Clinical trial NCT03393013
Conditions: Lupus Nephritis Systemic Lupus Erythematosus
Keywords: immunoproteasome inhibition selective proteasome inhibition proteasome lupus nephritis lupus nephritis active proliferative lupus nephritis open-label systemic lupus erythematosus lupus erythematosus
Sponsor: Kezar Life Sciences, Inc.
Start date: 2018-02-20; Completion date: 2022-08-04
Enrollment: 69 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This was a Phase 1b/2, multi-center study in which patients received KZR-616, administered as a subcutaneous (SC) injection weekly for 13 weeks (Phase 1b) or 24 weeks (Phase 2).

Detailed description:
This was a Phase 1b/2, open-label, multi-center study in which patients received zetomipzomib administered as a SC injection weekly for either 13 weeks (Phase 1b) or for 24 weeks (Phase 2). In both phases, safety assessments continued for up to 12 weeks following the last dose of zetomipzomib.

Phase 1b was an open-label, multiple dose escalation study designed to evaluate the safety and tolerability of escalating doses of zetomipzomib when administered in addition to standard-of-care therapy in patients with SLE with or without nephritis. For each cohort, at least 6 patients were to be enrolled to assure the availability of at least 4 evaluable patients. Decisions to escalate, expand, or decrease the dose level or dosing frequency following the first 4 weeks of dosing for at least 4 evaluable patients in a cohort were made following review by a data monitoring committee (DMC).

The zetomipzomib formulations and doses administered by cohort in Phase 1b were:

* Cohort 1: zetomipzomib frozen maleate, 45 mg weekly × 13 weeks
* Cohort 2: zetomipzomib frozen maleate, 60 mg weekly × 13 weeks
* Cohort 2a: zetomipzomib frozen maleate, 30 mg weekly × 2 weeks, followed by 45 mg weekly × 2 weeks, followed by 60 mg weekly × 9 weeks
* Cohort 2b: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks
* Cohort 2c: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 60 mg weekly × 12 weeks (tolerability strategies cohort)
* Cohort 3: zetomipzomib lyophile, 30 mg weekly × 1 week, followed by 75 mg weekly × 12 weeks

The Phase 2 portion of the open-label study was designed to evaluate the renal response, safety, and tolerability of a single dose level (60 mg) of zetomipzomib administered weekly in addition to standard therapy in patients with active proliferative lupus nephritis (LN) (Class III or IV, with or without Class V disease) with a UPCR ≥1.0. Patients must have been on standard therapy for LN including at least 1 immunosuppressive agent. Zetomipzomib was administered as a SC injection weekly for 24 weeks (including a step up from an initial Week 1 dose of 30 mg).

Arms: arm 1: Dose escalation cohort of patients with SLE with and without nephritis to receive 45 mg dose level of KZR-616 in combination with standard of care therapy.

Two Phase 1b cohorts received 45 mg at some point during the study.

Cohort 1 received 45 mg zetomipzomib frozen maleate weekly for 13 weeks.

Cohort 2a followed a step-up dosing procedure. Patients received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks.

KZR-616 was administered as a SC injection. arm 2: Dose escalation cohort of patients with SLE with and without nephritis to receive 60 mg dose level of KZR-616 in combination with standard of care therapy.

Four Phase 1b cohorts received 60 mg at some point during the study.

Cohort 2 received 60 mg zetomipzomib frozen maleate weekly for 13 weeks.

Cohorts 2a, 2b, and 2c all followed a step-up dosing procedure. Patients in Cohort 2a received zetomipzomib frozen maleate, 30 mg weekly for 2 weeks, followed by 45 mg weekly for 2 weeks then followed by 60 mg weekly for 9 weeks. Patients in Cohort 2b received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks. Patients in Cohort 2c (tolerability strategies cohort) received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 60 mg weekly for 12 weeks.

KZR-616 was administered as a SC injection. arm 3: Dose escalation cohort of patients with SLE with and without nephritis to receive 75 mg dose level of KZR-616 in combination with standard of care therapy.

One Phase 1b cohort received 75 mg at some point during the study.

Cohort 3 followed a step-up dosing procedure. Patients in Cohort 3 received zetomipzomib lyophile, 30 mg weekly for 1 week, followed by 75 mg weekly for 12 weeks.

KZR-616 was administered as a SC injection. arm 4: 60 mg dose level of KZR-616 selected based on data from the phase 1b dose escalation and administered to patients with active lupus nephritis in combination with standard therapy including at least one immunosuppressive agent.

KZR-616 was administered as a SC injection weekly at a dose of 60 mg for 24 weeks (including a step-up from an initial Week 1 dose of 30 mg).

\*\* See Limitations/Caveats for additional information
Interventions: intervention 1: KZR-616
Intervention descriptions: intervention 1: Subcutaneous Injection of KZR-616

Protocol documents:
Prot_SAP_000.pdf: 
 
KZR-616-002 
A PHASE 1B/2 STUDY OF KZR-616 IN 
PATIENTS WITH SYSTEMIC LUPUS 
ERYTHEMATOSUS WITH AND WITHOUT 
NEPHRITIS 
TITLE PAGE 
 
 
Clinicaltrials.gov Identifier 
NCT03393013 
Release date of report: 
07 July 2020, version 5.0 
 
 
 


CLINICAL STUDY PROTOCOL
A Phase 1b/2 Study of KZR-616 in Patients with Systemic Lupus 
Erythematosus with and without Nephritis 
Protocol Number:
KZR-616-002
EudraCT Number:
2019-004390-21
Investigational Product:
KZR-616
Phase:
Phase 1b/2
Sponsor:
Kezar Life Sciences 
4000 Shoreline Court, Suite 300 
South San Francisco, CA 94080
Contract Research Organization:
 
Original Protocol:
10 OCT 2017, Version 1.0 
Protocol Amendment 1:
04 MAY 2018, Version 2.0 
Protocol Amendment 2:
23 OCT 2018, Version 3.0 
Protocol Amendment 3:
25 OCT 2019, Version 4.0 
Protocol Amendment 4:
07 JUL 2020, Version 5.0 
CONFIDENTIAL
This protocol may not be reproduced or communicated to a third party without the 
written permission of Kezar Life Sciences 






















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9.
Female patients of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test at Baseline and must agree to employ adequate birth control 
measures for the duration of the study. Women of childbearing potential (WOCBP) must use 
highly effective and medically acceptable methods of contraception to prevent pregnancy during 
Screening and must agree to continue to practice adequate contraception during the study and for 
4 weeks after administration of the last dose of the study drug. 
 
For the purposes of this study, WOCBP are defined as: all postpubescent female patients, unless 
the patient is postmenopausal (defined by amenorrhea for at least 2 years or amenorrhea for at 
least 1 year with confirmatory follicle stimulating hormone [FSH] level in the postmenopausal 
range as documented historically or measured by the central laboratory at Screening and if patient 
is not on supplementary hormonal therapy) or if the patient is surgically sterile (i.e., tubal 
ligation, hysterectomy, bilateral salpingoophorectomy). 
 
Highly effective contraception is defined as the use of an intrauterine device or hormonal 
contraceptives (e.g., implant or oral), or having a vasectomized partner. If using a hormonal form 
of contraception, it must have been stable for at least 4 weeks prior to Screening, and if using 
concomitant mycophenolate, the patient must use another nonhormonal form of highly effective 
contraception. Abstinence will be acceptable only if it is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation) and withdrawal are not 
acceptable methods of contraception. 
10. Male patients with a partner of childbearing potential must be either congenitally sterile or 
surgically sterile (by vasectomy) or willing to use a condom in addition to having their female 
partner use another form of contraception (such as an intrauterine device, barrier method with 
spermicide, or hormonal contraceptive [e.g., implant, injectable, patch, or oral]) from Screening 
until 12 weeks after the last dose of study drug, unless their partners are infertile or surgically 
sterile. 
11. Willing and able to provide written informed consent prior to any study-related procedures and to 
comply with all study requirements 
 
Exclusion Criteria: 
1. Any of the following:  
a) Dialysis within 12 months prior to Screening or expected need for renal replacement 
therapy (dialysis or renal transplant) within a 6-month period after enrollment 
b) Rapidly progressive glomerulonephritis (RPGN) and/or renal disease other than ISN/RPS 
Classes III, IV-S or IV-G, [A] or [A/C] with or without Class V LN) 
c) Chronic kidney disease not due to LN  
d) > 50% sclerosed glomeruli on most recent renal biopsy  
2. Presence of another rheumatic (overlap) disease that may confound clinical assessments in the 
study. Secondary sicca or Sjogren’s syndrome and antiphospholipid antibody syndrome are 
allowed 
3. History of antiphospholipid syndrome with history of thromboembolic event within 12 months of 
screening  
4. Active central nervous system involvement by autoimmune disease (e.g., neuropsychiatric SLE 
including seizures, psychosis, acute confusional state or cerebrovascular accident) requiring 




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7.
Clinical evidence of significant unstable or uncontrolled acute or chronic diseases (e.g., cardiac 
[including congestive heart failure, hypertension, angina, or history of myocardial infarction], 
pulmonary [including chronic obstructive pulmonary disease, asthma requiring corticosteroid 
therapy, pulmonary hypertension, or pulmonary fibrosis], hematologic, gastrointestinal, hepatic, 
renal, neurological, or infectious diseases) that, in the opinion of the investigator or sponsor, 
could confound the results of the study, put the patient at undue risk, or interfere with protocol 
adherence  
8. QT interval with Fridericia’s correction (QTcF) or Bazett’s correction (QTcB) > 480 msec on 
ECG 
9.
Major surgery within 12 weeks before signing the ICF or major surgery planned during the study 
period 
10. Any active or suspected malignancy or history of documented malignancy within the last 5 years 
before Screening. Exceptions include history of appropriately excised and cured cervical 
carcinoma in situ or excised basal or squamous cell carcinomas of the skin 
11. Women who are pregnant or lactating  
12. Hypersensitivity to the Investigational Medicinal Products or any of its excipients. 
13. Use of investigation medical therapy or device, and/or participation in an investigational trial < 8 
weeks or 5 half-lives, whichever is longer, prior to Baseline; Patients who participated in Phase 
1b of KZR-616-002 are excluded from Phase 2 
 
Overview of Assessments 
Assessments of clinical and laboratory activity of KZR-616 will be performed as detailed in 
Appendix A and Appendix B, respectively. 
Safety: Safety assessments will begin after the patient provides written informed consent and 
continue through 12 weeks follow-up visit. Severity of AEs will be assessed according to the NCI-
CTCAE, Version 4.03. 
Efficacy: SLE disease activity (clinical and laboratory assessments and patient reported outcomes) 
will be assessed approximately every 4 weeks.  
Concomitant Medications: concomitant medications will be recorded at start of study and with 
changes 
Pharmacokinetics (Phase 1b only): Blood samples for determination of plasma concentrations of 
KZR-616 and its metabolites will be collected on Day 1 of Weeks 1 and 5 before dosing and at 5, 15, 
and 30 minutes and 1, 2, 4, and 8 hours after the injection. Urine samples will be pooled from 0 to 5 
hours and 5 to 8 hours. 
Pharmacodynamics: Blood samples for the determination of proteasome activity in whole blood and 
peripheral blood mononuclear cells will be assessed in blood samples collected as follows: 
Phase 1b – Day 1 of Week 1 and Week 5, before dosing and 4 hours after  
Phase 2 – Day 1 of Week 1, before dosing and 4 hours after injection, and Day 1 of Week 5, before 
dosing 






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TABLE OF CONTENTS
1
SYNOPSIS ................................................................................................................. 4
TABLE OF CONTENTS ..................................................................................................... 17
LIST OF ABBREVIATIONS .............................................................................................. 21
2
BACKGROUND INFORMATION ...................................................................... 24
2.1
Disease Background ....................................................................................... 24
2.1.1 
Systemic Lupus Erythematosus ............................................................... 24
2.1.2 
Lupus Nephritis ....................................................................................... 25
2.2
Treatment of Lupus Nephritis ...................................................................... 25 
2.3
Proteasome Background ............................................................................... 26 
2.3.1 
Proteasome Inhibitors for the Treatment of Inflammatory 
Disorders .................................................................................................. 26
2.4
KZR-616 Background ................................................................................... 27 
2.5
Study Rationale .............................................................................................. 28 
2.5.1 
Summary of Potential Risks and Benefits ............................................... 28
2.5.2 
Dosing Rationale ..................................................................................... 29
2.5.3 
Design Rationale ...................................................................................... 31
3
STUDY OBJECTIVES .......................................................................................... 33
3.1
Objectives (Phase 1b) ..................................................................................... 33 
3.2
Objectives (Phase 2) ....................................................................................... 33 
4
STUDY DESIGN .................................................................................................... 34
4.1
Overall Study Design ..................................................................................... 34
4.1.1 
Phase 1b ................................................................................................... 34
4.1.2 
Phase 2 ..................................................................................................... 36
4.2
Estimated Study Duration ............................................................................. 36 
4.3
Minimizing Bias ............................................................................................. 36 
5
PATIENT SELECTION ........................................................................................ 37
5.1
Number of Planned Patients ......................................................................... 37 
5.1.1 
Patient Screening ..................................................................................... 37
5.2
Inclusion and Exclusion Criteria .................................................................. 37 
5.2.1 
Inclusion Phase 1b ................................................................................... 37
5.2.2 
Exclusion Phase 1b .................................................................................. 39


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5.2.3 
Inclusion Phase 2 ..................................................................................... 41
5.2.4
Exclusion Phase 2 .................................................................................... 43
6
STUDY DRUG ........................................................................................................ 45
6.1
KZR-616.......................................................................................................... 45
6.1.1
Physical Description ................................................................................ 45
6.1.2 
Packaging and Labeling ........................................................................... 45
6.1.3 
Storage of KZR-616 ................................................................................ 45
6.2
Study Drug Accountability............................................................................ 46 
7
DOSAGE AND TREATMENT ADMINISTRATION ........................................ 47
7.1
KZR-616 Treatment Administration ........................................................... 47
7.1.1
Dosing Criteria ......................................................................................... 47
7.1.2 
Administrative Site .................................................................................. 47
7.1.3 
Monitoring of Dose Administration ........................................................ 47
7.1.4 
Dose Modification Guidelines for KZR-616 ........................................... 49
7.2
Prior and Concomitant Medications ............................................................ 49 
7.2.1 
Excluded Concomitant Medications ........................................................ 51
7.2.2 
Required Concomitant Medications ........................................................ 51
8
STUDY PROCEDURES ........................................................................................ 53
8.1
Schedule of Study Procedures....................................................................... 53 
8.2
Description of Study Procedures .................................................................. 53 
8.2.1 
Medical History ....................................................................................... 53
8.2.2 
Vital Signs ............................................................................................... 53
8.2.3
Physical Examination .............................................................................. 53
8.2.4 
Electrocardiogram .................................................................................... 54
8.2.5 
Chest X-ray .............................................................................................. 54
8.2.6 
Clinical Laboratory Evaluations .............................................................. 54
8.3
Pharmacokinetic Measurements .................................................................. 61 
8.4
Pharmacodynamics ........................................................................................ 62 
8.5
Biomarker Measurements ............................................................................. 62 
8.5.1 
Cytokine Activity ..................................................................................... 62
8.5.2 
Gene Expression/Pharmacogenomics ...................................................... 62
8.5.3 
Urine Biomarkers ..................................................................................... 62
8.5.4 
Sample Management/Future Research .................................................... 63
9
STUDY DISCONTINUATION ............................................................................. 64
9.1
Individual and Study Stopping Rules for Safety (Phase 1b/2) ................... 64 


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9.2
Early Withdrawal of Patients from Study ................................................... 64 
9.3
Early Withdrawal (or Discontinuation) Visit .............................................. 65
9.4
Study Termination ......................................................................................... 66
10 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................. 67
10.1
Adverse Event Reporting .............................................................................. 67
10.1.1 
Definitions ............................................................................................... 67
10.1.2 
Assessment of Severity ............................................................................ 67
10.1.3 
Assessment of Causality .......................................................................... 67
10.1.4
Action Taken ........................................................................................... 68
10.1.5 
Follow-up of Adverse Events .................................................................. 68
10.1.6 
Documentation and Reporting of Adverse Events .................................. 68
10.2
Serious Adverse Events ................................................................................. 69
10.2.1 
Serious Adverse Events Definition .......................................................... 69
10.2.2 
Serious Adverse Event Reporting and Documentation 
Requirements ........................................................................................... 69
10.3
Pregnancy Reporting ..................................................................................... 70 
10.4
New or Worsening Disease Manifestations.................................................. 71 
10.5
AEs of Special Interest................................................................................... 71 
10.5.1 
Systemic Injection Reactions ................................................................... 71
10.5.2 
Thrombotic Microangiopathy (TMA) ..................................................... 71
10.6
Unexpected Adverse Reactions ..................................................................... 72 
10.6.1 
Unexpected Adverse Reaction Definition ............................................... 72
10.7
Data Monitoring Committee ......................................................................... 72 
11 
STATISTICS ........................................................................................................... 73
11.1
Endpoints ........................................................................................................ 73 
11.1.1 
Phase 1b Endpoints .................................................................................. 73
11.1.2 
Phase 2 Endpoints .................................................................................... 73
11.2
Statistical Methods ......................................................................................... 74 
11.2.1 
Methods of Analysis ................................................................................ 74
11.2.2 
Analysis Population ................................................................................. 75
11.3
Assessments .................................................................................................... 75 
11.3.1 
Criteria for Evaluation – Safety Analysis ................................................ 75
11.3.2 
Criteria for Evaluation – Pharmacokinetic Analyses ............................... 76
11.3.3 
Criteria for Evaluation – Pharmacodynamic Analyses ............................ 76
11.3.4 
Criteria for Evaluation – Biomarker and Other Analyses ....................... 77
11.3.5 
Criteria for Evaluation – Efficacy Analyses ............................................ 77


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11.3.6 
Handling of Missing Data ........................................................................ 78
11.4
Determination of Sample Size ....................................................................... 78
11.5
Interim Analysis ............................................................................................. 78
12 
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ............................ 79
12.1
Compliance Statement ................................................................................... 79
12.2
Institutional Review Board or Independent Ethics Committee ................ 79 
12.3
Informed Consent and Human Patient Protection ..................................... 79 
12.4
Direct Access to Source Data, Source Documents, and Study Records .... 80 
12.5
Data Collection and Handling....................................................................... 80
12.6
Confidentiality ................................................................................................ 80 
12.7
Financing and Insurance ............................................................................... 81 
12.8
Audit and Inspection...................................................................................... 81 
12.9
Monitoring ...................................................................................................... 81 
12.10 Data Management and Coding ..................................................................... 81 
12.11 Reporting and Publication, Including Archiving ........................................ 82 
13 
REFERENCES ....................................................................................................... 83
14 
APPENDICES ......................................................................................................... 87
14.1
APPENDIX A: SCHEDULE OF ASSESSMENTS – PHASE 1B ............. 88 
14.2
APPENDIX B: SCHEDULE OF ASSESSMENTS – PHASE 2 ................ 91 
14.3
APPENDIX C: INTERNATIONAL SOCIETY OF 
NEPHROLOGY/RENAL PATHOLOGY SOCIETY (ISN/RPS) 2003 
CLASSIFICATION OF LUPUS NEPHRITIS ........................................... 94
14.4
APPENDIX D: INVESTIGATOR SIGNATURE PAGE ........................... 95 
14.5
APPENDIX E: EXCLUDED MEDICATIONS .......................................... 96 
 






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WHO
World Health Organization
 


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2
BACKGROUND INFORMATION
2.1
Disease Background 
2.1.1
Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is a complex multi-organ autoimmune disease that is 
characterized by the development of a wide variety of autoantibodies, especially to 
components of the nucleus, specifically to DNA, RNA, and histones, in addition to red blood 
cells, platelets, serum proteins, and phospholipids.  
SLE affects young adults, occurs more frequently in females than males (9:1 ratio), and is 
more common in African American, African Caribbean, Hispanic, and Asian populations 
(approximately 200 cases per 100,000) than in Caucasians (approximately 40 cases per 
100,000). It is estimated that there are approximately 250,000 patients with SLE in the 
United States of America (U.S.). 
1, 2 
Clinical manifestations range from relatively mild skin rashes and arthritis to 
glomerulonephritis, antibody mediated hemolytic anemia and thrombocytopenia, vasculitis, 
cardiac disease, and central nervous system disorders including seizures, psychosis, and 
cerebral vascular accidents
3, 4. Accurate diagnosis of SLE can be difficult because the clinical 
manifestations vary considerably between patients, and the individual signs and symptoms of 
SLE can have multiple etiologies. Classification criteria have been developed by the 
American College of Rheumatology (ACR) 
4, 5, with a proposed revision by the Systemic 
Lupus International Collaborating Clinics (SLICC)
6.  
SLE is thought to be the result of dysfunction of multiple components of the immune system, 
including defective clearance of apoptotic cellular components, a break in T-cell tolerance 
induction, and generation of antinuclear antibodies (ANAs) such as anti-double stranded 
DNA (anti-dsDNA) 
7. These ANAs complex with antigens to create antigen-antibody 
(Ag-Ab) complexes which are deposited in various tissues and initiate inflammatory 
reactions via complement activation (e.g., arthritis and glomerulonephritis). Type II 
hypersensitivity reactions can also occur in which antibodies directly target host cells and 
activate immune effector mechanisms that lead to phagocytosis (e.g., hemolytic anemia or 
immune thrombocytopenia). These inflammatory reactions lead to excessive complement 
activation, secretion of inflammatory cytokines, and activation of macrophages and 
neutrophils. 
Currently, there is no cure for SLE. Treatment is targeted at controlling inflammation with a 
variety of anti-inflammatory and immunosuppressive agents including mycophenolate 
mofetil (MMF), azathioprine (AZA), cyclophosphamide, corticosteroids, aspirin, other 
nonsteroidal anti-inflammatory drugs (NSAIDs), and antimalarials 
8. Of the 3 types of 
treatments approved for SLE, NSAIDs were approved in 1948; hydroxychloroquine and 
corticosteroids were approved in 1955; and belimumab, a monoclonal antibody targeting the 
B-lymphocyte stimulator (BLyS), was approved in 2011 
9.  


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2.1.2
Lupus Nephritis 
Lupus nephritis (LN) is one of the most serious complications of SLE. LN is a disease 
comprising a spectrum of vascular, glomerular, and tubulointerstitial lesions and develops in 
about 50% of SLE patients within 10 years of their initial diagnosis 
10 (also see: EMA Draft 
Guideline Feb 2015 
11). LN is associated with considerable morbidity, including an increased 
risk of end-stage renal disease requiring dialysis or renal transplantation and an increased risk 
of death. The prevalence of LN is approximately 74,000 in the U.S. and varies by race, 
occurring in approximately 20% of Caucasians and up to 60% of Blacks, Hispanics, and 
Asians with SLE
2, 12, 13.  
LN results when Ag-Ab complexes (predominantly DNA-anti-DNA) are deposited in the 
glomerular mesangium and glomerular basement membrane and activate serum complement.
The resulting inflammatory response causes damage to the glomerular epithelium with loss 
of function. It is often accompanied by mesangial proliferation and subsequent sclerosis of 
the glomeruli. Histopathologically, LN can take many forms, ranging from a normal 
glomerular architecture with Ag-Ab complexes identified by immunofluorescence, to 
proliferative glomerulonephritis or wide-spread sclerosis of the glomeruli associated with 
end-stage renal disease. The proliferative and membranous forms of glomerulonephritis are 
most frequently associated with proteinuria which often reaches nephrotic levels. LN is 
classified according to the International Society of Nephrology/Renal Pathology Society 
2003 classification of lupus nephritis (ISN/RPS) (see Section 14.3).
14  
2.2 
Treatment of Lupus Nephritis  
There are no approved therapies for the treatment of LN. Management typically consists of 
induction therapy to achieve remission and long-term maintenance therapy to prevent 
relapse. The ACR and European League Against Rheumatism guidelines 
15, 10 recommend 
treatment with corticosteroids, including an optional initial pulse intravenous (IV) 
methylprednisolone, then prednisone or equivalent, in combination with either MMF or high- 
or low-dose cyclophosphamide, followed by maintenance treatment with either MMF or 
AZA. 
Approximately 50% of patients respond to these treatment regimens with improvement in 
proteinuria, but only about 25% attain a complete renal response that is frequently defined as 
normalization of proteinuria and stabilization or improvement in serum creatinine, after 
1 year of treatment 
16,17. Attainment of complete renal response leads to a dramatic decrease 
in risk of end-stage renal disease 
18. Thus, approximately 75% of patients with LN have a 
sub-optimal response to induction therapy. These patients may subsequently receive 
treatment with a variety of alternative immunosuppressive or experimental agents, including 
rituximab, cyclosporine, tacrolimus, or other agents, in combination with long-term 
corticosteroids 
19. These patients remain at risk for the development of end-stage renal 
disease, in addition to complications from continued treatment with immunosuppressive 
agents and long-term corticosteroids.  














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In the Phase 1b portion, at least 6 patients per dose level will be enrolled to receive SC 
injections of KZR-616. Patients eligible for this part of the study must demonstrate adequate 
SLE disease activity at screening, be serologically positive, and may currently be on at least 
one SLE therapy, including oral corticosteroid, immunosuppressant (MMF, AZA, MTX, or 
leflunomide), and/or antimalarial agents, with stable dosage regimen. As these patients 
continue to have active SLE disease despite standard of care therapy, they are in need of an 
effective new treatment. As this is the first multiple dose study of KZR-616 in SLE patients, 
dose administration and step-wise evaluation is carefully outlined, including a sentinel 
patient in each dose cohort. Decisions to escalate, expand, or decrease dose level or 
frequency following the first 4 weeks of treatment for at least 4 evaluable patients in a cohort 
will depend on review by a Data Monitoring Committee (DMC).  
In the Phase 1b portion of the study, a 4-week period of dose-limiting toxicity (DLT) 
evaluation for at least 4 evaluable patients in each cohort is proposed. Based on nonclinical 
toxicity studies, tolerability after 4 weeks of treatment is predictive of safety through 
13 weeks of treatment. In addition, exposure data in healthy subjects show that KZR-616 is 
rapidly cleared and has no accumulation. Weekly administration of KZR-616 could be 
interpreted as serial episodic dosing, with potential AEs and DLTs likely to occur upon initial 
exposure and with a reduced risk with repeat dosing based on the results of KZR-616-001. 
These safety data will support the use of the RP2D of KZR-616 in patients with active 
proliferative LN for which there is a potential to increase the depth or frequency of response 
to background standard therapy. In addition, these data will be used to inform the design of 
future studies in non-renal SLE.  
In the Phase 2 portion of the study, a total of 20 patients with active proliferative Class III or 
IV LN (with or without Class V disease) will be enrolled to receive KZR-616 for a total of 
24 weeks. Safety will be assessed throughout the 24 weeks of dose administration and the 
follow-up which will continue for 12 weeks post last dose. As this will be the first study of 
KZR-616 in patients with active proliferative LN, the data obtained are anticipated to be 
sufficient to enable design of future development studies for KZR-616.  
Proof of activity is based on multiple disease response assessments in LN and SLE including 
evaluation for improvements in kidney function (changes in proteinuria and estimated 
glomerular filtration rate [eGFR]), changes in lupus disease assessments (Systemic Lupus 
Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and, for the Phase 1b only, the 
British Isles Lupus Assessment Group [BILAG]), changes in serum biomarkers of disease 
(ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein [anti-RNP], anti-Ro/La [anti-
SSA/SSB], C3/C4, and 50% hemolytic complement [CH50]), and changes in daily 
corticosteroid use.  
 
 




























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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such 
as receipt, reconciliation and final disposition records).  
6.2 
Study Drug Accountability
On receipt of the study drug, the investigator (or deputy) will conduct an inventory of the 
supplies and verify that study drug supplies are received intact and in the correct amounts. 
The monitor may check the study supplies at each study center at any time during the study. 
It is the responsibility of the study monitor to ensure that the investigator (or deputy) has 
correctly documented the amount of the study drug received, dispensed, and returned on the 
dispensing log that will be provided. A full drug accountability log will be maintained at the 
study center at all times. The study monitor will perform an inventory of study drug at the 
closeout visit to the study center. All discrepancies must be accounted for and documented. 
 
















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changes from physical examination will be recorded as AEs. SLE signs captured in the SLE 
assessment instruments will not be recorded for the brief physical examination unless they 
are classifiable as SAEs.
8.2.4 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) is to be performed prior to vital signs, following 
10 minutes of supine rest. The investigator or qualified designee will review and indicate if 
the ECG is normal or abnormal, and whether clinically significant. Any medically significant 
changes from the screening ECG will be recorded as an AE. 
8.2.5 
Chest X-ray 
A chest x-ray will be obtained during the screening period if there is no previous chest x-ray 
performed within the 12 weeks prior to signing informed consent. A chest x-ray that has no 
evidence of malignancy, active infection, or clinically significant abnormalities (unless due 
to SLE) is required for enrollment. 
8.2.6 
Clinical Laboratory Evaluations  
Clinical laboratory tests for safety (hematology, serum chemistries, urinalyses, coagulation 
tests, serum pregnancy) and other tests during scheduled visits will be performed at a central 
laboratory. Urine pregnancy tests may be performed at the site using a licensed test.
Abnormal safety laboratory results that are considered clinically significant (or potentially 
clinically significant) should be repeated as soon as possible (preferably within 24-48 hours).  
Unscheduled or additional laboratory samples may be collected and analyzed by local 
laboratories if immediate results are necessary for management of treatment-emergent AEs 
or dosing determination. Unless otherwise noted, when scheduled simultaneously with a 
dosing visit, samples for laboratory evaluations should be collected prior to administration of 
study medications.  
Detailed instructions for sample collection, processing, storage and shipment will be 
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CLASI
The CLASI consists of 2 scores; the first summarizes the activity of the disease and the 
second is a measure of the damage done by the disease 46. Activity is scored on the basis of 
erythema, scale/hypertrophy of skin and mucous membranes, acute hair loss, and nonscarring 
alopecia. Damage is scored in terms of dyspigmentation and scarring, including scarring 
alopecia. Patients are asked whether dyspigmentation due to cutaneous lupus erythematosus 
lesions usually remains visible for more than 12 months, which is taken to be permanent. If 
so, the dyspigmentation score is doubled. The scores are calculated by simple addition based 
on the extent of the symptoms. The extent of involvement for each of the skin symptoms is 
documented according to specific anatomic areas that are scored according to the worst 
affected lesion within that area for each symptom.  
Physician Global Assessment of Disease Activity  
The Physician Global Assessment of Disease Activity (PGA) is used to quantify disease 
activity and is measured using an anchored visual analog scale (VAS). The PGA will be 
determined on a continuous VAS that asks the investigator to assess the patient’s current 
disease activity from a score of 0 (none) to 3 (severe) on a 100-mm VAS, with the 
assessment made relative not to the patient’s most severe state but the most severe state of 
SLE per the investigator’s assessment. 
When scoring the PGA, the assessor should always look back at the score from the previous 
visit. This assessment by the investigator must be blinded to the Patient Global Assessment 
of Disease Activity performed at the same visit.  
Patient Reported Outcomes 
Patient Global Assessment of Disease Activity
Patients will rate their global assessment of their SLE disease activity for the day of the visit 
in response to the statement “Considering all the ways your SLE affects you, please mark a 
vertical line on the scale below for how you are feeling today” using a 100-mm VAS where 0 
is “very good, no symptoms” and 100 is “very poor, very severe symptoms.”  
Patient Global Assessment of Pain
Patients are asked to assess the severity of pain in the past week on a 100-mm VAS with 0 
being no pain and 100 being severe pain. The assessment should be completed prior to the 
painful, tender, and swollen joint count examination. This assessment is part of the Health 
Assessment Questionnaire-Disability Index (HAQ-DI). 
Health Assessment Questionnaire-Disability Index 
The HAQ-DI will be used to assess the functional status of each patient.47 This 20-question 
instrument assesses the degree of difficulty a person has in accomplishing tasks of daily 
living in 8 functional areas (domains; i.e., dressing, arising, eating, hygiene, walking, 
reaching, grip, and outside activities) over the past week. Scores range from 0 (without any 


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difficulty) to 3 (unable to do). The highest scoring item in each domain is chosen. If an aid or 
device is used, or if assistance is required from another individual, then minimum score for 
that functional area/domain is 2. The final scores are equal to the mean of these 8 highest 
scores and range from 0-3, with higher scores indicating greater functional disability.  
8.3 
Pharmacokinetic Measurements  
Phase 1b only:  
Blood and urine samples will be collected from all patients to measure the blood and urine 
concentration of KZR-616 (and its metabolites, e.g., KZR-59587) as outlined in the 
Schedule of Assessments (Section 14.1, Appendix A).
Blood samples will be collected as outlined in the Schedule of Assessments (Section 14.1, 
Appendix A) to measure the plasma concentration of KZR-616 (AUC, maximum 
concentration [Cmax], time to maximum plasma concentration [Tmax]), and other PK 
calculations, etc.). At the visits and times specified, blood samples of approximately 4 mL 
will be collected. 
Urine samples will be collected over 0 to 5 and 5 to 8 hours and then pooled for analysis to 
measure amount of KZR-616 and its metabolites. 
Samples collected to measure investigational product concentration and metabolism and/or 
protein binding will be retained for as long as legally permitted in the country of origin. 
 


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8.4
Pharmacodynamics 
Phase 1b and Phase 2: 
The extent of proteasome activity in whole blood and isolated PBMCs will be assessed in 
blood samples collected as outlined in the Schedule of Assessments (Section 14.1, 
Appendix A, and Section 14.2, Appendix B, for Phase 1b and Phase 2, respectively).  
CT-L peptidase activity will be measured by a cleavable fluorogenic substrate enzymatic 
activity assay.  
KZR-616 occupancy of individual subunits of the proteasome in whole blood and PBMCs is 
measured by the Proteasome Constitutive/Immunoproteasome Subunit enzyme-linked 
immunosorbent assay (ELISA) (ProCISE), a subunit-specific proteasome active site ELISA.
8.5 
Biomarker Measurements 
8.5.1 
Cytokine Activity 
Phase 1b and Phase 2:  
Blood samples will be collected for assessment of cytokine activity and circulating 
leukocytes as outlined in the Schedule of Assessments (Section 14.1, Appendix A, and 
Section 14.2, Appendix B, for Phase 1b and Phase 2, respectively). 
8.5.2 
Gene Expression/Pharmacogenomics 
Phase 1b and Phase 2:  
Gene expression (RNA) profiling and genomic DNA genotyping will be assessed in blood 
samples. A whole blood sample will be collected for pharmacogenomic analysis for storage 
and analysis at a later date as specified in the Schedule of Assessments (Section 14.1, 
Appendix A, and Section 14.2, Appendix B, for Phase 1b and Phase 2, respectively) and to 
the extent permitted by the national and/or local laws and regulations. 
Samples will be used to conduct retrospective disease or population genetic research as a 
separate analysis not included in this study. Samples will be used to investigate variable 
response to KZR-616 and to investigate genetic variants thought to play a role in the diseases 
under investigation in this study. Assessment of variable response may include evaluation of 
AEs or differences in efficacy. The results may be reported in the separate report.  
8.5.3 
Urine Biomarkers 
Phase 1b (LN only)/Phase 2 (all): 
For patients who provide separate written consent, a portion of 24-hour urine collections will 
be utilized by the central laboratory to identify biomarkers for response and/or safety.  


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8.5.4
Sample Management/Future Research
All samples will be coded with the patient number. Samples and any data generated can be 
linked back to the patient as detailed in Section 4.3.
Biomarker samples donated for future research may be retained by the sponsor or its 
designee indefinitely or as permitted by the applicable laws and regulations in the relevant 
country in which the study is conducted. Additional consent for storage of samples will be 
requested as a separate approval line on the ICF. Remaining de-identified unused clinical 
samples (blood/urine) will be retained by the sponsor and used for the sponsor’s future 
research, including but not limited to the evaluation of immunoproteasome activity and of 
additional targets for novel therapeutic agents, the biology of the immunoproteasome, and to 
identify biomarkers for response and/or safety.  
If additional written consent is not provided, any remaining biological samples will be 
destroyed by sponsor or its designee following study completion.  
 






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9.4
Study Termination
The sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug or the company itself occur that makes further 
treatment of patients impossible. In this event, the investigator(s) will be informed of the 
reason for study termination. 
 


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10
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
10.1
Adverse Event Reporting
10.1.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical study patient 
administered a medicinal product, 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 it is related to the medicinal 
(investigational) product. This includes an exacerbation of pre-existing conditions or events, 
intercurrent illnesses, drug interaction or the significant worsening of the indication under 
investigation that is not recorded elsewhere in the eCRF under specific efficacy assessments. 
Anticipated fluctuations of pre-existing conditions, including the disease under study, that do 
not represent a clinically significant exacerbation or worsening need not be considered AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. 
AEs will be elicited by asking the patient a nonleading question, for example, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?” AEs 
should be reported on the appropriate page of the eCRF.
10.1.2 
Assessment of Severity 
Severity of AEs will be graded according to NCI-CTCAE version 4.03. If there is a change in 
severity of an AE, it must be recorded as a separate event. 
10.1.3 
Assessment of Causality 
AEs will be deemed related to study medication unless clearly unrelated to study medication.  
The principal investigator will assess the causal relationship. One of the following categories 
should be selected based on medical judgment, considering the definitions below and all 
contributing factors. 










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10.6
Unexpected Adverse Reactions
10.6.1
Unexpected Adverse Reaction Definition
An unexpected adverse reaction is any untoward and unintended response that is related to 
the administration of the study drug at any dose and that is not consistent with the applicable 
product information (e.g., investigators brochure for an unauthorized investigational 
medicinal product or summary of product characteristics for an authorized product). 
All suspected unexpected serious adverse reactions (SUSARs) will be subject to expedited 
reporting. The sponsor and/or the CRO shall ensure that all relevant information about a 
SUSAR that is fatal or life-threatening is reported to the relevant competent authorities and 
IEC/IRB within 7 days after knowledge by the sponsor of such a case and that relevant 
follow-up information is communicated within an additional 8 days. All other SUSARs will 
be reported to the relevant competent authorities and IEC/IRB within 15 days after 
knowledge by the sponsor of such a case. All investigators should follow up SUSARs until 
the event is resolved or until, in the opinion of the investigator, the event is stabilized or 
determined to be chronic. Post study SUSARs that occur prior to completion of the 12 weeks 
follow-up must be reported by the investigator to the sponsor. 
10.7 
Data Monitoring Committee 
To enhance the safety and integrity of the study data, a study-specific DMC consisting of 
principal investigators, medical monitors, and Kezar Life Sciences (hereafter, Kezar) 
designees will be convened to review the accumulating safety data for the study.  
For Phase 1b, safety review will occur for each cohort as it completes the first 4 weeks of 
treatment. The first safety review by the DMC will occur after the first 6 patients have been 
enrolled and received study drug and progressed to Week 4. Decisions to escalate, expand, or 
modify dose level(s) or frequency will depend on review of safety data by the DMC.  
The DMC will review cumulative Phase 1b study data and provide a recommendation for the 
Phase 2 dose.  
For Phase 2, the DMC will convene and review cumulative data on a periodic basis to be 
defined in a separate DMC charter. 
The specific responsibilities and composition of the DMC are outlined in a separate DMC 
Charter. In addition, the details of outputs provided for the meetings will be referenced in the 
separate document.  
 
 






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Laboratory, vital sign, ECG, and efficacy data will be summarized descriptively (mean, 
median, standard deviation [SD], and minimum and maximum values) by dose/treatment 
group and overall and will be summarized by protocol specified time point along with a 
summary of change from baseline at each protocol specified time point. Changes in physical 
examinations will be listed for each patient and described.  
PK analyses will include determination of plasma levels of KZR-616 including Cmax, Tmax, 
and AUC.  
All patients who receive any amount of study drug (Safety Population) will be included in 
the safety analyses. Descriptive statistics, including the numbers and percentages for 
categorical variables and the numbers, means, SDs, medians, minimums and maximums for 
continuous variables will be provided by dose/treatment group overall. 
11.2.2 
Analysis Population
Safety Population 
All patients who receive any amount of study drug will be included in the safety analyses.  
PK Analysis Population 
All patients who receive the Day 1 dose of KZR-616 and who have at least one post-dose 
concentration of KZR-616 measured will be included in the PK analysis population. Any 
protocol deviations affecting PK analyses may result in exclusion from summaries for 
individual time point concentrations, complete profiles, and/or PK parameters. These 
exclusions will be reviewed before database lock and confirmed with the sponsor before the 
implementation. 
Pharmacodynamics Analysis Population  
All patients who receive any amount of study drug and who have any measured results for 
PD assessment will be included in the PD analysis population. Any protocol deviations 
affecting PD analyses may result in exclusion from summaries for individual time point 
concentrations and/or complete profiles. These exclusions will be reviewed before database 
lock and confirmed with the sponsor before the implementation. 
11.3 
Assessments 
11.3.1 
Criteria for Evaluation – Safety Analysis  
Safety and tolerability is the primary endpoint for Phase 1b and a secondary endpoint for 
Phase 2. 
Safety for the study will be evaluated through monitoring and assessment of all AEs, 
physical examination findings, vital sign measurements (blood pressure, pulse, and body 
temperature), ECGs, and clinical laboratory test results (hematology, serum chemistry, 
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Severity of AEs will be assessed using the NCI-CTCAE, Version 4.03.  
All AEs occurring on or after treatment on Week 1, Day 1 through Week 25, Day 169 for 
Phase 1b and through Week 37, Day 253 for Phase 2 will be summarized by MedDRA
system organ class, preferred term, grade, and investigator assessment of causality.  
In addition, all SAEs, including deaths, will be listed separately and summarized. Extent of 
exposure to the study treatment will be summarized using descriptive statistics.
Full details of the analyses will be specified in the statistical analysis plan (SAP). With 
regard to inconsistencies, the SAP will take precedence over the protocol.  
11.3.2 
Criteria for Evaluation – Pharmacokinetic Analyses 
Phase 1b: 
Assessment of the Secondary Endpoint: 
Blood samples will be collected from all patients to measure the plasma concentration of 
KZR-616 on Days 1 and 29 of Weeks 1 and 5, respectively. Blood samples will be collected 
before dosing and 5, 15, 30 minutes and 1, 2, 4, and 8 hours after the injection. Plasma PK 
parameters, including Cmax, Tmax, AUC from time 0 to the last measured concentration 
(AUClast), and other applicable parameters such as elimination parameters data permitting, 
will be calculated for KZR-616. The PK parameters will be listed and summarized by 
dose/treatment group and type of the disease as applicable. Dose proportionality assessments 
and other comparisons such as effect of the type of disease may be performed. 
Concentrations will be listed and summarized for all patients by dose level and type of the 
disease as applicable. The excluded data will be flagged and explained in the footnotes. 
Urine PK of the drug will be analyzed from urine samples pooled from 0 to 8 hours post-dose 
(see Section 8.3). Total amount of excreted unchanged and metabolized drug (Ae) and 
percent fraction of dose excreted (%Fe) will be listed and summarized by dose/treatment 
group and type of disease, where applicable. Exploratory correlation between %Fe and eGFR 
may be evaluated. 
The PK results will be presented graphically as individual and mean plasma concentration 
plots. Statistical models will be presented by regression plots vs dose and box plots for 
different treatments. The details of the analysis will be further described in the SAP. 
11.3.3 
Criteria for Evaluation – Pharmacodynamic Analyses 
Pharmacodynamic analyses will be performed in both Phase 1b and Phase 2. The extent of 
proteasome activity in whole blood and isolated PBMCs will be assessed in blood samples 
collected.  
The PD effects of KZR-616 will be assessed by evaluating levels of proteasome activity. 
Proteasome CT-L peptidase activity will be measured by a cleavable fluorogenic substrate 
enzymatic activity assay. The inhibition of proteasome activity will be expressed relative to 


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individual patient matched pre-dose levels in whole blood and PBMCs, representing selective 
inhibition of constitutive proteasome and immunoproteasome, respectively.  
KZR-616 occupancy of individual subunits of proteasome in whole blood and PBMCs is 
measured by subunit-specific proteasome active site ELISA (ProCISE). KZR-616 
occupancy/ inhibition of constitutive and immune-proteasome specific subunits will be 
expressed relative to individual patient matched pre-dose levels. ProCISE will further 
confirm selective inhibition of constitutive proteasome and immunoproteasome by KZR-616. 
11.3.4 
Criteria for Evaluation – Biomarker and Other Analyses 
Obtain material to assess gene transcriptional and proteomic changes following KZR-616 
treatment including (i.e., RNA) profiling through ex vivo analysis of whole blood and PBMC 
samples. In the Phase 1b, blood samples will be collected on Day 1 of Weeks 1, 5, 17, and 25 
(For DNA genotyping a sample will be collected only on Day 1, Week 1). In the Phase 2, 
blood samples will be collected on Day 1 of Weeks 1, 17, 25, and 37 (For DNA genotyping a 
sample will be collected only on Day 1, Week 1). 
The immunomodulatory activity of KZR-616 will be assessed by evaluating levels of 
cytokines, including change from baseline.  
11.3.5 
Criteria for Evaluation – Efficacy Analyses
Phase 2:  
Assessment of Primary and/or Secondary Endpoints  
Please see Section 11.1.2 for a listing of secondary endpoints for Phase 2. 
Rate of renal response will be assessed at 24 weeks. Renal response will be classified as 
complete, partial [50% reduction in UPCR], or no renal response. Summary statistics (e.g., 
total number of patients with observed data, mean, median, SD, min, max for continuous 
endpoints; for binary endpoints: total number of patients observed, number of patients with 
the event of interest, percent) will be provided by dose in Phase 1b and for all patients 
combined in Phase 2. The primary efficacy endpoint in Phase 2 is percent of patients with 
50% reduction in UPCR after 24 weeks of treatment when compared to baseline. The null 
hypothesis is that the percentage is < = 20%; the alternative hypothesis is that the percentage 
is > 20%. The test of hypotheses will be carried out with an exact binomial test. The 
KZR-616-002 Statistical Analysis Plan contains details of the planned analysis.  
Phase 1b and Phase 2: Exploratory Endpoints:  
The efficacy of KZR-616 on SLE will be assessed using changes from baseline in study 
administered questionnaires/disease assessment tools and changes from baseline in 
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11.3.6
Handling of Missing Data
All withdrawals will be included in all analyses up to the time of withdrawal. Patients who 
are withdrawn prematurely from investigational product and/or the study will be included in 
all analyses regardless of the duration of treatment. There will be no imputation for missing 
data, unless otherwise specified. 
11.4 
Determination of Sample Size  
The study is not powered using statistical hypothesis testing.
11.5 
Interim Analysis 
Review of safety data will be carried out after each cohort in Phase 1b as explained above. 
There is no formal statistical interim analysis planned. 
 
 


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12
ETHICAL AND ADMINISTRATIVE CONSIDERATIONS
12.1
Compliance Statement 
The investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, International 
Council for Harmonisation (ICH) guidelines for current Good Clinical Practice (cGCP), and 
the applicable national and local laws and regulatory requirements. 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 
before the beginning of the study. On completion of the study, the regulatory authorities will 
be notified that the study has ended. 
12.2 
Institutional Review Board or Independent Ethics Committee  
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be submitted 
to the appropriate IEC/IRB. Written approval of the study and all relevant study information 
must be obtained before the study center can be initiated or the study drug is released to the 
investigator. Any necessary extensions or renewals of IEC/IRB approval must be obtained 
for changes to the study (i.e., amendments to the protocol, the ICF, or other study 
documentation). The written approval of the IEC/IRB together with the approved ICF must 
be filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the patients or the conduct of the study. The investigator will 
submit written summaries of the study status to the IEC/IRB as required. On completion of 
the study, the IEC/IRB will be notified that the study has ended. 
12.3 
Informed Consent and Human Patient Protection
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to current Good Clinical Practice (GCP). 
Patients will provide written informed consent before any study-related procedures are 
performed.
The investigator is responsible for ensuring that no patient undergoes any study-related 
examination or activity before that patient has given written informed consent to participate 
in the study. 
The investigator or designated personnel will inform the patient of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The patient should 
be given every opportunity to ask for clarification of any points s/he does not understand and, 
if necessary, ask for more information. At the end of the interview, the patient will be given 
ample time to consider the study. Patients will be required to sign and date the ICF. After 
signatures are obtained, the ICF will be kept and archived by the investigator in the 


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investigator’s study file. A signed and dated copy of the patient ICF will be provided to the 
patient or their authorized representative.
It should be emphasized that the patient may refuse to enter the study or to withdraw from 
the study at any time, without consequences for their further care or penalty or loss of 
benefits to which the patient is otherwise entitled. Patients who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
regulatory authorities, if required). The study patients will be informed about this new 
information and reconsent will be obtained. 
12.4 
Direct Access to Source Data, Source Documents, and Study Records  
Kezar or its representatives may periodically check a sample of the patient data recorded 
against source documents at the study site. The study may be audited by Kezar and/or 
regulatory agencies at any time. Investigators will be given notice before an audit occurs. 
The investigator will keep records of all original source data. This might include laboratory 
tests, medical records, and clinical notes. If requested, the investigator will provide the 
sponsor, applicable regulatory agencies, and applicable review boards with direct access to 
the original source documents. 
12.5 
Data Collection and Handling  
An EDC system will be used in this study. The site must define and retain all source records 
and must maintain a record of any data where source data are directly entered into the data 
capture system.  
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor. 
12.6 
Confidentiality  
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the FDA, as well as that of any other applicable 
agency(ies), will be granted direct access to the study patients’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of 
the patients to the extent permitted by the law and regulations. In any presentations of the 
results of this study or in publications, the patients’ identity will remain confidential.
All personal data collected and processed for the purposes of this study should be managed 
by the investigator and his/her staff with adequate precautions to ensure confidentiality of 


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those data, and in accordance with the Health Insurance Portability and Accountability Act, 
applicable to national and/or local laws and regulations on personal data protection. 
12.7
Financing and Insurance
Financing and insurance of this study will be outlined in a separate agreement between the 
CRO and the sponsor. 
12.8 
Audit and Inspection
Study centers and study documentation may be subject to Quality Assurance audit during the 
course of the study by the sponsor or its nominated representative. In addition, inspections 
may be conducted by regulatory authorities at their discretion. 
12.9 
Monitoring 
Data for each patient will be recorded on an eCRF. Data collection must be completed for 
each patient who signs an ICF and is administered study drug. 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the eCRF are 
accurate and reliable.  
The investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors, and 
representatives from regulatory authorities’ direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs.
12.10 
Data Management and Coding 
The sponsor or the CRO will be responsible for activities associated with the data 
management of this study. This will include setting up a relevant database and data transfer 
mechanisms, along with appropriate validation of data and resolution of queries. Data 
generated within this clinical study will be handled according to the relevant standard 
operating procedures of the data management and biostatistics departments of sponsor or the 
CRO. 
Study centers will enter data directly into an EDC system by completing the eCRF via a 
secure internet connection. Data entered into the eCRF must be verifiable against source 
documents at the study center. Data to be recorded directly on the eCRF will be identified 
and the eCRF will be considered the source document. Any changes to the data entered into 
the EDC system will be recorded in the audit trail and will be FDA CFR 21 Part 11 
compliant.
Medical coding will use MedDRA for concomitant diseases and AEs with World Health 
Organization (WHO) drug classifications being used for medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification.
Subsequent modifications to the database will be documented.  


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12.11
Reporting and Publication, Including Archiving
Essential documents are those documents that individually and collectively permit evaluation 
of the study and quality of the data produced. After completion of the study (end of study 
defined as the date of the last visit of the last patient), all documents and data relating to the 
study will be kept in an orderly manner by the investigator in a secure study file. This file 
will be available for inspection by the sponsor or its representatives. Essential documents 
should be retained for 2 years after the final marketing approval in an ICH region or for at 
least 2 years since the discontinuation of clinical development of the investigational product. 
It is the responsibility of the sponsor to inform the study center when these documents no 
longer need to be retained. The investigator must contact the sponsor before destroying any 
study-related documentation. In addition, all patient medical records and other source 
documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives 
of the study. Data from individual study centers in multicenter studies must not be published 
separately


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APPENDICES






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n
All AEs must be recorded on the patient’s electronic case report form (eCRF), starting at the time of informed consent and continuing through 12 weeks post 
last dose. Prior medications will be collected at the screening visit. Concomitant medications will be collected at each visit. 
Abbreviations: AEs = adverse events; ANA = antinuclear antibody; APTT = activated partial thromboplastin time; BILAG = British Isles Lupus Assessment Group; 
C3/C4 = complement 3 and 4; CH50 = 50% hemolytic complement; CRP = C-reactive protein; D = day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
EOS = End of Study; ESR = erythrocyte sedimentation rate; FCBP = females of child bearing potential; HAQ-DI = Health Assessment Questionnaire-Disability 
Index; HIV = Human immunodeficiency virus; hr = hour; Immunoglobulin (Ig); INR = international normalized ratio; min = minutes; m = month; 
PD = pharmacodynamics; PGA = Physician Global Assessment of Disease Activity; PK = pharmacokinetic; PtGA = Patient Global Assessment of Disease Activity; 
PtGP = Patient Global Assessment of Pain; SLE = Systemic Lupus Erythematosus (includes lupus nephritis); SLEDAI-2K = Systemic Lupus Erythematosus 
Disease Activity Index 2000; SLICC = Systemic Lupus International Collaborating Clinics; TB = tuberculosis; UPCR = Urine Protein to Creatinine Ratio.






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DI = Health Assessment Questionnaire-Disability Index; hr = hour; Immunoglobulin (Ig); INR = international normalized ratio; min = minutes; PGA = Physician 
Global Assessment of Disease Activity; PK = pharmacokinetic; PtGA = Patient Global Assessment of Disease Activity; PtGP = Patient Global Assessment of 
Pain; SLE = Systemic Lupus Erythematosus (includes lupus nephritis); SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000; SJC-
28 = Swollen 28-Joint Count; TJC-28 = Tender 28-Joint Count; SLICC = Systemic Lupus International Collaborating Clinics; TB = tuberculosis; UPCR = Urine 
Protein to Creatinine Ratio. 


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APPENDIX C: INTERNATIONAL SOCIETY OF NEPHROLOGY/RENAL 
PATHOLOGY SOCIETY (ISN/RPS) 2003 CLASSIFICATION OF LUPUS 
NEPHRITIS
Full text of the ISN/RPS article (The ISN/RPS 2003 classification of lupus nephritis: an 
assessment at 3 years. Markowitz GS, D'Agati VD, Kidney Int. 2007 Mar;71(6):491-5. Epub 
2007 Jan 31) is available from Elsevier here:  
http://www.kidney-international.com/article/S0085-2538(15)52418-6/pdf 
 


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APPENDIX D: INVESTIGATOR SIGNATURE PAGE
Protocol Title:
A Phase 1b/2 Study of KZR-616 in Patients with Systemic Lupus 
Erythematosus with and without Nephritis
 
Protocol Number:
KZR-616-002
Confidentiality and cGCP Compliance Statement
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and I 
will conduct the study as described in compliance with this protocol (and amendments), GCP, 
and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Kezar Life Sciences and of the IEC/IRB. I will submit the protocol 
amendments and/or any ICF modifications to Kezar Life Sciences and IEC/IRB, and approval 
will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
patients’ state of health will be regarded as confidential. No patients’ names will be disclosed. 
All patients will be identified by assigned numbers on all CRFs, laboratory samples, or source 
documents forwarded to the sponsor. Clinical information may be reviewed by the sponsor or its 
agents or regulatory agencies. Agreement must be obtained from the patient before disclosure of 
patient information to a third party. 
Information developed in this clinical study may be disclosed by Kezar Life Sciences, to other 
clinical investigators, regulatory agencies, or other health authority or government agencies as 
required. 
Investigator Signature
Date
Printed Name
Institution