
regarding management and process of this committee are found in the DMC Charter. 
The DMC may recommend termination of BOS161721 treatment arm or the entire BOS161721 
MAD/POC trial for any safety concern that is felt to outweigh potential benefits.  The 
recommendation must be supported by the sponsor as indicated in the DMC Charter. 
3.5. Interim Analysis (IA) 
 
One interim analysis is planned for this study and will be conducted at the time of the POC 
decision for dose selection.  The POC dose will be selected based on the MAD data.  Since there 
is no IA during the POC part of the study, there is no impact on the type 1 error.   
Interim analysis outputs will be a subset of those to be performed for the final analysis. 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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3.6. Timing of Analyses 
 
The following analyses are planned: 
• An IA will be performed during the last cohort of the MAD portion to determine dose 
selection for the POC portion.   
• The final analysis will be performed when all patients have either completed the POC 
safety follow up or withdrawn from the study.   
• Safety analyses will be performed for DMC reviews throughout the study to evaluate 
dose escalation decisions and accumulating safety data.  The frequency and details of the 
content and format of the safety review meetings are described in the DMC charter and 
SAP/mock shells. 
4. DATA ANALYSIS CONSIDERATIONS 
 
All analyses will be conducted based on SAS 9.3 or higher. 
All data in the database will be presented in by-patient data listings. 
Unless otherwise stated, all listings will be sorted by study phase, treatment group, patient 
number, and assessment date (and time, if available).  If assessment date is missing, 
chronological visit will be used for sorting. 
Unless stated otherwise, continuous data will be summarized by treatment group based on 
number of patients (n), mean, median, standard deviation (SD), 25th percentile/first quartile (Q1), 
75th percentile/third quartile (Q3), minimum value, and maximum value. 
The geometric % coefficient of variation is calculated as 100*sqrt(exp(SDlog^2)-1) where SDlog 
is standard deviation of log-transformed values. 
Unless stated otherwise, categorical data will be summarized by treatment group using n and 
percentage based on the number of non-missing values. 
• The number of missing values will be presented as a separate category with no 
percentage, but only if one or more patients are missing data. 
• Counts of zero will be presented without percentages. 
 Statistics will be presented in the summary tables based on the following: 
• Minimum and Maximum: same number of significant digits as the raw value 
• Mean, Median, Q1, and Q3: one additional decimal place to that reported for 
Minimum and Maximum 
• SD: two additional decimal places than presented for the Minimum and 
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• Percentages: reported to one decimal place with the exception of 100% which will 
be displayed without decimals. 
• P-values will be reported to four decimal places.  If the value is below 0.0001 it 
will be noted as < 0.0001; if the value above 0.9999 it will be noted as > 0.9999. 
Unless otherwise noted, statistical inference will be based on a 10% significance level (i.e. 90% 
confidence intervals will be produced). 
Statistical testing will be performed on data from the Phase 2 study only. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of duration of treatment. 
Numbering for data displays will be based on ICH E3. 
4.1. Stratification and Covariates 
 
The effects of noncompliance, background therapy use, treatment discontinuations, premature 
withdrawal from study and covariates will be assessed to determine the impact on the general 
applicability of results from this study.  Exploratory analyses of the data may be conducted as 
deemed appropriate to evaluate factors for which analyses are not controlled. 
Continuous efficacy endpoints will be assessed via analysis of variance (ANOVA) or analysis of 
covariance (ANCOVA) when applicable, adjusting for the baseline value. 
4.2. Evaluation of Subgroups 
 
There are no formal plans for examining subgroups. 
4.3. Multiple Comparisons and Multiplicity 
 
The Type 1 error rate will not be adjusted for multiplicity.  
5. GENERAL DATA HANDLING CONVENTIONS 
5.1. Assigned and Actual Treatment 
 
Patients are assigned to a study treatment and cohort based on the study schematic in Section 3.    
Full analysis set (FAS) and per protocol (PP) analyses will be conducted on the basis of the 
randomized (assigned) treatment.  Safety analyses will be conducted on the basis of the actual 
treatment received based on the exposure data collected in the case report form (CRF). 


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5.2. Reference Dates 
 
• Screening date is defined as the CRF provided date on which a patient was screened for 
trial entry. 
• Randomization date is defined as the date on which the patient is randomized to study 
treatment. 
• Treatment start date is defined as the date of first dose of study drug. 
• Treatment end date is defined as the date of last dose of study drug. 
• Age will not be calculated and will come directly from the CRF.  The CRF uses the 
informed consent date as its reference date for age calculation. 
• Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date. 
• Efficacy data will use the randomization date as a reference date. 
• Study day will be based on treatment start date as a reference date. 
5.3. Study Day and Duration Variables 
 
Reference date calculations will be defined as follows, assuming non-missing dates:  
• date of interest – reference date + 1 when the date of interest is on or after the reference 
date; 
• otherwise, date of interest – reference date. 
 
If either date is missing or incomplete, reference date calculations will not be performed.  Date 
imputation will be performed as identified in Section 5.6. 
 
Study day will either have a negative value if collected before dosing or a positive value if 
collected on or after the day of drug dosing; there will be no study day zero.  
Duration of time is dependent on reference dates and will be calculated in a manner similar to 
that of the reference date calculation.  Duration on study is defined as the end of study date –
randomization date + 1.  Duration of treatment is defined as treatment end date – treatment start 
date + 1, where treatment end date is the date of last dose of study drug. 
Time-to-event endpoints are followed until first event or censoring.  As a result, event time will 
be calculated as: event or censoring date – reference date + 1.  These are further described in 
Section 7. 
When reporting time-to-event data (Time to Medication Failure, Time to first SRI-4 Response, 
Time to BILAG A Flare or >1 BILAG B flare) or duration outcomes, the results (in days) above 
will be converted to an appropriate unit.  When reporting in months it will be divided by 
30.4375; for reporting in weeks it will be divided by 7; and for reporting in years it will be 
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5.4. Study Time Periods 
 
Where applicable, data reporting will be classified by the following study periods for analysis: 
• Pre-treatment is defined as the period prior to a patient’s treatment start date. 
• On-treatment is defined as the period between a patient’s treatment start date and 
treatment end date, inclusive. 
• Post-treatment is defined as the period of time following the on-treatment period. 
5.5. Baseline, Post-Baseline Changes, and Last Observation Carried Forward 
(LOCF) 
 
Unless stated otherwise, baseline and post-baseline change values will be based on the following: 
• Baseline will be based on the last non-missing value collected prior to or on the treatment 
start date (and time, if applicable). 
• Post-baseline values will be those collected after the date/time of first dose of study drug. 
• Change from baseline is defined as: value – baseline value.  
• Most extreme change:  The maximum most extreme change will be the maximum post-
baseline value; the minimum most extreme change will be the smallest post-baseline 
value. This calculation will consider all assessments collected after the first dose of study 
drug, scheduled or unscheduled. 
LOCF will be based on the last non-missing value collected.  This calculation will consider all 
assessments, scheduled or unscheduled, including baseline.  If a patient withdraws from the 
study, their most recent non-missing assessment prior to withdraw will be carried forward.  
Additional details regarding LOCF for specific endpoints are provided in Section 7. 
Observed values do not incorporate any imputations and are presented as collected. 
5.6. Imputation of Partial Dates 
 
Adverse Events  
• If the AE start date is completely missing, or if the patient was not treated, no imputation 
will be conducted. 
• If the AE start date is missing day and month, do the following: 
o If the treatment start date is missing or the AE start year does not fall in the same 
year as that of the treatment start date or if the AE record contains information to 
indicate that the event ended before the treatment start date (e.g. the AE end date 
month and year are earlier than the treatment start date or the full AE end date is 


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known and occurs earlier than the treatment start date), then set the AE start 
month and day to January 1st. 
o Otherwise, set the AE start date to the treatment start date.  
• If only the AE start day is missing, do the following: 
o If the study treatment start date is missing or the AE start month and year does not 
fall in the same month/year as that of the treatment start date or if the AE contains 
information to indicate that the event ended before the treatment start date, then 
set the AE start month and day to the 1st day of the month of the treatment start 
date. 
o Otherwise, set the AE start date to the treatment start date. 
• AE end dates will not be imputed.  
Prior, Concomitant, and Subsequent Medications 
• The imputation rules for AE start dates will be used for medication start dates. 
• Medication stop dates will be imputed as follows: 
o If the stop date is only missing the day, then the stop day is the last day of the 
month 
o If the stop date is missing both the day and month and the year matches the last 
study date, then the stop month and day is the earlier of the last study date and 
December 31 
o If the stop date is missing both the day and month and the year is earlier than the 
last study date, then the stop month and day is December 31 
o If the stop date is completely missing, no imputation is performed, and the 
medication will be classified as a concomitant medication for subjects who were 
treated unless the medication began after the end of study treatment. 
5.7. Multiple Assessments and Visit Windows 
 
Nominal visits (e.g. those identified by the study CRF) will be the basis of summarization and 
statistical analysis; no visit date windowing will be conducted. Unscheduled data may be 
included in summaries of most extreme, baseline, and endpoint values; summaries of specific 
abnormalities any time post-baseline; and patient data listings 
5.8. Treatment Group Display 
 
Treatment groups will be displayed with the following columns.  See the mock shells for 
additional details and a visual representation of the treatment group display. 
• Phase 1b MAD: Cohort 1 BOS 20mg 
• Phase 1b MAD: Cohort 2 BOS 60mg 
• Phase 1b MAD: Cohort 3 BOS 120mg 
• Phase 1b MAD: Placebo 


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• Phase 1b MAD: Total BOS (All patients treated with BOS161721, excludes placebo) 
• Phase 2 POC: BOS <dose> where <dose> is the value determined during the IA 
• Phase 2 POC: Placebo 
• Overall: Total BOS <dose>mg where <dose> is the common dose between the Phase 1b 
MAD and Phase 2 POC portions of the study (to be determined during the IA).  If a 
common dose is not determined, this column will be omitted. 
• Overall: Total BOS (Patients treated with BOS161721 in MAD and POC, excludes 
placebo) 
• Overall: Total Placebo (Placebo patients in MAD and POC, excludes patients treated 
with BOS161721) 
5.9. Missing Data 
 
Missing data imputation for the efficacy endpoints are discussed in the corresponding efficacy 
sections.  AE and concomitant medication date imputations are described in Section 5.6.  
Missing data for noncompartmental analysis of pharmacokinetics will follow standard 
imputation methods, as described in a separate Clinical Pharmacology Analysis Plan (CPAP).  
Otherwise, missing data will not be imputed. 
6. STUDY PATIENT DATA 
6.1. Analysis Populations/Sets 
 
Full Analysis Set (FAS):  Defined as all patients who receive at least one dose of study treatment 
and have at least one evaluable post-baseline efficacy evaluation (BILAG, PGA, SLEDAI-2K, 
CLASI, ACR-28, SLICC/ACR, 
, or 
).  FAS analyses will be conducted on the 
basis of the randomized treatment.  The FAS will be used as the basis for the primary efficacy 
analysis. 
Safety Analysis Set (SS): Defined as all patients who receive at least one dose of study 
treatment.  Safety analyses will be conducted on the basis of actual treatment received.  The SS 
will be the basis of all safety reporting. 
Per Protocol Set (PP): Defined to exclude major protocol violations from the efficacy analysis.  
The PP will include all patients from the FAS except those with major violations to the protocol 
deemed to impact the analysis of the primary endpoint.  These violations will be identified based 
on blinded data prior to study unblinding.  PP analyses will be conducted on the basis of the 
randomized treatment.  Additional information on inclusion into this population can be found in 
Section 6.3. 
Pharmacokinetic Analysis Set (PK): Defined as the FAS patients who received at least one dose 
of BOS161721 with sufficient concentration data for the calculation of at least one PK 
parameter. 
CCI
CCI


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6.2. Patient Disposition 
 
Disposition data will be summarized for all randomized patients.  The number of patients in each 
analysis population, the number of patients who discontinued study treatment including reasons, 
and the number of patients who discontinued the study including reasons will be summarized.  
The number of patients who completed the study will also be summarized.  Data will be 
presented by study phase and treatment group. 
A by-patient listing of patient disposition data including reason for discontinuation, if applicable, 
will be presented for all randomized patients.  A by-patient listing of randomization details will 
also be provided for all randomized patients. 
A by-patient listing of inclusion/exclusion criteria and screen failures will be produced for all 
enrolled patients.  Screen failures will otherwise not be included in any analyses. 
6.3. Protocol Deviations 
 
Protocol deviations will be identified and classified as major violations before database lock and 
unblinding. Major protocol deviations may include but are not limited to: 
• Violation of Inclusion/Exclusion Criteria 
• Use of prohibited therapies 
• Incorrect treatment 
Protocol deviations will be summarized by protocol version, deviation category, and 
major/minor designation.  Protocol deviations will be summarized by study phase and treatment 
group for all randomized patients. 
A listing of protocol deviations will be provided for all randomized patients. 
6.4. Demographic and Baseline Characteristics 
 
Patient demographics and baseline characteristics will be summarized in the SS.  These will 
include age (years), gender (Male / Female), ethnicity (Hispanic or Latino / Not Hispanic or 
Latino), race (American Indian or Alaska Native / Asian / Black or African American / Native 
Hawaiian or Pacific Islander / White / Other), baseline height (cm), baseline weight (kg), and 
baseline BMI (kg/m2).  Age is reported as collected in the clinical database and will also be 
categorized as a categorical variable (≤45, >45-<65, ≥65) for reporting.  Patient eligibility for 
central review will be summarized.  Childbearing potential and birth control methods for female 
and male patients will be summarized for the DMC meetings and interim analysis only.  
Demographics and baseline characteristics will be summarized by study phase and treatment 
group. 
 


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Demographics and baseline characteristics will be listed for all randomized patients.  A separate 
by-patient listing will be created for childbearing potential and birth control for all randomized 
patients. 
 
The following conversions and equations will be used as applicable: 
Height (in cm) = height (in inches) * 2.54 
Weight (in kg) = weight (in lbs) * 0.4536 
BMI (kg/m2) = weight(kg)/[height(m)2] 
 
6.5. Medical History 
 
Medical history will be presented in data listings for all randomized patients.  Medical history 
coded terms will be provided, including the system organ class and preferred term.  The data 
management plan specifies the version of MedDRA used for medical history coding. 
6.6. Prior and Concomitant Medication and Procedures 
 
The incidence of medication use will be summarized by WHO Drug Dictionary anatomic 
therapeutic class (ATC) Level 2 classification (i.e. therapeutic main group) and preferred name. 
A patient will be counted only once at each level of reporting.  Prior medications are those which 
have been identified to have been discontinued prior to the first dose of study medication.  
Concomitant medications are those which have been identified to have been taken at any point 
during the period of time between the first and last dose of study medication, including 
medications which started prior to first dose of study medication but are ongoing at first dose.  
Subsequent medications are those which have been started after the last dose date.  The data 
management plan specifies the version of WHO Drug used. 
Partial dates will be imputed according to Section 5.6 for the determination of prior, 
concomitant, and subsequent medications. 
Concomitant medication use will be summarized and presented by study phase and treatment 
group in the SS.  
All prior and concomitant medication data will be provided together in a by-patient listing 
including the verbatim and preferred drug name and WHO ATC Class (ATC Level 2) for all 
randomized patients.  Past biological, immunosuppressant, antimalarial and corticosteroid SLE 
medication history data will be listed separately for all randomized patients. 
Concomitant procedures will be presented in a data listing for all randomized patients. 
 


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6.7. Study Drug Exposure and Compliance 
 
The total dose administered (mL) and the number of doses received will be summarized as 
continuous variables.  The number and percentage of patients dosed and the number of patients 
who received the total planned dose at each nominal, protocol specified, visit (Day 0 / Day 30 / 
Day 60 / Day 90 / Day 120 / Day 150 / Day 180) will be summarized.  The denominator for the 
number of patients dosed will be the number of patients in the SS.  The denominator for the 
number of patients who received the total planned dose will be the number of patients dosed at 
the corresponding nominal visit. 
The percent compliance will be calculated descriptively and is defined as 100 * (total actual dose 
summed across all visits)/total planned dose summed across all visits). 
The duration of exposure in days will also be summarized descriptively and is defined as the last 
dose date – first dose date +1.   
Study drug exposure and compliance will be presented by study phase and treatment group in the 
SS. 
By-patient listings of BOS161721 and placebo dosing data will be produced for all patients in 
the SS. 
7. EFFICACY  
7.1. Primary Efficacy Endpoint and Analyses 
 
Safety is the primary endpoint for the Phase 1b MAD portion of the study and is discussed 
in Section 9.  Efficacy will be evaluated for the Phase 1b MAD portion of the study as an 
exploratory endpoint and details will be included in relation to the Phase 2 POC portion of the 
study within this section.  
7.1.1. 
The proportion of patients with a SRI-4 response at Day 210 
 
The primary efficacy endpoint is the proportion of patients who achieve a SRI-4 response at Day 
210.  
 
The SRI-4 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-4 is defined by:  
 
1) ≥ 4-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 


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2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm.   
 
The proportion of patients who achieve a SRI-4 response at Day 210 will be presented and 
assessed using Pearson’s chi-square test.  The number of SRI-4 responders, treatment difference 
versus placebo, odds ratio, and 90% confidence interval will be displayed.  The 90% confidence 
interval will be calculated with Wilson (score) confidence limits for the binomial proportion by 
treatment group.  If any of the expected cell counts are less than 5, Fisher’s exact test will be 
used and exact confidence intervals will be constructed.  The analyses will be repeated for each 
of the three components contributing to the SRI-4 response.  The primary analysis of the primary 
efficacy endpoint will be performed in the FAS and presented by treatment group. The analysis 
will be repeated in the PP analysis set.   
 
The superiority of BOS161721 relative to placebo will be evaluated.  If the proportion of SRI-4 
responders for the selected POC dose in BOS161721 arm is higher than that of the placebo arm, 
then BOS161721 will be considered superior to placebo if the 2-sided p-value is less than 0.10. 
Evaluability/Non-Responders: 
Patients who received prohibited medications or unallowable corticosteroid (CS) usage will be 
considered “medication failures” and will be treated as non-responders for the primary efficacy 
analysis.  Prohibited medications are detailed in Appendix 4 of the study protocol.  Prohibited 
medications and unallowable CS usage will be recorded as protocol deviations in the clinical 
database.   
A patient is considered to have unallowable CS usage if any of the following is not met: 
• After Day 0 (after initiation of study therapy), no up-titration above 10 mg/day is allowed 
except for up to 1 CS burst for increased disease activity.  
• Tapering is allowed after randomization except within 60 days of the primary (Day 210) 
and secondary (Day 120) endpoint assessments.  Between Day 60 and Day 120, and 
between Day 150 and Day 210, oral CS doses must be held constant. 
• A maximum of 1 oral CS “burst” for increased SLE disease activity will be allowed 
during the study between Day 0 and Day 60, according to the following:   
o An oral CS “burst” between Day 0 and Day 60; (an increase of ≤ 40 mg/day of 
prednisone or equivalent), which must be tapered down to a maximum of 
10 mg/day within 2 weeks of initiation of the “burst” 


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o Alternatively, a single intramuscular (IM) dose of methylprednisolone (40 mg or 
equivalent) is permitted 
o The course of the oral CS “burst” is not permitted to extend beyond Day 60 
Patients who received an allowable CS burst but having missing data at Day 210 will be 
considered a medication failure and will be treated as non-responders for the primary efficacy 
analysis.  The determination of medication failures will be reviewed using blinded data and 
finalized prior to unblinding.  Once a patient is determined to be a non-responder, they will not 
be considered for response at a later visit. 
 
If a patient has a BILAG, SLEDAI-2K, or PGA assessment outside of a 30 day +/-4 day window 
since the previous assessment (0-25 or >35 days since the prior assessment), the corresponding 
result will be considered not evaluable and will be excluded from all analyses.  The excluded 
result will not contribute to LOCF analyses.  In these cases, the individual assessment (i.e. 
BILAG, SLEDAI-2K, or PGA) will be considered as if it was missed and analyses will be 
handled per the below details. 
 
Missing Data: 
 
• If a patient is missing data during the pre-treatment period for SLEDAI-2K, PGA, or 
BILAG, the patient will be excluded from the primary efficacy analysis. 
 
• Missing data at Day 210 for overall components for SLEDAI-2K, BILAG, and PGA will 
be addressed by employing a last observation carried forward (LOCF) analysis within 
each overall component as described in Section 5.5.  For example, if a patient has data for 
SLEDAI-2K and BILAG at Day 210 but is missing PGA at Day 210, the PGA 
component would employ LOCF.  Data collection and scoring will be performed in the 
clinical database for BILAG, SLEDAI-2K, and PGA.  As such, missing individual items 
contributing to any of the overall components will not be imputed/carried forward.   
 
• Missing data for visits other than Day 210 will be handled in the same way as Day 210. 
 
• If one or more consecutive visits are missed, LOCF analyses will be carried forward from 
the most recent prior assessment.  For example, if the Day 150, Day 180 and Day 210 
assessments are all missed but the Day 120 assessment was performed, the Day 120 
assessment would be carried forward to Days 150, 180, and 210 for analysis. 
 
Several sensitivity analyses will be performed: 
Analysis 
Criteria 
Sensitivity Analysis 1 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (including LOCF methods) for patients in the full analysis 
set excluding patients with: 


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(1) Positive anti-drug antibodies at baseline through Day 210.   
AND 
(2) Confirmed nAb at Day 90 and Day 180 OR missing Day 90 and 
missing Day 180 nAb OR missing Day 90 nAb and confirmed nAb at 
Day 180. 
 
Missing ADA and missing nAb results will be handled with a LOCF 
approach as discussed in Section 5.5.  Additional analyses exploring 
impact of baseline factors such as baseline disease severity, race, and 
other characteristics may be performed. 
Sensitivity Analysis 2 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (including LOCF methods) for patients in the full analysis 
set; however, if a patient has a BILAG, SLEDAI-2K, or PGA 
assessment outside of a 30 day +/-4 day window since the previous 
assessment (0-25 or >35 days since the prior assessment), the 
corresponding result will be considered evaluable and will be 
included in the analysis and will contribute to LOCF. 
Sensitivity Analysis 3 
A sensitivity analysis of the primary efficacy endpoint will be 
performed (excluding LOCF methods) to consider the effect of 
missing data by excluding patients with either or both of the 
following criteria: 
(1) Missing assessments at Day 210 (patients with a missed 
assessment of any of BILAG, SLEDAI-2K, or PGA at Day 210 
would be excluded). 
AND/OR 
(2) Patients with any Day 210 assessment which occurred outside  of 
the 30 day +/- 4 day window (patients with an out of window 
assessment of any of BILAG, SLEDAI-2K, or PGA at Day 210 
would be excluded). 
 
Additional sensitivity analyses may be performed to consider the effect of missing data. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
A summary of disposition of SRI-4 response at day 210 will be presented by study phase and 
treatment group in the FAS and PP.  Sensitivity analysis 1 will also be performed for disposition 
of SRI-4 response at day 210.  These summaries will include the number of SRI-4 responders 
and the number of SRI-4 non-responders with a breakdown of reasons for non-response (early 
withdrawal, medication failure, <4-point reduction from baseline in SLEDAI-2K global score, 
new BILAG 1A/2B, and PGA worsening).  Denominators for percentages will be the number of 
patients eligible for SRI-4 response analysis. 
 


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A listing of SRI Response data at Day 150, Day 180, and Day 210 will be presented in the FAS.  
A listing of patients excluded from the efficacy analysis will also be provided for all randomized 
patients. 
 
7.2. Secondary Efficacy Endpoints and Analyses 
Pharmacokinetics and pharmacodynamics are the secondary endpoints for the Phase 1b MAD 
part of the study and are described in Section 8.  Efficacy will be evaluated for the Phase 1b 
MAD part of the study as an exploratory endpoint and details will be included in relation to the 
Phase 2 POC part of the study within this section.  
7.2.1. 
Proportion of Patients with SRI-4 Response at Each Visit 
The analyses described in Section 7.1.1, including sensitivity analyses allowing out of window 
assessment results (Sensitivity Analysis 2) and excluding patients with missing or out of window 
assessments (Sensitivity Analysis 3), will be repeated for each nominal visit and will be 
presented by study phase and treatment group in the FAS.  The 3 components will not be 
summarized separately by visit. 
A graphical display of SRI-4 response by study phase, treatment group, and visit in the FAS will 
be presented. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.2. 
Proportion of Patients with SRI-5 Response at Each Visit 
The SRI-5 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-5 is defined by:  
1) ≥ 5-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The analyses described in Section 7.1.1, including sensitivity analyses excluding patients with 
missing or out of window assessments (Sensitivity Analysis 3), will be repeated for each nominal 
visit based on the SRI-5 response definition and will be presented by study phase and treatment 
group in the FAS.  The 3 components will not be summarized separately by visit for SRI-5 
response. 


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Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.3. 
Proportion of Patients with SRI-6 Response at Each Visit 
The SRI-6 is a composite index of SLE disease improvement that consists of scores derived from 
the SLEDAI-2K and the BILAG 2004 Index.  Response based on the SRI-6 is defined by:  
1) ≥ 6-point reduction from baseline in SLEDAI-2K global score  
 
AND 
 
2) No new severe disease activity (BILAG A organ score) or more than 1 new moderate organ 
score (BILAG B) compared with baseline 
 
AND 
 
3) No deterioration from baseline in the PGA by ≥ 30mm. 
The analyses described in Section 7.1.1, including sensitivity analyses excluding patients with 
missing or out of window assessments (Sensitivity Analysis 3), will be repeated for each nominal 
visit based on the SRI-6 response definition and will be presented by study phase and treatment 
group in the FAS.  The 3 components will not be summarized separately by visit for SRI-6 
response. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.4. 
Proportion of Patients with a sustained reduction of oral corticosteroid 
(CS) between Day 120 and Day 210 
The proportion of patients with a sustained reduction of oral corticosteroid, defined as 
≤ 10 mg/day and ≤ Day 0 dose, between Day 120 and Day 210 will be summarized by study 
phase and treatment group in the FAS.  LOCF and imputation for missing values will not be 
performed.  Otherwise, statistical methods described in Section 7.1.1 will be implemented.   
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 


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Protocol Number: BOS161721-02 
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7.2.5. 
Proportion of new BILAG A flare or >1 BILAG B flare relative to 
baseline through Day 210 
The proportion of new BILAG A flare or >1 BILAG B flare relative to baseline through Day 210 
will be summarized by study phase and treatment group in the FAS.  Statistical methods 
described in Section 7.1.1 will be implemented, including LOCF methods within a body system.  
The analyses will also be repeated in observed data only (no LOCF).  A BILAG A flare is 
defined as a new A score in at least one body system when compared to baseline.  A BILAG B 
flare is defined as a new B score in at least two body systems at the same assessment when 
compared to baseline.  BILAG grading is collected at each protocol specified visit as an 
assessment of “the past 4 weeks”.  As such, the BILAG grade will be compared to baseline and 
the most recent prior assessment, as appropriate, to determine a new flare.  The proportion of 
new BILAG A flare or >1 BILAG B flare relative to baseline will be summarized overall and by 
nominal visit. 
 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
Observed results will be presented in separate data listings for BILAG SLE history, BILAG-
2004 index, and BILAG grading for all randomized patients. 
 
7.2.6. 
Proportion of patients with PGA worsening 
The PGA is used to assess investigator’s general impression on the patient’s overall status of 
SLE disease activity via visual analogue scale (100 mm) with 0 being “very good, asymptomatic 
and no limitation of normal activities” with 100 mm being “most severe possible disease ever 
seen in all SLE patients.”  The proportion of patients with PGA worsening, defined as an 
increase of >30mm from baseline, will be summarized by study phase and treatment group in the 
FAS overall and by nominal visit.  Statistical methods described in Section 7.1.1 will be 
implemented, including LOCF methods.  The analyses will also be repeated in observed data 
only (no LOCF). 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
PGA observed results will be presented in a data listing for all randomized patients. 
 
7.2.7. 
Proportion of patients with BICLA response 
The BICLA is a responder index developed to measure response to therapy, and it includes 
scores from the BILAG, SLEDAI-2K, and PGA.  BICLA response is defined as:  
1) at least 1 gradation of improvement in baseline BILAG 2004 scores in all body systems with 
moderate disease activity at entry (e.g., all B [moderate disease] scores falling to C [mild], or D 
[no activity]) 
AND 


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2) no new BILAG A or more than 1 new BILAG B scores 
AND 
3) no worsening of total SLEDAI-2K score from baseline 
AND 
4) ≤ 10% deterioration in PGA score 
AND 
5) no medication failure. 
LOCF and imputation for missing values will not be performed.  Otherwise, statistical methods 
described in Section 7.1.1 will be implemented. The analyses will be repeated overall and for 
each nominal visit based on the BICLA response definition and will be presented by study phase 
and treatment group in the FAS. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.8. 
Cutaneous Lupus Erythematosus Area and Severity Index (CLASI) 
The CLASI is a comprehensive tool for assessment of disease activity and damage in cutaneous 
lupus, shown to be valid, reliable, and sensitive to changes in disease activity. 
The total activity score will be calculated by summing the scores on the left side of the form 
(erythema, scale/hypertrophy, mucous membrane, alopecia – recent hair loss and clinically not 
obviously scarred). 
The total damage score will be calculated by: 
(1) Sum the responses for “Dyspigmentation” in all anatomical locations 
(2) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts at least 12 months”, then multiply the sum in #1 by 2. 
(3) If a response for “Report duration of dyspigmentation after active lesions have resolved” is 
“Dyspigmentation usually lasts less than 12 months”, then the sum in #1 will not change. 
(4) If the sum in #1 is 0 and a response for “Report duration of dyspigmentation after active 
lesions have resolved” is missing, then the sum in #1 will not change. 
(5) Determine the Dyspigmentation Score based on the results from 2, 3, or 4. 
(6) Sum the remaining scores on the right side of the form (scarring/atrophy/panniculitis, 
alopecia - scarring of the scalp judged clinically). 


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(7) Sum the scores from #5 and #6 to obtain the total damage score. 
If the total activity score or total damage score cannot be calculated, the total activity score or 
total damage score will be imputed using the LOCF method described in Section 5.5.  If one of 
the total scores can be calculated and the other cannot, LOCF will be implemented for only the 
total score which cannot be calculated.  If any individual scores which contribute to the total 
activity score or the total damage score, the total score in question will not be calculated and 
LOCF methods for total score will be implemented.  LOCF methods will be implemented for 
CLASI response analyses only.   
A sensitivity analysis for CLASI response will also be performed in the FAS excluding patients 
with missing CLASI results within a visit.  If one or both of the total activity score or total 
damage score are missing at a visit, the patient will not be included in the response analysis at 
that visit.  LOCF methods will not be implemented for the sensitivity analysis. 
The mean and standard deviation of the change from baseline in CLASI total activity and total 
damage scores will be presented graphically over time by study phase and treatment group. 
7.2.8.1. Proportion of patients with CLASI response 
CLASI response is defined as 50% improvement from baseline in “A” (total activity) or “B” 
(total damage) scores.  This assessment will be applied to all patients as all are required to have 
cutaneous disease activity. 
The analyses described in Section 7.1.1 will be repeated overall and for each nominal visit based 
on the CLASI response definition and will be presented by study phase and treatment group in 
the FAS. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
7.2.8.2. Results and Changes from Baseline in CLASI 
The analysis of CLASI total activity score and CLASI total damage score will be performed 
separately using an analysis of covariance (ANCOVA) model with change from baseline to each 
nominal visit as the dependent variable, treatment group as the factor, and the corresponding 
baseline CLASI score as a covariate.  The p-value for the difference between the BOS161721 
and placebo groups at each nominal visit is based on the F-test. 
Descriptive statistics for the activity score and damage score will be summarized separately at 
baseline and each visit.  Change from baseline will be summarized at each post-baseline visit.  
The LS Mean estimate, its standard error and 90% CI will be tabulated by treatment group and 
for the difference between treatment groups (BOS161721 versus placebo) for change at each 
visit.  Missing CLASI results will not be imputed.  Observed results only will be presented for 
the change from baseline analysis. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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CLASI observed results will be presented in data listings for all randomized patients. 
7.2.9. 
Results and Changes from Baseline in Swollen and Tender Joints ACR-
28 
The ACR-28 joint count evaluates the number of tender and swollen joints in the shoulder, 
elbow, wrist, hand, knee joints.  Joints of the feet are excluded. 
The analysis of Swollen and Tender Joints ACR-28 for the sum of tenderness (left and right) and 
the sum of swelling (left and right) will be performed separately using an analysis of covariance 
(ANCOVA) model with change from baseline to each nominal visit as the dependent variable, 
treatment group as the factor, and the baseline ACR-28 score as a covariate.  The derived sum 
for tenderness and swelling is calculated and provided in the clinical database.  A missing total 
sum of swelling or sum of tenderness will not be imputed.  Observed results only will be 
presented for the change from baseline analysis.  The p-value for the difference between the 
BOS161721 and placebo groups at each nominal visit is based on the F-test.   
Descriptive statistics for the tenderness and swelling derived sums will be summarized separately 
at baseline and each visit.  Change from baseline will be summarized at each post-baseline visit.  
The LS Mean estimate, its standard error and 90% CI will be tabulated by treatment group and 
for the difference between treatment groups (BOS161721 versus placebo) for change at each 
visit. 
The mean and standard deviation of the change from baseline in ACR-28 sum of tenderness and 
sum of swelling will be presented graphically over time by study phase and treatment group. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
Swollen and Tender Joints ACR-28 observed results will be presented in data listings for all 
randomized patients. 
7.2.10. 
Results and Changes from Baseline in SLEDAI-2K 
The SLEDAI-2K is a validated instrument that measures disease activity in SLE patients at the 
time of the visit and in the previous 30 days.  It is a global index and includes 24 clinical and 
laboratory variables that are weighted by the type of manifestation, but not by severity.  The total 
score falls between 0 and 105, with higher scores representing increased disease activity.  The 
SLEDAI-2K has been shown to be a valid and reliable disease activity measure in multiple 
patient groups.  A SLEDAI-2K of 6 or more generally represents moderately to severely active 
disease. 
The analysis of SLEDAI-2K will be performed using an analysis of covariance (ANCOVA) 
model with change from baseline to each nominal visit as the dependent variable, treatment 
group as the factor, and the baseline SLEDAI-2K score as a covariate.  The SLEDAI-2K total 
score is calculated and provided in the clinical database.  A missing total SLEDAI-2K score will 
not be imputed.  Observed results only will be presented for the change from baseline analysis.  


Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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The p-value for the difference between the BOS161721 and placebo groups at each nominal visit 
is based on the F-test.   
Descriptive statistics for the SLEDAI-2K total score will be summarized separately at baseline 
and each visit.  Change from baseline will be summarized at each post-baseline visit.  The LS 
Mean estimate, its standard error and 90% CI will be tabulated by treatment group and for the 
difference between treatment groups (BOS161721 versus placebo) for change at each visit. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
SLEDAI-2K observed results will be presented in a data listing for all randomized patients. 
7.2.11. 
Results and Changes from Baseline in SLICC/ACR Damage Index 
The SLICC/ACR damage index is a validated instrument to assess damage, defined as 
irreversible impairment, continuously persistent for 6 months (ascertained by clinical 
assessment), occurring since the onset of lupus, and it is based on a weighted scoring system.  
This index records damage occurring in patients with SLE regardless of cause, with 
demonstrated content, face, criterion, and discriminant validity.  It will be performed on Days 0 
and 180. 
The analysis of SLICC/ACR Damage Index total score will be performed using an analysis of 
covariance (ANCOVA) model with change from baseline to each nominal visit as the dependent 
variable, treatment group as the factor, and the baseline SLICC/ACR Damage Index total score 
as a covariate.  The SLICC/ACR Damage Index total score is calculated and provided in the 
clinical database.  A missing total SLICC/ACR Damage Index score will not be imputed.  
Observed results only will be presented for the change from baseline analysis.  The p-value for 
the difference between the BOS161721 and placebo groups at each nominal visit is based on the 
F-test.   
Descriptive statistics for the SLICC/ACR Damage Index total score will be summarized 
separately at baseline and each visit.  Change from baseline will be summarized at each post-
baseline visit.  The LS Mean estimate, its standard error and 90% CI will be tabulated by 
treatment group and for the difference between treatment groups (BOS161721 versus placebo) 
for change at each visit. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Observed SLICC/ACR Damage Index data will be presented in a by-patient listing for all 
randomized patients.  SLICC Criteria for SLE at screening will also be presented in a by-patient 
listing for all randomized patients. 


Sponsor: Boston Pharmaceuticals, Inc. 
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SAP Version and Date: Version 1.0, 05Sep2018 
 
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7.2.12. 
Medication Failure 
7.2.12.1. Proportion of patients with medication failures 
Patients who received prohibited medications or unallowable CS usage as described in Section 
4.6 of the study protocol will be considered “medication failures” and will be treated as non-
responders for the primary efficacy analysis and selected sensitivity and secondary efficacy 
analyses.  Patients who received an allowable CS burst but having missing data at Day 210 will 
considered a medication failure.  The determination of medication failures will be reviewed 
using blinded data and finalized prior to unblinding.   
The proportion of patients with medication failures will be summarized by study phase and 
treatment group in the FAS overall and by visit.  A patient will be counted as a medication 
failure at each visit occurring on or after the date in which a patient is considered a medication 
failure.  Statistical methods described in Section 7.1.1 will be implemented for observed data 
only.  LOCF and missing data imputation will not be performed. 
Statistical testing data will be omitted from MAD Phase 1b treatment group displays. 
 
7.2.12.2. Time to Medication Failure (TTMF) 
Medication failure is defined in Section 4.6 of the study protocol and discussed in Section 7.1.1. 
Time to medication failure will be computed as the event date (as described below) – 
randomization date + 1. 
The date of medication failure will be reviewed by Boston Pharmaceuticals and agreed upon 
prior to database lock and unblinding. 
Kaplan-Meier methods will be used to estimate TTMF for each treatment group.  Estimates of 
median TTMF will be provided along with 90% confidence intervals.  Q1 and Q3 will also be 
tabulated. Comparisons between treatment groups will use the one-sided log-rank test.  In 
addition, hazard ratio (HR) estimates with 90% CIs will be calculated from a Cox proportional 
hazards regression analysis that includes treatment as a factor.  Censoring rules are defined as 
follows. 
 


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Protocol Number: BOS161721-02 
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Situation 
Date of Event or Censoring 
Outcome 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Event 
Patient withdraws from study (no medication 
failure) 
Censored at date of withdrawal Censored 
Patient completes the study (no medication 
failure) 
Censored at last study visit 
Censored 
Patient dies during study (no medication 
failure) 
Censored at the date of death 
Censored 
 
Kaplan-Meier curves of TTMF will be plotted over time. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
Time to medication failure data will be provided in a by-patient listing in the full analysis set. 
7.2.13. 
Duration of Longest SRI-4 Response 
Duration of longest SRI-4 response will be computed for patients who have been identified as a 
responder at least once based on criteria defined in Section 7.1.1.  The duration of longest 
response will be defined as the longest period a patient meets the SRI-4 responder criteria at 
consecutive visits.  This will be computed as the date of last consecutive SRI-4 response – date 
of first consecutive response + 1. 
The duration of longest SRI-4 response will be analyzed using an analysis of variance (ANOVA) 
model with treatment group as the effect.  The p-value for the difference between the 
BOS161721 and placebo group is based on the F-test. 
The mean, standard deviation, median, minimum, maximum, Q3, Q4, LS Mean estimate, its 
standard error and 90% CI will be tabulated by treatment group and for the difference between 
treatment groups (BOS161721 versus placebo). 
If a patient has missed a visit between two scheduled visits with a response at both, the patient 
will be counted as having a response at the missed visit.   


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Duration of longest SRI-4 response will be displayed in the SRI response listing. 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 
7.2.14. 
Time to First SRI-4 Response 
SRI-4 response is defined in Section 7.1.1.  Time to first SRI-4 response will be computed as the 
event date (as described below) – randomization date + 1. 
Time to first SRI-4 response will be analyzed with Kaplan-Meier methods described for TTMF 
and censoring as described below.  Kaplan-Meier curves will be plotted over time. 
Situation 
Date of Event or Censoring 
Outcome 
Patient has SRI-4 Response (prior to 
medication failure, withdrawal, or death) 
First date where a patient has 
been documented to have 
achieved a SRI-4 responder 
designation 
Event 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) prior to SRI-4 response/non-responder 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Censored 
Patient withdraws from study (no SRI-4 
response, no medication failure) 
Censored at date of last visit 
with non-missing SRI-4 
assessments (BILAG, 
SLEDAI-2K, and PGA) prior 
to withdrawal 
Censored 
Patient completes the study (no SRI-4 
Response, no medication failure) 
Censored at date of last visit 
with non-missing SRI-4 
assessments (BILAG, 
SLEDAI-2K, and PGA) 
Censored 
Patient dies during study (no SRI-4 response, 
no medication failure) 
Censored at the date of death 
Censored 
 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 


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Time to first SRI-4 response data will be provided in a by-patient listing in the full analysis set. 
7.2.15. 
Time to First BILAG A Flare or >1 BILAG B Flare Compared to 
Baseline through Day 210 
Time to first BILAG A Flare or >1 BILAG B Flare will be will be computed as the event date (as 
described below) – randomization date + 1.  If a patient is designated as a medication failure 
prior to or on their day 210 visit, they will be considered as having a BILAG flare (event) as of 
the date of first dose of the medication leading to the medication failure designation due to 
prohibited medication or unallowable CS burst. 
Time to first BILAG A Flare or >1 BILAG B Flare will be analyzed with Kaplan-Meier methods 
described for TTMF and censoring as described below.  Kaplan-Meier curves will be plotted 
over time. 
Situation 
Date of Event or Censoring 
Outcome 
Patient has a BILAG A Flare or >1 BILAG B 
Flare compared to baseline (Noted as BILAG 
1A/2B Flare) prior to or on their day 210 visit 
Date of first BILAG 1A/2B 
Flare 
Event 
Patient is designated a medication failure 
(received prohibited meds or unallowable CS 
burst) prior to or on their day 210 visit 
Date of first dose of 
medication leading to 
medication failure designation.  
These dates will be obtained 
from the date of deviation on 
the protocol deviation CRF 
form. 
Censored 
Patient withdraws from study (no BILAG 
1A/2B Flare, no medication failure) prior to or 
on their day 210 visit 
Censored at date of last non-
missing BILAG assessment 
(prior to withdrawal) through 
day 210 
Censored 
Patient completes the study (no BILAG 
1A/2B Flare, no medication failure) 
Censored at date of last non-
missing BILAG assessment 
through day 210 
Censored 
Patient dies during study (no BILAG 1A/2B 
Flare, no medication failure) prior to or on 
their day 210 visit 
Censored at the day of death 
Censored 
 
These analyses will also be performed for the MAD Phase 1b with the exception of the statistical 
testing. 


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Protocol Number: BOS161721-02 
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Time to first BILAG A Flare or >1 BILAG B Flare data will be provided in a by-patient listing 
in the full analysis set. 
8. PHARMACOKINETICS/PHARMACODYNAMICS  
 
Pharmacokinetics and pharmacodynamics are secondary endpoints for the Phase 1b MAD study 
and exploratory endpoints for the Phase 2 POC study.   
PK concentrations and PD results reported as less than the lower limit of quantification (LLOQ) 
will be counted as 0 to calculate summary linear statistics, 0.5*LLOQ for geometric statistics, 
and will be reported as <LLOQ in listings. 
PK blood sampling as collected on the CRF will be provided in by-patient data listings.  All 
observed PK concentrations and PD data will also be presented in by-patient listings, including 
, nAb, and ADA.  PK parameters, as provided by Human Predictions, LLC, 
will be displayed in by-patient data listings. 
Additional details surrounding the PK and PD analysis, modeling, and evidence of PK/PD 
relationships will be provided in a separate CPAP. 
8.1. Pharmacokinetics 
BOS161721 PK concentrations will be summarized and listed in the PK set by study phase, 
treatment group, visit, and timepoint.  Summary statistics will include the geometric mean, 
geometric standard deviation, geometric % coefficient of variation, n, mean, standard deviation, 
median, minimum, and maximum.  BOS161721 concentrations will be plotted over time by 
treatment group and visit. 
PK parameters for the PK analysis set will be calculated by Human Predictions, LLC and will be 
provided to Array Biostatistics to prepare outputs for the MAD Phase 1b.  Details surrounding 
the PK parameter calculations will be provided in a separate CPAP.  Summary statistics will be 
presented for Cmax, Tmax, AUC, t½, CL, and Vd and will include the same statistics as PK 
concentrations except Tmax which will include n, median, minimum, and maximum, only.   
8.2. Pharmacodynamics 
Descriptive statistics for the observed results of the following PD endpoints/results will be 
summarized separately at baseline and each visit.  Change from baseline will be summarized at 
each post-baseline visit.  In cases where both numeric and qualitative results are provided, the 
summaries will be based on the numeric results.  Graphical presentations of mean and standard 
deviation of the change from baseline over time will also be presented for the below parameters. 
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Sponsor: Boston Pharmaceuticals, Inc. 
Protocol Number: BOS161721-02 
SAP Version and Date: Version 1.0, 05Sep2018 
 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
Phosphorylated signal 
transducer and activator of 
transcription 3 (pSTAT3) 
MAD only 
% pSTAT3+ Lymphocytes –Stimulated; 
Ratio MEF (Stimulated / Unstimulated) 
 MAD and POC 
NA (all) 
Leukocyte immunophenotype 
(B and NK Cells) 
MAD and POC 
CD19+% of CD45+ Lymphocytes; 
IgD+C27-% of CD19+; 
IgD+CD27-CD38++CD24++% of 
CD19+; 
IgD-CD27-% of CD19+; 
IgD+CD27+% of CD19+; 
IgD-CD27+% of CD19+; 
IgD-CD27+CD38++CD138-% of 
CD19+; 
IgD-CD27+CD38++CD138+% of 
CD19+; 
CD56+% OF CD45+ Lymphocytes 
Leukocyte  imunophenotype 
(T-Cells) 
MAD and POC 
CD4+CD8-% of CD3+; 
CXCR5+% of CD4+CD8-; 
PD-1+% of CD4+CD8-; 
ICOS+% of CD4+CD8-; 
CD25+CD127-% of CD4+CD8-; 
CXCR5+% of CD25+CD127-; 
PD-1+% of CD25+CD127-; 
ICOS+% of CD25+CD127-; 
CD8+CD4-% of CD3+ 
 
MAD and POC 
 
 
 
 
 
 
 
 
 
 
 
 
MAD and POC 
NA (all) 
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PD Endpoint 
Applicable Study 
Portion(s) 
Parameters to be Included in 
Summary Tables and Figures (‘NA 
(all)’ is displayed if all collected 
parameters are to be included) 
 
MAD and POC 
NA (all) 
 
MAD and POC 
NA (all) 
 
 
MAD and POC 
NA (all) 
 
MAD and POC 
All parameters for ‘average target CP’ 
values 
 
 
Additional immunogenicity and PD results may be plotted over time by treatment group and 
visit. 
9. QUALITY OF LIFE  
 
9.1. 
 
 
 
 
 
 
 
 
 
 
 
   
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9.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. SAFETY  
 
All safety analysis reporting will be based on the Safety Analysis Set. 
10.1. Adverse Events 
Adverse events (AEs) will be collected and recorded for each patient from the date of the first 
dose of study drug until the end of their participation in the study, including the safety follow up 
period.  Severity of adverse events will be graded according to National Cancer Institute 
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Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.  AEs will also 
be assessed for relationship to study drug, and seriousness.  Adverse events will be marked as 
adverse events of special interest (AESIs), dose-limiting toxicities (DLTs), or injection site 
reactions (ISRs), where applicable.  AEs will be considered treatment-emergent adverse events 
(TEAEs) if they started any time after first dose or if the start date was missing.  Any missing 
severity assessments will be assumed to be Grade 3, missing relationship assessments will be 
assumed to be related, and missing seriousness assessments will be assumed as serious. 
An overview of TEAEs will be produced, including counts and percentages of patients with any 
incidences of TEAE, TEAEs related to study treatment, Serious adverse events (SAEs), SAEs 
related to study treatment, CTCAE grade 2 or higher TEAEs, CTCAE grade 2 or higher TEAEs 
related to study treatment, CTCAE grade 3 TEAEs, CTCAE grade 3 or higher TEAEs related to 
study treatment, CTCAE grade 4 TEAEs, CTCAE grade 4 or higher TEAEs related to study 
treatment, TEAEs leading to study treatment discontinuation, Related TEAEs leading to study 
treatment discontinuation, TEAEs of special interest, Dose-limiting toxicities, TEAEs resulting 
in death, and injection site reactions. 
Adverse events will be coded based on the Medical Dictionary for Regulatory Affairs 
(MedDRA) for reporting by system organ class (SOC) and preferred term (PT) in descending 
order of overall incidence.  The MedDRA version used is defined in the study data management 
plan. 
Summaries of adverse events by SOC and PT will include the following types:  
• TEAEs; 
• TEAEs related to study treatment;  
• SAEs; 
• CTCAE Grade 3 or higher TEAEs related to study treatment; 
• TEAEs leading to treatment discontinuation; and 
• Dose-Limiting Toxicities 
• TEAEs of Special Interest 
A summary of TEAEs by SOC, PT, and maximum CTCAE grade will also be prepared.  For 
these summaries, TEAEs will be sorted for each patient by SOC/PT and CTCAE grade; patients 
will be counted once within a SOC/PT based on their maximum CTCAE grade.  Missing 
CTCAE grade will be counted in a missing row.   
A summary of TEAEs by PT and maximum CTCAE grade will also be prepared with sections 
for any TEAE and related TEAEs.  For these summaries, patients will be counted once within a 
PT based on their maximum CTCAE grade.  Missing CTCAE grade will be counted as grade 3.  
Preferred terms will be included if at least one patient has a CTCAE grade 3 or higher for the PT.  
PTs will also be included if 10% or more of patients experience a CTCAE grade 1 or 2 TEAE.  
The summary will be sorted by the total incidence of the PT in the any TEAE section.   
A comprehensive listing of all AEs will be provided in a by-patient data listing for the safety 
analysis set. In addition, the following listings will be provided for the safety analysis set:  


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• TEAEs related to study treatment;  
• SAEs;  
• TEAEs leading to treatment discontinuation; and 
• Adverse Events of Special Interest 
10.2. Clinical Laboratory Evaluations 
Laboratory tests will be performed at times defined in the protocol Schedule of Assessments.  
Clinical chemistry and hematology parameters will be reported based on the International 
System of Units (SI).  The following laboratory evaluations will be reported in data summaries, 
with asterisks indicating those that will be graded using CTCAE.  Grading will be performed by 
the Central Lab based on the details provided in Appendix 13.2 for relevant laboratory 
parameters.  If a grade is not present in the central lab database for a graded lab parameter, the 
grade will be analyzed as grade 0. 
Hematology: Hemoglobin*, Hematocrit, RBC count, RDW, MCV, MCH, MCHC, Platelet 
count*, WBC count*, CD4+ count*, Total neutrophils (Abs)*, Eosinophils (Abs), Monocytes 
(Abs), Basophils (Abs), Lymphocytes (Abs)* 
 
Clinical chemistry: Alanine Aminotransferase*, Albumin*, Alkaline Phosphatase*, Aspartate 
Aminotransferase*, Bicarbonate, Bilirubin*, Blood urea nitrogen, C Reactive Protein, Calcium, 
Chloride, Creatine Kinase*, Creatinine*, Glucose (fasting)*, Glucose (random)*, Potassium*, 
Protein, Sodium*, Uric acid*, eGFR (Cockcroft-Gault)*, eGFR (MDRD)*, Total cholesterol 
(fasting)*, LDL-C (fasting), HDL-C (fasting), Triglycerides (fasting)*, Gamma Glutamyl 
Transferase*. 
 
Coagulation: Prothrombin Intl. Normalized Ratio*, Activated Partial Thromboplastin Time* 
Urinalysis: pH, Glucose (qual), Protein (qual)*, Blood (qual)*, Ketones, Nitrites, Leukocyte 
esterase, Urobilinogen, Urine bilirubin, Microscopy 
 
Observed values and changes from baseline for hematology, clinical chemistry, and coagulation 
laboratory evaluations will be summarized at each visit and most extreme change.  Endpoint 
analyses will be based on changes from baseline assessments at Days 120 and 210. 
The number and percent of patients with a NCI-CTCAE toxicity grade of 3 or higher will be 
tabulated by laboratory evaluation with defined NCI-CTCAE grading at each visit for 
hematology, clinical chemistry, and coagulation.  Patients with missing values post-baseline will 
be excluded from the summary. The denominator for percentages will be the number of patients 
with at least one post-baseline assessment for the laboratory parameter in question. 
Hematology, clinical chemistry, and coagulation shift tables displaying the shift from baseline to 
the worst value of NCI-CTCAE grade will be presented based on the most extreme change as it 
relates to the relevant NCI-CTCAE definition. NCI-CTCAE relating to “high/hyper” conditions 
will depend on the maximum post-baseline value while NCI-CTCAE “low/hypo” will be 


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reported based on the minimum post-baseline value.  Separate shift tables will be prepared for 
parameters with bi-directional toxicity grading.  Lab parameters which are optional, such as 
gamma glutamyl transferase, will not be included in the shift tables. 
Hematology and clinical chemistry laboratory data which is not graded will also be summarized 
in shift tables of baseline to each visit and most extreme change based on range categories of low 
(below lower limit of normal [LLN], normal, and high [above upper limit of normal [ULN]]). 
Selected hematology and clinical chemistry laboratory results will be plotted over time for 
treatment group for MAD phase 1b portion of the study in the safety analysis set.  The mean and 
standard deviation of the change from baseline for selected hematology and clinical chemistry 
laboratory results will be plotted over time for the POC Phase 2 portion of the study in the safety 
analysis set. 
All laboratory parameters as well as a summary of central laboratory tests and chest x-ray will be 
provided in patient data listings for all randomized patients.  By patient listings of clinical 
chemistry and hematology data will be presented in the safety analysis set for the DMC and 
interim analysis only. 
10.3. Other Safety Evaluations 
10.3.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was 
developed by Columbia University researchers for the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events 
through any treatment.  It is a clinical interview providing a summary of both ideation and 
behavior that can be administered during any evaluation or risk assessment to identify the level 
and type of suicidality present.  The C-SSRS can also be used during treatment to monitor for 
clinical worsening. i   The C-SSRS evaluation will be performed as specified in the protocol 
Schedule of Assessments. 
The C-SSRS has 11 binary (yes/no) outcomes corresponding to five categories of suicidal 
ideation, five categories of suicidal behavior, and the category of self-injurious behavior without 
suicidal intent: 
Suicidal ideation is present if there is a “yes” response to any of the 5 suicidal ideation category 
questions. Suicidal behavior is present if there is a “yes” response to any of the 5 suicidal 
behavior category questions.  Suicidal ideation or behavior is present if there is a “yes” response 
to any of the 10 suicidal or ideation or behavior category questions. 
The number and percentage of patients with any post-baseline occurrence of the following 
ideations and behaviors will be presented by study phase and treatment group: 
• Suicidal ideation (overall and by individual question),  
• Suicidal behavior (overall and by individual question),  


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• Suicidal ideation or behavior,  
 
A similar tabulation of the occurrence of any of the above ideations and behaviors at baseline or 
as part of their lifetime history/past 12-month history (collected at the screening visit) will be 
presented by study phase and treatment group. 
 
A shift table displaying the shift from worst pre-treatment category to the worst post-baseline 
category will be presented by study phase and treatment group.  Best to worst C-SSRS category 
is defined in the following order: no suicidal ideation or behavior, suicidal ideation, and suicidal 
behavior.  The worst post-baseline shift is calculated based on all post-baseline visits, including 
unscheduled visits.  Worst pre-treatment will include all C-SSRS assessments prior to first dose 
date/time (screening or baseline).  The denominator will be the number of patients with at least 
one non-missing baseline and post-baseline C-SSRS assessment. 
Missing data will not be imputed. 
All C-SSRS individual items will be presented in data listings for screening and post-screening 
(since last visit), separately.  A separate listing will be presented for patients with suicidal 
ideation, suicidal behavior, or non-suicidal self-injurious behavior for all randomized patients. 
10.3.2. 
Vital Signs 
Vital signs include: heart rate (beats/min); temperature (oC); systolic and diastolic blood pressure 
(mmHg); and weight (kg).  Observed values and changes from baseline for vital signs will be 
summarized at each visit and time point, as well as for most extreme change by study phase and 
treatment group.  
All vital signs data will be presented in patient data listings for all randomized patients. 
10.3.3. 
12-Lead Electrocardiogram (ECG) 
ECG will be assessed as specified in the protocol Schedule of Assessments.  The following ECG 
parameters will be collected:  PR interval (msec), QRS interval (msec), RR interval (msec), QT 
interval (msec), and QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
(msec).  ECG parameters and ECG evaluation will come directly from the database and will not 
be calculated during analysis.   
Observed values and changes from baseline for ECG parameters will be summarized at each 
visit, as well as for most extreme change by study phase and treatment group.  
The number and percent of patients with the following parameters at any post-baseline visit and 
at each visit will be summarized:  
• Abnormal, not clinically significant ECGs 
• Abnormal, clinically significant ECGs 


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The number and percent of patients with each ECG evaluation result will be summarized by 
visit.  The worst ECG evaluation at any post-baseline visit will also be summarized in the order 
of: Normal, Abnormal, not clinically significant, Abnormal, clinically significant. 
For the summary of incidence at any post-baseline visit, the denominators for percentages will 
include patients with one or more non-missing value at any post-baseline visit.  For the by-visit 
summaries, the denominators for percentages will include patients with a non-missing value at 
that visit.  
Investigator reported ECG result shifts from baseline to each visit and worst case post-baseline 
will be summarized.  Worst case post-baseline will be based on the most abnormal observed 
value on or after the randomization date. 
All ECG data will be presented in a by patient data listing for all randomized patients.  A 
separate by patient listing for patients with abnormal, clinically significant 12-lead ECGs will 
also be provided in the safety analysis set for DMC meetings and the interim analysis only. 
10.3.4. 
Physical Examinations 
Targeted physical examination data and full physical examination data will be presented in 
patient data listings.  A separate by patient listing for patients with abnormal, clinically 
significant physical examination findings will also be provided in the safety analysis set for 
DMC meetings and the interim analysis only. 
10.3.5. 
Anti-Drug Antibodies (ADAs) 
The serum samples to measure the presence of ADA will be collected as specified in the protocol 
Schedule of Assessments.  ADAs will be summarized and listed according to details provided in 
Section 8. 
 
11. CHANGES TO THE PLANNED ANALYSIS 
 
No changes have been made to the planned analysis. 
 
 
 
 


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12. REFERENCES 
 
i Posner K, Melvin G a, Stanley B, Oquendo M a, Gould M. Factors in the assessment of 
suicidality in youth. CNS Spectr. 2007;12(2):156-162. 
 
 
 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E3 Guideline: Structure and content of clinical study 
reports questions & answers (R1). 2012.            
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_
R1_Step4.pdf.  Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonised Tripartite Guideline: Structure and content of 
clinical study reports E3. Step 4. 
1995. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3
_Guideline.pdf. Accessed 13 Jan 2016. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH E9: Statistical principles for clinical trials. 
1998. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Ste
p4/E9_Guideline.pdf . Accessed 15 June 2016. 
FDA Guidance for Industry Systemic Lupus Erythematosus – Developing Medical Products for 
Treatment. 
2010. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/ucm072063.pdf.  Accessed 23February2018. 
Committee for Medicinal Products for Human use (CHMP).  EMA Guideline on clinical 
investigation of medicinal products for the treatment of systemic lupus erythematosus and lupus 
nephritis. 
2015.  http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/
WC500184889.pdf. Accessed 04March2018. 
 
Nilsson M, Suryawanshi S, Gassmann-Mayer C, Dubrava S, McSorley P, Jiang K.  Columbia-
Suicide Severity Rating Scale Scoring and Data Analysis Guide. V2 
2013.  https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-
Clinical-Trials-1.pdf.  Accessed 18May2018. 
 
 
  
 
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13. APPENDICES 
 


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13.1. 
   
 
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13.2. CTCAE Grading Details from the Central Laboratory 
 


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13.3. Table of Contents for Tables, Listings, and Figures 
 
The table of contents for tables, listings, and figures will be provided in a corresponding mock 
shell document.