A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VIS649 Administered Intravenously in Healthy Subjects
Phase: PHASE1
Conditions: Immunoglobulin A Nephropathy, IgAN - IgA Nephropathy, IgA Nephropathy
Sponsor: Visterra, Inc.

Clinical Study Protocol 
A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose First-in-Human Study 
to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of VIS649 
Administered Intravenously in Healthy Subjects
Sponsor: 
Visterra Inc. 
275 2nd Avenue 
Waltham, MA 02451 
Contract Research Organization: 
PAREXEL International 
Early Phase Clinical Unit–Los Angeles 
1560 Chevy Chase Drive, Suite 140 
Glendale, CA 91206 
USA 
 
 
 
 
Sponsor Study Number: 
VIS649-101 
  
 
IMP Name: 
VIS649 
Development Phase: 
Phase 1 safety and pharmacokinetics 
Version (Date) of Final Protocol: 
Amendment 1, Version 2.0 (Final) (20 Dec 2018) 
This clinical study will be conducted in accordance with the International Council for Harmonisation Tripartite 
Guideline for Good Clinical Practice (GCP) (E6), the protocol and with other applicable regulatory requirements. 
Confidentiality Statement 
This document contains confidential information of Visterra Inc. Do not copy or distribute without written permission 
from the Sponsor. 

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Clinical Study Protocol 
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Amendment 1, Version 2.0 (Final) 
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PROTOCOL AMENDMENTS 
Protocol Amendment No.1, dated 20 Dec 2018. 
The following changes were made to final version 1.0 of the Clinical Study Protocol, dated 20 Aug 
2018. 
1. The study design was revised to indicate that back-up subjects who are not randomized 
into the cohort, but otherwise meet eligibility, may be re-screened after discussion among 
the Principal Investigator, Medical Monitor, and the Sponsor. 
2. It was clarified that the Modification of Diet in Renal Disease will be used for the eGFR 
calculation. 
3. Timeframe limitations for prescription or over-the-counter medications were clarified. 
4. Exclusion criteria regarding grapefruit and Seville-oranges were removed. 
5. A cotinine test at Screening and admission was added. 
6. It was clarified that the Site 11-panel urine drug screen will also test for 
methylenedioxymethamphetamine, 
tricyclic 
antidepressants, 
oxycodone, 
and 
propoxyphene, and that if a subject tests positive on these 4 tests, inclusion of that subject 
into the study will be based on the Principal Investigator’s judgment with consultation, if 
needed, with the Medical Monitor and Sponsor. 
7. It was revised to indicate that the study drug will be destroyed by carbonization rather than 
incineration. 
8. It was revised to indicate that subject weight will be captured after admission to the 
research unit (Day -1) and will be used by the pharmacy staff for subject-specific dose 
calculation. 
9. It was clarified that electrocardiograms will be evaluated by a qualified physician or by a 
qualified physician’s assistant for the presence of abnormalities. 
10. Individual blood volumes as well as the total amount of blood to be collected over the 
course of the study were revised. 
11. The days of collection for pharmacodynamic (lymphocyte populations) were revised 
(removal of Week 1/Day 7, Week 7/Day 49, and Week 12, Day 84). 

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12. It was clarified that vital signs will be tested at Screening and Day -1 and that temperature 
will be measured at Day -1 and Day 1 (pre-dose only). 
13. It was clarified that post-dose blood pressure, pharmacodynamics, and safety laboratory 
data collection should be based on the end of infusion time. 
14. The term “whole blood” was removed from the phrase “circulating lymphocyte 
populations.” 
 
 
 
 
17. Regarding the “changes in circulating lymphocyte populations assessment,” it was clarified 
that this assessment will be done for all lymphocytes, and also for lymphocyte subjects that 
are noted to show changes from baseline. 
18. In Section 8.2.3, it was clarified that the PD populations are safety subsets. 
19. AUC0-112d and AUC0-last were added to the list of PK parameters. 
20. Where it was appropriate the term “race” was changed to “ethnicity.” 
21. ADA population was removed from the analysis. 
22. Minor numerical corrections were made to Table 8. 
23. Minor typographical errors were corrected. 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1, Randomized, Placebo-Controlled, Single Ascending Dose 
First-in-Human Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of VIS649 Administered Intravenously in Healthy Subjects 
Study Numbers 
 
Sponsor Protocol No.: VIS649-101 
Development Phase 
Phase 1, safety and pharmacokinetics (PK) 
Sponsor 
Visterra Inc. 
Principal Investigator 
 
Study Center 
PAREXEL Early Phase Clinical Unit–Los Angeles 
Study Objectives 
Primary Objective: 
To evaluate the safety and tolerability of VIS649 in healthy subjects 
Secondary Objectives: 
 
To characterize the PK profile of VIS649 
 
To evaluate the effect of ethnicity on the pharmacokinetic profile of a 
single intravenously (IV) administered dose of VIS649 in healthy 
Japanese and non-Japanese subjects 
 
To characterize the levels of anti-drug antibodies 
 
To characterize the effect of VIS649 on pharmacodynamic (PD) 
parameters including: 
o 
changes in serum total IgA, IgG and IgM concentrations and 
time to recovery 
o 
changes in circulating lymphocyte populations (this 
assessment will be done for all lymphocytes, and also for 
lymphocyte subsets that are noted to show changes from 
baseline). 
o 
assess ADA status impact on VIS649 PK parameters 
 
 
 
 
 
 
 
 
 
 
 
Study Design 
This is a Phase 1, randomized, placebo-controlled, double-blind, single ascending 
dose study of IV VIS649 in healthy subjects. 
Potential subjects will be carefully screened for eligibility prior to study 
enrollment. Randomization and blinding will occur according to a core 
randomization list administered by the site’s unblinded pharmacist. 
The study will enroll up to 45 subjects and will be conducted in four sequential 
dosing cohorts at four different dose levels (0.5, 2.0, 6.0 and 12 mg/kg), enrolling 
9 subjects per cohort. Subjects will be randomized to VIS649 or placebo in a ratio 
of 7:2 (7 active, 2 placebo). Safety, PK and PD data from the initial cohorts will 
be assessed, to determine whether to initiate a fifth dosing cohort at a dose not to 
exceed 20 mg/kg. Back-up subjects who are not randomized into the cohort, but 

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otherwise meet eligibility, may be re-screened after discussion among the 
Principal Investigator, Medical Monitor, and the Sponsor. 
Eligible subjects will report to the Clinical Pharmacology Unit (CPU) at study 
check-in (Day -1) and will be required to stay in the CPU until Day 2 (24 hours 
post infusion). On Day 1, a single dose of VIS649 or placebo will be administered 
IV in the morning after a light meal (as per the clinical unit standard). 
Pharmacokinetics sampling will occur on Day 1 starting with a collection prior to 
the start of infusion, at the end of infusion (60 minutes), and at 2 hours, 8 hours 
and 24 hours post end of infusion. Pharmacokinetics samples will also be drawn 
on Days 3, 7, 14, 28, 42, 56, 70, and 112. Pharmacodynamics sampling (serum 
immunoglobulin levels) will occur at baseline, Day 3 and weekly thereafter 
through the Week 8 visit, then once every two weeks through Week 16 (i.e., 
Weeks 10, 12, 14, and 16). 
Sentinel subjects will be utilized; the first two subjects in each cohort will be 
randomized to receive either VIS649 (n=1) or placebo (n=1) and will receive 
study drug at least 24 hours before the remaining subjects in the cohort 
(7 subjects) are dosed. These 2 subjects shall remain confined to the study center 
for 24 hours after study drug administration. 
The safety profile of these subjects over the 24 hour post-administration period 
will be reviewed to determine whether it is appropriate to proceed with enrollment 
of the remaining subjects in the cohort as planned. This will occur for each dose 
escalation. The remaining 7 subjects in each cohort will be randomized to receive 
VIS649 (n=6) or matched placebo (n=1). 
The maximum duration of participation (Screening through End-of-study) for 
individual subjects will be approximately 20 weeks (5 months) with the 
possibility to extend up to 28 weeks (7 months). Each subject will participate in a 
Screening period lasting 1 to 28 days (0 to 4 weeks), an in-house stay for 2 to 3 
days, and a post-administration period of 16 weeks. The scheduled final visit will 
occur 16 weeks post-dosing (112 days); however, two additional follow-up visits 
may be performed, at Weeks 20 and 24 post-dosing, if serum immunoglobulins 
have not returned to>lower limits of normal by the Week 16 visit or if emerging 
trial data suggest a value of later follow-up (i.e., for detection of anti-drug 
antibody responses). 
Investigational 
Medicinal 
Product (IMP) 
A single dose of VIS649 administered IV over approximately one hour, at four 
different dose levels: 0.5, 2.0, 6.0 and 12 mg/kg, with an optional fifth cohort, to 
receive up to but not exceeding 20 mg/kg. 
Number of Subjects 
Up to 45 subjects may be enrolled. A total of 20 Japanese subjects (4 subjects per 
cohort) and 25 non-Japanese subjects (5 subjects per cohort) may be enrolled and 
randomized to receive a single dose of VIS649 or placebo. No more than one 
Japanese subject per cohort, may be randomized to receive placebo. Safety, PK 
and PD data from the initial four dosing cohorts will be assessed, to determine 
whether to initiate a fifth dosing cohort at a dose not to exceed 20 mg/kg. 
Study Population 
Healthy, non-smoking male and female subjects, 18 to 55 years of age with a body 
mass index between 18 and 32 kg/m2, are planned for enrollment. 
Criteria for Evaluation 
Safety Endpoints 
The proportion of subjects with adverse events (AEs) and serious adverse events 
(SAEs) following administration of VIS649; safety will be assessed from the time 
of study drug administration to the end-of-study participation. 
The following safety variables will be assessed from the time of study drug 
administration to the end-of-study participation: 
 
Adverse event assessments 
 
Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 

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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
SIGNATURE PAGE ...................................................................................................................... 3 
LIST OF STUDY STAFF ............................................................................................................... 4 
PROTOCOL SYNOPSIS................................................................................................................ 5 
TABLE OF CONTENTS ................................................................................................................ 8 
SIGNATURE PAGE ...................................................................................................................... 2 
SIGNATURE PAGE ...................................................................................................................... 3 
LIST OF STUDY STAFF ............................................................................................................... 4 
PROTOCOL AMENDMENTS ...................................................................................................... 5 
PROTOCOL SYNOPSIS................................................................................................................ 7 
TABLE OF CONTENTS .............................................................................................................. 11 
List of Tables ............................................................................................................................. 15 
List of Figures ........................................................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 16 
1. 
INTRODUCTION ................................................................................................................. 19 
1.1. 
Background .................................................................................................................... 19 
1.2. 
Rationale for the Clinical Study ..................................................................................... 21 
1.3. 
Risk-benefit Assessment ................................................................................................ 21 
2. 
STUDY OBJECTIVES ......................................................................................................... 25 
2.1. 
Primary Objective .......................................................................................................... 25 
2.2. 
Secondary Objectives ..................................................................................................... 25 
2.3. 
Exploratory Objectives ................................................................................................... 25 
3. 
OVERALL DESIGN AND PLAN OF THE STUDY........................................................... 26 
3.1. 
Overview ........................................................................................................................ 26 
3.2. 
Endpoints ........................................................................................................................ 30 
3.2.1. 
Primary Endpoint .................................................................................................... 30 
3.2.2. 
Secondary Endpoints .............................................................................................. 30 

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3.2.2.1. 
Pharmacokinetics Endpoints............................................................................ 30 
3.2.2.2. 
Pharmacodynamics Endpoints ......................................................................... 31 
3.2.2.3. 
Exploratory Endpoints ..................................................................................... 31 
3.3. 
Justification of the Study Design ................................................................................... 31 
3.4. 
Stopping Criteria for the Clinical Study and Dose Escalation Criteria .......................... 32 
4. 
STUDY POPULATION ........................................................................................................ 34 
4.1. 
Number of Subjects ........................................................................................................ 34 
4.2. 
Inclusion Criteria ............................................................................................................ 34 
4.3. 
Exclusion Criteria ........................................................................................................... 36 
4.4. 
Subject Withdrawal and Replacement ........................................................................... 38 
4.5. 
Termination of the Clinical Study .................................................................................. 39 
5. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................ 40 
5.1. 
Identity of the Investigational Medicinal Products ........................................................ 40 
5.2. 
Rationale for Starting Dose and Dose Escalation .......................................................... 40 
5.3. 
Supply, Packaging, Labeling and Storage ...................................................................... 42 
5.4. 
Drug Accountability, Dispensing and Destruction ........................................................ 43 
5.5. 
Subject Identification and Randomization ..................................................................... 43 
5.5.1. 
Screening Numbers ................................................................................................. 43 
5.5.2. 
Randomization Numbers ........................................................................................ 43 
5.6. 
Administration of Investigational Medicinal Products .................................................. 44 
5.7. 
Compliance ..................................................................................................................... 44 
5.8. 
Blinding and Breaking the Blind .................................................................................... 45 
5.9. 
Prior and Concomitant Medications ............................................................................... 45 
5.10. 
Treatment of Overdose ............................................................................................... 45 
6. 
MEASUREMENTS AND METHODS OF ASSESSMENT ................................................ 46 
6.1. 
Medical History, Demographic and Other Baseline Information .................................. 46 
6.2. 
Safety Variables ............................................................................................................. 46 
6.2.1. 
Adverse Events ....................................................................................................... 46 

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6.2.1.1. 
Definitions ....................................................................................................... 47 
6.2.1.2. 
Recording of Adverse Events .......................................................................... 48 
6.2.1.3. 
Assessment of Adverse Events ........................................................................ 49 
6.2.1.4. 
Reporting of Serious Adverse Events .............................................................. 50 
6.2.1.5. 
Follow-up of Adverse Events .......................................................................... 52 
6.2.1.6. 
Pregnancy ........................................................................................................ 52 
6.2.2. 
Clinical Laboratory Assessments ............................................................................ 52 
6.2.2.1. 
Anti-drug Antibody Response ......................................................................... 54 
6.2.3. 
Vital Signs ............................................................................................................... 54 
6.2.4. 
Standard 12-lead Electrocardiograms ..................................................................... 55 
6.2.5. 
Physical Examinations ............................................................................................ 55 
6.3. 
Pharmacokinetics Variables ........................................................................................... 55 
6.3.1. 
Blood Sample Collection ........................................................................................ 55 
6.4. 
Pharmacodynamics Variables ........................................................................................ 56 
6.5. 
Total Amount of Blood .................................................................................................. 56 
7. 
STUDY CONDUCT.............................................................................................................. 58 
7.1. 
Schedule of Assessments ............................................................................................... 58 
7.2. 
Order of Assessments ..................................................................................................... 64 
7.3. 
Early Termination .......................................................................................................... 64 
7.4. 
End-of-Study .................................................................................................................. 64 
7.5. 
Restrictions ..................................................................................................................... 64 
7.5.1. 
Dietary and Fluid Restrictions ................................................................................ 64 
7.5.2. 
Other Restrictions ................................................................................................... 65 
8. 
STATISTICAL METHODS.................................................................................................. 66 
8.1. 
Determination of Sample Size ........................................................................................ 66 
8.2. 
Study Population ............................................................................................................ 66 
8.2.1. 
Disposition of Subjects ........................................................................................... 66 
8.2.2. 
Protocol Deviations ................................................................................................. 66 

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8.2.3. 
Analysis Populations ............................................................................................... 66 
8.3. 
General Considerations .................................................................................................. 67 
8.4. 
Demographic and Anthropometric Information and Baseline Characteristics .............. 67 
8.5. 
Prior and Concomitant Medication ................................................................................ 67 
8.6. 
Drug Administration ...................................................................................................... 67 
8.7. 
Safety Analyses .............................................................................................................. 68 
8.7.1. 
Adverse Events ....................................................................................................... 68 
8.7.2. 
Clinical Laboratory Tests ........................................................................................ 68 
8.7.3. 
Vital Signs ............................................................................................................... 68 
8.7.4. 
Standard 12-lead Electrocardiogram ....................................................................... 68 
8.7.5. 
Physical Examination.............................................................................................. 69 
8.8. 
Pharmacokinetics Analyses ............................................................................................ 69 
8.9. 
Pharmacodynamics Analyses ......................................................................................... 69 
8.10. 
Pharmacokinetics/Pharmacodynamics Analyses ........................................................ 69 
8.11. 
Immunogenicity Data (Antibody to VIS649) ............................................................. 70 
8.12. 
Interim Data Reviews ................................................................................................. 70 
9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ................................................ 71 
9.1. 
Data Quality Assurance .................................................................................................. 71 
9.2. 
Institutional Review Board............................................................................................. 71 
9.3. 
Access to Source Data/Documents ................................................................................ 71 
9.4. 
Archiving Study Documents .......................................................................................... 72 
9.5. 
Good Clinical Practice ................................................................................................... 72 
9.6. 
Informed Consent ........................................................................................................... 73 
9.7. 
Protocol Approval and Amendment(s) .......................................................................... 73 
9.8. 
Confidentiality Data Protection ...................................................................................... 74 
9.9. 
Publication Policy .......................................................................................................... 74 
10. 
REFERENCE LIST ........................................................................................................... 75 
 

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List of Tables 
Table 1 
Serum Immunoglobulin Normal Ranges, Inclusion Criteria, Predicted Maximal Nadirs, 
and Stopping Rule Thresholds ...................................................................................................... 24 
Table 2 
Cohorts and Dose Administration .............................................................................. 28 
Table 3 
Identity of Investigational Products ............................................................................ 40 
Table 4 
Safety margins for targeted clinical doses .................................................................. 42 
Table 5 
Randomization Numbers and Treatment Assignment ................................................ 44 
Table 6 
Assessment of Relationship of Adverse Events to Investigational Product ............... 50 
Table 7 
Clinical Laboratory Assessments ............................................................................... 53 
Table 8 
Approximate Total Amount of Blood for Each Subject ............................................. 57 
Table 9 
Schedule of Assessments ............................................................................................ 59 
List of Figures 
Figure 1 
Study Flow Chart – Single Ascending Dose Design .................................................. 29 
Figure 2 
Rationale for VIS649 Starting Dose ........................................................................... 41 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
a-g IgA 
Aberrantly glycosylated IgA (synonymous with GD IgA) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
APRIL 
A Proliferation Inducing Ligand 
AST 
Aspartate aminotransferase 
AUC0-inf 
Area under the concentration-time curve from pre-dose (time 
0) extrapolated to infinite time (AUClast + Clast/λz) 
AUC 0-112d 
Area under the concentration-time curve from pre-dose 
(time 0) to the concentration on Day 112 
AUC 0-last 
Area under the concentration-time curve from pre-dose 
(time 0) to the last quantifiable concentration 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CL 
Apparent clearance 
Cmax 
Maximum serum concentration 
CPU 
Clinical Pharmacology Unit 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
CVID 
Common variable immunodeficiency 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
FDA 
United States Food and Drug Administration 
Fe 
Percentage of drug excreted unchanged in the urine 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GD IgA 
Galactose deficient IgA (synonymous with a-g IgA) 

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GLP 
Good Laboratory Practice 
GMR 
Geometric Mean Ratio 
hCG 
Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HBsAg 
Hepatitis B surface antigen 
IB 
Investigator’s Brochure 
ICD 
Informed consent document 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgAN 
IgA nephropathy 
IgG2 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
KLH 
Keyhole limpet hemocyanin 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Minimum Intolerable Dose 
MTD 
Maximum tolerated dose 
NOAEL 
No-observed-adverse-effect level 
OTC 
Over-the-counter 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QTcF 
QT interval corrected for heart rate using Fridericia’s 
correction 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SID 
Subject identification 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 

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SOP 
Standard operating procedure 
TACI 
Transmembrane activator and CAML interactor 
t½ 
Terminal elimination half-life 
Tmax 
Time of maximum serum concentration 
US 
United States 
ULN 
Upper level of normal 
Vd 
Apparent volume of distribution 
WBC 
White Blood Cells 
WHO 
World Health Organization 

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1. 
INTRODUCTION 
1.1. 
Background 
VIS649 is a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks 
the biological actions of the B-cell growth factor, APRIL (A Proliferation Inducing Ligand), 
preventing binding to its receptors, transmembrane activator and CAML interactor (TACI) and 
B-cell maturation antigen (BCMA). Through these receptor interactions, APRIL regulates B-cell 
mediated immune responses through several mechanisms, including the induction of class switch 
recombination as well as promotion of plasma cell survival. 
 
 
 
 
 
 
 
 
 
 
 
VIS649 binds human APRIL with picomolar affinity/avidity as measured by antigen-binding 
enzyme-linked immunosorbent assay using recombinant trimeric APRIL. VIS649 blocks 
recombinant APRIL-APRIL receptor interactions, thereby inhibiting APRIL-mediated signaling 
and B-cell proliferation. VIS649 also binds cynomolgus monkey APRIL, with similar affinity and 
inhibition of APRIL mediated signaling in both species. The physiological and toxicological 
effects of VIS649 were therefore evaluated in cynomolgus monkeys, in three preclinical studies. 
In an initial non- Good Laboratory Practice (non-GLP) in-vivo toxicology study, weekly 
administration of IV VIS649 at a dose of 25 mg/kg for 8 weeks resulted in an approximately 70% 
reduction in serum IgA levels (in comparison with control animals) with minimal effect on serum 
IgM, and an approximately 40% reduction in serum IgG levels. Hematology assessment did not 
reveal significant perturbation in white blood cell (WBC), lymphocyte, or leukocyte counts and 
there were no significant differences between treatment groups noted in the peripheral blood and 
tissue immune profiling, which included markers for total T cells, helper T cells, cytotoxic T cells, 
natural killer cells, and B cells. In a subsequent, non-GLP dose range-finding study, VIS649 was 

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administered weekly over 4 weeks to groups of cynomolgus monkeys at doses of 0 (control), 0.5, 
2.5, and 10 mg/kg, with an 8-week recovery observation period. Following treatment with 0.5 and 
2.5 mg/kg doses, there was a 
 reduction from baseline in serum IgA 
levels. Monkeys treated with 10 mg/kg doses had a
reduction in serum IgA 
levels, similar to the effect observed in the prior study with 25 mg/kg dosing for 8 weeks, and thus 
providing evidence that APRIL inhibition does not completely suppress IgA production. Serum 
IgA level suppression was reversible, with a dose response in time to recovery during the 8-week 
follow-up period. The observation of a maximal suppressive effect of VIS649 on serum IgA levels 
 in monkeys was further supported in the third toxicology 
study, described below. There was a lesser effect of VIS649 on serum IgG levels
, 
and IgM levels were not altered notably, in comparison with control animals. Peripheral blood 
lymphocyte counts were not significantly affected, including the following cell populations: 
T-lymphocytes (including T-helper and cytotoxic T-cell subsets), natural killer cells, monocytes, 
and B-lymphocytes (including naïve, resting memory and activated memory B-lymphocyte 
subsets). 
These studies led to the conduct of a United States Food and Drug Administration (US FDA) 
GLP-compliant 4-week repeat-dose IV toxicology study of VIS649 in cynomolgus monkeys, with 
a 20-week recovery period. Monkeys received weekly VIS649 injections for 4 weeks, at doses of 
0 mg/kg (control), 25 mg/kg, 50 mg/kg, or 100 mg/kg. 
VIS649-related reductions in total serum IgA levels were observed in all VIS649-treated animals 
 and the reductions were reversible as trends towards return to baseline were 
observed at all doses. All 3 dose levels demonstrated maximal pharmacologic effect that were 
consistent with previous studies in reduction in serum IgA and IgG levels with a minimal effect 
on IgM levels in VIS649 treated animals in comparison to the controls. 
Serum IgG levels were moderately reduced, 
 
 for a majority of animals at all timepoints. Serum IgM concentrations did not 
differ significantly between groups, including control animals. 
There was no effect of VIS649 on measured plasma cytokine concentrations in the monkey 
toxicology studies (nor did VIS649 stimulate significant cytokine release in an in vitro human 
peripheral blood lymphocyte cytokine release assay). 
To test the effect of VIS649 on de-novo humoral immune responses to a novel (T-cell dependent) 
antigen challenge, monkeys were vaccinated with keyhole limpet hemocyanin (KLH) at Day 7 
during dosing, with measurement of KLH-specific IgG and IgM levels through 21 days post 

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immunization. The kinetics of IgM and IgG responses were similar between VIS649 treated and 
control animals, with moderate suppression of KLH-specific IgG levels which was consistent with 
the non-specific suppression seen in total IgG levels. 
Based on results from this pivotal toxicology study, the no-observed-adverse-effect level 
(NOAEL) was considered to be 100 mg/kg/dose 
 
 
 The 100 mg/kg dose is 5-fold greater than the highest dose 
(20 mg/kg) permitted in this first-in-human study and 200-fold greater than the lowest dose 
(0.5 mg/kg) to be administered in this FIH study. 
 
 
 
 
 
The relatively selective and reversible effect of VIS649 on serum immunoglobulin levels 
, with maximal (but not completely suppressive) effect on IgA 
suggests that APRIL inhibition may be uniquely suited as a therapeutic strategy for IgA 
nephropathy. 
Further details can be found in the IB [2]. 
1.2. 
Rationale for the Clinical Study 
This first-in-human (FIH) study will assess the safety and tolerability, pharmacokinetics 
(PK)/pharmacodynamics (PD) of VIS649, a humanized IgG2 mAb that binds to and blocks the 
biological actions of the B-cell growth factor, APRIL. 
The study is being conducted to establish a dose range that is well tolerated by the majority of 
study subjects and to provide exploratory data on the potential for the treatment of IgAN, an 
autoimmune glomerulonephritis characterized by the deposition of IgA-containing immune 
complexes in the kidney. The results of the clinical study will inform the design and dose selection 
of subsequent studies. 
1.3. 
Risk-benefit Assessment 
While VIS649 has not been evaluated in humans, the known effects of mAbs in humans suggest 
the following potential toxicities for single dose administration: 

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1. Infusion reactions: Anaphylaxis, fever, chills, rigors, nausea, vomiting, pain, headache, 
dizziness, shortness of breath, bronchospasm, hypotension, hypertension, pruritus, rash, 
urticaria, angioedema, diarrhea, tachycardia, and chest pain 
2. Delayed allergic reactions: Serum sickness (i.e., urticaria, fever, general glandular 
enlargement, joint pains) 
3. General: Injection site reaction 
Mechanism based potential toxicities that might be anticipated based on VIS649 mechanism of 
action and preclinical studies include: 
IgA suppression risks: VIS649 treatment is expected to reduce human IgA levels, with a predicted 
maximal reduction (with repeated dosing) to approximately 75% below baseline. In this 
single-ascending dose study, this degree of suppression is unlikely to be achieved, but it is 
anticipated that at least in the higher dose cohorts, IgA levels will be reduced below baseline, with 
effect persisting over weeks. 
The normal range for serum IgA is approximately 70 to 400 mg/dL in adults 
 
 
 
Selective IgA deficiency (defined as persistently undetectable IgA, 
) is 
the most common inherited immunodeficiency syndrome (occurring in about 1 in 500 Caucasian 
individuals). []. While this condition has heretofore been considered generally benign and is 
asymptomatic in the majority of patients, there is increasing recognition that selective IgA 
deficiency may be associated with recurrent sinopulmonary infection, allergy, autoimmunity and 
gastrointestinal microbiome perturbation [4, 5]. The risk for occurrence of these complications in 
the current study is low for multiple reasons: 1) IgA is expected to be suppressed, but not reduced 
to undetectable levels, 2) in this single dose-study, the effects on IgA levels are expected to be 
transient, and 3) the syndrome of selective IgA deficiency is often associated with additional 
immunologic impairments including T-cell disorders and common variable immunodeficiency 
syndrome. 
IgG suppression risks: VIS649 is expected to have a moderate effect on serum IgG levels (with 
approximately 40% suppression-below-baseline nadir values predicted). 
The normal range for serum IgG is approximately 600 to 1600 mg/dL in adults,
 
 
 

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In 
common 
variable 
immunodeficiency 
(CVID), 
also 
known 
as 
acquired 
hypogammaglobulinemia, total IgG levels are typically below 250 mg/dL with median values at 
diagnosis in two recent US cohort studies of 210 mg/dL and 120 mg/dL, respectively [6]. The 
condition is of heterogenous origin, with loss of function mutations in an APRIL receptor, TACI, 
identified as one causal association [7]. Proposed diagnostic criteria for CVID include: presence 
of hypogammaglobulinemia 
plus a history of recurrent or 
chronic infection or autoimmunity and with associated IgA deficiency 
or IgM 
deficiency 
 [8Error! Reference source not found.]. Common variable 
immunodeficiency is associated with recurrent otitis media, chronic sinusitis, and recurrent 
pneumonia often resulting in bronchiectasis [9]. Longitudinal studies have demonstrated high rates 
of lymphoma and diseases of autoimmunity [10]. The risk of these complications in the current 
study is considered quite low, given the moderate and transient reductions in IgG levels that are 
anticipated. 
Non-specific immunosuppression risks: In preclinical toxicology studies, de-novo humoral 
immune responses to a novel antigen were not suppressed, and peripheral blood myeloid cell line 
populations were unaffected. However, there is the possibility of non-specific immunodeficiency 
with potential risk of exacerbation of pre-existing latent infection or poor response to new 
infection. These risks are considered minimal due to the single-dose design of this trial, and the 
expected transient nature of effects. 
Pharmacodynamic data including measurement of changes in serum IgG, IgA, and IgM levels in 
relation to VIS649 exposure will provide valuable information for refinement of the human PK/PD 
model and selection of appropriate doses for a repeat-dose study. Predicted maximal effects on 
serum IgG, IgA and IgM levels versus normal range, inclusion criteria thresholds, and stopping 
rule IG thresholds are summarized in Table 1. 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
 To evaluate the safety and tolerability of VIS649 in healthy subjects. 
2.2. 
Secondary Objectives 
 To characterize the PK profile of VIS649 
 To evaluate the effect of ethnicity on the pharmacokinetic profile of a single intravenously (IV) 
dose of VIS649 in healthy Japanese and non-Japanese subjects 
 To characterize the levels of anti-drug antibodies 
 To characterize the effect of VIS649 on PD parameters including: 
o changes in serum total IgA, IgG and IgM concentrations and time to recovery 
o changes in circulating lymphocyte populations (this assessment will be done for 
all lymphocytes, and also for lymphocyte subsets that are noted to show changes 
from baseline) 
 
 
 
 
 
 
 
 
 
 

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3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1. 
Overview 
This is a Phase 1, randomized, placebo-controlled, double-blind, single ascending dose study to 
investigate the safety, tolerability, PK/PD of the IV administration of VIS649 in healthy subjects. 
The study will be conducted in four sequential dosing cohorts enrolling nine subjects per cohort, 
with an optional fifth cohort. Each cohort will have 4 Japanese subjects. Subjects will be 
randomized to VIS649 or placebo in a ratio of 7:2 (7 active, 2 placebo). No more than one Japanese 
subject per cohort may be randomized to receive placebo. Safety, PK and PD data from the initial 
cohorts will be assessed, to determine whether to initiate a fifth dosing cohort at a dose not to 
exceed 20 mg/kg. 
The study comprises of: 
 A Screening Visit up to 28 days before dosing 
 An in-house stay for approximately 2-3 days, with admission to the study center on Day -1, 
dosing on Day 1, and discharge in the morning of Day 2 
 A post-administration period of 16 weeks 
 Outpatient visits, on Day 3 (+1 day), 7 (± 1 day), 14, 21, 28, 35, 42, 49, 56, 70, 84 and 98 
(all visits± 3 days) 
 A final Follow-up visit on Day 112 (± 3 days); Two additional follow-up visits may occur, 
at Weeks 20 and 24 post-dosing, if serum immunoglobulins have not returned to >lower 
limits of normal by the Week 16 (Day 112) visit, or if emerging trial data suggest a value 
of later follow-up (i.e., for detection of ADA responses). 
The total duration of the clinical study per subject will be up to approximately 20 weeks 
(5 months), including the Screening period with the possibility of duration extending to 28 weeks 
(7 months) if follow-ups visits are required. 
Potential subjects will be carefully screened for eligibility prior to study enrollment. 
Randomization and blinding will occur according to a core randomization list administered by the 
site’s unblinded pharmacist. Back-up subjects who are not randomized into the cohort, but 
otherwise meet eligibility, may be re-screened after discussion among the Principal Investigator, 
Medical Monitor, and the Sponsor. 

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Eligible subjects will report to the Clinical Pharmacology Unit (CPU) at study check-in (Day -1) 
and will be required to stay in the CPU until Day 2 (24 hours post infusion). On Day 1, a single 
dose of VIS649 or placebo will be administered intravenously in the morning after a light meal (as 
per the clinical unit standard). Pharmacokinetics sampling will occur on Day 1 starting with a 
collection prior to the start of infusion, end of infusion, and at 2 hours, 8 hours and 24 hours post 
end of infusion. Pharmacokinetics samples will also be drawn on Days 3, 7, 14, 28, 42, 56, 70, and 
112. Pharmacodynamics sampling (serum immunoglobulin levels, lymphocytes and sub Ig types) 
will occur as outlined in the Schedule of Assessments (Table 9). 
 
 
 
 
 
 
 
 
The initial cohort will be dosed with 0.5 mg/kg of VIS649. Escalation to next dosing level 
(2.0 mg/kg) will occur after review of blinded safety data through Day 14 by the Safety Monitoring 
Committee (SMC) comprised of the Principal Investigator, an independent Medical Monitor, and 
the Sponsor. For subsequent cohorts (6.0 mg/kg and 12 mg/kg, and the optional fifth dosing 
cohort), escalation will occur after review of safety data through Day 28 by the SMC. Assessment 
of safety will be determined by evaluation of: 
 Vital sign measurements 
 Physical examinations 
 Hematology, chemistry, and urinalysis laboratory testing 
 12-lead electrocardiograms (ECG) 
 Adverse events, and 
 Serum immunoglobulin levels 
Pharmacokinetic data will not be available for dose escalation decision making. Pharmacokinetic 
data will be reviewed in a blinded fashion after each cohort is available, and may result in a dose 
adjustment for subsequent cohorts (including optional cohort 5, and none to exceed 20 mg/kg). 

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Any adjustments will be reviewed and approved by the Principal Investigator, Medical Monitor, 
and the Sponsor. 
If dose escalation is stopped based on available blinded safety data, the current dose level will be 
considered as the minimum intolerable dose (MID). The dose just below the MID will be regarded 
as the maximum tolerated dose (MTD). If the dose escalation is stopped due to reaching exposure 
limit without dose limiting safety findings, the MTD will not be determined. Dose de-escalation 
may occur in additional cohorts, to further refine clinically relevant dose levels. 
Stopping rules are described in Section 3.4. 
Procedures related to the clinical study are detailed in the Schedule of Assessments (Table 9). 
Doses will be administered intravenously to subjects in approximately 4 dose cohorts (see Table 
2). An additional cohort may be enrolled and proceed at a dose not to exceed 20 mg/kg (given the 
safety coverage described in Section 5.2), if deemed appropriate by the SMC. Cohorts are planned 
as follows: 
Table 2 
Cohorts and Dose Administration 
Cohorts 
Number of Subjects 
Treatment 
Cohort 1 
N=7 
VIS649 0.5 mg/kg1 
N=2 
Placebo 
Cohort 2 
N=7 
VIS649 2.0 mg/kg2 
N=2 
Placebo 
Cohort 3 
N=7 
VIS649 6.0 mg/kg2 
N=2 
Placebo 
Cohort 4 
N=7 
VIS649 12 mg/kg2 
N=2 
Placebo 
Optional Cohort 5 
N=7 
VIS649 TBD, not >20 mg/kg 
N=2 
Placebo 
TBD: To be decided 
1 After all subjects have completed assessments through Day 14, blinded safety data will be reviewed and a dose 
escalation decision for the subsequent cohort will be made by the SMC. If dose escalation is stopped, dose 
de-escalation may occur in additional cohorts, to further refine clinically relevant dose levels. 
2 After all subjects have completed assessments through Day 28, blinded safety data will be reviewed and a dose 
escalation decision for the subsequent cohort will be made by the SMC. If dose escalation is stopped, dose 
de-escalation may occur in additional cohorts, to further refine clinically relevant dose levels. 
Please refer to Table 9 for a detailed list of procedures performed on each study day and visit. 
 

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Figure 1 
Study Flow Chart – Single Ascending Dose Design 
 
VISIT 1 
 
VISIT 2 
 
Follow-Up Visits 
Enrollment 
 
Residential period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
Admission 
 
Randomization  
and dosing 
 
 
 
Discharge 
(24 hours post-dose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
 
 
 
 
 
 
 
 
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max. 
28 days 
before  
dosing 
 
 
 
Day -1 
 
 
 
Day 1 
 
 
 
 
 
Day 2 
 
 
 
Days 3, 7, 
14, 21, 28, 
35, 42, 49, 
56, 70, 84, 
98, and 112 
 
 

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3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
 Safety Endpoint 
 The proportion of subjects with AEs and serious adverse events (SAEs) following 
administration of VIS649; safety will be assessed from the time of study drug 
administration to the end-of-study participation. 
 The following safety variables will be collected and recorded at regular intervals during the 
study: 
 Adverse event assessments 
 Clinical laboratory tests (hematology, clinical chemistry and urinalysis) 
 Vital signs (sitting BP, pulse, body temperature and respiratory rate [RR]) 
 12-lead ECG 
 Adjunctive procedures 
 Physical examination 
3.2.2. 
Secondary Endpoints 
 Characterization of anti-drug antibodies (ADA) levels 
3.2.2.1. 
Pharmacokinetics Endpoints 
The following PK parameters for VIS649 will be determined, as appropriate: 
 Cmax: Maximum serum VIS649 concentration determined directly from the concentration-time 
profile 
 Tmax: Time of maximum serum VIS649 concentration determined directly from the 
concentration-time profile 
 AUC0-inf: Area under the concentration-time curve from pre-dose (time 0) extrapolated to 
infinite time 
 
 
 
 0) to the 
concentration on Day 112 
 AUC 0-last: Area under the concentration-time curve from pre-dose (time 0) to the last 
quantifiable concentration 

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 t1/2: Apparent terminal elimination half-life 
 Vd: Apparent volume of distribution 
 
 CL: Apparent clearance 
 
3.2.2.2. 
Pharmacodynamics Endpoints 
 Changes in total serum IgG, IgA and IgM concentrations and time to recovery 
 Changes in circulating lymphocyte populations (this assessment will be done for all 
lymphocytes, and also for lymphocyte subsets that are noted to show changes from baseline). 
 
 
 
 
 
 
 
 
 
 
 
 
3.3. 
Justification of the Study Design 
This study evaluates the safety, tolerability, and PK/PD of ascending single doses of VIS649 
administered as an IV infusion. The design is standard and is considered appropriate to meet the 
objectives of the study. 
A double-blind, placebo-controlled study is appropriate and standard for a single ascending dose 
study. This design will minimize bias and provide reference data (i.e., data from placebo-treated 
subjects) which will aid in the interpretation of results. The SMC will review available blinded 
safety, tolerability, and Ig level data after each cohort to confirm whether it is safe to proceed with 
the next planned dose, whether the dose escalation should be stopped or if the dose should be 
lowered, repeated, or titrated in the subsequent cohort. 
The safety assessments for the study are accepted measures for ensuring safety of subjects during 
a clinical trial. The PK sampling schedule is considered appropriate given the information 
available. The rationale for dose selection is discussed in Section 5.2. 

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3.4. 
Stopping Criteria for the Clinical Study and Dose Escalation Criteria 
If any of the dose limiting toxicities listed below are met, the relevant subject(s) data may be 
unblinded. If the toxicity is present in ≥ 1 subject randomized to active drug, then dose escalation 
will pause. Depending upon the nature of the event, a decision may be made to resume dosing, to 
proceed into the next cohort at a lower dose level, or to stop the study. 
Based on safety criteria, the dose adjustment/stopping criteria are as follows: 
 Adverse event stopping criteria: 
 Any AE of severe intensity and related causality 
 Any SAE of related causality 
 Vital sign stopping criteria: 
 Symptomatic hypotension (systolic blood pressure [SBP] <85 mmHg). If symptomatic 
hypotension that is related to the study drug is observed during the study, then a 
minimum of two repeat BP measurements should be obtained over a brief period. The 
mean of the three SBP measurements will be used to determine stopping criteria 
 Tachycardia defined as heart rate >120 beats per minute (bpm) lasting longer than 
30 minutes or with impaired consciousness 
 Electrocardiogram stopping criteria: 
 QT interval 
 >500 msec 
(If a prolonged QTc interval is observed during the study, then a minimum of two repeat 
ECGs should be obtained over a brief period. The mean of the three ECGs will be used 
to determine stopping criteria.) 
 Clinical laboratory stopping criteria: 
 Alanine aminotransferase (ALT) ≥3 times the upper limit of normal (ULN) 
 Aspartate aminotransferase (AST) ≥3 times the ULN 
 Serum creatinine >1.5 times the ULN 
 A decrease from baseline in hemoglobin concentration >3 g/dL 
 White blood cell count <1,500/mm3 
 Platelets <50,000/mm3 

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4. 
STUDY POPULATION 
The study population will consist of healthy Japanese and non-Japanese male and female 
volunteers. Subjects must be able to provide written informed consent and meet all the inclusion 
criteria and none of the exclusion criteria. 
4.1. 
Number of Subjects 
Up to 45 subjects may be enrolled in this clinical study. Up to 20 Japanese subjects (4 subjects per 
cohort) and up to 25 non-Japanese subjects (5 subjects per cohort) will be enrolled (N=9 per dose 
cohort) and randomized to receive a single dose of VIS649 (N=7) or placebo (N=2) across up to 
five cohorts. No more than one Japanese subject per cohort may be randomized to receive placebo. 
The fifth dosing cohort is considered optional: safety, PK and PD data from the initial cohorts will 
be assessed, to determine whether to initiate dosing in this cohort at a dose not to exceed 20 mg/kg. 
4.2. 
Inclusion Criteria 
Subjects who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1.  Subject voluntarily agrees to participate in this study and signs an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC)-approved informed consent form prior to 
performing any of the Screening Visit procedures and be able to sign and date an appropriate 
Health Insurance Portability and Accountability Act (HIPAA) authorization form or subject 
privacy form, if appropriate. 
2.  Male and female subjects between 18 to 55 years of age, inclusive, at the Screening Visit. 
3.  For Japanese subjects: Subject is of Japanese descent as evidenced by verbal confirmation of 
familial heritage (a subject has all four Japanese grandparents born in Japan). 
4. For non-Japanese subjects: Subjects must be of non-Asian descent, as evidenced by verbal 
confirmation that all four grandparents are non-Asian. 
5. The following applies to female subjects: 
 Non-childbearing potential (surgically sterile [hysterectomy or bilateral tubal ligation]) for 
at least 6 months, or postmenopausal ≥ 1 year, or 
 Non-pregnant, non-lactating females of childbearing potential must report prior use (over 
the 28 days prior to dosing of study drug) of  medically acceptable forms of birth control 
(hormonal contraception, abstinence, diaphragm with spermicide, condom with spermicide 

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or intrauterine device, or partner with vasectomy), with agreement to continue to use a 
medically acceptable form of birth control (as described) through the end of their 
participation in the study.  Alternatively, a reported history of abstinence beginning at least 
28 days prior to study drug dosing, with agreement to continue abstinence through the end 
of their participation in the study are required. Females of childbearing potential must also 
have a negative serum human chorionic gonadotropin (hCG) pregnancy test at Screening 
and a negative urine hCG pregnancy test at baseline (Day -1). Female subjects must also 
agree not to donate eggs/bank eggs for the duration of their participation in the study. 
6.  For male, subject and/or his partner must use a highly effective form of contraception (i.e., 
double-barrier as described above, have had a vasectomy, or have a female partner of 
non-childbearing potential) or agree to abstinence following study drug dosing, through the 
end of the subject’s participation in the study. Male subjects must also agree to not donate 
sperm for the duration of their participation in the study, following study drug dosing. 
7. Screening laboratory values must meet the following criteria: 
 White blood cells  
3,000-12,000/mm3 
 Platelets 
 
>150,000/mm3 
 Hemoglobin  
>13 gm/dL for male and>11 gm/dL for female 
 Estimated glomerular filtration rate >80 mL/min/1.73 m2 (using the Modification of Diet 
in Renal Disease study equation) 
 Serum creatinine <1.25x ULN 
 Blood Urea Nitrogen (BUN) ≤25mg/dL 
 Aspartate aminotransferase (AST) 
≤50 U/L 
 Alanine aminotransferase (ALT) 
≤67 U/L 
 Alkaline phosphatase  
≤150 U/L 
 Total Bilirubin 
 
≤1.4 mg/dL 
unless patient has Gilbert Syndrome, in which case direct bilirubin must be within normal 
range 
 Glucose (fasting) 
 
 
<115 mg/dL 
 Drug and alcohol screen 
 
Negative 
 
 
 

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8.  Body mass index (BMI) between 18 and 32 kg/m2, inclusive, at the Screening Visit. 
9.  Healthy, determined by pre-study medical evaluation (medical history, physical examination, 
vital signs, 12-lead ECG, and clinical laboratory evaluations), as judged by the Principal 
Investigator. 
10.  Is willing and able to comply with study restrictions and to remain at the CPU for the in-patient 
duration of the study and return for all follow-up outpatient visits. 
11. QTcF < 450 msec at Screening (may be repeated once). 
4.3. 
Exclusion Criteria 
Subjects who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 
1. Is participating in another clinical study of any investigational drug, device, or intervention or 
has received any investigational medication during the last 30 days or 5 half-lives, whichever 
is longer, before baseline (Day -1). 
2. Subject is judged by the Principal Investigator or the Medical Monitor to be inappropriate for 
the study. 
3. Subject has a history or current evidence of a serious and/or unstable cardiovascular, 
respiratory, gastrointestinal, hematologic, autoimmune, blood dyscrasias or other medical 
disorder, including psychiatric disorders, cirrhosis or malignancy. History of minor skin 
cancers (not including melanoma) or surgically treated, limited cervical carcinomas (i.e., 
carcinoma in situ) are not exclusionary. 
4. Subject has a history or presence of proteinuria, chronic kidney disease, disease requiring 
immunosuppressive therapy (including systemic steroids), or is considered to be 
immunosuppressed for any other reason. 
5. Previous receipt of antibody or biologic therapy whether licensed or investigational 
(immunoglobulin products, monoclonal antibodies or antibody fragments) within 30 days prior 
to dosing or 5 half-lives within the dose of Investigational medicinal product (IMP), whichever 
is longer. 

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6. History of a previous severe allergic reaction with generalized urticaria; angioedema or 
anaphylaxis. 
7. Blood pressure >160/100 mmHg or <90/50 mmHg (may be repeated once if abnormal), at the 
Screening visit and Day -1. 
8. Known hypoglobulinemia disorder (i.e., common variable immunodeficiency), X-linked 
agammaglobulinemia, selective IgA deficiency, selective IgM deficiency). 
9. History of pre-existing latent infections (e.g., tuberculosis) or any infection requiring 
hospitalization or treatment with antivirals or antibiotics, or vaccination within 30 days prior 
to administration of study medication.  
10. Concomitant use of marketed or investigational systemic immunosuppressive or 
immunomodulatory medications (e.g., corticosteroids, methotrexate, azathioprine, etc. and/or 
biologics) is prohibited and require a washout period prior to Screening (30 days or 5 half-lives, 
whichever is longer). 
11. Has received any prescription or non-prescription (over-the-counter [OTC]) medication during 
the last 30 days or 5 half-lives, whichever is longer, preceding baseline (Day -1), with the 
exception of acetaminophen, ibuprofen, hormonal contraceptives, topical medications, 
vitamins, and dietary or herbal remedies. 
12. Subjects who consume more than 21 units of alcohol per week (7 days) or those who have a 
history of alcohol or drug/chemical abuse; one unit of alcohol is equivalent to eight ounces of 
beer, 4 ounces of wine, or one ounce of spirits. 
13. Subject is a user or former user of nicotine-containing products (including but not limited to 
cigarettes, cigars, and chewing or dipping tobacco) who stopped use or consumption (i.e., 
smoking, chewing, or pinching) of these nicotine-containing products less than 3 months 
before study drug administration or is using or has used topical or oral nicotine preparations 
for smoking cessation within the past 90 days before study drug administration. 
14. Subjects who consume greater than 500 mg of caffeine or xanthine-containing products per 
day (e.g., coffee, tea, soft drinks, energy drinks, or chocolate). 
15. Subjects who refuse to abstain from alcohol, xanthine-containing or caffeine-containing foods 
or beverages from 48 hours prior to check-in on Day-1 through the end of the study. 
16. Subjects with a positive urine drug (inclusive of marijuana),alcohol, or cotinine Screening test 
result 
at 
Screening 
and 
Day -1. 
The 
urine 
drug 
screen 
also 
screens 
for 
methylenedioxymethamphetamine, tricyclic antidepressants, oxycodone, and propoxyphene. 

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If a subject tests positive on these extra 4 tests, inclusion of that subject into the study will be 
based on the Principal Investigator’s judgment with consultation, as needed, with the Medical 
Monitor and the Sponsor. 
17. Subjects with a positive hepatitis B surface antigen test or evidence of chronic hepatitis C virus 
infection at Screening (a negative HCV antibody assay at Screening is sufficient to rule-out 
chronic HCV infection for this study). 
18. Subjects with a known history of a positive Human Immunodeficiency Virus (HIV) or a 
positive test result at Screening. 
19. Subjects who have donated >500 mL or blood within 60 days prior to start of Screening. 
20. The subject has donated any plasma within 7 days prior to baseline (Day -1). 
21. Is an employee of the clinical research team (any Sponsor or research site employee), or has a 
family member who is an employee of these organizations. 
4.4. 
Subject Withdrawal and Replacement 
While subjects 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 subject 
withdraws from the study prematurely. All subjects who withdraw from the study with an ongoing 
AE must be followed until the event is resolved or deemed stable. If a subject withdraws 
prematurely after dosing, all data to be collected prior to discharge from the clinical site should be 
collected at the time of premature discontinuation or at the scheduled discharge. Subject 
participation may be terminated prior to completing the study and the reason recorded as follows: 
1.  Adverse event 
2.  Protocol violation 
3.  Loss to follow-up 
4.  Subject withdrew consent at own request 
5.  Other 
A genuine effort must be made to determine the reason(s) why a subject fails to return for the 
necessary visits or is discontinued from the study. If the subject is unreachable by telephone, a 
registered letter, at the minimum, should be sent to the subject requesting him/her to contact the 
clinic. 

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Subjects can be replaced, and a replacement randomization number will be generated. The same 
treatment will be allocated to the replacement subject. 
4.5. 
Termination of the Clinical Study 
If the Principal Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or 
events that suggest a possible hazard to subjects if the clinical study continues, then the clinical 
study may be terminated after appropriate consultation among the involved parties. The clinical 
study may be terminated at the Sponsor’s discretion also in the absence of such a finding. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
 The discovery of an unexpected, relevant or unacceptable risk to the subjects enrolled in the 
clinical study; 
 Failure to enroll subjects at the required rate; 
 A decision of the Sponsor to suspend or discontinue development of the study drug. 
Should the study be terminated and/or the site closed for whatever reason, all documentation 
pertaining to the study and VIS649 must be returned to the Sponsor. Any actions of PAREXEL 
required for assessing or maintaining subject safety will continue as required, despite termination 
of the study by the Sponsor. 

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safety factor to account for potential interspecies differences and other unknowns arrives at a 
NOAEL justified starting dose of 5 mg/kg, which is expected to be well tolerated in humans based 
on cynomolgus monkey studies. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The minimum pharmacologically active dose of 0.5 mg/kg was selected as the starting dose for 
evaluation in healthy volunteers; this is 10-fold lower than the maximum recommended starting 
dose based on the NOAEL. Doses from 0.5 to 12 mg/kg will be evaluated in single dose escalation 
in four cohorts, while a final cohort to receive a dose greater than 12 mg/kg but no greater than 
20 mg/kg may be enrolled, based on emerging clinical, PK and/or PD data. Dose escalations will 
not exceed a 4-fold increase. The safety margins for targeted clinical doses are provided in Table 
4. 
Simulations using the previously described PK model [2] were performed under the conservative 
assumption of zero nonlinearity for the purpose of the safety margin calculation. 
 
 
 
 
 
 
5.3. 
Supply, Packaging, Labeling and Storage 
Investigational medicinal products will be packaged and labeled according to applicable local and 
regulatory requirements. 
VIS649 is formulated at a concentration of 25 mg/mL 
 
 will be supplied in vials containing a nominal 10 mL. 
All supplies of study drug VIS649 must be stored between≥2°C and ≤8°C and protected from light. 
The study drug VIS649 will be stored in a securely locked area, accessible to authorized persons 
only. 

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5.4. 
Drug Accountability, Dispensing and Destruction 
The Principal Investigator or designee is responsible for maintaining accurate accountability 
records of the study drug 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. When the Study 
Monitor visits PAREXEL, he/she will reconcile the drug accountability log with the products 
stored in the PAREXEL pharmacy. 
The PAREXEL pharmacist (or designee under the direction of the pharmacist) will dispense study 
drug in a blinded manner for each subject according to the protocol, randomization list and 
pharmacy manual, if applicable. 
After receiving Sponsor approval in writing, PAREXEL is responsible for returning all unused or 
partially used study drug to the Sponsor or designated third party or for preparing the study drug 
for destruction via carbonization. 
5.5. 
Subject Identification and Randomization 
5.5.1. 
Screening Numbers 
All screened subjects are assigned a unique 3-digit subject identification (SID) number (001 - 999). 
The SID numbers identify subjects from time of Screening until time of randomization. Enrolled 
subjects who drop out of the clinical study before randomization will retain their SID numbers. 
5.5.2. 
Randomization Numbers 
Prior to dosing on Day 1, eligible subjects will be assigned a randomization number in accordance 
with the randomization code generated by PAREXEL International. The randomization code will 
be maintained in a room with restricted access to pharmacy personnel only. The randomization 
code will include 4-digit subject numbers 
, Cohort and randomization numbers 
list in Table 5. 

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Table 5 
Randomization Numbers and Treatment Assignment 
Dose 
Group 
Randomization 
Numbers 
Replacement 
Numbers 
Treatment Assignment 
Cohort 1 
 
 
0.5 mg/kg VIS649 (N=7) 
Placebo (N=2) 
Cohort 2 
 
 
2.0 mg/kg VIS649 (N=7) 
Placebo (N=2) 
Cohort 3 
 
 
6.0 mg/kg VIS649 (N=7) 
Placebo (N=2) 
Cohort 4 
 
 
12 mg/kg VIS649 (N=7) 
Placebo (N=2) 
Optional 
Cohort 5 
 
 
Up to but not greater than 
20 mg/kg VIS649 (N=7) 
Placebo (N=2) 
Once a randomization number has been allocated to one subject, it may not be assigned to another 
subject. If subjects withdrawn prematurely from the study and are replaced under the direction of 
the Sponsor, then a replacement randomization number will be assigned. A replacement 
randomization code will be generated such that replacement subjects are assigned to the same 
treatment as the discontinued subjects. The replacement randomization code will differ only in 
randomization numbers, which will be 4-digit numbers 
 
 
 
No more than one Japanese subject per cohort may be randomized to receive placebo. 
5.6. 
Administration of Investigational Medicinal Products 
The amount of VIS649 will be calculated on a per subject weight basis and administered diluted 
in 100 mL of 0.9 % sodium chloride. Subject weight will be captured after admission to the 
research unit (Day -1) and will be used by the pharmacy staff for subject-specific dose calculation. 
VIS649 will be administered intravenously using a volumetric pump and through a 0.22µm in line 
IV filter at a rate of 100 mL/hr over the course of one hour. A saline flush is performed after the 
infusion is complete to ensure that any drug product remaining in the infusion line is administered. 
Placebo will be 100 mL of 0.9% sodium chloride administered IV in an identical manner. Refer to 
the pharmacy manual for specific details on storage, handling, and preparation information. 
5.7. 
Compliance 
Dosing will be performed by trained, qualified personnel designated by the Principal Investigator. 
The date, time and volume of the administered dose will be documented. Comments will be 
recorded if there are any deviations from the planned dosing procedures. 

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5.8. 
Blinding and Breaking the Blind 
The clinical study will be performed in a double-blind manner, for clinical research unit staff 
interacting with study participants, with the exception of the persons involved in the preparation 
of the IMPs. These persons will not be involved in any other study activities. 
Prior to scheduled unblinding as described below, the study blind should not be broken except in 
a medical emergency (where knowledge of the study drug administered would affect the treatment 
of the emergency). The decision to break the blind will be made on a case-by-case basis, at the 
discretion of the Principal Investigator in collaboration with the Sponsor/Medical Monitor. The 
applicable Standard operating procedure (SOP) will be followed for blind breaking procedures. 
As participants in each dosing cohort complete their Week 16 visit, data clean-up and soft-lock 
will be performed for each cohort, to allow interim assessments of blinded data. PK/PD analysts 
will have access to unblinded data at all times, but those individuals will not be involved in study 
participant interactions. Summaries of treatment specific PD responses (principally, individual 
immunoglobulin levels over time and group mean, median, minimum and maximum parameters 
by treatment assignments) will be prepared and shared with the Sponsor, in a manner that does not 
unblind individual patient treatment assignments. A registry of dummy subject identifiers will be 
created. A physician who is not involved in the study will review Ig results to maintain the blind 
for the Principal Investigator.  
5.9. 
Prior and Concomitant Medications 
Any medicinal product, prescribed or OTC, including herbal and other nontraditional remedies, is 
considered a concomitant medication. Prior and concomitant medication use will be recorded for 
the 30 days prior to the Screening Visit until the End-of-study Visit. Prior and concomitant 
medication use is not permitted during the last 30 days or 5 half-lives, whichever is longer, 
preceding baseline (Day -1) until end-of-study (including prescription or non-prescription 
[over-the-counter]) medication, except for acetaminophen, ibuprofen, hormonal contraceptives, 
topical medications, vitamins, dietary or herbal remedies). However, concomitant medication use 
may be warranted for the treatment of AEs. The use of concomitant medications to treat AEs 
should be discussed between the Principal Investigator and the Medical Monitor. 
5.10. Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. No antidotes are available. 

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6. 
MEASUREMENTS AND METHODS OF ASSESSMENT 
For timing of assessments, refer to the Schedule of Assessments Table 9. 
A Safety Management Plan will be signed between the Sponsor and PAREXEL. 
6.1. 
Medical History, Demographic and Other Baseline Information 
The medical history comprises: 
 General medical history 
 Medication history 
 Reproductive history 
The following demographic information will be recorded: 
 Age 
 Ethnicity: Japanese or non-Japanese 
 Race: White, Black, Hispanic/Latino, American Indian/Alaska native, Asian, Pacific Islander 
 Height, without shoes (cm) 
 Body weight, without shoes (kg) 
 BMI (kg/m2) 
Other baseline characteristics will be recorded as follows: 
 History of drug abuse 
 History of alcohol abuse 
 Smoking history 
 History of caffeine use (or other stimulating beverages) 
 History of blood or plasma donation 
6.2. 
Safety Variables 
6.2.1. 
Adverse Events 
Adverse event reporting will begin for each subject from baseline (Day -1) and will continue until 
the End-of-study Visit. 

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6.2.1.1. 
Definitions 
6.2.1.1.1. 
Definition of Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
Other untoward events occurring in the framework of a clinical study will be recorded as AEs, e.g. 
those occurring during treatment-free periods (including post-dosing periods), in association with 
study-related procedures and assessments, or under placebo. For study drugs, lack of efficacy may 
be an expected potential outcome and should not be reported as an AE unless the event is unusual 
in some way, e.g., greater in severity. 
Concomitant illnesses, which existed prior to entry into the clinical study, will not be considered 
AEs unless they worsen during the treatment period. Pre-existing conditions will be recorded as 
part of the subject’s medical history. 
6.2.1.1.2. 
Definition of Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening; this means that the subject 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 in-patient hospitalization or prolongation in existing hospitalization 
 Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
 Is a congenital anomaly/birth defect, or 
 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 subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or in a physician’s office, blood dyscrasias or seizures 

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that do not result in in-patient hospitalization, and the development of drug dependency or drug 
abuse. 
A distinction should be drawn between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above. For example, a mild degree of gastrointestinal 
bleeding requiring an overnight hospitalization for monitoring purposes would be considered an 
SAE, but is not necessarily severe. Similarly, an AE that is severe in intensity is not necessarily an 
SAE. For example, alopecia may be assessed as severe in intensity but would not be considered 
an SAE. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if 
expedited reporting is appropriate. 
6.2.1.1.3. 
Adverse Events of Special Interest 
An adverse event of special interest (serious or non-serious) is one of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the Principal Investigator to the Sponsor can be appropriate. Such an event 
might warrant further investigation in order to characterize and understand it. Depending on the 
nature of the event, rapid communication by the Sponsor to other parties might also be warranted. 
Examples of these are all AEs of 
 Infusion reactions: Fever, chills, rigors, nausea, vomiting, pain, headache, dizziness, shortness 
of breath, bronchospasm, hypotension, hypertension, pruritus, rash, urticaria, angioedema, 
diarrhea, tachycardia, and chest pain 
 Delayed allergic reactions: Serum sickness (i.e., urticaria, fever, general glandular enlargement, 
joint pains) 
 General: Injection site reaction 
 Any documented infection 
6.2.1.2. 
Recording of Adverse Events 
Adverse events should be collected and recorded for each subject from the baseline (Day -1) until 
the end of their participation in the study, i.e. the subject has discontinued or completed the study. 
Adverse events may be volunteered spontaneously by the subject, or discovered by the study staff 
during physical examinations or by asking an open, non-leading question such as ‘How have you 
been feeling since you were last asked?’ All AEs and any required remedial action will be 

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recorded. The nature of AE, date (and time, if known) of AE onset, date (and time, if known) of 
AE outcome to date, severity and action taken of the AE will be documented together with the 
Principal Investigator’s assessment of the seriousness of the AE and causal relationship to study 
drug and/or study procedure. 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the 
opinion of the Principal Investigator, the AEs constitute components of a recognized condition, 
disease or syndrome. In the latter case, the condition, disease or syndrome should be named rather 
than each individual symptom. The AEs will subsequently be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA version 21.0 or higher). 
6.2.1.3. 
Assessment of Adverse Events 
Each AE will be assessed by the Principal Investigator with regard to the categories discussed in 
the following sections. 
6.2.1.3.1. 
Intensity 
The Principal Investigator will assess all AEs for severity in accordance with the following 
standard ratings. 
 Mild: Ordinarily transient symptoms, does not influence performance of subject’s daily 
activities. Treatment is not ordinarily indicated. 
 Moderate: Marked symptoms, sufficient to make the subject uncomfortable. Moderate 
influence on performance of subject’s daily activities. Treatment may be necessary. 
 Severe: Symptoms cause considerable discomfort. Substantial influence on subject’s daily 
activities. May be unable to continue in the study and treatment may be necessary. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity 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. 
6.2.1.3.2. 
Causality 
The Principal Investigator will assess the causality/relationship between the study drug and the 
AE. One of the categories described in Table 6 should be selected based on medical judgment, 
considering the definitions below and all contributing factors. 

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Table 6 
Assessment of Relationship of Adverse Events to Investigational Product 
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 (de-challenge*) 
should be clinically plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory re-challenge† procedure if necessary. 
Probably related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the treatment, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(de-challenge). Re-challenge information is not required to fulfil this definition. 
Possibly related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the treatment, but which could also be explained by concurrent disease 
or other drugs or chemicals. Information on treatment withdrawal may be lacking or 
unclear. 
Unlikely to be 
related 
A clinical event, including laboratory test abnormality, with a temporal relationship to 
treatment administration which makes a causal relationship improbable, and in which 
other drugs, chemicals or underlying disease provide plausible explanations. 
Unrelated 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. May have negative de-challenge and 
re-challenge information. Typically explained by extraneous factors (e.g., concomitant 
disease, environmental factors or other drugs or chemicals). 
*De-challenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation, this is termed a positive de-challenge. 
If the symptoms continue despite withdrawal of the drug, this is termed a negative de-challenge. 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). 
†Re-challenge is when a drug suspected of causing an AE in a specific subject in the past is re-administered to that 
subject. If the AE recurs upon exposure, this is termed a positive re-challenge. If the AE does not recur, this is 
termed a negative re-challenge. 
6.2.1.3.3. 
Seriousness 
Severity is a measure of intensity whereas seriousness is defined by the criteria in 
Section 6.2.1.1.2. 
6.2.1.4. 
Reporting of Serious Adverse Events 
The Principal Investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to study drug. All SAEs will be recorded from signing of the ICD until 
the End-of-study Visit. Serious AEs occurring after the End-of-study 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. 
The Principal Investigator is responsible for providing notification to the Clinical Research 
Organization (CRO)/Sponsor of any SAE, whether deemed IMP-related or not, that a subject 
experiences during their participation in study within 24 hours of becoming aware of the event. 

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As a minimum requirement, the initial notification should provide the following information: 
 Study number 
 Patient number 
 Sex 
 Date of birth 
 Name of Principal Investigator and full clinical site address 
 Details of SAE 
 Criterion for classification as ‘serious’ 
 Study drug name, or code if unblinded, and treatment start date 
 Date of SAE onset 
 Causality assessment (if sufficient information is available to make this classification) 
The CRO/Sponsor will request clarification of omitted or discrepant information from the initial 
notification. The Principal Investigator or an authorized delegate is responsible for emailing or 
faxing the requested information to the CRO/Sponsor within 24 hours of the request. 
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), with the subject’s personal identifiers removed. All relevant information obtained by the 
Principal Investigator through review of these documents will be recorded and faxed to the 
Sponsor within 24 hours of receipt of the information. If a new SAE Report Form is faxed, then 
the Principal Investigator must sign and date the form. The CRO/Sponsor may also request 
additional information on the SAE, which the Principal Investigator or an authorized delegate must 
fax to the Sponsor within 24 hours of the request. 
Serious Adverse Event Reporting: 
PAREXEL Safety Services 
 
 
 

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6.2.1.5. 
Follow-up of Adverse Events 
All AEs experienced by a subject, 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 subject is lost to follow-up. 
6.2.1.6. 
Pregnancy 
The Sponsor has a responsibility to monitor the outcome of all pregnancies reported during the 
clinical study. 
Pregnancy alone is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be regarded as AEs, unless they were therapeutic abortions (see below). 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Each pregnancy must be reported by the Principal Investigator to the Sponsor within 24 hours after 
becoming aware of the pregnancy. The Principal Investigator must follow-up and document the 
course and the outcome of all pregnancies even if the subject was withdrawn from the clinical 
study or if the clinical study has finished. 
All outcomes of pregnancy must be reported by the Principal Investigator to the Sponsor on the 
pregnancy outcome report form within 24 to 48 hours after he/she has gained knowledge of the 
normal delivery or elective abortion. 
Any SAE that occurs during pregnancy must be recorded on the SAE Report Form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 
6.2.2. 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected at the time points detailed in the 
Schedule of Assessments Table 9. Clinical laboratory tests will be performed by the laboratories 
mentioned in the List of Study Staff of this clinical study protocol. Samples will be collected in 
appropriate tubes and handled according to standard procedures of the applicable laboratory. 
Table 7 lists the biochemistry, hematology and urinalysis tests that will be performed by the local 
laboratory for safety blood samples. 

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Table 7 
Clinical Laboratory Assessments 
Hematology 
White blood cell (WBC) count 
Neutrophils (percentage and absolute count) 
Red blood cell (RBC) count 
Lymphocytes (percentage and absolute count)  
Hemoglobin (Hb) 
Monocytes (percentage and absolute count)  
Hematocrit (HCT) 
Eosinophils (percentage and absolute count)  
Mean corpuscular volume (MCV) 
Basophils (percentage and absolute count)  
Mean corpuscular hemoglobin (MCH) 
Platelet count 
Mean corpuscular hemoglobin concentration (MCHC) 
RBC distribution width  
Coagulation 
Prothrombin time (PT) 
International Normalized Ratio (INR) 
Activated partial thromboplastin time (aPTT) 
 
Clinical Chemistry 
Alanine aminotransferase (ALT) 
Glucose 
Albumin 
Lactate dehydrogenase (LDH) 
Alkaline phosphatase (ALP) 
Phosphorus 
Aspartate aminotransferase (AST) 
Potassium 
Blood urea nitrogen (BUN) 
Sodium 
Calcium 
Total bilirubin 
Chloride 
Total protein 
Cholesterol 
Triglycerides 
Creatinine 
Uric acid 
Gamma glutamyl transferase (GGT) 
 
FSH (Screening Visit only; all female subjects) 
Urinalysis 
Bilirubin 
Blood 
Glucose 
pH and specific gravity 
Ketones 
Protein 
Leukocytes 
Urobilinogen 
Nitrite 
 
Microscopic (only for abnormal urine stick test findings) 
Viral Serology 
Human immunodeficiency virus (HIV)  
(Types 1 and 2) antibodies 
Hepatitis C virus antibody (anti-HCV) 
Hepatitis B surface antigen (HBsAg) 
 
Urine Drug Screening and Cotinine Test 
Amphetamines 
Cocaine 
Barbiturates 
Opiates 
Benzodiazepines 
Phencyclidine 
Cannabinoids 
Cotinine 
Urinary creatinine (to exclude dilution effect)                     Ethanol 
Pregnancy Testing 
Serum/urine human beta chorionic gonadotrophin (women of childbearing potential only) 
 

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Abnormal laboratory results should be recorded as AEs (e.g., Principal Investigator judgment or 
outside the specific reference range). 
Any value outside the normal range will be flagged for the attention of the Principal Investigator 
or designee at the site. The Principal Investigator or designee will indicate whether or not the value 
is of clinical significance. If the result of any test (or repeat test, if done) from the samples taken 
during the Screening period is indicated as clinically significant, the subject will not be allowed 
into the study without permission of the Medical Monitor. Additional testing during the study may 
be done if medically indicated. If a clinically significant abnormality is found in the samples taken 
after dosing, during the study, and/or at the End-of-study Visit, it should be recorded as an AE and 
the subject will be followed until the test(s) has (have) normalized or stabilized, at the discretion 
of the Principal Investigator. 
6.2.2.1. 
Anti-drug Antibody Response 
The serum samples to measure the presence of ADA will be collected on Days 1, Week 4,8,16 and 
if required Weeks 20 and 24. 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 Week 16 from all subjects. Samples for anti-VIS649 antibody titers and neutralizing 
capabilities will be drawn according to the Schedule of Assessments Table 9. Further procedures 
for sample collection, shipment, processing and storage will be described in the Laboratory 
Manual. 
6.2.3. 
Vital Signs 
Vital signs will be assessed at the time points detailed in the Schedule of Assessments Table 9. 
The following vital signs will be measured: 
 Blood pressure (systolic and diastolic [mmHg]) 
 Pulse (bpm) 
 Respiratory rate (breaths per minute) 
 Temperature 
Blood pressure and pulse recordings will be made after the subject has been in a seated or supine 
position and at rest≥ 5 minutes. 

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6.2.4. 
Standard 12-lead Electrocardiograms 
Standard safety 12-lead ECGs will be performed at the time points detailed in the Schedule of 
Assessments Table 9. 
The12-lead ECGs will be performed after the subject has been resting supine for≥ 5 minutes. 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/sec. The following ECG parameters will be 
collected: PR interval, QRS interval, RR interval, QT interval and QTc interval (QTcF). 
All ECGs must be evaluated by a qualified physician or physician’s assistant for the presence of 
abnormalities. 
6.2.5. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in the Schedule of Assessments 
Table 9. 
Full physical examination: 
An assessment of general appearance and a review of systems (dermatologic, head, eyes, ears, 
nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, 
extremities, musculoskeletal, neurologic and psychiatric systems). 
Brief physical examination: 
An assessment of the general appearance, skin, cardiovascular system, respiratory system and 
abdomen. 
The brief physical examination may be extended to a full physical examination if considered 
necessary by the Principal Investigator. Other evaluations may be performed as deemed necessary 
by the Principal Investigator. This will be commented upon in the clinical study report (CSR), if 
performed. 
6.3. 
Pharmacokinetics Variables 
6.3.1. 
Blood Sample Collection 
Blood for the analysis of VIS649 will be collected at the time points detailed in the Schedule of 
Assessments Table 9. 

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Blood sample collection, processing and shipping details will be outlined in a separate laboratory 
manual. In brief, PK sampling will occur on Day 1 starting with a collection prior to the start of 
infusion, at the end of infusion (60 minutes) and at 2 hours, 8 hours and 24 hours post end of 
infusion. Pharmacokinetics samples will also be drawn on Days 3, 7, 14, 28, 42, 56, 70, and 
112 days. Serum samples for determination of the concentration of VIS649 will be analyzed under 
the responsibility of the Sponsor. Further procedures for sample collection, shipment, processing, 
and storage will be described in the Laboratory Manual. 
6.4. 
Pharmacodynamics Variables 
For assessing the effect of VIS649 on PD parameters, serum samples will be drawn and evaluated 
for immunoglobulin levels (total IgA, IgG and IgM), immunoglobulin subtypes (IgA and IgG), 
and lymphocytes.
 
 
 Samples for PD parameters will be collected at the time 
points detailed in the Schedule of Assessments Table 9. Further procedures for sample collection, 
shipment, processing, and storage will be described in the Laboratory Manual. 
6.5. 
Total Amount of Blood 
The approximate volume of blood (391.5 mL) planned for collection from each subject over the 
course of the entire study (from the Screening Visit to the End-of-study Visit, but not including 
repeat or additional tests ordered by the Principal Investigator) presents no undue risk to the 
subjects. 
For all subjects enrolled, the approximate blood volumes to be collected during the study are 
outlined in Table 8. 

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7. 
STUDY CONDUCT 
7.1. 
Schedule of Assessments 
The study will be comprised of: 
 A Screening Visit up to 28 days before dosing 
 An in-house stay for approximately 2 to 3 days, with admission to the study center on 
Day -1, dosing on Day 1 and discharge in the morning of Day 2 
 A post-administration period of 16 weeks 
 Outpatient visits, on Day 3 (+1 day), 7 (± 1 day), 14, 21, 28, 35, 42, 49, 56, 70, 84 and 98 
(all visits± 3 days) 
 A final Follow-up visit on Day 112 (± 3 days); however, two additional follow-up visits 
may be performed, at Weeks 20 and 24 post-dosing, if serum immunoglobulins have not 
returned to > lower limits of normal by the Week 16 (Day 112) visit or if emerging trial 
data suggest a value of later follow-up (i.e. detection of ADA responses). 
The total duration of the clinical study per subject will be up to approximately 20 weeks 
(5 months), including the Screening period with the possibility of duration extending to 28 weeks 
(7 months) if follow-ups visits are required. For details of Schedule of Assessments, please see: 
Table 9. 
 

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Table 9 
Schedule of Assessments 

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Activity 
Scre
en 
Bas
elin
e 
Post-Dosing Period Assessments 
Additional 
Visits7 
Time Point (Day) 
Days 
-30  
to -1 
BL 
D-1 
pre-
dos
e 
D1 
D2 
D3 
W1/
D7 
W2/
D14 
W3/
D21 
W4/
D28 
W5/
D35 
W6/
D42 
W7/
D49 
W8/
D56 
W10/
D70 
W12/
D84 
W14/
D98 
W16/
D112 
W20 
W24 
+/- visit allowance 
N/A 
N/A 
N/A 
N/A 
+1 
+/-1 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-5 
+/-5 
Physical 
Examination - 
Brief 
 
 
 
 
x 
x 
 
 
 
X 
 
X 
 
 
X 
 
 
Vital Signs3 
x 
x 
x 
 
x 
x 
x 
x 
 
 
 
x 
 
x 
 
x 
 
 
ECG 
x 
X 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications  
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE Check 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IV Study Infusion  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
Assessments  
 
Serum Chemistry / 
Coagulation 
x 
x 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis  
x 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Hematology (CBC 
with differential) 
x 
x 
 
 
x 
x 
x 
 
 
 
x 
 
x 
 
 
 
 
Blood Sampling 
for PK5 
 
 
X5 
X5 
x 
x 
x 
 
x 
 
x 
 
x 
x 
 
 
x 
 
 
Blood Sampling 
for PD 
(Immunoglobulins) 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

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Activity 
Scre
en 
Bas
elin
e 
Post-Dosing Period Assessments 
Additional 
Visits7 
Time Point (Day) 
Days 
-30  
to -1 
BL 
D-1 
pre-
dos
e 
D1 
D2 
D3 
W1/
D7 
W2/
D14 
W3/
D21 
W4/
D28 
W5/
D35 
W6/
D42 
W7/
D49 
W8/
D56 
W10/
D70 
W12/
D84 
W14/
D98 
W16/
D112 
W20 
W24 
+/- visit allowance 
N/A 
N/A 
N/A 
N/A 
+1 
+/-1 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-3 
+/-5 
+/-5 
Blood Sampling 
for Ig subtypes 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
Blood Sampling 
for PD 
(lymphocyte 
populations) 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
x 
Blood sampling for 
ADA 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Abbreviations: ADA: Anti-drug Antibody; AE: Adverse event; D: Day; ECG: Electrocardiogram; HBsAG: Hepatitis B surface antigen; HIPAA: Health Insurance 
Portability and Accountability Act; HIV: Human Immunodeficiency Virus; Ig: Immunoglobulin; IV: Intravenous; N/A: Not Applicable, 
PD: Pharmacodynamics; PK: Pharmacokinetics; W: Week. 
1. The first two subjects of each cohort will be discharged 24 hours (Day 2) after the study infusion. All other subjects are discharged on Day 2, 24 hours 
after study infusion. Discharge from the Phase 1 unit will not occur prior to performing the 24 h post infusion study procedures. 
2. Optional Visit at Week 20 is only to be made if immunoglobulin levels (IgG, IgM, or IgA) have not returned to normal range by Week 16; the Optional 
Visit at Week 24 is only to be made if immunoglobulin levels have not returned to normal range by Week 20. 
3. Vitals signs at Screening and Day -1 will include height and weight, to permit estimated creatinine clearance calculation, as well as blood pressure (bp), 
heart rate (hr), respiratory rate (rr) and temperature. Subject weight will be measured after admission to the research unit (Day -1) and will be used by 
pharmacy staff for subject-specific dose calculation. Vital signs at other timepoints will be limited to temperature (Day -1 and Day 1 pre-dose only), bp, 
hr, and rr. Vital signs measurements on Day 1 will be recorded within 30 minutes prior to the start of the infusion, then every 15 minutes until the infusion 

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7.2. 
Order of Assessments 
The following priority order will be in effect when more than one assessment is required at a 
pre-dose and post-dose time point, with PK blood sampling being performed nearest to the 
specified time: 
1.  12-lead ECG 
2.  Vital signs 
3.  PK blood sampling 
4.  Blood sampling for safety assessments 
7.3. 
Early Termination 
If a subject withdraws prematurely after dosing, all data normally collected at discharge from the 
clinical site should be collected at the time of premature discontinuation or at the scheduled 
discharge. If deemed necessary by the Principal Investigator, the subject will be asked to return at 
the regularly scheduled End-of-study Visit. 
7.4. 
End-of-Study 
End-of-study is defined as completion of the final follow-up visit. For those subjects that withdraw 
prematurely, end-of-study is defined as the time of the subject’s last data collection. 
7.5. 
Restrictions 
7.5.1. 
Dietary and Fluid Restrictions 
Nicotine 
Nicotine-containing products (including but not limited to cigarettes, cigars, and 
chewing or dipping tobacco) is prohibited within less than 3 months before study 
drug administration. Use of topical or oral nicotine preparations for smoking 
cessation is also prohibited within less than the past 90 days before study drug 
administration. Included subjects must abstain from consumption of nicotine-
containing products for the duration of the study. 
Caffeine: 
Consumption of greater than 500 mg of caffeine or xanthine-containing products 
per day (e.g., coffee, tea, soft drinks, energy drinks, or chocolate) is prohibited. 
Included subjects must abstain from consuming caffeine or xanthine-containing 
products from 48 hours prior to check-in on Day -1 through the end of the study. 

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Alcohol: 
Consumption of more than 21 units of alcohol (1 unit of alcohol is equivalent to 
8 ounces of beer, 4 ounces of wine, or one ounce of spirits) per week (7 days) is 
prohibited. Included subjects must abstain from consuming alcohol from 48 hours 
prior to check-in on Day -1 through the end of the study. 
7.5.2. 
Other Restrictions 
Medications: Use of prescription or OTC medication is prohibited during the last 30 days or 5 
half-lives, whichever is longer, preceding baseline (Day -1) except for 
acetaminophen, ibuprofen, hormonal contraceptives, topical medications, vitamins, 
dietary or herbal remedies. Concomitant use of marketed or investigational 
systemic 
immunosuppressive 
or 
immunomodulatory 
medications 
(e.g., 
corticosteroids, methotrexate, azathioprine, etc. and/or biologics) is prohibited 
during the last 30 days or 5 half-lives, whichever is longer. 
Other: 
Blood donation (>500 mL) within 60 days prior to start of Screening and/or 
donation of any plasma within 7 days prior to baseline (Day -1) and for the duration 
of the study is prohibited. 

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8. 
STATISTICAL METHODS 
Before database lock, a statistical analysis plan will be issued as a separate document, providing 
detailed methods for the analyses outlined below. Any deviations from the planned analyses will 
be described and justified in the CSR. 
8.1. 
Determination of Sample Size 
The sample size for this FIH Phase 1 study was not based on formal statistical determinations. The 
sample size for this study was chosen in consideration of limiting exposure to this new chemical 
entity while providing sufficient information to evaluate the safety and tolerability of VIS649 in a 
Phase 1 setting. 
8.2. 
Study Population 
8.2.1. 
Disposition of Subjects 
Subjects entering and completing the clinical study will be listed and summarized using number 
and percentage  
Subjects excluded from the safety, PK and PD analysis sets and data excluded from the PK and 
PD analysis sets will be listed including the reason for exclusion. Subject disposition will be 
summarized. Disposition data will be presented based on all subjects randomized. 
8.2.2. 
Protocol Deviations 
Protocol deviations will be listed by subject. 
8.2.3. 
Analysis Populations 
 Safety population: All randomized subjects who received at least one dose of study drug. 
Subjects will be included in the analysis according to the dose and study drug received. 
 PK population: All randomized subjects with at least one quantifiable VIS649 
concentration. Subjects will be included in the analysis according to the dose and study 
drug received. 
 PD population: The safety population subset with at least one PD parameter assessment 
(IgA, IgG, IgM) post study drug (VIS649 or placebo) dosing. Subjects will be included in 
the analysis according to the dose and study drug received. 

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8.3. 
General Considerations 
In general, descriptive statistics for continuous variables will be summarized by treatment group 
using number of subjects, arithmetic mean, standard deviation, median, minimum and maximum; 
descriptive statistics for categorical data will be summarized by treatment group using frequency 
counts and percentages. Descriptive statistics for PK parameters will include number of 
observations, arithmetic mean, standard deviation, arithmetic %CV, and geometric mean, median, 
geometric %CV, minimum and maximum. 
The placebo subjects from all cohorts will be pooled into a single placebo group for all summaries 
and presentations. 
8.4. 
Demographic and Anthropometric Information and Baseline Characteristics 
Demographic and anthropometric variables (age, sex, ethnicity, race, height, weight and BMI) will 
be listed by subject. Demographic characteristics (age, sex, ethnicity and race) and anthropometric 
characteristics (height, weight and BMI) will be summarized by treatment and for all subjects in 
the safety population. The denominator for percentages will be the number of subjects in the safety 
population for each treatment or for all subjects as applicable. 
Medical history data will be listed by subject including visit, description of the disease/procedure, 
MedDRA System Organ Class (SOC), MedDRA Preferred Term (PT), start date, and stop date (or 
ongoing if applicable). 
8.5. 
Prior and Concomitant Medication 
Prior medications are those that started and stopped prior to the first dose of IMP. Concomitant 
medications are those taken after first dosing (including medications that started prior to dosing 
and continued after). 
Prior and concomitant medication will be listed by subject and will include the following 
information: reported name, preferred term, the route of administration, dose, frequency, start 
date/time, duration and indication. 
Prior and concomitant medication will be coded according to the World Health Organization Drug 
Dictionary latest version. 
8.6. 
Drug Administration 
A listing of drug administration will be created and will include the date and time of administration. 
When appropriate, a summary table of compliance will also be created. 

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8.7. 
Safety Analyses 
8.7.1. 
Adverse Events 
Adverse events will be coded using the MedDRA version 21.0 or higher. All AEs will be listed. 
The incidence of treatment-emergent AEs will be summarized by SOC and PT for each treatment 
and overall, by severity, and by relationship to IMP. 
The categories of the relationship to IMP will be summarized as related (Related, Probably related, 
and Possibly related) and not related (Unlikely to be related and Unrelated). 
Serious AEs will be listed. 
Injection site tolerability is defined as AEs demonstrating significant injection site irritation or 
tissue damage. Injection site tolerability will be reported by treatment group, and time point. 
8.7.2. 
Clinical Laboratory Tests 
Individual data listings of laboratory results will be presented for each subject. Flags will be 
attached to values outside of the laboratory’s reference limits along with the Principal 
Investigator’s assessment. Clinically significant laboratory test abnormalities that were considered 
AEs by the Principal Investigator will be presented in the AE listings. 
Clinical laboratory tests (observed values) will be summarized descriptively in tabular format. 
Safety laboratory data collection should be based on the end of infusion time. Shift tables will be 
presented for select laboratory parameters. 
8.7.3. 
Vital Signs 
Individual data listings of vital signs (observed and change from baseline) will be presented for 
each subject. Individual clinically significant vital signs findings that were considered AEs by the 
Principal Investigator will be presented in the AE listings. 
Observed values as well as change from baseline data will be summarized descriptively in tabular 
format. 
8.7.4. 
Standard 12-lead Electrocardiogram 
Standard 12-lead ECG data (observed and change from baseline) will be listed for each subject 
and time point. Observed values will be classified using frequency counts for normal, abnormality 
that is not clinically significant, and clinically significant abnormality by dose cohort and 
time point of collection. Descriptive statistics will be calculated for ECG parameters. The 

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8.11. Immunogenicity Data (Antibody to VIS649) 
Anti-VIS649 ADA evaluations will be listed including the confirmatory assay (positive/negative). 
A summary table of the ADA response (positive or negative) will be presented, by treatment (dose 
of VIS649 or pooled placebo), based on the safety analysis set. In addition, the ADA titers (n, 
median, minimum and maximum) will be summarized by treatment (dose of VIS649 or pooled 
placebo) for all subjects with a positive confirmatory assay at each time point; this tabulation will 
include a summary of the highest titer across all time points for each subject. 
 
 
8.12. Interim Data Reviews 
As participants in each dosing cohort complete their Week 16 visit, data clean-up and soft-lock 
will be performed for each cohort, in order to allow an interim assessment of PK, PD and safety 
data. PK/PD analysts will be permitted access to unblinded data, to facilitate preparation of blinded 
data summaries for presentation to the Sponsor. The randomization code will be provided to the 
bioanalytical laboratories responsible for the analysis PK and PD endpoints. Following analysis of 
the samples but prior to provision of the data to PAREXEL’s statistician, the laboratory will 
re-code the data back to the corresponding original unique sample ID numbers, enabling 
differentiation but not identification of the subjects in order to maintain blinding integrity for the 
other assessments of the clinical study, until after database lock. The full randomization code will 
be broken only for purposes of data analysis and reporting or safety reasons. This will occur once 
all final data have been entered into the database and all data queries have been resolved, coding 
is complete, the assignment of subjects to the analysis sets has been completed and the database 
has been locked. 
Interim summaries of PK, PD and safety data for entire cohorts (inclusive of both VIS649 and 
placebo recipients, and therefore, still blinded) may be utilized for various reporting purposes prior 
to full database lock and unblinding. 

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9. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
9.1. 
Data Quality Assurance 
The monitoring of the study will be conducted under the responsibility of the Sponsor by the CRO. 
The monitor will perform on-site and/or remote monitoring visits as frequently as necessary per 
the individual study monitoring plan. 
The Principal Investigator must prepare and maintain adequate and accurate records of all 
observations and other data pertinent to the clinical study for each study participant. Frequent 
communication between the clinical site and the Sponsor is essential to ensure that the safety of 
the study is monitored adequately. The Principal Investigator will make all appropriate safety 
assessments on an ongoing basis. The Medical Monitor may review safety information as it 
becomes available throughout the study. 
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (GCP) 
and SOPs for compliance with applicable government regulations. The Study Monitor will be an 
authorized individual designated by the Sponsor. The Study Monitor will have access to all records 
necessary to ensure integrity of the data and will periodically review the progress of the study with 
the Principal Investigator. The Sponsor will be entitled to audit the facilities used in the clinical 
and laboratory parts of the study, as well as to access all the data files pertaining to the study. 
Similar procedures may also be conducted by agents of any regulatory body, either as part of the 
national GCP compliance program or to review the results of this study in support of a regulatory 
submission. The Principal Investigator should immediately notify the Sponsor if they have been 
contacted by a regulatory/ethics agency concerning an inspection. 
9.2. 
Institutional Review Board 
Before implementing this study, the protocol, the proposed ICF and HIPAA authorization, and 
other information given to study volunteers must be reviewed by the IRB of the study site. A 
signed and dated statement that the protocol and ICF and HIPAA authorization have been 
approved by the IRB must be given to the Sponsor before study initiation. The name and 
occupation of the chairperson and the members of the IRB or the IRB’s Health and Human 
Services (assurance number must be supplied to the Sponsor). 
9.3. 
Access to Source Data/Documents 
PAREXEL will use an electronic data capture system to manage data collection during this trial. 
The electronic data capture system (ClinBase) is a software tool designed to ensure quality 

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assurance and facilitate data capture during clinical trials. Through a system regulated workflow 
that includes barcode scanning and interfaces to medical equipment to avoid manual data entry, 
study operations performance is controlled and captured in real time. The system is fully 
CFR 21 part 11 compliant. 
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 subject receiving 
study drug. 
The Principal Investigator will allow Sponsor representatives, contract designees, authorized 
regulatory authority inspectors and the IRB/IEC to have direct access to all documents pertaining 
to the study. 
9.4. 
Archiving Study Documents 
According to ICH SOP 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 the study drug. However, these 
documents should be retained for a longer period if required by the applicable legal requirements. 
9.5. 
Good Clinical Practice 
The procedures set out in this clinical study protocol are designed to ensure that the Sponsor and 
the Principal Investigator abide by the principles of the ICH guidelines on GCP. The clinical study 
also will be carried out in keeping with national and local legal requirements in accordance with 
US investigational new drug [IND] regulations [21 CFR 56]). 

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9.6. 
Informed Consent 
Before each subject is enrolled in the clinical study, written informed consent will be obtained 
from the subject 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 subject is 
aware of the potential risks, inconveniences or AEs that may occur. The subject 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/IEC-approved ICD prior to the start of the study. 
The ICD must be signed and dated; one copy will be handed to the subject, 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 a protocol amendment is required, then the ICD may need to be revised to reflect the changes to 
the protocol. If the ICD is revised, it must be reviewed and approved by the responsible IRB/IEC, 
and signed by all subjects subsequently enrolled in the clinical study as well as those currently 
enrolled in the clinical study. 
9.7. 
Protocol Approval and Amendment(s) 
Before the start of the clinical study, the clinical study protocol and other relevant documents will 
be approved by the IRB/IEC, in accordance with local legal requirements. The Sponsor must 
ensure that all ethical and legal requirements have been met before the first subject is enrolled in 
the clinical study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, which 
must be released by the responsible staff and receive IRB/IEC approval prior to implementation 
(as appropriate). 
Administrative changes may be made without the need for a formal amendment, but will also be 
mentioned in the integrated CSR. All amendments will be distributed to all study protocol 
recipients, with appropriate instructions. 
All protocol deviations will be documented and reported in the final CSR. 

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9.8. 
Confidentiality Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, IBs and other material) will be stored appropriately to ensure their confidentiality. The 
Principal Investigator and members of his/her research team (including the IRB/IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from subjects who wish to participate in the trial or to comply 
with regulatory requirements. 
The anonymity of participating subjects must be maintained. Subjects will be specified on study 
documents by their subject number, initial or birth date, not by name. Documents that identify the 
subject (e.g., the signed ICD) must be maintained in confidence by the Principal Investigator. 
9.9. 
Publication Policy 
By signing the clinical study protocol, the Principal Investigator agrees with the use of results of 
the clinical study by the Sponsor for the purposes of national and international registration, 
publication and information for medical and pharmaceutical professionals. If necessary, the 
regulatory 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 the 
express written consent of the Sponsor. 

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10. 
REFERENCE LIST 
1. Kiryluk K, Li Y, Scolari F, et al. Discovery of new risk loci for IgA nephropathy implicates 
genes involved in immunity against intestinal pathogens. Nat Genet. 2014; 46(11):1187-1196. 
2. VIS649 Investigator’s Brochure, Version 1.0, dated 15 Aug 2018. 
3. Yel L. Selective IgA deficiency. J Clin Immunol. 2010; 30(1):10-16. 
4. Yazdani R, Azizi G, Abolhassani H and Aghamohammadi. Selective IgA deficiency: 
epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Scand 
J of Immunol 2016; 85:3-12. 
5. Fadlallah J, Kafsi HE, Sterlin D, et al. Microbial ecology perturbation in human IgA 
deficiency. Sci. Transl. Med. 2018; 10(439). pii: eaan1217. 
6. Furst DE. Serum immunoglobulins and risk of infection: how low can you go? Semin Arthritis 
Rheum 2009; 39(1):18-29. 
7. Salzer U, Chapel HM, Webster ADB, et al. Mutations in TNFRSF13B encoding TACI are 
associated with common variable immunodeficiency in humans. Nat Genet. 2005; 37:820-828. 
8. Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for 
common variable immune deficiency (CVID) which may assist with decisions to treat with 
intravenous or subcutaneous immunoglobulin. Clin Exp Immunol 2013; 174:203-211. 
9. Ballow M. Primary immunodeficiency disorders: antibody deficiency. J Allergy Clin Immunol 
2002;109(4):581-591. 
10. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency-an update. Arthritis 
Research & Therapy 2012; 14:223-233.