Clinical trial NCT04287985
Conditions: Immunoglobulin A Nephropathy Glomerular Disease IgAN
Keywords: VIS649 Kidney Diseases Glomerulonephritis, IGA Glomerulonephritis Nephritis Autoimmune Diseases Immune System Diseases Immunoglobulins Antibodies Immunoglobulin A Immunologic Factors Physiological Effects of Drugs Proteinuria
Sponsor: Visterra, Inc.
Start date: 2020-07-20; Completion date: 2023-06-18
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of VIS649 in participants with immunoglobulin A (IgA) Nephropathy (IgAN)

Detailed description:
This is a Phase 2, double-blind, randomized, placebo-controlled study in patients aged 18 years and above with biopsy confirmed diagnosis of IgAN. The study is designed to test the safety and effectiveness of multiple doses of VIS649. The main objectives are to evaluate the safety and tolerability of VIS649 and to evaluate the dose response of different doses of VIS649 by measuring proteinuria.

The study is comprised of three main periods, Screening, Treatment (12 months) and Follow-Up (4 months). Approximately 144 patients will be enrolled. The findings from this study will form the basis for subsequent clinical development of VIS649.

VIS649 is a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of the cytokine A PRoliferation Inducing Ligand (APRIL), a key factor in the production of aberrantly glycosylated IgA1 (a-g- IgA1), which is critical to the pathogenesis of IgAN.

Arms: arm 1: Placebo, normal saline (0.9% NaCl) will be administered IV arm 2: Low dose of VIS649 administered IV arm 3: Medium dose of VIS649 administered IV arm 4: High dose of VIS649 administered IV
Interventions: intervention 1: Dose-Placebo intervention 2: Low Dose-VIS649 intervention 3: Medium Dose-VIS649 intervention 4: High Dose-VIS649
Intervention descriptions: intervention 1: Unit Dose Strength - 0.9%. intervention 2: Dose Level = Low intervention 3: Dose Level = Medium intervention 4: Dose Level = High

Protocol documents:
Prot_002.pdf: 
 
 
TITLE PAGE 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose Study to Evaluate the 
Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy 
PROTOCOL NUMBER: 
VIS649-201 
COMPOUND 
VIS649 
STUDY PHASE 
Phase 2 
SHORT TITLE: 
Phase 2 Study of VIS649 for IgA Nephropathy 
VERSION: 
2.0 
VERSION DATE: 
01 November 2019 
SPONSOR: 
Visterra, Inc.  
275 2nd Avenue 
Waltham, MA 02451 
 
 
REGULATORY AGENCY IDENTIFIER NUMBER(S) 
IND Number: 
135,282 
NCT 
TBD 
EudraCT Number:  
2019-002531-29 


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VIS649-201 Protocol Version 2.0 
 
 
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APPROVAL PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Multiple Dose Study to Evaluate the Efficacy and Safety of 
VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy 
 
This Clinical Study Protocol has been reviewed and approved by the Sponsor in order to ensure 
compliance with Good Clinical Practice. 
 
Sponsor Signatory: 
 
 
 
 


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VIS649-201 Protocol Version 2.0 
 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................7 
1.1 
Synopsis ........................................................................................................................7 
1.2 
Schema ........................................................................................................................16 
1.3 
Schedule of Assessments ............................................................................................17 
2. 
INTRODUCTION ......................................................................................................20 
2.1 
Study Rationale ...........................................................................................................20 
2.2 
Background .................................................................................................................21 
2.3 
Benefit/Risk Assessment ............................................................................................23 
2.3.1 
Risk Assessment .........................................................................................................23 
2.3.2 
Benefit Assessment .....................................................................................................26 
2.3.3 
Overall Benefit: Risk Conclusion ...............................................................................26 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................28 
4. 
STUDY DESIGN .......................................................................................................31 
4.1 
Overall Design ............................................................................................................31 
4.2 
Scientific Rationale for Study Design ........................................................................33 
4.3 
Justification for Dose ..................................................................................................35 
4.4 
End of Study Definition ..............................................................................................36 
5. 
STUDY POPULATION .............................................................................................37 
5.1 
Inclusion Criteria ........................................................................................................37 
5.2 
Exclusion Criteria .......................................................................................................38 
5.3 
Lifestyle Considerations .............................................................................................40 
5.4 
Screen Failures ............................................................................................................40 
6. 
STUDY INTERVENTION ........................................................................................41 
6.1 
Study Intervention(s) Administered ...........................................................................41 
6.2 
Preparation/Handling/Storage/Accountability ............................................................42 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................42 
6.4 
Study Intervention Compliance ..................................................................................43 
6.5 
Concomitant Therapy .................................................................................................43 
6.5.1 
Concomitant Therapy to be Avoided ..........................................................................43 


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6.6 
Dose Modification ......................................................................................................44 
6.7 
Intervention after the End of the Study .......................................................................44 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................45 
7.1 
Discontinuation of Study Intervention Dosing ...........................................................45 
7.1.1 
Temporary Discontinuation ........................................................................................45 
7.1.2 
Rechallenge .................................................................................................................45 
7.2 
Participant Discontinuation/Withdrawal from the Study ...........................................46 
7.3 
Lost to Follow-up .......................................................................................................46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................47 
8.1 
Efficacy Assessments .................................................................................................47 
8.1.1 
Twenty-four-hour Urine Sample Collection ...............................................................47 
8.2 
Safety Assessments .....................................................................................................47 
8.2.1 
Physical Examinations ................................................................................................47 
8.2.2 
Vital Signs ..................................................................................................................47 
8.2.3 
Electrocardiograms .....................................................................................................48 
8.2.4 
Clinical Safety Laboratory Assessments ....................................................................48 
8.3 
Adverse Events and Serious Adverse Events .............................................................48 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................49 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...........................49 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events .......................................50 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .............................50 
8.3.5 
Pregnancy ...................................................................................................................51 
8.4 
Treatment of Overdose ...............................................................................................51 
8.5 
Pharmacokinetics ........................................................................................................51 
8.6 
Pharmacodynamics .....................................................................................................52 
8.7 
Genetics ......................................................................................................................52 
8.8 
Biomarkers ..................................................................................................................52 
8.9 
Immunogenicity Assessments ....................................................................................53 
8.10 
Medical Resource Utilization and Health Economics ................................................53 


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9. 
STATISTICAL CONSIDERATIONS .......................................................................54 
9.1 
Statistical Hypothesis ..................................................................................................54 
9.2 
Sample Size Determination ........................................................................................54 
9.3 
Populations for Analyses ............................................................................................54 
9.4 
Statistical Analyses .....................................................................................................54 
9.4.1 
General considerations ................................................................................................55 
9.4.2 
Randomization and Stratification ...............................................................................55 
9.4.3 
Participant Disposition ................................................................................................55 
9.4.4 
Participant Demographics ...........................................................................................55 
9.4.5 
Efficacy Analysis ........................................................................................................55 
9.4.6 
Safety Analyses ..........................................................................................................56 
9.4.7 
Other Analyses ............................................................................................................56 
9.5 
Interim Analysis ..........................................................................................................57 
9.6 
Data Safety Monitoring Board ....................................................................................57 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................59 
10.1 
Appendix 1 ..................................................................................................................59 
10.1.1 
Regulatory and Ethical Considerations ......................................................................59 
10.1.2 
Financial Disclosure ...................................................................................................59 
10.1.3 
Data Protection ...........................................................................................................60 
10.1.4 
Dissemination of Clinical Study Data ........................................................................60 
10.1.5 
Source Documents ......................................................................................................61 
10.1.6 
Study and Site Start and Closure ................................................................................61 
10.1.7 
Publication Policy .......................................................................................................61 
10.2 
Appendix 2 ..................................................................................................................62 
10.3 
Appendix 3 ..................................................................................................................63 
10.3.1 
Definition of Adverse Event and Adverse Reaction ...................................................63 
10.3.2 
Definition of Serious Adverse Event ..........................................................................64 
10.3.3 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............65 
10.3.4 
Reporting of Serious Adverse Events .........................................................................66 


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10.4 
Appendix 4 ..................................................................................................................67 
10.4.1 
Definitions ..................................................................................................................67 
10.4.2 
Contraception Guidance .............................................................................................67 
10.4.3 
Collection of Pregnancy Information .........................................................................68 
10.5 
Appendix 5 ..................................................................................................................70 
11. 
REFERENCES ...........................................................................................................72 
 LIST OF TABLES  
Table 1:  
Schedule of Assessments ............................................................................................17 
Table 2: 
Summary of Potential Risks Associated with VIS649 ...............................................23 
Table 3: 
Study Objectives and Endpoints .................................................................................28 
Table 4: 
Study Interventions .....................................................................................................41 
Table 5: 
Pharmacokinetic and Serum Immunoglobulin Sampling Schedule ...........................52 
Table 6: 
Populations for Analysis .............................................................................................54 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews ...................................................57 
Table 8:  
Protocol-Required Safety Laboratory Assessments ...................................................62 
LIST OF FIGURES 
Figure 1:  Study Design Schema .................................................................................................16 
Figure 2: 
Simulated Percent Baseline Immunoglobulin A by Dose ..........................................35 
  


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1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Name of Sponsor: Visterra, Inc. 
Name of Investigational Intervention:  VIS649 
Protocol Title:  
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose 
Study to Evaluate the Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy (IgAN) 
Short Title:  
Phase 2 Study of VIS649 for IgA Nephropathy 
Rationale: 
VIS649 is a humanized immunoglobulin G (IgG2) monoclonal antibody that 
binds to and blocks the biological actions of the cytokine A PRoliferation 
Inducing Ligand (APRIL), a key factor in the production of aberrantly 
glycosylated IgA1 (a-g- IgA1), which is critical to the pathogenesis of IgAN. 
The central mechanism for the development of IgAN is the production of a-g 
IgA1. These a-g IgA1 act as autoantigens and trigger formation of 
autoantibodies forming circulating immune complexes which deposit in the 
mesangium of the glomeruli and trigger an inflammatory response and 
complement activation, causing damage to the kidneys. 
In data from a single-ascending dose study of VIS649 in healthy volunteers, 
VIS649 reduced serum levels of IgA and a-g IgA1. The current study will test 
the hypothesis that blocking the biological actions of APRIL in IgAN patients 
leads to reduction of serum IgA (including a-g IgA1) levels and will reduce or 
halt the progression of IgAN, as measured by decrease in proteinuria.  
The findings from this study will form the basis for subsequent clinical 
development of VIS649. 
Objectives and 
Endpoints: 
The key objectives and endpoints of the study are: 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and 
tolerability of multiple, monthly 
doses of VIS649 at each of 3 dosing 
levels, administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
AEs graded by severity, clinical 
laboratory tests, vital sign 
measurements, and physical 
examinations 
 
 


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Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of 
multiple, monthly doses of VIS649 
on proteinuria at each of 3 dosing 
levels, administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
Change from baseline in uPCR 
(measured on natural log scale from 
24-hour urine collection or the 
intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days 
after the twelfth dose is 
administered)  
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated 
doses of VIS649 at 3 dosing levels 
versus placebo on the following 
parameters: 
o uPCR at Month 9 and 15 (ie, 
4 months following the final 
[12th] monthly dose 
administration) 
 
 
o 24-hour urine protein excretion at 
Months 9, 12, and 15 
 
o ≥ 30% decline from baseline in 
uPCR at Months 9,12, and 15 
 
 
o Clinical remission, defined as 
reduction in 24-hour urine protein 
excretion to < 300 mg/day for at 
least 3 consecutive months.  
 
 
 
 
o 
Change from baseline in uPCR 
(measured on natural log scale 
from 24-hour urine collection or 
the intended 24-hour urine 
collection) at Months 9 and 15 
 
o 
Change from baseline in 
24-hour urine protein excretion 
from baseline to Months 9, 12, 
and 15 
o 
Participants in each group 
achieving a ≥ 30% decline from 
baseline in uPCR at Months 9, 
12, and 15 
o 
Participants in each group 
achieving clinical remission 
• 
eGFR at Months 12 and 15 
 
• 
To evaluate the effect of repeated 
doses of VIS649 at each dosing level 
compared with placebo on the 
following PD parameters: IgA, IgG, 
and IgM concentrations 
• 
To determine the PK profile of 
repeated dose of VIS649, at each 
dosing level 
• 
Change from baseline in eGFR at 
Months 12 and 15 
• 
Change from baseline in serum total 
IgA, IgG, and IgM concentrations at 
Months 9, 12, and 15 
 
 
• 
Serum PK parameters 
• 
To determine the PK/PD profile of 
VIS649, relating VIS649 PK 
parameters and biomarkers such as 
• 
Correlation of VIS649 PK 
parameters with changes in IgA, 
uPCR, and eGFR 


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changes in IgA to changes in 
proteinuria and eGFR 
• 
To screen for ADA responses 
• 
Serum ADA levels 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = anti-drug 
antibody; AE = adverse event; a-g IgA = aberrantly glycosylated immunoglobulin A; 
APRIL= A PRoliferation Inducing Ligand; ARB = angiotensin receptor blocker; 
eGFR = estimated glomerular filtration rate; Ig = immunoglobulin; 
IgAN = immunoglobulin A nephropathy; IV = intravenous(ly); MEST = Mesangial 
cellularity, endocapillary proliferation, segmental sclerosis, tubular atrophy; PD = 
pharmacodynamic; PK = pharmacokinetic; SOC = standard of care; uACR = urinary 
albumin/creatinine ratio; uPCR = urinary protein/creatinine ratio. 
Overall Design:  
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, 
multiple-dose study to evaluate the safety and efficacy of intravenously (IV) 
administered VIS649 over a 12-month treatment course in participants with 
IgAN. Participants will be enrolled from approximately 80 global sites in 
approximately 16 countries. 
Screening evaluations, including physical examinations, vital signs, 12-lead 
electrocardiogram (ECG), safety laboratory testing (serum chemistry, 
hematology, urinalysis, serology, and pregnancy), and 24-hour urine collection, 
will take place approximately 30 days prior to the first dose of study 
intervention.  
To be eligible, the participants should be on stable and maximally tolerated 
doses of either angiotensin-converting enzyme inhibitor (ACEI) or angiotensin 
receptor blocker (ARB) therapy, as per standard of care (SOC) and applicable 
guidelines, for at least 3 months. Participants must be on at least 50% of the 
maximum recommended dose of the ACEIs or ARB to be considered as having 
adequate renin-angiotensin-aldosterone system (RAAS) blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study, if their overall management of IgAN, including blood 
pressure control, is as per SOC and applicable guidelines. 
Enrolled participants must be adults, 18 years of age or older, with IgAN 
diagnosis confirmed by biopsy.  
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have 
been interpreted using the Mesangial cellularity, endocapillary proliferation, 
segmental sclerosis, tubular atrophy (MEST) (Cattran et al, 2009) or MEST-C 
scoring system (Trimarchi, Barratt et al. 2017) from the Oxford classification of 
IgAN.  
A MEST-C score finding on kidney biopsy of T2 or C2 is exclusionary for this 
study. If the biopsy was not reported using the Oxford classification schema, 
the following findings are exclusionary: a) > 50% tubular atrophy, and/or b) 
≥ 25% crescents.  
Participants must have Screening urinary protein/creatinine ratio (uPCR) 
≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 24-hour urine 
collection (or an intended 24-hour urine collection).  


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Participants must have estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Levey, Stevens et al. 2009).  
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. A total of 144 participants will be randomized with equal allocation 
(1:1:1:1) across the 4 intervention groups (approximately 36 participants per 
group). Randomization will be stratified first by region (Japan vs rest of world). 
A target of twelve or more participants are planned to be randomized in Japan; 
these participants will be randomized with equal allocation and without further 
stratification. The randomization for the rest of world will be stratified by 
screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
VIS649 or placebo will be administered as 12-monthly IV infusions starting on 
Day 1/Month 0. Participants will return to the study center on Day 8 and then 
monthly through Month 12 for safety, pharmacokinetic (PK) and/or 
pharmacodynamic (PD) assessments.  
Safety assessments will include review of adverse events (AEs) (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, 
injection site tolerability (including pain, irritation and tissue damage), clinical 
laboratory assessments (including biochemistry, hematology, and urinalysis), 
laboratory testing including serum Ig levels, vital sign measurements, and use 
of concomitant medications. 
Participants will return to the study center on Month 15, approximately 
120 days following the last dose of study intervention (Dose 12) for additional 
safety, PK, PD, and efficacy assessments. Participants discontinuing dosing 
earlier will attend an early termination visit at the time of study intervention 
discontinuation and will be encouraged to attend the study visits as per schedule 
of assessments (SOA).  
It is anticipated that a roll-over extension study will be designed to enable 
longer term therapy for randomized participants. Further details will be 
provided in a separate protocol. 
Number of 
Participants: 
Approximately 144 participants. A target of twelve or more participants are 
planned to be randomized and enrolled in Japan. The remaining participants 
will be enrolled at sites in the rest of world; there are no country specific 
enrollment targets.  
Intervention Groups 
and Duration: 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. VIS649 or placebo will be administered as a single, monthly IV 
infusion for 12 monthly doses.  
VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL 
infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The 
dose of study intervention for the duration of the study will be based on the 
participant’s Month 0 predose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour as a single 100 mL 
infusion, followed by a 25 mL saline flush. 


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An unblinded pharmacist will prepare drug or placebo for infusion. Participants, 
the Sponsor, the Investigator, and all other site study staff will be blinded to 
study intervention.  
The total study duration for each participant (from screening to end-of-study) 
will be up to 16 months [assuming 1 month for screening, 12 months for twelve 
monthly doses (including 30 days after the twelfth dose), and a 3-month safety 
follow-up].  
Target Population: 
Key inclusion criteria for eligibility into the study are the following: 
1. Participant is a male or female ≥ 18 years of age at the time of signing 
the informed consent. 
2. Participants must have source verified biopsy-confirmed IgAN. 
3. Participants has medical records showing that they have been on stable 
and maximally tolerated doses of either ACEI or ARB, as per SOC and 
applicable guidelines, for at least 3 months preceding screening. 
Participants should be on at least 50% of the maximum recommended 
dose of these agents to be considered as having adequate RAAS 
blockade. Participants who are unable to tolerate ACEI/ARB therapy 
may be eligible for participation in the study, if their overall 
management of IgAN, including blood pressure (BP) control, is as per 
SOC and applicable guidelines. 
4. Participants must have screening uPCR ≥ 0.75 g/g measured from a 
24-hour urine sample (or an intended 24-hour urine sample) or 24-hour 
urine protein ≥ 1.0 g/d, as measured from 24-hour urine sample (or an 
intended 24-hour urine sample). The proteinuria should be stable, 
defined as < 25% change when compared to values from ≥ 3 months 
previously (if available). If previous values are not available or if the 
change from a prior value is > 25%, a repeat measurement of 
proteinuria will be done after 15 days and the participant should fulfill 
the above proteinuria criteria to be eligible for randomization in the 
study. The proteinuria should be assessed when the participant is 
considered to be in steady state with no recent heavy exercise, fever, or 
other potential issues that could impact the result. 
5. Participants must have eGFR ≥ 45 mL/min/1.73 m2, calculated using 
the CKD-EPI formula. The eGFR should be stable, as defined by a 
< 25% change when compared to values from ≥ 3 months previously (if 
available). If previous values are not available or if the change from a 
prior value is > 25%, a repeat measurement of eGFR will be done after 
15 days and the participant should fulfill the eGFR criteria to be eligible 
for randomization in the study. The eGFR should be measured when 
the participant is considered to be in a steady state without recent 
changes in volume status, medications that could impact the result (eg, 
nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides, 
co-trimoxazole) or changes in dietary protein intake. 


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6. Participant’s serum Ig values must meet the criteria below: 
a. IgG: ≥ 700 mg/dL 
b. IgM: ≥ 40 mg/dL 
c. IgA: ≥ 70 mg/dL 
Key exclusion criteria:  
1. Participant has secondary forms of IgAN as defined by the treating 
physician (eg, Henoch-Schӧnlein purpura, minimal change disease with 
IgA deposits, infections associated with IgAN or IgAN associated with 
hepatic cirrhosis). 
2. Participant has co-existing chronic kidney disease, other than IgAN. 
3. Participant has evidence of additional pathological findings in the 
kidney biopsy (eg, diabetic kidney disease, membranous nephropathy, 
or lupus nephritis lupus). However, hypertensive vascular changes are 
acceptable. 
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 
from the Oxford IgAN classification schema. If MEST-scoring was not 
performed, the presence of > 50% tubulointerstitial fibrosis, or 
crescents in > 25% of glomeruli is exclusionary. 
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour 
urine protein > 3.5 g with concurrent hypoalbuminemia (serum albumin 
< 2.5 g/dL), hyperlipidemia (total cholesterol > 350 mg/dL), and 
edema. 
6. Participant has received a solid organ transplant, including kidney. 
7. Participant has received bone marrow or hematologic stem cell 
transplantation 
8. Participant is currently receiving systemic immunosuppression 
(excluding topical, ophthalmic, per rectum or inhaled corticosteroids).  
9. Participant has received systemic steroids within the 12 weeks prior to 
initial screening.  
10. Participant has received treatment with 2 or more systemic 
immunosuppressive agents within 2 years prior to initial screening 
11. Participant has chronic infectious diseases (eg, chronic urinary tract 
infection, chronic sinusitis, bronchiectasis, active pulmonary or 
systemic tuberculosis, chronic viral hepatitis, hepatitis C virus or 
hepatitis B virus or HIV infection).  
12. Participant has acute infectious disease at the time of screening. 
Participants may be rescreened following resolution of acute infection 
(such as urinary tract infection or respiratory tract infection), provided 
there is no evidence of an immunosuppressive condition that 
predisposed the participant to this infection.  
13. Participant has Type 1 diabetes. 


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14. Patient has uncontrolled Type 2 diabetes, as evidenced by a screening 
hemoglobin A1c value > 8%. 
15. Participant has uncontrolled blood pressure (> 160 mm Hg systolic or 
> 110 mm Hg diastolic) 
16. Participant has a history of chronic autoimmune neurodegenerative 
disorders such as multiple sclerosis. 
Data Safety 
Monitoring Board: 
An independent data safety monitoring board (DSMB) will review unblinded 
safety data. The DSMB will meet at 5 scheduled data review meetings and on 
an ad hoc basis as needed. Details regarding the content and scope of safety 
assessments, as well as the governing of the DSMB, will be described in a 
separate DSMB charter. 
Data safety monitoring board meetings will be scheduled as the following 
requirements are met: 
Scheduled DSMB Review 
Number of Participants and Treatment Exposure 
DSMB review #1 
Scheduled once 12 participants have been randomized 
and have completed at least 3 months of dosing. 
DSMB review #2 
Scheduled once 24 participants have been randomized 
and have completed at least 3 months of dosing. 
DSMB review #3 
Scheduled once ~25% of participants have been 
randomized and have completed 3 months of dosing. 
DSMB review #4 
Scheduled once ~50% of participants have been 
randomized and have completed 6 months of dosing 
and ~ 20 participants have completed 12 months of 
dosing 
DSMB review #5 
Scheduled once ~50% of participants have been 
randomized and have completed 12 months of dosing. 
Abbreviations: DSMB = data safety monitoring board. 
Statistical Methods: 
General Considerations 
All data collected will be documented using summary tables, figures, and/or 
data listings presented by intervention and dose group. For continuous 
variables, descriptive statistics (number [n], mean, geometric mean and 
coefficient of variation [%CV], as appropriate, median, standard deviation, 
minimum, and maximum) will be presented. For categorical variables, 
frequencies and percentages will be presented. As appropriate, a 95% CI will be 
presented. Graphical displays may be presented. 
Randomization and Stratification 
Participants will be randomly assigned in a 1:1:1:1 ratio to receive VIS649 at 2, 
4, or 8 mg/kg, or placebo, with approximately 36 participants randomized per 
intervention group. Randomization will be stratified first by region (Japan vs 
rest of world). Japanese participants will be randomized with equal allocation 
and without further stratification. Randomization for the rest of world will then 




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as implemented in NONMEM or equivalent software. Additional 
analyses and summaries may be generated as appropriate. 




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1.3 
Schedule of Assessments 
Table 1:  
Schedule of Assessments 
Procedures 
Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12/ 
ET3 
M15 
Nominal Study Day 
-301 
D1 Pre 
infusion 
D1 Post 
infusion 
D8 
D30 
D60 
D90 
D120 
D150 
D180 
D210 
D240 
D270 
D300 
D330 
D360 D450 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study Visit 
N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria review 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review of kidney biopsy4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Weight 
x 
x 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
Vital signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
    x 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
infusion7 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AE monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV, HCV, HIV 
serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β-hCG (females 
only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCG (females 
only) 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum chemistry8 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology9 
x 
x 
 
 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
x 


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VIS649-201 Protocol Version 0.2 
 
 
18 
Procedures 
Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12/ 
ET3 
M15 
Nominal Study Day 
-301 
D1 Pre 
infusion 
D1 Post 
infusion 
D8 
D30 
D60 
D90 
D120 
D150 
D180 
D210 
D240 
D270 
D300 
D330 
D360 D450 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Study Visit 
N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Urinalysis (dipstick and 
microscopy)10  
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
24-hour urine collection11 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
x 
Urine sample for uPCR 
determination 
x12 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x12 
x 
x 
x12 
x12 
Urine sample for uACR 
determination 
x12 
 
 
 
 
 
 
 
 
 
 
 
x12 
 
 
x12 
x12 
Blood sample for 
lymphocytes  
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
X 
x 
Serum for PK13 
 
x 
x 
x 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x 
x 
Blood for total IgA, IgG, 
and IgM13 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
Blood for IgA subtypes  
 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
Serum for APRIL1 
 
x 
x 
 
x 
x 
x14 
x 
x 
x14 
x 
x 
x14 
x 
x14 
x 
x 
Serum for a-g IgA1 and 
anti-IgA1 
x 
x 
 
 
 
 
x 
 
 
x 
 
 
 x 
 
 
x 
x 
Serum for ADA15 
 
x 
 
 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
Blood sample for DNA16 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample for 
exploratory biomarker 
assessments17 
 
x 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
Blood for markers of 
complement activity13 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Saliva samples for IgA 
levels  
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = anti-drug antibody; AE = adverse event; a-g IgA = aberrantly glycosylated immunoglobulin A; 
APRIL= A PRoliferation Inducing Ligand; ARB = angiotensin receptor blocker; β-hCG = beta-human chorionic gonadotropin; BAFF = B-cell activating factor; BP = blood 


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VIS649-201 Protocol Version 0.2 
 
 
19 
pressure; D = Day; ECG = electrocardiogram; eCRF = electronic case report form; EOS = end-of-study; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; HR = heart rate; Ig = immunoglobulin; IgAN = immunoglobulin A nephropathy; M = Month; N/A = not applicable; PD = 
pharmacodynamics; PK = pharmacokinetics; RR = respiratory rate; Scr = screening; SOC = standard of care; uACR = urinary albumin/creatinine ratio; uPCR = urinary 
protein/creatinine ratio. 
 
1 
All participants will undergo screening. To be eligible, participants should be on stable and maximally tolerated treatment with either ACEI or ARB, as per SOC and 
applicable guidelines, for at least 3 months. Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in the study, if their overall 
management of IgAN, including BP control, is as per SOC and applicable guidelines. 
2 
Participants must complete EOS assessments approximately 120 days after the last dose of study intervention. Participants discontinuing early will be encouraged to attend 
study visits as per the schedule, including the EOS visit. Adverse event and concomitant medication monitoring should be performed through the EOS visit; AEs that are 
ongoing at EOS should be monitored until resolution or 30 days after the EOS, whichever is shorter. 
3 
Participants discontinuing early must complete ET assessments at the time of treatment discontinuation. 
4 
A biopsy diagnostic of IgAN must have been performed and source-verified documentation must be available. 
5 
A complete physical examination, to include assessments of the cardiovascular, respiratory, gastrointestinal and neurological systems will be completed at the screening and 
end-of-treatment visit.  
6 
Vitals signs include BP, HR, RR, and temperature. Vital signs measurements on dosing days will be recorded within 15 (±5) minutes prior to the start of the infusion, every 
15 minutes until the infusion is complete, and 60 minutes and 2 hours postinfusion. 
7 
The dose of study intervention will be based on the M0 predose weight. 
8 
The comprehensive list of serum chemistry tests to be performed is provided in Appendix 2. A full serum chemistry panel will be obtained at screening and on M0, M3, M6, 
M9, M12, and M15; the following tests are required at other visits: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, and glucose. Local laboratory 
assessments may be performed at Investigator discretion throughout the study in the course of patient care (but not assessments that would potentially unblind treatment 
status, such as measurement of immunoglobulin levels). Any clinically significant abnormalities should be recorded in the eCRF.  
9 
The comprehensive list of hematology tests to be performed is provided in Appendix 2.  
10 
The comprehensive list of urinalysis tests to be performed is provided in Appendix 2. On days of 24-hour urine collection, the uPCR sample will be collected from the 
24-hour urine collection and routine urinalysis will be performed on a sample freshly voided during the clinic visit. 
11 
Participants will discard the first void and begin a 24-hour urine collection the day prior to the clinic visit. For all 24-hour urine collection, the following parameters will be 
obtained or derived: 24-hour urine volume, protein, albumin, and creatinine, uPCR, and uACR. 
12 
Samples should be taken from the 24-hour urine sample. 
13 
Up to 60 participants (approximately 15 per cohort) may have a more extensive PK and PD sampling schedule, as described in Table 5. Study participants agreeing to 
participate in this more intensive PK and PD sample collection sub-study will sign an additional informed consent for this activity.  
14 
Blood samples to be collected before and after study intervention infusion at all visits.  
15 
Samples for ADA assessment will be collected before the start of infusion. 
16 
Samples for evaluation of host genetic markers related to IgAN susceptibility loci, the APRIL/BAFF pathway, and/or immunity will be collected before the start of infusion. 
17 
On days of 24-hour urine collection, urine samples for exploratory biomarker analysis will be collected and stored from a sample freshly voided during the clinic visit. 
 


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20 
2. 
INTRODUCTION 
VIS649 is a humanized IgG2 monoclonal antibody being developed for the treatment of 
immunoglobulin A nephropathy (IgAN), an autoimmune glomerulonephritis characterized by the 
deposition of immunoglobulin A (IgA)-containing immune complexes in the kidney. 
2.1 
Study Rationale 
Immunoglobulin A nephropathy is a chronic disease affecting the kidneys. It is clinically 
characterized by proteinuria, hematuria and progressive decline of glomerular filtration rate 
(GFR). IgAN is characterized histologically by dominant or co-dominant deposition of IgA in 
the kidney glomerulus (Rodrigues, Haas et al. 2017). The central mechanism for the 
development of IgAN is the production of aberrantly glycosylated IgA1 (a-g IgA1) which has 
been attributed to a combination of genetic and environmental factors. These a-g IgA1 act as 
auto-antigens and trigger formation of autoantibodies forming circulating immune complexes 
which deposit in the mesangium of glomeruli and trigger an inflammatory response and 
complement activation (Kiryluk, Moldoveanu et al. 2011, Berthoux, Suzuki et al. 2012, Kiryluk, 
Novak et al. 2013, Kiryluk, Li et al. 2014, Kiryluk and Novak 2014). This results in episodic and 
cumulative kidney damage. Natural history studies indicate that IgAN may progress to end stage 
kidney disease in approximately 30% of patients, over the course of 10 years (Lai, Tang et al. 
2016).  
Proteinuria is an important marker of progression of renal disease in patients with IgAN. Patients 
with significant proteinuria (> 1.0 g/day) have a faster decline of eGFR and progression to 
end-stage renal disease (ESRD), when compared to patients with lower degrees of proteinuria 
(< 500 mg/day). Hence reduction in proteinuria is a crucial aspect in the management of IgAN 
(Reich, Troyanov et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016). 
The cytokine A PRoliferation Inducing Ligand (APRIL), which belongs to the tumor necrosis 
factor ligand superfamily, has emerged as a key factor in the pathogenesis of IgAN through 
mediation of the immunoglobulin isotype switch during B-cell development, production of IgA, 
plasma-cell survival, and possibly specifically influencing production of a-g IgA1 as well 
(Castigli, Scott et al. 2004, Varfolomeev, Kischkel et al. 2004, Endo, Nishio et al. 2007, Bossen, 
Cachero et al. 2008). Studies in IgAN patients have shown that elevated APRIL levels correlate 
with poor kidney outcomes, when compared with patients with lower APRIL levels (Han, Yang 
et al. 2016, Zhai, Zhu et al. 2016). A similar trend is also seen with a-g IgA1 levels, with higher 
levels associated with faster and more frequent progression to kidney failure when compared to 
patients with lower a-g IgA1 levels (Castigli, Scott et al. 2004, Berthoux, Suzuki et al. 2012, 
Zhao, Hou et al. 2012). 
VIS649 is a humanized IgG2 monoclonal antibody (mAb) that binds to and blocks the biological 
actions of APRIL, preventing its binding to its receptors, transmembrane activator and CAML 
interactor (TACI), and B-cell maturation antigen (BCMA). Blocking the biological actions of 
APRIL reduces the production of IgA. The hypothesis to be tested in this study is that a decrease 
in the production of IgA and a-g IgA1 will diminish the formation of circulating immune 
complexes and their deposition in the glomeruli, allowing injury repair and clinical 
improvement, as measured by reduction in proteinuria. 


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21 
In data from a single-ascending dose study (VIS649-101) of VIS649 in healthy participants, 
VIS649 reduced serum levels of IgA and a-g IgA1. The current study will test the hypothesis that 
blocking the biological actions of APRIL in IgAN patients leads to reduction of serum IgA 
(including a-g IgA1) levels and will reduce or halt the progression of IgAN as measured by 
reduction in proteinuria (the study’s primary efficacy endpoint). The current study will also 
assess the safety of VIS649 in patients with IgAN and collect extensive data on 
pharmacokinetics (PK) and pharmacodynamics (PD).  
The findings from this study will form the basis for subsequent clinical development of VIS649. 
2.2 
Background 
Immunoglobulin A nephropathy is one of the most common primary glomerular diseases and 
affects patients globally, with some geographical variation in incidence and prevalence (Wyatt 
and Julian 2013, Rodrigues, Haas et al. 2017, Schena and Nistor 2018). Clinical presentation 
varies from incidentally detected asymptomatic hematuria and proteinuria to rapidly progressive 
glomerulonephritis requiring dialysis. Immunoglobulin A nephropathy is a significant cause of 
chronic kidney disease (CKD) and ESRD, with 30–40% of patients reaching ESRD 20–30 years 
after the first clinical presentation. Immunoglobulin A nephropathy can occur in either sporadic 
(90–95%) or familial (5%–10%) patterns. Patients with familial IgAN might have poorer 
prognoses than those with sporadic disease, with an increased risk of progression to renal failure 
(Lai, Tang et al. 2016). 
Immunoglobulin A nephropathy is diagnosed by kidney biopsy, which shows dominant or 
co-dominant IgA deposition on immunofluorescence. The pathogenesis of IgAN is currently 
thought to be a multi-hit process, the “first hit” being the production of a-g-IgA1. The primary 
defect is the deficiency of galactose in the hinge region of IgA1. As a consequence, the 
N-acetylgalactosamine in the truncated IgA1 hinge region glycan is exposed and acts as an 
autoantigen. Multiple cohort studies have shown the relationship between elevated a-g IgA1 and 
IgAN, with higher a-g IgA1 levels having more rapid disease progression. The “second hit” 
consists of IgA and IgG auto-antibody production against these a-g IgA1. The “third hit” consists 
of formation of circulating immune complexes consisting of the IgG/IgA auto antibody and 
a-g IgA1 antigen complex. The “fourth hit” consists of deposition of these circulating immune 
complexes in the mesangium of the glomeruli. These antigen-antibody complexes are 
nephritogenic and trigger an inflammatory response leading to infiltration of macrophages, 
monocytes and T cells, local release of cytokines, complement activation and activation of 
renin-angiotensin cascade. This leads to glomerular injury and tubulointerstitial fibrosis, 
clinically manifesting as proteinuria, hematuria, hypertension and reduced GFR (Berthoux, 
Suzuki et al. 2012, Floege, Moura et al. 2014, Knoppova, Reily et al. 2016, Mestecky, Novak et 
al. 2016). 
Proteinuria is a common manifestation of IgAN and the degree of proteinuria correlates with 
disease progression, with faster decline of estimated glomerular filtration rate (eGFR) and 
progression to ESRD in patients with high-grade proteinuria (> 1.0 gm/day) when compared to 
patients with low-grade proteinuria (< 0.5 gm/day) (Reich, Troyanov et al. 2007, Nam, Kie et al. 
2014, Inker, Mondal et al. 2016, Thompson, Carroll et al. 2019). Control of proteinuria is a key 
therapeutic target in patients with IgAN. Measures to control proteinuria often consist of 
renin-angiotensin-aldosterone system (RAAS) blockade in the form of angiotensin-converting 


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22 
enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy, blood pressure (BP) 
control, statins to control cholesterol, smoking cessation, low-salt diet, low-protein diet and 
avoidance of nephrotoxic drugs. If patients continue to have significant proteinuria despite these 
measures, they are usually treated with nonspecific immunosuppressive agents such as steroids, 
azathioprine, mycophenolate mofetil, or cyclophosphamide (Boyd, Cheung et al. 2012, KDIGO 
2012, Radhakrishnan and Cattran 2012, Barbour and Feehally 2017, Rodrigues, Haas et al. 
2017). These drugs, especially steroids (Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 2015, 
Tesar, Troyanov et al. 2015, Lv, Zhang et al. 2017) have been shown to be beneficial from a 
renal perspective in some studies, but their use is often complicated by significant adverse effects 
such as increased risk of infections, metabolic derangements, cosmetic changes, weight gain, 
fractures, and neuropsychiatric manifestations. Some of these agents have other significant risks 
such as increased risk of malignancies with prolonged administration. The significant side effects 
of these drugs preclude chronic use of these agents and limit their benefits in a chronic disease 
such as IgAN. 
APRIL is a member of the tumor necrosis factor (TNF) superfamily of ligands and is emerging 
as a key mediator in IgAN pathogenesis and disease progression based on a convergence of 
genetic, biochemical, and clinical data. APRIL is produced by myeloid and mucosal epithelial 
cells. APRIL regulates B cell-mediated immune responses through several mechanisms, 
including class-switch recombination, principally through its 2 receptors, TACI and BCMA. 
APRIL is also important for plasmablast differentiation in secondary lymphoid organs. In 
addition, myeloid-derived APRIL mediates plasma cell survival by promoting the formation of 
so-called “survival niches” within the bone marrow microenvironment and mucosal 
compartments, leading to the establishment of a reservoir for long-lived antibody-secreting cells 
(Bossen, Cachero et al. 2008). 
Evidence of the critical role of APRIL in IgAN includes the following: (a) serum a-g IgA1 
(auto-antigen) levels are elevated in patients with IgAN and correlate with APRIL levels and 
disease severity; (b) genome-wide association studies link APRIL to the disease; (c) serum 
APRIL is elevated in patients with IgAN and higher APRIL levels among IgAN patients are 
associated with more rapid progression to kidney failure (Mestecky, Raska et al. 2013, Han, 
Yang et al. 2016, Muto, Manfroi et al. 2017). 
In a mouse model of IgAN, administration of an anti-APRIL antibody similar to VIS649 led to 
lower IgA deposits in the kidney, lower proteinuria, and less glomerular sclerosis compared with 
animals administered a control antibody that does not bind APRIL. These data suggest that 
APRIL plays a key role in the pathogenesis of IgAN and that blocking APRIL could be an 
attractive approach for the treatment of IgAN (Myette, Kano et al. 2019).  
VIS649 is a humanized IgG2 mAb against the biologically active form of APRIL. VIS649 was 
tested in healthy human participants in a Phase 1, randomized, placebo-controlled, 
single-ascending dose first-in-human study to assess the safety, tolerability, PK and PD of 
VIS649 (Study VIS649-101). The study enrolled 51 participants in 5 sequential dosing cohorts. 
Participants in Cohorts 1 to 4 received 4 different dose levels of VIS649 (0.5, 2.0, 6.0, and 
12 mg/kg respectively), enrolling 9 participants per cohort (7 participants receiving VIS649 and 
2 participants receiving placebo). Cohort 5 had 15 participants with 10 receiving VIS649 and 
5 participants receiving placebo. Participants in Cohort 5 received 6.0 mg/kg of VIS649 on 
Day 1 and subsequently received a tetanus and diphtheria (Td) vaccine on Day 28. Blinded group 


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VIS649-201 Protocol Version 2.0 
 
 
23 
data are available, including IgA levels. Preliminary data show that the total serum IgA declined 
by up to 70% from normalized baseline values in these healthy participants. The vaccine 
response in Cohort 5 was intact, with a comparable IgG response to Td vaccine in participants 
receiving VIS649 and participants receiving placebo. Mean serum IgG levels declined by up to 
30% below normalized baseline values and mean immunoglobulin M (IgM) levels showed a 
marked decline and were up to 80% below the normalized levels. These declines in the 
immunoglobulin (Ig) levels were reversible and the time taken to restoration of the Ig levels to 
baseline was dependent on the dose of VIS649, with higher doses requiring a longer time period. 
VIS649 was very well tolerated across all dose levels and there were no serious adverse events 
(SAEs) attributed to VIS649. Further details can be found in the Investigator’s Brochure.  
The adverse risk–benefit ratio of nonspecific immunosuppressive agents, preclude the chronic 
use of such agents and highlight the need for the development of an effective alternative that acts 
specifically at relevant pathophysiological factors in IgAN and is also likely safe for chronic use. 
2.3 
Benefit/Risk Assessment 
2.3.1 
Risk Assessment 
Table 2 summarizes the important potential risks that have been recognized during the conduct 
of VIS649 nonclinical and clinical development programs. At present, all are considered 
potential risks.  
More detailed information about the risks and reasonably expected adverse events (AEs) of 
VIS649 may be found in the Investigator’s Brochure. 
Table 2: 
Summary of Potential Risks Associated with VIS649 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
IgA suppression risk 
Based on the mechanism of action of 
VIS649, preclinical studies, and human data 
from healthy volunteers, total serum IgA 
levels are expected to be suppressed to nadir 
levels 
 
There is increasing recognition that selective 
IgA deficiency, which has typically been 
associated with IgA levels below the lower 
limit of detection 
 
, may be associated with recurrent 
sinopulmonary infection, allergy, 
autoimmunity, and gastrointestinal 
microbiome perturbation (Yazdani, Azizi et 
al. 2017, Fadlallah, El Kafsi et al. 2018).  
VIS649 is expected to reduce but not ablate 
IgA expression. Additionally, the syndrome 
of selective IgA deficiency is often associated 
with additional immunologic impairments, 
including T-cell disorders which are not 
expected to occur with VIS649 dosing. 
• 
Serum IgA, IgG, and IgM will 
be measured on a monthly 
basis (as blinded data, to be 
made available for routine 
DSMB review). The DSMB 
will assess unblinded safety 
data on a scheduled and ad hoc 
basis as needed, including 
AEs, laboratory data and Ig 
data. The DSMB charter calls 
for assessment of the 
relationship of AEs to 
observed Ig levels (IgA, IgG 
and IgM) in study participants. 
• 
If needed, the DSMB charter 
also calls for specific 
risk-mitigation strategies 
including, but not limited to, 
change in inclusion/exclusion 
criteria, establishing criteria 
for stopping study intervention 
in a participant or a cohort, 




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25 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
increased risk of auto-immune diseases(Yel, 
Ramanuja et al. 2009, Louis and Gupta 2014, 
Louis, Agrawal et al. 2016, Janssen, Macken 
et al. 2018). Selective IgM deficiency is 
usually associated with other defects such as 
decreased T-helper cell activity, increased 
isotype specific suppressor T cells, increased 
CD8 Treg cells, and intrinsic B cell defects.  
VIS649 is not expected to have effects such 
as these on cellular immunity. 
Nonspecific 
immunosuppression risk 
There is the possibility of nonspecific 
immunodeficiency with potential risk of 
exacerbation of pre-existing latent infection 
or poor response to new infection. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
Participants with acute or 
chronic infections at the time 
of screening are prohibited 
from enrollment.  
• 
Participants with underlying 
iatrogenic or primary 
immunodeficiency syndromes 
are prohibited from 
enrollment.  
• 
DSMB monitoring will 
include careful attention to 
infection-related AEs. 
• 
Concurrent treatment with 
systemic corticosteroids or 
other immunosuppressive 
therapy is prohibited during 
study conduct. 
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) 
There was no effect of VIS649 on measured 
plasma cytokine concentrations in the 
monkey toxicology studies, and VIS649 did 
not stimulate significant cytokine release in 
an in vitro human peripheral blood 
lymphocyte cytokine release assay. There 
were no SAEs attributable to VIS649 among 
participants in the Phase 1 VIS649-101 study 
at dose levels up to 12 mg/kg. 
 
Severe infusion reactions such as anaphylaxis 
have not been observed with VIS649 in 
humans.  
Additional information can be found in the 
Investigator’s Brochure. 
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for the occurrence 
of infusion reactions.  
Delayed allergic reactions 
(SSLR [ie, urticaria, 
fever, general glandular 
enlargement, joint pains]) 
Delayed allergic reactions to a mAb such as 
serum sickness (ie, urticaria, fever, general 
glandular enlargement, joint pains) have been 
reported with other mAb’s and may not 
appear until several days or weeks after the 
infusion.  
Additional information can be found in the 
Investigator’s Brochure. 
• 
Participants will be monitored 
for AEs throughout the 
duration of the study. 


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26 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Injection site reactions 
Injection site reactions may occur following 
administration of any intravenous therapy.  
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for injection site 
reactions. 
Abbreviations: AE = adverse event; APRIL= A Proliferation Inducing Ligand; CVID = common variable immunodeficiency; 
DSMB = data safety monitoring board; Ig = immunoglobulin; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = 
immunoglobulin M; IVIG = intravenous immunoglobulin; LLN = lower limit of normal; mAb = monoclonal antibody; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); SAE = serious adverse event; SSLR = serum-sickness like reaction. 
2.3.2 
Benefit Assessment 
Immunoglobulin A nephropathy is a chronic disease with periodic flares. IgAN is a significant 
cause of chronic kidney disease (CKD) and ESRD, the clinical progression varies, with 
30 – 40% of patients reaching ESRD 20 to 30 years after the first clinical presentation (Lai, Tang 
et al. 2016). These patients have significantly increased mortality and morbidity, with life 
expectancy reduced by 6 to 10 years when compared to healthy individuals. (Hastings, Bursac et 
al. 2017, Jarrick, Lundberg et al. 2019). There are currently no approved therapies for IgAN, and 
the current treatment strategies consist of 2 main aspects: nonspecific supportive treatments 
consisting of blood pressure control, treatment with ACEI/ARB, smoking cessation, lipid 
reduction, low-salt diet, or fish oil and immunosuppressive therapies such as steroids, 
cyclophosphamide, or azathioprine. The immunosuppressive therapies are usually employed in 
patients with a high risk of progression, as characterized by proteinuria >  1.0 g/d and declining 
GFR (Cheng, Zhang et al. 2009, Boyd, Cheung et al. 2012, KDIGO 2012, Radhakrishnan and 
Cattran 2012, Barbour and Feehally 2017, Rodrigues, Haas et al. 2017). Recent trials have 
shown some benefit in proteinuria reduction with steroids in these patients, thought they are at 
high risk for developing significant complications like infections, metabolic derangements, 
osteoporosis, and diabetes mellitus with these immunosuppressive agents; thus, limiting the 
duration for which these drugs can be given to patients despite benefit from a renal perspective 
(Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 2015, Tesar, Troyanov et al. 2015, Lv, Zhang et 
al. 2017). Hence, there is a critical need for a safe and specific treatment for IgAN. 
VIS649 has the potential to provide a significant advancement in the therapeutic approach to 
IgAN. It has a very specific mechanism of action in the form of APRIL inhibition, which plays a 
critical pathophysiological role in the production of a-g IgA1 in patients with IgAN.  
VIS649 has an attractive safety profile based on currently available data, including data from the 
first-in-human study, Study VIS649-101, in which no SAEs attributable to VIS649 were 
observed. It is anticipated that VIS649 will be used as a chronic therapy and will significantly 
improve the outcomes in patients with IgAN when compared to intermittent therapies like 
steroids that are currently being used to treat these patients. 
2.3.3 
Overall Benefit: Risk Conclusion 
Given the mechanism of action of VIS649 and data from a Phase 1 single-ascending dose study 
(Study VIS649-101) in healthy participants, it is expected that participants receiving VIS649 will 


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27 
have a decline in the Immunoglobulin levels 
. To mitigate the risk of IgG 
reduction, serum IgG thresholds for enrollment have been established so as to prevent the 
development of clinically significant hypogammaglobulinemia. In addition, studies in both 
healthy human participants and nonhuman primates have demonstrated that the ability to develop 
an IgG response to novel antigens and recall T-cell dependent antigen challenge is not 
significantly impaired. As mentioned earlier, there were no SAEs considered attributable to 
VIS649 in the Phase 1 single ascending dose study (VIS649-101), and in the nonhuman primate 
6-month toxicology study, the no-adverse effect level for the antibody was the highest dose 
evaluated.  
An independent data safety monitoring board (DSMB) for this study will be reviewing all 
available safety data, including unblinded Ig data and AEs on a periodic and ad-hoc basis as 
needed.  
Given these encouraging preliminary data and the precautions built into the protocol, evaluation 
of the potential benefit of VIS649 in slowing or halting CKD progression in IgAN patients is 
warranted. 


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3. 
OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints are outlined in Table 3. 
Table 3: 
Study Objectives and Endpoints 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and tolerability of 
multiple, monthly doses of VIS649 at each of 
3 dosing levels, administered IV to IgAN 
participants over the course of 12 months as 
an add-on to SOC treatment with ACEI/ARB 
therapy, compared with saline placebo 
infusions as an add-on to SOC treatment with 
ACEI/ARB therapy 
• 
AEs graded by severity, clinical laboratory 
tests, vital sign measurements, and physical 
examinations  
Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of multiple, 
monthly doses of VIS649 on proteinuria at 
each of 3 dosing levels, administered IV to 
IgAN participants over the course of 12 
months as an add-on to SOC treatment with 
ACEI/ARB therapy, compared with saline 
placebo infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
Change from baseline in uPCR (measured on 
natural log scale from 24-hour urine collection 
or the intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days after the 
twelfth dose is administered) 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated doses of 
VIS649 at 3 dosing levels versus placebo on 
the following parameters: 
o uPCR at Months 9 and 15 (ie, 4 months 
following the final [12th] monthly dose 
administration) 
 
o 24-hour urine protein excretion at Months 
9, 12, and 15 
 
o ≥ 30% decline from baseline in uPCR at 
Months 9, 12, and 15.  
 
o Clinical remission, defined as reduction in 
24-hour urine protein excretion to < 
300 mg/day for at least 3 consecutive 
months.  
• 
eGFR at Months 12 and 15 
 
 
 
 
o Change from baseline in uPCR (measured 
on natural log scale from 24-hour urine 
collection or the intended 24-hour urine 
collection) at Months 9 and 15 
o Change from baseline in 24-hour urine 
protein excretion from baseline to 
Months 9, 12, and 15 
o Participants in each group achieving a ≥ 
30% decline from baseline in uPCR at 
Months 9, 12, and 15 
o Participants in each group achieving 
clinical remission 
 
 
• 
Change from baseline in eGFR at Months 12 
and 15 






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4. 
STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, multiple-dose study 
to evaluate the safety and efficacy of IV administered VIS649 over a 12-month treatment course 
in participants with IgAN.  
Participants will be enrolled from approximately 80 global sites in approximately 16 countries. 
Screening evaluations (including physical examinations, vital signs, 12-lead electrocardiogram 
[ECG], safety laboratory testing [serum chemistry, hematology, urinalysis, serology, and 
pregnancy], and 24-hour urine collection) will take place during a 30-day time period prior to the 
first dose of study intervention.  
To be eligible, participants should be on stable and maximally tolerated doses of either ACEI or 
ARB therapy, as per standard of care (SOC) and applicable guidelines, for at least 3 months. 
Participants must be on at least 50% of the recommended maximum dose of the ACEI or ARB to 
be considered as having adequate RAAS blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in 
the study if their overall management of IgAN, including BP control, is as per SOC and 
applicable guidelines. 
Patient education regarding temporary cessation of ACEIs/ARBs during acute illness and 
resumption of these drugs after resolution of the acute illness will be as per local practice and 
SOC and this therapy will be resumed at the dose closest to the level at the time of 
randomization. During the course of the study, the doses of ACEIs or ARBs should not change; 
however, minor changes are allowed depending on the clinical situation. Control of BP should be 
as per SOC and applicable guidelines. Although additional anti-hypertensives can be used to 
control BP as per the Investigator’s preference and local practice, combination of ACEIs and 
ARBs (or direct renin inhibitors) is prohibited and addition of mineral-corticoid receptor 
antagonists such as spironolactone or eplerenone should be avoided. 
Enrolled participants must be adults, 18 years of age or older, with IgAN diagnosis confirmed by 
biopsy. 
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have been interpreted 
using the mesangial cellularity, endocapillary proliferation, segmental sclerosis, tubular atrophy 
(MEST) (Cattran et al, 2009) or MEST-C scoring system (Trimarchi, Barratt et al. 2017) from 
the Oxford classification of IgAN. Components of the MEST-C score include:  
• 
M – Mesangial hypercellularity, defined as more than 3 mesangial cells in any mesangial 
area of a glomerulus; a score of M0 indicates hypercellularity in < 50% of glomeruli and 
a score of M1 is for hypercellularity noted in ≥ 50% of glomeruli. 
• 
E – Endocapillary proliferation, defined as hypercellularity due to an increased number of 
cells within glomerular capillary lumina causing narrowing. E0 represents absence of 
hypercellularity; E1 is hypercellularity in any glomeruli. 
• 
S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of 
capillary lumina by matrix) in part of but not the whole glomerular tuft; S0 represents 


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absence of segmental glomerulosclerosis, S1 is presence of segmental glomerulosclerosis 
in any glomerulus. 
• 
T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical 
area showing tubular atrophy or interstitial fibrosis, whichever is greater; T0 is 0-25%; 
T1 is 25-50%; T2 is > 50% atrophy/interstitial fibrosis. 
• 
C – Crescents: C0 (no crescents), C1 (crescents in < 25% of glomeruli), and C2 
(crescents in ≥ 25% of glomeruli). 
A MEST-C score finding on kidney biopsy of T2 or C2 is exclusionary for this study. If the 
biopsy was not reported using the Oxford classification schema, the following findings are 
exclusionary: a) > 50% tubular atrophy, and/or b) ≥ 25% crescents.  
Eligible participants must have sufficient proteinuria at Screening, defined as urine protein to 
creatinine ratio (uPCR) ≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 
24-hour urine collection (or an intended 24-hour urine collection). The proteinuria should be 
stable, as defined by a < 25% change when compared to values from ≥ 3 months ago (if 
available). If previous values are not available, or if the change from a prior value is > 25%, a 
repeat measurement of proteinuria will be done after 15 days and the patient should fulfill the 
above proteinuria criteria to be eligible for randomization in the trial. Eligible participants must 
have an eGFR ≥ 45 mL/min/1.73 m2, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula  (Levey, Stevens et al. 2009), before dosing on 
Day 1. The eGFR should be stable, as defined by a < 25% change when compared to values from 
≥ 3 months ago (if available). If previous values are not available or if the change from a prior 
value is > 25%, a repeat measurement of eGFR will be done after 15 days and the patient should 
fulfill the eGFR criteria to be eligible for randomization in the trial.  
If the patient fulfills the proteinuria and eGFR criteria based on 2 measurements performed for 
each during the screening period, the second measurement (for each) will be considered as the 
baseline for analysis  
Participants known to have chronic infectious diseases (eg, chronic sinusitis, chronic urinary 
tract infections, bronchiectasis) will be excluded. Participants in countries with high prevalence 
of tuberculosis may undergo appropriate investigations such as chest X-ray or interferon 
gamma-release assay, as deemed appropriate by the Investigator to rule out tuberculosis. 
Participants will be excluded from the study if they test positive for the screening serology 
markers listed in Table 7. Participants with a positive anti-hepatitis C virus (HCV) antibody test 
must undergo testing for HCV RNA; if HCV RNA is undetectable, the participant can be 
included in the study. 
Participants must be vaccinated as per respective national guidelines and other relevant 
guidelines. Participants should continue to receive annual influenza vaccine and pneumococcal 
vaccine as per local guidelines. 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus placebo. A total of 
144 participants will be randomized with equal allocation (1:1:1:1) across the 4 intervention 
groups (approximately 36 participants per group). Randomization will be stratified first by 
region (Japan vs rest-of-world). A target of twelve or more participants are planned to be 
randomized in Japan; these participants will be randomized with equal allocation and without 


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further stratification. The randomization for the rest-of-world will be stratified by screening 
uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
VIS649 or placebo will be administered as twelve-monthly IV infusions starting on Day 1. 
Participants will return to the study center on Day 8 and then monthly through Month 12 for 
safety, PK and/or PD assessments. Participants will be encouraged to follow the schedule of 
visits for their monthly infusions as close to the prescribed interval as possible. If under special 
circumstances, a participant is unable to visit the study center within 7 days of the schedule 
infusion they may still be able to receive the infusion within the next 7 days, and this will be 
recorded as a protocol deviation. However, if there is any further delay, that dose should be 
skipped, and the participant should receive subsequent doses as per the schedule. The participant 
will not receive additional doses to make up for the missed dose. 
Safety assessments will include review of AEs (including hypersensitivity reaction and 
anaphylactic reaction), physical examinations, injection site tolerability (including pain, irritation 
and tissue damage), clinical laboratory assessments (including biochemistry, hematology, and 
urinalysis), laboratory testing including serum Ig levels, vital sign measurements, and use of 
concomitant medications. 
Participants will return to the study center on Month 15, approximately 120 days following the 
last dose of study intervention (Dose 12) for additional safety, PK, PD, and efficacy assessments. 
Participants discontinuing dosing prior to Dose 12 will attend an early termination visit at the 
time of dosing discontinuation and will be encouraged to attend the study visits as per schedule 
of assessments (Table 1).  
An independent DSMB will review safety data at regular intervals (see Section 9.6). 
It is anticipated that a roll-over extension study will be designed to enable longer term therapy 
for randomized participants. Further details will be provided in a separate protocol. 
The total study duration for each participant (from screening to end-of-study [EOS]) will be up 
to 16 months (assuming 1 month for screening, 12 months for 12 monthly doses [through 
30 days after the twelfth dose], and a 3-month safety follow-up).  
4.2 
Scientific Rationale for Study Design 
This study is designed as a randomized, double-blind, placebo-controlled multiple-dose study to 
evaluate the safety and efficacy of intravenous (IV) administered VIS649 in IgAN participants 
over a 12-month intervention course.  
Immunoglobulin A nephropathy is a chronic, slowly progressing disease. The underlying 
pathogenic factor in IgAN is the formation of a-g IgA1, which is attributed to a culmination of 
genetic and environmental factors in susceptible individuals. The hypoglycosylated hinge region 
of a-g IgA1 presents as a novel antigen, against which IgG and IgA autoantibodies may be 
generated. This leads to formation of circulating IgG/a-g IgA1 immune complexes, which are 
deposited (in part) in the mesangium of the glomerulus, inciting an inflammatory, nephritogenic 
response (Boyd, Cheung et al. 2012, Mestecky, Raska et al. 2013, Lv, Zhang et al. 2017). This 
manifests clinically as proteinuria, hematuria and decline in eGFR. High grade proteinuria 
(> 1.0 g/d) is a critical marker of progressive IgAN and remission of proteinuria is a crucial 


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therapeutic target in the management of IgAN (Donadio, Bergstralh et al. 2002, Reich, Troyanov 
et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016, Thompson, Carroll et al. 2019). 
VIS649 inhibits the biological actions of APRIL and reduces the levels of IgA and other Ig. In 
patients with IgAN, it is hypothesized that this reduction in APRIL and a-g IgA1 will reduce the 
deposition of circulating immunocomplexes in the glomerulus. This should lead to cessation of 
ongoing renal damage and lead to recovery of the damaged glomeruli, as reflected by a reduction 
in proteinuria. 
Based on the PK/PD data from the Phase 1 single-ascending dose study (VIS649-101) and on 
simulation models, full therapeutic suppression of IgA through APRIL signaling inhibition will 
be achieved at 12 weeks, with the selected doses administered monthly. Considering the 
time-dependent and indirect effect of VIS649, a 12-month study intervention duration is deemed 
necessary to achieve therapeutic effect and assess for clinically relevant benefit of VIS649, as 
measured by reduction in proteinuria. 
The primary efficacy endpoint will be the change from baseline in uPCR, at Month 12, 30 days 
after the twelfth dose of study intervention, as measured from a 24-hour urine collection. Studies 
have shown that in patients with IgAN, reduction of proteinuria leads to clinically relevant 
improvements like reduction in the rate of decline of eGFR and progression to ESRD.  
In an analysis of data from the Toronto Glomerulonephritis Registry of 542 patients followed for 
a mean of 6.5 years (61% males, 50% whites, 23% Asians, with mean initial proteinuria 2.4 g/d, 
and creatinine clearance of 77 mL/min/1.73 m2), time-averaged proteinuria (defined as an 
average of the mean of the proteinuria measurements for every 6-month period) was the most 
important predictor of kidney function decline and risk of ESRD, independently of BP and use of 
renin-angiotensin blockers. If time-averaged proteinuria was maintained < 1 g/d, the 10-year risk 
of ESRD was 5%, versus 20% with a  time-averaged proteinuria of 1–2 g/d, 40% with a 
time-averaged proteinuria of 2 to 3 g/d, and 60% with > 3 g/d (Reich, Troyanov et al. 2007). 
This study highlights the primary importance of proteinuria reduction as a therapeutic target in 
the management of IgAN.  
A comprehensive series of safety evaluations, including review of AEs (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, injection site 
tolerability (including pain, irritation and tissue damage), clinical laboratory assessments 
(including biochemistry, hematology, and urinalysis), laboratory testing including serum Ig 
levels, anti-drug antibody concentrations, vital sign measurements, and use of concomitant 
medications will be conducted to evaluate the safety profile of VIS649. 
It is expected that VIS649 will result in obvious reductions in serum IgA, IgG, and IgM, which, 
if visible to the site or Sponsor, would effectively unblind treatment. Therefore, unblinded Ig 
data will only be available to designated unblinded personnel.  
The DSMB will have access to the unblinded Ig data and will be responsible for monitoring Ig 
and AE data periodically (see Section 9.6). 


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4.3 
Justification for Dose 
Three dose levels of monthly IV doses of VIS649 at 2, 4, and 8 mg/kg will be explored in this 
study.  
Dose selection was informed by the totality of available nonclinical and clinical evidence, 
including safety margins from a 4-week and 6-month chronic toxicology study in cynomolgus 
monkeys and emerging data from the Phase 1 study using single doses from 0.5 to 12 mg/kg in 
healthy participants (Study VIS649-101).  
Pharmacokinetic data from Study VIS649-101 demonstrate that there are no safety concerns 
when VIS649 levels are maintained above the effective concentration that inhibits APRIL and 
total serum IgA for ~2 and ~3 months, respectively, with single VIS649 doses of 6 and 
12 mg/kg.  
The anticipated pharmacologically active dose range in humans was evaluated using a PK/PD 
model based on data from Study VIS649-101. Simulation results predict that 2 mg/kg is the 
minimal dose that will achieve desired pharmacological activity with monthly dosing (Figure 2). 
Therefore, 2 mg/kg has been selected as the low dose for this study. It is possible, however, that 
higher APRIL levels and marked proteinuria in IgAN patients (versus healthy controls) could 
significantly accelerate VIS649 clearance. To mitigate this risk, 2 higher dose levels will be 
evaluated; 4 mg/kg and 8 mg/kg. Based on the PK/PD model simulations, VIS649 exposure after 
monthly 8 mg/kg doses is within the exposure range observed at 12 mg/kg in the Phase 1 
single-dose study. 
Figure 2: 
Simulated Percent Baseline Immunoglobulin A by Dose  
 
Abbreviations: IgA = immunoglobulin A. 
Note: Lines and shaded regions represent the median model prediction and model uncertainty (5th and 95th 
percentiles), respectively. 
The results of Study VIS649-101 and of PK/PD model simulations and the safety coverage from 
the 6-month toxicology study all support the planned dosing strategy for the current study.  


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4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the EOS visit.  
The end of the study is defined as the date of the last visit of the last participant in the study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. Re-screening is typically not permitted, possible 
exceptions include re-testing of samples due to issues arising during shipping/storage/handling of 
samples. Re-screening of a participant may also be permitted if initial participation in the study 
was precluded due to an acute infection or an acute illness that subsequently resolved 
completely, and the participant is able to fulfill all study eligibility criteria.  
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant is a male or female ≥ 18 years of age at the time of signing the informed 
consent. 
2. Participant must have biopsy-confirmed IgAN.  
3. Participant medical records show they have been on stable and maximally tolerated doses 
of either ACEI or ARB, as per SOC and applicable guidelines, for at least 3 months 
preceding screening. Participants should be on at least 50% of the maximum 
recommended dose of these agents to be considered as having adequate RAAS blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study if their overall management of IgAN, including BP control, is as 
per SOC and applicable guidelines. 
4. Participants must have screening uPCR ≥ 0.75 g/g measured from a 24-hour urine (or an 
intended 24-hour urine sample) or 24-hour urine protein ≥ 1.0 g/d, as measured from 
24-hour urine collection (or an intended 24-hour urine sample). The proteinuria should be 
stable, defined as < 25% change when compared to values from ≥ 3 months previously (if 
available).  
• If previous values are not available or if the change from a prior value is > 25%, a 
repeat measurement of proteinuria will be done after 15 days and the participant 
should fulfill the above proteinuria criteria to be eligible for randomization in the 
study.  
• The proteinuria should be assessed when the participant is considered to be in a 
steady state with no recent heavy exercise, fever, or other potential issues that 
could impact the result. 
5. Participants must have eGFR ≥ 45 mL/min/1.73 m2, calculated using the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) formula. The eGFR should be stable, as 
defined by a < 25% change when compared to values from ≥ 3 months previously (if 
available).  
• If previous values are not available or if the change from a prior value is > 25%, a 
repeat measurement of eGFR will be done after 15 days and the participant should 
fulfill the eGFR criteria to be eligible for randomization in the study.  
• The eGFR should be measured when the participant is considered to be in a 
steady state without recent changes in volume status, medications that could 


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impact the result (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], 
aminoglycosides, co-trimoxazole) or changes in dietary protein intake. 
6. Participant’s serum Ig values must meet the criteria below: 
• IgG: ≥ 700 mg/dL 
• IgM: ≥ 40 mg/dL 
• IgA: ≥ 70 mg/dL 
7. Female participants of childbearing potential must have a negative serum pregnancy test 
prior to the first dose. 
8. Participant is willing to adhere to contraceptive requirements outlined in Appendix 4. 
9. Participant or a legally authorized representative is able to understand the purpose and 
risks of the study and is willing to give voluntary written informed consent as described 
in Appendix 1. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if they meet any of the following criteria: 
1. Participant has secondary forms of IgAN as defined by the treating physician (eg,, 
Henoch-Schӧnlein purpura, minimal change disease with IgA deposits, infection 
associated IgAN or IgAN associated with hepatic cirrhosis). 
2. Participant has co-existing CKD, other than IgAN.  
3. Participant has evidence of additional pathological findings in the kidney biopsy (eg, 
diabetic kidney disease, membranous nephropathy or lupus nephritis lupus). However, 
hypertensive vascular changes are acceptable.  
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 from the Oxford 
IgAN classification schema. If MEST-scoring was not performed, the presence of > 50% 
tubule-interstitial fibrosis or crescents in > 25% of glomeruli is exclusionary. 
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour urine protein 
> 3.5 g with concurrent hypoalbuminemia (serum albumin < 2.5 g/dL), hyperlipidemia 
(total cholesterol > 350 mg/dL) and edema. 
6. Participant has received a solid organ transplant, including kidney. 
7. Participant has received bone marrow or hematologic stem cell transplantation. 
8. Participant is currently receiving systemic immunosuppression (excluding topical, 
ophthalmic, per rectum or inhaled corticosteroids).  
9. Participant has received systemic steroids within the 12 weeks prior to initial screening.  
10. Participant has received treatment with 2 or more systemic immunosuppressive agents 
within 2 years prior to initial screening. 
11. Participant has chronic infectious diseases (eg, chronic urinary tract infection, chronic 
sinusitis, bronchiectasis, active pulmonary or systemic tuberculosis, chronic viral HCV or 
hepatitis B virus or HIV infection).  


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12. Participant has a known allergy or intolerance to any component of the study 
intervention. 
13. Participant has acute infectious disease at the time of screening. Participants may be 
rescreened following resolution of acute infection (such as urinary tract infection or 
respiratory tract infection), provided there is no evidence of an immunosuppressive 
condition that predisposed the participant to this infection.  
14. Participant has Type 1 diabetes. 
15. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin 
A1c value > 8%. 
16. Participant has uncontrolled blood pressure (> 160 mm Hg systolic or > 110 mm Hg 
diastolic). 
17. Participant has poorly compensated or controlled ischemic heart disease or 
cardiomyopathy, as judged by the Investigator. 
18. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has 
required systemic steroid therapy during the prior year. If COPD is present, severity must 
not exceed Global Initiative for Chronic Obstructive Lung Disease 1 (mild), defined as a 
forced 1-second expiratory volume (FEV1) > 80% of predicted. 
19. Participant has known cirrhosis or liver dysfunction, defined as presence of 
coagulopathy, platelet count < 100,000/µL or alanine aminotransferase > 3× upper limit 
of normal (ULN). 
20. Participant has history of chronic autoimmune neurodegenerative disorders (eg, multiple 
sclerosis). 
21. Participant has active malignancy or is receiving chemotherapy for malignancy, except 
for nonmelanoma skin cancers and cervical carcinoma in situ. Participants with prior 
malignancy who have been documented to be cancer-free for ≥ 5 years may be enrolled. 
22. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is 
acceptable. 
23. Participant enrolled in another investigational drug or device study within 3 months prior 
to initial screening. 
24. Participant with a pre-existing illness other than those listed above that, in the opinion of 
the Investigator, would place the participant at increased risk through participation in this 
study. 
25. Participant is unable to comply with study protocol procedures and/or study visit 
schedules. 
26. Participant wit known or suspected alcohol or drug abuse that would compromise the 
safety or study participation and adherence of participant, in the opinion of the 
Investigator. 


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5.3 
Lifestyle Considerations 
Lifestyle recommendations applicable to IgAN patients such as, but not limited to, BP control, 
low-salt diet, low-protein diet, smoking cessation, weight reduction, and avoidance of 
nephrotoxic drugs such as NSAIDs will be followed as per local practice and guidelines. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1 
Study Intervention(s) Administered 
The study interventions to be administered under this protocol are detailed in Table 4. 
VIS649 is for investigational use only and should only be used within the context of this study.  
VIS649 will be administered as a mg/kg dosage determined by dose assigned at time of 
randomization. VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL 
infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The dose of study 
intervention will be based on the Month 0 predose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour as a single 100 mL infusion, followed 
by a 25 mL saline flush. 
Infusions should preferentially be administered to the participant’s dominant arm. 
Table 4: 
Study Interventions 
Study Arm 
VIS649 
Placebo 
Intervention Name 
VIS649 
Placebo 
Intervention Type 
Drug (IMP) 
Placebo (NIMP) 
Dose Formulation 
Solution 
NaCl (normal saline solution) 
Unit Dose Strength 
VIS649 is formulated at a 
concentration of 25 mg/mL 
0.9% 
Dosage Levels 
2.0, 4.0 and 8.0 mg/kg 
as a single, final volume of 100 mL 
N/A 
Dosing Frequency 
Monthly for 12 months 
Monthly for 12 months 
Route of Administration 
1-hour IV infusion, followed by a 
25-mL saline flush 
1-hour IV infusion, followed by a 
25-mL saline flush 
Use 
Experimental 
Placebo-comparator 
Sourcing 
Provided centrally by the Sponsor. 
Supplies will be obtained locally  
Packaging and Labeling 
VIS649 will be supplied in vials 
containing a nominal volume of 10 mL 
and will be labeled according to local 
regulations 
Per local supplies 
Storage Conditions 
VIS649 must be stored at a 
temperature between ≥ 2°C and ≤ 8°C 
and protected from light. Must be 
infused within 4 hours of 
reconstitution 
Per package insert 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; IMP = investigational 
medicinal product; IV = intravenous(ly); N/A = not applicable; NIMP = noninvestigational medicinal product; SOC = standard of 
care. 


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6.2 
Preparation/Handling/Storage/Accountability 
The required amount of VIS649 to be dosed will be diluted in normal saline up to a maximum 
total volume of 100 mL; for placebo participants, 100 mL of normal saline will be prepared. The 
length of the IV line will be set to a maximum volume of 25 mL, so that the 25-mL saline flush 
following administration will ensure all VIS649/placebo has been administered. 
The VIS649/placebo infusion will be administered IV using a 0.20-µm in-line filter and will be 
controlled by a volumetric pump. Standard, uniform-length infusion lines will be used. 
In addition: 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for study intervention during transit to and storage in the 
investigational pharmacy, as well as post infusion solution preparations. Any deviations 
from Pharmacy Manual guidance are to be reported and resolved before use of the study 
intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This study is double-blinded. An unblinded pharmacist will prepare study intervention doses for 
infusion. Participants, the Sponsor, the Investigator, and all other site study staff will be blinded 
to study intervention.  
All eligible participants will be centrally assigned to randomized study intervention using an 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the 
telephone number and call-in directions for the IVRS and/or the log in information and directions 
for the IWRS will be provided to each site. 
Participants will be randomly assigned in a 1:1:1:1 allocation ratio to receive VIS649 at 2, 4, or 
8 mg/kg, or placebo, with approximately 36 participants randomized to each intervention group. 
Randomization will be stratified first by region (Japan vs rest of world). A target of twelve or 
more participants are planned to be randomized at Japanese sites. Japanese participants will be 
randomized with equal allocation and without further stratification. Randomization for the rest of 
world will then be stratified by screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
Each assignment will have a unique randomization number, assigned to eligible participants after 
the screening. Once a randomization number has been assigned via the IVRS/IWRS, it may not 
be reassigned. 


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In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is required for participant safety, the Investigator should make every effort to contact 
the Sponsor prior to unblinding a participant’s intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s intervention assignment is unblinded, 
the Sponsor must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and electronic case report 
form (eCRF), as applicable. 
Local laboratory testing such as Albumin:Globulin ratio (often tested as part of routine liver 
function panel) or serum protein electrophoresis, may reveal obvious reduction in the total 
globulin levels in participants receiving study intervention and will effectively unblind the 
participant, hence performing such investigations are prohibited, unless this has been discussed 
with the sponsors and if such investigations are deemed to be necessary for clinical management 
of the participant. 
6.4 
Study Intervention Compliance 
Preparation of individual doses of study intervention will be confirmed by a second (unblinded) 
member of the study site pharmacy staff.  
Participants will receive study intervention at the study center directly from the Investigator or 
designee, under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention.  
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter and prescription medicines, vitamins, 
herbal supplements, fish oil, and NSAIDs) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Concomitant Therapy to be Avoided 
Participants should avoid using drugs that are relatively contraindicated in IgAN (eg, NSAIDs, 
aminoglycosides, co-trimoxazole) during the study, per local practice. 
During conduct of the study, administration of systemic corticosteroids or other 
immunosuppressive therapy (for IgAN or other conditions) is prohibited due to the risk of over 
immune suppression due to overlapping actions of VIS649 and other immunosuppressive agents. 
If the Investigator believes that treatment with such therapy is required, and the potential benefits 


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outweigh the possible risks, the sponsor must be notified, as continued dosing with study 
intervention may, in this circumstance, be discontinued.  
6.6 
Dose Modification 
Participants will be encouraged to follow the schedule of visits for their monthly infusions as 
close to the prescribed interval as possible. If under special circumstances, a participant is unable 
to visit the study center within 7 days of the schedule infusion they may still be able to receive 
the infusion within the next 7 days, and this will be recorded as a protocol deviation. However, if 
there is any further delay, that dose should be skipped, and the participant should receive 
subsequent doses as per the schedule. The participant will not receive additional doses to make 
up for the missed dose. 
There will be no other alterations from the dosing schedule outlined in Section 6.1.  
6.7 
Intervention after the End of the Study 
It is anticipated that a rollover extension study will be designed to enable longer term therapy for 
randomized participants. Further details will be provided in a separate protocol. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention Dosing 
Participants have the right to discontinue study intervention or withdraw from the study at any 
time for any reason. Participants may withdraw or be withdrawn from study-related procedures 
and intervention for the following reasons: 
• Withdrawal of consent 
• Adverse event 
• Protocol deviation 
• Investigator decision 
• Pregnancy (Appendix 4) 
• Sponsor decision to terminate the study 
• Loss to follow-up 
In particular, study intervention should be discontinued if participants experience the following:  
• Grade ≥ 3 infusion reaction such as severe anaphylaxis or cytokine release syndrome 
• At the discretion of the Investigator, study intervention may be stopped if the participant 
has an unexplained decline of eGFR of > 30% sustained over 3 months that is not 
reversed after correction of all reversible factors such as volume depletion, NSAID, 
ACEI/ARB, other nephrotoxic drug use, or resolution of acute illness or infection. 
All AEs should be followed until resolution or for a period of 30 days after the EOS, whichever 
is shorter (Section 8.3.1). If the participant withdrew because of an AE, every effort must be 
made to perform protocol-specified safety follow-up procedures. 
If study intervention dosing is definitively discontinued, participants are encouraged to continue 
with assessments as per the schedule of assessments. At a minimum, if study participation is 
terminated by the participant or Investigator, the participant should complete all early 
termination assessments and will be encouraged to return for the EOS assessments outlined in 
Table 1. The primary reason for discontinuation should be recorded in the appropriate section of 
the eCRF. 
7.1.1 
Temporary Discontinuation 
Study intervention may be interrupted for up to 2 doses in participants who experience the 
following:  
• Severe or intractable infection  
• Acute severe illness or injury requiring hospitalization 
7.1.2 
Rechallenge 
VIS649 doses may be re-initiated (at the same dose) under the following conditions: 


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• If study intervention was interrupted due to acute illness or infection, study intervention 
can be re-initiated if the participant has recovered from the acute illness or infection, as 
determined by the Investigator. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, the participant should complete all ET 
assessments outlined in Table 1. The participant will be encouraged to attend an EOS visit 
approximately 120 days following the last dose of study intervention. The participant will be 
permanently discontinued both from the study intervention and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are outlined in Table 1. Protocol waivers or exemptions are 
not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. A pathology report that confirms the IgAN diagnosis will be submitted with eCRFs. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Efficacy Assessments 
8.1.1 
Twenty-four-hour Urine Sample Collection 
Twenty-four-hour urine collection for derivation of 24-hour urine volume, protein, albumin, and 
creatinine, uPCR, and uACR will be performed at the time points outlined in Table 1.  
Participants will discard the first morning void and begin a 24-hour urine collection the day prior 
to the clinic visit. Care should be taken to avoid over-collection or under-collection of urine, 
however if this occurs, the sample may still be used to calculate the proteinuria and uPCR. On 
days of 24-hour urine collection (or the intended 24-hour urine collection), the uPCR sample will 
be collected from the 24-hour urine collection and routine urinalysis will be performed on a 
sample freshly voided during the clinic visit. 
8.2 
Safety Assessments 
8.2.1 
Physical Examinations 
A complete physical examination, to include assessments of the cardiovascular, respiratory, 
gastrointestinal and neurological systems will be completed at the screening and ET visit.  
8.2.2 
Vital Signs 
Vital sign measurements will be performed at the visits outlined in Table 1 and will include 
weight, temperature, pulse rate, respiratory rate, and systolic and diastolic BP. Height will be 
measured and recorded during Screening.  
Vital signs measurements on dosing days will be recorded within 15 (±5) minutes prior to the 
start of the infusion, every 15 minutes until the infusion is complete, and 60 minutes and 2 hours 
post infusion. 
Systolic and diastolic BP and pulse measurements will be assessed while the participant is seated 
or supine with a completely automated device. Manual techniques will be used only if an 
automated device is not available. Blood pressure and pulse measurements should be preceded 


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by at least 5 minutes of rest for the participant in a quiet setting without distractions (eg, 
television, cell phones). 
Vital signs should be to be collected before blood collection for laboratory tests, when possible, 
and before dosing with study intervention. 
8.2.3 
Electrocardiograms 
A single 12-lead ECG, heart rate, and measures of PR, QRS, QT, and QTc intervals will be 
obtained at the screening visit. The 12-lead ECG should be conducted after 5 minutes in 
recumbence or semi-recumbency.  
8.2.4 
Clinical Safety Laboratory Assessments 
Clinical laboratory evaluations for safety will be performed by a central laboratory whenever 
possible, however, local laboratory tests may be utilized for more urgent safety monitoring. 
Before starting the study, the Investigator will provide the Sponsor (or its designee) copies of all 
laboratory certifications and normal ranges for all laboratory assessments to be performed by that 
laboratory. Local laboratory assessments to make intervention-related decisions may be 
performed at all visits. 
A list of clinical safety laboratory tests to be performed is provided in Appendix 2 and the timing 
for these assessments is provided in Table 1. All protocol-required laboratory assessments must 
be conducted in accordance with the laboratory manual. Details of laboratory tests to be 
conducted for assessment of VIS649 PK, PD, exploratory biomarkers, and immunogenicity are 
provided in Sections 8.5, 8.6, 8.8, and 8.9, respectively.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal, with the exception 
of disease defining abnormalities such as eGFR and proteinuria considered to be a part of the 
natural history of IgAN, during participation in the study or within 30 days after the last dose of 
study intervention should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the Investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified, and the Sponsor notified. 
8.3 
Adverse Events and Serious Adverse Events 
Adverse event and SAE definitions are provided in Appendix 3. 
All AEs (serious and nonserious) reported by the participant must be recorded on the source 
documents and eCRF provided by the Sponsor. Medical terminology should be used for AE 
reporting. Adverse events should be reported as a single unifying diagnosis whenever possible 
or, in the absence of a unifying diagnosis, as individual signs or symptoms. 


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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS; AEs and SAEs 
that are ongoing at the EOS should be monitored until resolution or 30 days after EOS, 
whichever is shorter (see Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information about AEs or SAEs after conclusion 
of study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. For example, participants should be asked the nonleading question: “How have 
you felt since your last visit?”  
Exacerbation or disease progression should be reported as an AE only if there are unusual or 
severe clinical features that were not present, or experienced earlier, or not expected based on the 
course of the condition. 
In addition, the Sponsor must be notified immediately by telephone, fax, or e-mail of any 
immediately reportable events. Immediately reportable events (IRE) include the following:  
• SAEs 
• Pregnancies. Although normal pregnancy is not an AE, it will mandate study intervention 
discontinuation and must be reported on an IRE form and the Pregnancy Surveillance 
Form(s) to the Sponsor. Pregnancy will only be documented on the AE eCRF if there is 
an abnormality or complication. This includes pregnancy of the participant or the 
participant’s partner 
Adverse event, start date, end date, seriousness, severity, relationship to study intervention, 
action taken with study treatment and outcome will be recorded on the source documents and in 


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the eCRF. Special attention should be paid to recording hospitalization and concomitant 
medications. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
Nonserious AEs that are identified at any time during the study must be recorded on the AE 
eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious events (that 
are not IREs) that are ongoing at the last scheduled contact will be recorded as ongoing on the 
eCRF. For any AE having been identified throughout the study, additional relevant medical 
history information may be requested by the Sponsor during analysis to further ascertain 
causality (including, but not limited to, information such as risk-related behavior, family history 
and occupation). 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be collected from the signing of 
the ICF until the EOS; AEs and SAEs that are ongoing at the EOS should be monitored until 
resolution, stabilization, until the event is otherwise explained, the participant is lost to follow-up 
or 30 days after EOS, whichever is shorter (Section 1.3). 
Resolution means that the participant has returned to the baseline state of health and stabilized 
means that the Investigator does not expect any further improvement or worsening of the 
participant’s condition. The Investigator will continue to report any significant follow-up 
information to the Sponsor up to the point the event has resolved or stabilized, or the participant 
is lost to follow-up, or has died. 
Further information on follow-up procedures is provided in Appendix 3. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
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8.3.5 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 90 days after the last dose of study 
intervention. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4 
Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. No antidotes are available. 
8.5 
Pharmacokinetics 
For all participants, serial blood samples will be drawn prior to each VIS649/placebo IV infusion 
and at the end of each infusion in order to determine circulating serum concentrations of VIS649, 
as specified in Table 1 and Table 5. Up to 60 participants (approximately 15 participants in each 
cohort) may have a more intensive PK and PD sampling schedule, as described in Table 5. Study 
participants who agree to participate in this more intensive PK and PD sample collection 
sub-study will sign an additional informed consent for this activity.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate laboratory manual. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for analyses of serum VIS649 concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 






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9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis 
The primary efficacy objective of this study is to evaluate the effect of VIS649 on proteinuria. 
The hypothesis that there is a VIS649-related dose response in the change from baseline in 
natural log uPCR at Month 12 versus placebo will be formally tested.   
9.2 
Sample Size Determination 
A sample size of 144 participants, randomly assigned in a 1:1:1:1 schema to VIS649 2, 4, or 
8 mg/kg, or placebo, would provide sufficient power at 80% to detect a significant linear dose 
response relationship given a standard deviation of 0.49, and an assumed difference in uPCR 
reduction, for instance 15%, 30%, and 45%, between VIS649 2, 4, or 8 mg/kg and placebo, 
respectively. The study-wide type I error rate is a 2-sided alpha of 0.05. This sample size would 
account for a dropout rate of ~20%.   
9.3 
Populations for Analyses 
Populations for analysis in this study are defined in Table 6. 
Table 6: 
Populations for Analysis 
Population 
Description 
ITT 
All participants who are randomized; participants will be categorized by the 
intervention and dose they were randomized to receive.  
mITT 
All randomized participants who receive at least 1 dose of study intervention; 
participants will be categorized by the intervention and dose that they were 
randomized to receive. 
Safety 
All randomized participants who receive any amount of study intervention. 
Participants will be analyzed according to the intervention and dose they actually 
received. 
PK/PD 
All randomized participants who have at least 1 set of PK/PD measures taken. 
Biomarker 
All randomized participants who consented to participation in the biomarker 
sub-study. A separate consent process is required, as described in Section 8.8. 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s). 
Analysis of safety parameters will be performed on the Safety population. The Modified 
intent-to-treat (mITT) population will be the primary population for assessment of efficacy. The 
PK/PD population will be the primary population for PK/PD summaries. Analysis of biomarker 
data will be performed on the Biomarker population. 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints. 






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9.5 
Interim Analysis 
In addition to five DSMB safety reviews (Section 9.6), three PK/Ig analyses and one interim 
efficacy analysis are planned: 
• The first PK/Ig analysis will be performed when approximately 25% of participants have 
been randomized and have completed 3 months of study dosing. All the PK/Ig 
assessments will be performed by a separate, unblinded team. Summarized results will be 
made available to the study Sponsor for planning of future studies.   
• The second PK/Ig analysis will be performed when approximately 20 participants have 
been randomized and have completed 9 months of study dosing. This analysis will be 
used to update previously developed population PK/PD models. Summarized results will 
be made available to the study Sponsor for planning of future studies.  
• The third PK/Ig analysis will be performed when approximately 50% of the participants 
have been randomized and have completed 6 months of study dosing and approximately 
20 participants have completed 12 months of study dosing. Summarized results will be 
made available to the study Sponsor for planning of future studies.  
• An interim efficacy analysis will be performed at the time of the fourth scheduled DSMB 
meeting (when 50% of randomized participants have completed 6 months of study dosing 
and approximately 20 participants have completed 12 months of study dosing). Group-
unblinded efficacy summaries (with individual participant treatment blinded) will be 
prepared for Sponsor review to inform future study design.  
• The interim efficacy analysis will not include hypothesis testing and will be for the 
purpose of future study design and planning. The primary efficacy endpoint, change in 
proteinuria levels from baseline, will be analyzed. No modifications to this study protocol 
are planned based on results of the interim analyses. 
9.6 
Data Safety Monitoring Board 
An independent DSMB will review unblinded safety data. The DSMB will meet at 5 scheduled 
data review meetings and on an ad hoc basis as needed. Details regarding the content and scope 
of safety assessments, as well as the governing of the DSMB, will be described in a separate 
DSMB charter. Data safety monitoring board meetings will be scheduled as the requirements in 
Table 7 are met. 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews 
Scheduled DSMB Review Number of Participants and Treatment Exposure 
DSMB review #1 
The first scheduled meeting will occur after 12 participants have been 
randomized and have completed at least 3 months of dosing 
DSMB review #2 
The second scheduled meeting will occur after 24 participants have been 
randomized and have completed at least 3 months of dosing 
DSMB review #3 
The third scheduled meeting will occur after ~25% of participants have been 
randomized and have completed 3 months of dosing  


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DSMB review #4 
The fourth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 6 months of dosing and approximately 20 
participants have completed 12 months of dosing 
DSMB review #5 
The fifth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 12 months of dosing 
Abbreviations: DSMB = data safety monitoring board. 
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2 
Financial Disclosure 
All required information regarding financial certification or disclosure will be provided to the 
Sponsor for all investigators and sub investigators in accordance with the terms of the relevant 
regional regulation(s). 
Informed consent will be freely obtained from all participants (or their guardian or legally 
acceptable representative, as applicable for local laws).  
Each ICF will comply with the ICH (International Council for Harmonisation) Good Clinical 
Practice (GCP): Consolidated Guideline E61 and local regulatory requirements. The Investigator 
will ensure that the Sponsor reviews and authorizes any written site-specific ICF used in the 
study before submission to the IRB/IEC. 


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Investigators may discuss study availability and the possibility for entry with a potential 
participant without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose of 
determining eligibility for this study, including withdrawal from current medication(s).  
Potential participants are free to refuse entry into the study, or withdraw from the study at any 
time, without justification, and there will be no consequences to their further care. 
A separate and similar consent process will be followed for the optional blood samples for 
pharmacogenomic testing and future biospecimen research. Consent must be obtained before the 
blood sample is collected. 
10.1.3 
Data Protection 
All information generated in this study will be considered confidential and will not be disclosed 
to anyone not directly concerned with the study without the Sponsor’s prior written permission. 
Participant confidentiality requirements of the region(s) where the study is conducted will be 
met. However, authorized regulatory officials and Sponsor personnel (or their representatives) 
may be allowed full access to inspect and copy the records, consistent with local requirements. 
All IMPs, participant bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by the Sponsor. 
Participants will be identified only by unique participant ID in eCRF. If further participant 
identification is required, participants’ full names may be made known to a regulatory agency or 
other authorized officials if necessary, subject to local regulations. 
10.1.4 
Dissemination of Clinical Study Data 
This study will comply with the Clinical Trials Registration and Results Information Submission 
rule. As such, this study will be registered at ClinicalTrials.gov, and results information from this 
study will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish 
results in peer-reviewed journals. Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and by periodic monitoring visits by the Sponsor or 
designee. 
Written instructions will be provided for the collection, preparation, and shipment of samples. 
The Sponsor or its designee will review the EDC system for accuracy and completeness during 
(on-site) monitoring visits and after transmission to the Sponsor; any discrepancies will be 
resolved with the Investigator or designee, as appropriate. After upload of the data into the 
clinical study database, they will be verified for accuracy. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 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 a national GCP compliance 
program or to review the results of this study in support of a regulatory submission. The 


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Investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. 
10.1.5 
Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include but are not limited to medical records, electronic 
data, screening logs, and recorded data from automated instruments. All source documents 
pertaining to this study will be maintained by the Investigators and made available for direct 
inspection by authorized persons. 
Investigator(s)/institution(s) will permit study -related monitoring, audits, [IRB/IEC/EC] review, 
and regulatory inspection(s) by providing direct access to source data/documents by authorized 
persons as defined in the ICF. In all cases, participant confidentiality must be maintained in 
accordance with local regulatory requirements. 
10.1.6 
Study and Site Start and Closure 
Study site participation may be discontinued if the Sponsor or its designee, the Investigator, or 
the ethical review board (ERB) of the study site judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 10.3.2.  
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
10.1.7 
Publication Policy 
The publication policy for the study will be documented in the agreement between the Sponsor 
and the Investigator. Authorship for any Visterra-Sponsored publications resulting from the 
conduct of this study will be based on International Committee of Medical Journal Editors 
(ICMJE) authorship criteria (http://www.icmje.org/recommendations). According to ICMJE 
guidelines, one may be considered an author only if the following criteria are met: 
1. Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
2. Drafting the work or revising it critically for important intellectual content; AND 
3. Final approval of the version to be published; AND 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet the above criteria, and all who qualify for authorship based on the above 
criteria should be listed as authors. 


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10.2 
Appendix 2  
Clinical Laboratory Tests 
Table 7 provides a list of laboratory tests to be evaluated by the Investigator. 
The tests detailed in Table 7 will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF.  Local 
lab results will not be acceptable for qualifying a participant for the study. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8:  
Protocol-Required Safety Laboratory Assessments 
Serology (screening only) 
HBsAg, anti-HBc (IgG and IgM) antibody, anti-HCV antibody, HIV 
Hematology 
Hemoglobin, RBC, WBC with differential (including absolute 
neutrophil count), and platelet count 
Serum chemistry 
Sodium, potassium, BUN, bicarbonate (venous), creatinine, calcium, 
chloride, magnesium, phosphorus, albumin, AST, ALT, ALP, total 
bilirubin (direct bilirubin if total > ULN), total cholesterol and 
triglycerides. 
Urinalysis  
Color and appearance; pH, specific gravity, ketones, protein, glucose, 
bilirubin, nitrite, urobilinogen, and occult blood by dipstick 
Pregnancy (females only) 
Serum β-hCG (screening only) 
Urine β-hCG (all other visits) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
β-hCG = β -human chorionic gonadotropin; BUN = blood urea nitrogen; HBc = hepatitis B core; HBsAg = hepatitis 
B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = red blood cell; ULN = 
upper limit of normal; WBC = white blood cell. 
Note: eGFR will be calculated from Serum creatinine by the CKD-EPI formula, which is as follows: 
eGFR =141 x min (SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black] 
κ = 0.7 (females) or 0.9 (males), α = -0.329 (females) or -0.411 (males), min = indicates the minimum of SCr/κ or 1, 
max = indicates the maximum of SCr/κ or 1. Investigators must document their review of each laboratory safety 
report. 
Laboratory results that could unblind the study (eg, Ig) will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 










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10.4 
Appendix 4  
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from site personnel review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.2 
Contraception Guidance 
Women of childbearing potential must use a medically acceptable form of birth control 
(hormonal contraception, diaphragm with spermicide, condom with spermicide,  intrauterine 
device, or partner with vasectomy) for at least 28 days prior to first study intervention and agree 
to continue to use a medically acceptable form of birth control (as described) through 90 days 


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after the last dose of study intervention. Alternatively, a reported history of abstinence beginning 
at least 28 days prior to study intervention dosing, with agreement to continue abstinence 
through 90 days after the last dose of study intervention are required. Women of childbearing 
potential must also have a negative serum beta human chorionic gonadotropin (β-hCG) 
pregnancy test at screening and a negative urine β-hCG pregnancy test prior to the first study 
intervention on Day 0. Female participants must also agree not to donate eggs/bank eggs for the 
duration of their participation in the study. 
Male participants and/or his partner must use a highly effective form of contraception (ie, 
double-barrier as described above, have had a vasectomy, or have a female partner of 
nonchildbearing potential) from date of first study dose through 90 days after the last dose of 
study intervention. Following the first dose of study intervention, male participants must also 
agree to not donate sperm through 90 days after the last dose of study intervention. 
10.4.3 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  


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• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• Any poststudy pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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10.5 
Appendix 5 
Abbreviations 
Abbreviation 
Definition 
ACEI 
Angiotensin-converting enzyme inhibitor 
ADA 
Antidrug antibody 
AE 
Adverse event 
a-g 
Aberrantly glycosylated 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
APRIL 
Cytokine A proliferation inducing ligand 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
AUC 
Area under the serum concentration versus -time curve  
β-hCG 
Beta human chorionic gonadotropin 
BCMA 
B-cell maturation antigen 
BP 
Blood pressure 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum serum concentration 
COPD 
Chronic obstructive pulmonary disease 
%CV 
Coefficient of variation 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-study 
ESRD 
End-stage renal disease 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCV 
Hepatitis C virus 
HRT 
Hormone-replacement therapy 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 


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Abbreviation 
Definition 
IgA/G/M 
Immunoglobulin A/G/M 
IgAN 
Immunoglobulin A nephropathy 
IRB 
Institutional Review Board 
IRE 
Immediately reportable event 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice/web response system 
LS 
Least-squares 
mAb 
Monoclonal antibody 
MEST-C 
Mesangial cellularity, Endocapillary proliferation, Segmental sclerosis, 
Tubular atrophy, Crescents 
mITT 
Modified intent-to-treat 
MMRM 
Mixed Model Repeated Measurement 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TACI 
Transmembrane activator and CAML interactor 
Td 
Tetanus and diphtheria 
ULN 
Upper limit of normal 
uPCR 
Urine protein to creatinine ratio 
WOCBP 
Woman of childbearing potential 
 


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11. 
REFERENCES 
Ballow, M. (2002). "Primary immunodeficiency disorders: antibody deficiency." J Allergy Clin 
Immunol 109(4): 581-591. 
Barbour, S. and J. Feehally (2017). "An update on the treatment of IgA nephropathy." Curr Opin 
Nephrol Hypertens 26(4): 319-326. 
Berthoux, F., H. Suzuki, L. Thibaudin, H. Yanagawa, N. Maillard, C. Mariat, Y. Tomino, B. A. 
Julian and J. Novak (2012). "Autoantibodies targeting galactose-deficient IgA1 associate with 
progression of IgA nephropathy." J Am Soc Nephrol 23(9): 1579-1587. 
Bossen, C., T. G. Cachero, A. Tardivel, K. Ingold, L. Willen, M. Dobles, M. L. Scott, A. 
Maquelin, E. Belnoue, C. A. Siegrist, S. Chevrier, H. Acha-Orbea, H. Leung, F. Mackay, J. 
Tschopp and P. Schneider (2008). "TACI, unlike BAFF-R, is solely activated by oligomeric 
BAFF and APRIL to support survival of activated B cells and plasmablasts." Blood 111(3): 
1004-1012. 
Boyd, J. K., C. K. Cheung, K. Molyneux, J. Feehally and J. Barratt (2012). "An update on the 
pathogenesis and treatment of IgA nephropathy." Kidney Int 81(9): 833-843. 
Castigli, E., S. Scott, F. Dedeoglu, P. Bryce, H. Jabara, A. K. Bhan, E. Mizoguchi and R. S. 
Geha (2004). "Impaired IgA class switching in APRIL-deficient mice." Proc Natl Acad Sci U S 
A 101(11): 3903-3908. 
Cheng, J., W. Zhang, X. H. Zhang, Q. He, X. J. Tao and J. H. Chen (2009). "ACEI/ARB therapy 
for IgA nephropathy: a meta analysis of randomised controlled trials." Int J Clin Pract 63(6): 
880-888. 
Donadio, J. V., E. J. Bergstralh, J. P. Grande and D. M. Rademcher (2002). "Proteinuria patterns 
and their association with subsequent end‐stage renal disease in IgA nephropathy." Nephrology 
Dialysis Transplantation 17(7): 1197-1203. 
Endo, T., M. Nishio, T. Enzler, H. B. Cottam, T. Fukuda, D. F. James, M. Karin and T. J. Kipps 
(2007). "BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through 
activation of the canonical NF-kappaB pathway." Blood 109(2): 703-710. 
Fadlallah, J., H. El Kafsi, D. Sterlin, C. Juste, C. Parizot, K. Dorgham, G. Autaa, D. Gouas, M. 
Almeida, P. Lepage, N. Pons, E. Le Chatelier, F. Levenez, S. Kennedy, N. Galleron, J. P. de 
Barros, M. Malphettes, L. Galicier, D. Boutboul, A. Mathian, M. Miyara, E. Oksenhendler, Z. 
Amoura, J. Dore, C. Fieschi, S. D. Ehrlich, M. Larsen and G. Gorochov (2018). "Microbial 
ecology perturbation in human IgA deficiency." Sci Transl Med 10(439). 
Floege, J., I. C. Moura and M. R. Daha (2014). "New insights into the pathogenesis of IgA 
nephropathy." Semin Immunopathol 36(4): 431-442. 
Furst, D. E. (2009). "Serum immunoglobulins and risk of infection: how low can you go?" 
Semin Arthritis Rheum 39(1): 18-29. 


CONFIDENTIAL 
VIS649-201 Protocol Version 2.0 
 
 
73 
Han, S. S., S. H. Yang, M. Choi, H. R. Kim, K. Kim, S. Lee, K. C. Moon, J. Y. Kim, H. Lee, J. 
P. Lee, J. Y. Jung, S. Kim, K. W. Joo, C. S. Lim, S. W. Kang, Y. S. Kim and D. K. Kim (2016). 
"The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy." J Am Soc 
Nephrol 27(11): 3430-3439. 
Hastings, M. C., Z. Bursac, B. A. Julian, E. Villa Baca, J. Featherston, S. Y. Woodford, L. Bailey 
and R. J. Wyatt (2017). "Life Expectancy for Patients From the Southeastern United States With 
IgA Nephropathy." Kidney international reports 3(1): 99-104. 
Inker, L. A., H. Mondal, T. Greene, T. Masaschi, F. Locatelli, F. P. Schena, R. Katafuchi, G. B. 
Appel, B. D. Maes, P. K. Li, M. Praga, L. Del Vecchio, S. Andrulli, C. Manno, E. Gutierrez, A. 
Mercer, K. J. Carroll, C. H. Schmid and A. S. Levey (2016). "Early Change in Urine Protein as a 
Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis." Am J 
Kidney Dis 68(3): 392-401. 
Janssen, L. M. A., T. Macken, M. C. W. Creemers, J. F. M. Pruijt, J. J. J. Eijk and E. de Vries 
(2018). "Truly selective primary IgM deficiency is probably very rare." Clin Exp Immunol 
191(2): 203-211. 
Jarrick, S., S. Lundberg, A. Welander, J. J. Carrero, J. Hoijer, M. Bottai and J. F. Ludvigsson 
(2019). "Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study." J Am 
Soc Nephrol 30(5): 866-876. 
KDIGO (2012). "KDIGO Clinical Practice Guideline for Glomerulonephritis." Kidney 
International Supplements 2(2): 139-274. 
Kiryluk, K., Y. Li, F. Scolari, S. Sanna-Cherchi, M. Choi, M. Verbitsky, D. Fasel, S. Lata, S. 
Prakash, S. Shapiro, C. Fischman, H. J. Snyder, G. Appel, C. Izzi, B. F. Viola, N. Dallera, L. Del 
Vecchio, C. Barlassina, E. Salvi, F. E. Bertinetto, A. Amoroso, S. Savoldi, M. Rocchietti, A. 
Amore, L. Peruzzi, R. Coppo, M. Salvadori, P. Ravani, R. Magistroni, G. M. Ghiggeri, G. 
Caridi, M. Bodria, F. Lugani, L. Allegri, M. Delsante, M. Maiorana, A. Magnano, G. Frasca, E. 
Boer, G. Boscutti, C. Ponticelli, R. Mignani, C. Marcantoni, D. Di Landro, D. Santoro, A. Pani, 
R. Polci, S. Feriozzi, S. Chicca, M. Galliani, M. Gigante, L. Gesualdo, P. Zamboli, G. G. 
Battaglia, M. Garozzo, D. Maixnerova, V. Tesar, F. Eitner, T. Rauen, J. Floege, T. Kovacs, J. 
Nagy, K. Mucha, L. Paczek, M. Zaniew, M. Mizerska-Wasiak, M. Roszkowska-Blaim, K. 
Pawlaczyk, D. Gale, J. Barratt, L. Thibaudin, F. Berthoux, G. Canaud, A. Boland, M. Metzger, 
U. Panzer, H. Suzuki, S. Goto, I. Narita, Y. Caliskan, J. Xie, P. Hou, N. Chen, H. Zhang, R. J. 
Wyatt, J. Novak, B. A. Julian, J. Feehally, B. Stengel, D. Cusi, R. P. Lifton and A. G. Gharavi 
(2014). "Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity 
against intestinal pathogens." Nat Genet 46(11): 1187-1196. 
Kiryluk, K., Z. Moldoveanu, J. T. Sanders, T. M. Eison, H. Suzuki, B. A. Julian, J. Novak, A. G. 
Gharavi and R. J. Wyatt (2011). "Aberrant glycosylation of IgA1 is inherited in both pediatric 
IgA nephropathy and Henoch-Schonlein purpura nephritis." Kidney Int 80(1): 79-87. 
Kiryluk, K. and J. Novak (2014). "The genetics and immunobiology of IgA nephropathy." The 
Journal of Clinical Investigation 124(6): 2325-2332. 


CONFIDENTIAL 
VIS649-201 Protocol Version 2.0 
 
 
74 
Kiryluk, K., J. Novak and A. G. Gharavi (2013). "Pathogenesis of immunoglobulin A 
nephropathy: recent insight from genetic studies." Annual review of medicine 64: 339-356. 
Knoppova, B., C. Reily, N. Maillard, D. V. Rizk, Z. Moldoveanu, J. Mestecky, M. Raska, M. B. 
Renfrow, B. A. Julian and J. Novak (2016). "The Origin and Activities of IgA1-Containing 
Immune Complexes in IgA Nephropathy." Front Immunol 7: 117. 
Lai, K. N., S. C. Tang, F. P. Schena, J. Novak, Y. Tomino, A. B. Fogo and R. J. Glassock 
(2016). "IgA nephropathy." Nat Rev Dis Primers 2: 16001. 
Levey, A. S., L. A. Stevens, C. H. Schmid, Y. L. Zhang, A. F. Castro, 3rd, H. I. Feldman, J. W. 
Kusek, P. Eggers, F. Van Lente, T. Greene, J. Coresh and E. P. I. Ckd (2009). "A new equation 
to estimate glomerular filtration rate." Ann Intern Med 150(9): 604-612. 
Louis, A. G., S. Agrawal and S. Gupta (2016). "Analysis of subsets of B cells, Breg, CD4Treg 
and CD8Treg cells in adult patients with primary selective IgM deficiency." Am J Clin Exp 
Immunol 5(1): 21-32. 
Louis, A. G. and S. Gupta (2014). "Primary selective IgM deficiency: an ignored 
immunodeficiency." Clin Rev Allergy Immunol 46(2): 104-111. 
Lv, J., H. Zhang, M. G. Wong, M. J. Jardine, M. Hladunewich, V. Jha, H. Monaghan, M. Zhao, 
S. Barbour, H. Reich, D. Cattran, R. Glassock, A. Levin, D. Wheeler, M. Woodward, L. Billot, 
T. M. Chan, Z. H. Liu, D. W. Johnson, A. Cass, J. Feehally, J. Floege, G. Remuzzi, Y. Wu, R. 
Agarwal, H. Y. Wang and V. Perkovic (2017). "Effect of Oral Methylprednisolone on Clinical 
Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial." Jama 
318(5): 432-442. 
Mestecky, J., J. Novak, Z. Moldoveanu and M. Raska (2016). "IgA nephropathy enigma." Clin 
Immunol 172: 72-77. 
Mestecky, J., M. Raska, B. A. Julian, A. G. Gharavi, M. B. Renfrow, Z. Moldoveanu, L. Novak, 
K. Matousovic and J. Novak (2013). "IgA nephropathy: molecular mechanisms of the disease." 
Annu Rev Pathol 8: 217-240. 
Muto, M., B. Manfroi, H. Suzuki, K. Joh, M. Nagai, S. Wakai, C. Righini, M. Maiguma, S. Izui, 
Y. Tomino, B. Huard and Y. Suzuki (2017). "Toll-Like Receptor 9 Stimulation Induces Aberrant 
Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA 
Nephropathy." J Am Soc Nephrol 28(4): 1227-1238. 
Myette, J. R., T. Kano, H. Suzuki, S. E. Sloan, K. J. Szretter, B. Ramakrishnan, H. Adari, K. D. 
Deotale, F. Engler, Z. Shriver, A. M. Wollacott, Y. Suzuki and B. J. G. Pereira (2019). "A 
Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of 
murine IgA nephropathy." Kidney International 96(1): 104-116. 
Nam, K. H., J. H. Kie, M. J. Lee, T. I. Chang, E. W. Kang, D. W. Kim, B. J. Lim, J. T. Park, Y. 
E. Kwon, Y. L. Kim, K. S. Park, S. Y. An, H. J. Oh, T. H. Yoo, S. W. Kang, K. H. Choi, H. J. 
Jeong, D. S. Han and S. H. Han (2014). "Optimal proteinuria target for renoprotection in patients 
with IgA nephropathy." PLoS One 9(7): e101935. 


CONFIDENTIAL 
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75 
Pozzi, C., S. Andrulli, L. Del Vecchio, P. Melis, G. B. Fogazzi, P. Altieri, C. Ponticelli and F. 
Locatelli (2004). "Corticosteroid effectiveness in IgA nephropathy: long-term results of a 
randomized, controlled trial." J Am Soc Nephrol 15(1): 157-163. 
Radhakrishnan, J. and D. C. Cattran (2012). "The KDIGO practice guideline on 
glomerulonephritis: reading between the (guide)lines--application to the individual patient." 
Kidney Int 82(8): 840-856. 
Rauen, T., F. Eitner, C. Fitzner, C. Sommerer, M. Zeier, B. Otte, U. Panzer, H. Peters, U. Benck, 
P. R. Mertens, U. Kuhlmann, O. Witzke, O. Gross, V. Vielhauer, J. F. Mann, R. D. Hilgers and J. 
Floege (2015). "Intensive Supportive Care plus Immunosuppression in IgA Nephropathy." N 
Engl J Med 373(23): 2225-2236. 
Reich, H. N., S. Troyanov, J. W. Scholey and D. C. Cattran (2007). "Remission of proteinuria 
improves prognosis in IgA nephropathy." J Am Soc Nephrol 18(12): 3177-3183. 
Rodrigues, J. C., M. Haas and H. N. Reich (2017). "IgA Nephropathy." Clinical Journal of the 
American Society of Nephrology 12(4): 677-686. 
Schena, F. P. and I. Nistor (2018). "Epidemiology of IgA Nephropathy: A Global Perspective." 
Semin Nephrol 38(5): 435-442. 
Tesar, V., S. Troyanov, S. Bellur, J. C. Verhave, H. T. Cook, J. Feehally, I. S. Roberts, D. 
Cattran and R. Coppo (2015). "Corticosteroids in IgA Nephropathy: A Retrospective Analysis 
from the VALIGA Study." J Am Soc Nephrol 26(9): 2248-2258. 
Thompson, A., K. Carroll, L. A. Inker, J. Floege, V. Perkovic, S. Boyer-Suavet, R. W. Major, J. 
I. Schimpf, J. Barratt, D. C. Cattran, B. S. Gillespie, A. Kausz, A. W. Mercer, H. N. Reich, B. H. 
Rovin, M. West and P. H. Nachman (2019). "Proteinuria Reduction as a Surrogate End Point in 
Trials of IgA Nephropathy." Clinical Journal of the American Society of Nephrology 14(3): 469-
481. 
Trimarchi, H., J. Barratt, D. C. Cattran, H. T. Cook, R. Coppo, M. Haas, Z. H. Liu, I. S. Roberts, 
Y. Yuzawa, H. Zhang and J. Feehally (2017). "Oxford Classification of IgA nephropathy 2016: 
an update from the IgA Nephropathy Classification Working Group." Kidney Int 91(5): 1014-
1021. 
Varfolomeev, E., F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. 
Tom, S. Erickson, D. French, P. Schow, I. S. Grewal and A. Ashkenazi (2004). "APRIL-
deficient mice have normal immune system development." Mol Cell Biol 24(3): 997-1006. 
Working Group of the International Ig, A. N. N., S. the Renal Pathology, D. C. Cattran, R. 
Coppo, H. T. Cook, J. Feehally, I. S. Roberts, S. Troyanov, C. E. Alpers, A. Amore, J. Barratt, F. 
Berthoux, S. Bonsib, J. A. Bruijn, V. D'Agati, G. D'Amico, S. Emancipator, F. Emma, F. 
Ferrario, F. C. Fervenza, S. Florquin, A. Fogo, C. C. Geddes, H. J. Groene, M. Haas, A. M. 
Herzenberg, P. A. Hill, R. J. Hogg, S. I. Hsu, J. C. Jennette, K. Joh, B. A. Julian, T. Kawamura, 
F. M. Lai, C. B. Leung, L. S. Li, P. K. Li, Z. H. Liu, B. Mackinnon, S. Mezzano, F. P. Schena, 
Y. Tomino, P. D. Walker, H. Wang, J. J. Weening, N. Yoshikawa and H. Zhang (2009). "The 


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Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and 
classification." Kidney Int 76(5): 534-545. 
Wyatt, R. J. and B. A. Julian (2013). "IgA nephropathy." N Engl J Med 368(25): 2402-2414. 
Yazdani, R., G. Azizi, H. Abolhassani and A. Aghamohammadi (2017). "Selective IgA 
Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and 
Management." Scand J Immunol 85(1): 3-12. 
Yel, L., S. Ramanuja and S. Gupta (2009). "Clinical and immunological features in IgM 
deficiency." Int Arch Allergy Immunol 150(3): 291-298. 
Zhai, Y. L., L. Zhu, S. F. Shi, L. J. Liu, J. C. Lv and H. Zhang (2016). "Increased APRIL 
Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy." Medicine (Baltimore) 
95(11): e3099. 
Zhao, N., P. Hou, J. Lv, Z. Moldoveanu, Y. Li, K. Kiryluk, A. G. Gharavi, J. Novak and H. 
Zhang (2012). "The level of galactose-deficient IgA1 in the sera of patients with IgA 
nephropathy is associated with disease progression." Kidney Int 82(7): 790-796. 
 

SAP_003.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple 
Dose Study to Evaluate the Efficacy and Safety of VIS649 in Participants 
with Immunoglobulin A (IgA) Nephropathy  
Protocol VIS649-201 
Protocol Number: 
Protocol Version and Date: 
VIS649-201 
Version 4.0:  08 December 2020 
Version 3.0:  27 January 2020 
Version 2.0:  26 November 2019 
Name of Test Drug: 
VIS649 
Phase: 
Phase 2 
Methodology: 
Randomized, Double-Blind, Placebo-Controlled, Multiple Dose
Sponsor: 
Visterra, Inc. 
275 2nd Avenue 
Waltham, MA 02451 
Tel: (617) 498-1070 
 
 
 
 
 
 
 
 
 
Analysis Plan Date: 
27 Jun 2023 
Analysis Plan Version: 
Version 5.0 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of 
Visterra, Inc. and any unauthorized use or disclosure of such information without the prior written 
authorization of Visterra, Inc. is expressly prohibited. 
 
 


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CONFIDENTIAL 
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APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo- 
Controlled, Multiple Dose Study to Evaluate the Efficacy and 
Safety of VIS649 in Participants with Immunoglobulin A 
(IgA) Nephropathy 
Sponsor: 
Visterra, Inc. 
275 2nd Avenue 
Waltham, MA 02451 
Protocol Number: 
VIS649-201 
Document Date / Version: 
27 Jun 2023 / 5.0 
 
VeristatTM, LLC. Author:  
Veristat is a trademark of Veristat, LLC. All other trademarks are the property of their respective 
owners. 
 
 


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Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein.  I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report. 
Sponsor Signatory: 


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TABLE OF CONTENTS 
 
1. 
INFORMATION FROM THE STUDY PROTOCOL ......................................................... 11 
1.1. 
Introduction and Objectives ........................................................................................... 11 
1.1.1. 
Introduction ............................................................................................................. 11 
1.1.2. 
Study Objectives ..................................................................................................... 12 
1.2. 
Study Design .................................................................................................................. 14 
1.2.1. 
Synopsis of Study Design ....................................................................................... 14 
1.2.2. 
Randomization Methodology.................................................................................. 14 
1.2.3. 
Discontinuation of Study Intervention and Withdrawal from Study ...................... 15 
1.2.4. 
Study Procedures .................................................................................................... 15 
1.2.5. 
Study Endpoints ...................................................................................................... 15 
2. 
PARTICIPANT POPULATION .......................................................................................... 24 
2.1. 
Population Definitions.................................................................................................... 24 
2.2. 
Protocol Deviations ........................................................................................................ 25 
3. 
GENERAL STATISTICAL METHODS ............................................................................. 26 
3.1. 
Sample Size Justification ............................................................................................... 26 
3.2. 
General Methods ............................................................................................................ 26 
3.3. 
Computing Environment ................................................................................................ 27 
3.4. 
Baseline Definition and Change from Baseline ............................................................. 27 
3.5. 
Methods of Pooling Data................................................................................................ 27 
3.6. 
Adjustments for Covariates ............................................................................................ 28 
3.7. 
Multiple Comparisons/Multiplicity ................................................................................ 28 
3.8. 
Subgroup and Sensitivity Analyses ................................................................................ 28 
3.9. 
Withdrawals, Dropouts, Loss to Follow-up ................................................................... 28 
3.10. 
Missing Data ............................................................................................................... 28 
3.11. 
Visit Windows ............................................................................................................ 29 
4. 
STUDY ANALYSES ........................................................................................................... 32 
4.1. 
Participant Disposition ................................................................................................... 32 
4.2. 
Demographics and Baseline Characteristics .................................................................. 32 
4.3. 
Analysis of Primary Efficacy Endpoint ......................................................................... 32 
4.3.1. 
Primary Efficacy Analyses ..................................................................................... 33 
4.3.2. 
Subgroup Efficacy Analyses ................................................................................... 34 
4.3.3. 
Sensitivity Efficacy Analyses ................................................................................. 35 
4.4. 
Analysis of Secondary Efficacy Endpoints .................................................................... 35 


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4.4.1. 
Secondary Efficacy Analyses ................................................................................. 35 
4.4.2. 
Sensitivity Efficacy Analyses ................................................................................. 37 
4.5. 
Analyses of Exploratory Endpoints ............................................................................... 37 
4.6. 
Other Analyses ............................................................................................................... 38 
4.6.1. 
Pharmacokinetic Concentrations ............................................................................ 38 
4.6.2. 
Pharmacokinetic Parameters ................................................................................... 38 
4.6.3. 
Immunogenicity Evaluations .................................................................................. 38 
4.7. 
Analyses of Safety Endpoints ........................................................................................ 39 
4.7.1. 
Study Drug Exposure .............................................................................................. 39 
4.7.2. 
Adverse Events ....................................................................................................... 39 
4.7.3. 
Laboratory Data ...................................................................................................... 40 
4.7.4. 
Vital Signs and Physical Examination .................................................................... 41 
4.7.5. 
Prior and Concomitant Medications ....................................................................... 41 
4.8. 
Interim Analyses ............................................................................................................ 42 
4.8.1. 
Interim Efficacy and Safety Analyses..................................................................... 42 
4.8.2. 
Interim PK/Ig Analyses........................................................................................... 43 
5. 
CHANGES TO PLANNED ANALYSES ............................................................................ 44 
6. 
REFERENCES ..................................................................................................................... 45 
7. 
REVISION HISTORY.......................................................................................................... 47 
 
 
 
 


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TABLES INCLUDED IN THE TEXT 
Table 1 
TrucountTM Panel Lymphocytes ..........................................................................17
Table 2 
TBNK Panel Lymphocytes ..................................................................................18
Table 3 
Switch Panel Lymphocytes ..................................................................................18
Table 4 
Pharmacokinetic Parameters ................................................................................21
Table 5 
Visit Windows ..................................................................................................... 30
 
 
 
 


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Abbreviation 
Definition 
ACEi 
Angiotensin-converting enzyme indicator  
ADA 
Antidrug antibody 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
APRIL 
A Proliferation Inducing Ligand 
ARB 
angiotensin receptor blocker 
AUC  
Area under the plasma drug concentration  time curve from time 0 to 
infinite time 
AUC0-30day 
Area under the plasma drug concentration  time curve from time 0 to 
30 days post dose 
AUC  
Area under the plasma drug concentration  time curve from time 0 to 
the end of the dosing period 
BAFF 
B cell activating factor 
BCMA 
B-cell maturation antigen 
BMI 
Body Mass Index 
CI 
Confidence interval 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
ESRD 
End-stage renal disease 
Gd-IgA1 
Galactose deficient immunoglobulin A1 
HR 
Heart Rate 
Ig 
Immunoglobulin 
IgA 
Immunoglobulin A 


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Abbreviation 
Definition 
IgAN 
Immunoglobulin A nephropathy 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IMP 
Investigational medicine product 
ITT 
Intent-to-treat 
IV 
Intravenous 
LLOQ 
Lower limit of quantification 
LSM 
Least-square mean 
LSMD 
Least-square mean difference 
MAP 
Mean arterial pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-treat 
MMRM 
Mixed Model with Repeated Measurements 
MNC 
Mononuclear cell 
OR 
Odds ratio 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
ROW 
Rest of World 
SAP 
Statistical analysis plan 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SE 
Standard Error 
SIA 
Systemic immunosuppressive agent 
SOC 
Standard of care 
TACI 
Transmembrane activator and calcium-modulator cyclophilin ligand 
interactor 


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Abbreviation 
Definition 
TBNK 
Hematology/flow panel where T = T cells, B = B cells and NK = NK 
cells.  
TEAE 
Treatment-emergent adverse event 
TNC 
Total nucleated cell count 
uACR 
Urinary albumin/creatinine ratio 
uPCR 
Urine protein to creatinine ratio 
WHO 
World Health Organization 
 
 
 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
VIS649 is a humanized immunoglobulin G2 monoclonal antibody being developed for the 
treatment of immunoglobulin A nephropathy (IgAN), an autoimmune glomerulonephritis 
characterized by the deposition of immunoglobulin A (IgA)-containing immune complexes in 
the kidney. 
IgAN is one of the most common primary glomerular diseases and affects patients globally, with 
some geographical variation in incidence and prevalence (Wyatt and Julian 2013, Rodrigues, 
Haas et al. 2017, Schena and Nistor 2018). Clinical presentation varies from incidentally 
detected asymptomatic hematuria and proteinuria to rapidly progressive glomerulonephritis 
requiring dialysis. IgAN is a significant cause of chronic kidney disease and end-stage renal 
disease (ESRD), with 30 40% of patients reaching ESRD 20 30 years after the first clinical 
presentation. IgAN can occur in either sporadic (90 95%) or familial (5 10%) patterns. Patients 
with familial IgAN might have poorer prognoses than those with sporadic disease, with an 
increased risk of progression to renal failure (Lai, Tang et al. 2016). 
The primary parameter of this study, proteinuria, is an important marker of progression of renal 
disease in patients with IgAN. Patients with significant proteinuria (> 1.0 g/day) have a faster 
decline of estimated glomerular filtration rate (eGFR) and progression to ESRD, when 
compared to patients with lower degrees of proteinuria (< 500 mg/day). Hence, reduction in 
proteinuria is a crucial aspect in the management of IgAN (Reich, Troyanov et al. 2007, Nam, 
Kie et al. 2014, Inker, Mondal et al. 2016). Proteinuria is also gaining acceptance by health 
authorities as a surrogate marker of eGFR decline in IgAN (Inker, Lesley et al. 2021). 
The mechanistic target of VIS649 is the cytokine A Proliferation Inducing Ligand (APRIL). 
APRIL belongs to the tumor necrosis factor ligand superfamily and has emerged as a key factor 
in the pathogenesis of IgAN. APRIL mediates the immunoglobulin (Ig) isotype switch during 
B-cell development, production of IgA, and plasma-cell survival, and may specifically influence 
production of aberrantly Galactose deficient immunoglobulin A1 (Gd-IgA1) (Castigli, Scott et 
al. 2004, Varfolomeev, Kischkel et al. 2004, Endo, Nishio et al. 2007, Bossen, Cachero et al. 
2008). Studies in patients with IgAN have shown that elevated APRIL levels correlate with poor 
kidney outcomes when compared with patients with lower APRIL levels (Han, Yang et al. 2016, 
Zhai, Zhu et al. 2016). A similar trend is also seen with Gd-IgA1 levels, with higher levels 
associated with faster and more frequent progression to kidney failure when compared to 
patients with lower Gd-IgA1 levels (Castigli, Scott et al. 2004, Berthoux, Suzuki et al. 2012, 
Zhao, Hou et al. 2012).  
VIS649 binds to and blocks the biological actions of APRIL, preventing its binding to its 
receptors, transmembrane activator and calcium-modulator cyclophilin ligand interactor 
(TACI), and B-cell maturation antigen (BCMA). Blocking the biological actions of APRIL 


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reduces the production of IgA. The hypothesis to be tested in this study is that blocking the 
biological actions of APRIL in patients with IgAN will lead to reduction of serum IgA 
(including Gd-IgA1) levels and will reduce or halt the progression of IgAN, as measured by 
decrease in proteinuria and stabilization of eGFR decline. 
1.1.2. 
Study Objectives 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis 
of study data to assess the study objectives. Populations for analysis, data handling rules, 
statistical methods, and formats for data presentation are provided. The statistical analyses and 
summary tabulations described in this SAP will provide the basis for the efficacy interim and 
final analysis outputs and the results and appendices of the clinical study report (CSR) for this 
trial. 
This SAP will also outline any changes in the currently planned analytical objectives relative to 
those planned in the study protocol. 
1.1.2.1. 
Primary Safety Objective 
To evaluate the safety and tolerability of monthly doses of VIS649 at each of 3 dosing levels, 
administered intravenously (IV) to IgAN participants over the course of 12 months as an add-on 
to standard of care (SOC) treatment with angiotensin-converting enzyme indicator/angiotensin 
receptor blocker (ACEi/ARB) therapy compared with saline placebo infusions. 
1.1.2.2. 
Primary Efficacy Objective 
To evaluate the dose response of monthly doses of VIS649 on proteinuria at each of 3 dosing 
levels, administered IV to IgAN participants over the course of 12 months as an add-on to SOC 
treatment with ACEi/ARB therapy compared with saline placebo infusions. 
1.1.2.3. 
Secondary Objectives 
 
To evaluate the effect of repeated doses of VIS649 at 3 dosing levels versus placebo on the 
following parameters: 
o Urine protein to creatinine ratio (uPCR) at Months 9 and 16 (ie, 5 months following the 
final [12th] monthly dose administration)  
o 24-hour urine protein excretion at Months 9, 12, and 16   
o Number of participants in each group achieving a 
at Months 9, 12, and 16  
o Clinical remission, defined as reduction in 24-hour urine protein excretion to 
< 300 mg/day for at least 3 consecutive months  


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o eGFR at Months 12 and 16 
o Pharmacodynamic (PD) parameters, inclduing IgA, Immunoglobulin G (IgG), and 
Immunoglobulin M (IgM) concentrations 
 
To determine the pharmacokinetic (PK) profile of repeated dose of VIS649 at each dosing 
level  
 
To determine the PK/PD profile of VIS649, relating VIS649 PK parameters and biomarkers 
such as changes in IgA to changes in proteinuria and eGFR 
 
To screen for anti-VIS649 antibodies (ADA) responses 
1.1.2.4. 
Exploratory Objectives 


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1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, multiple-dose 
study to evaluate the safety and efficacy of IV administered VIS649 over a 12-month treatment 
course in participants with IgAN.  
Participants will be enrolled from approximately 100 global sites in approximately 16 countries. 
Enrolled participants will be 18 years of age or older with an IgAN diagnosis confirmed by 
biopsy. 
VIS649 (2, 4, and 8 mg/kg) or placebo will be administered as 12 monthly IV infusions 
(Months 0-11) as described in the schedule of assessments (Current Version of Protocol). The 
final efficacy assessments will be taken at the Month 12 Visit (ie, around Day 360, following 
approximately 12 months of exposure to study drug), and a final safety evaluation will be 
conducted at Month 16 (ie, approximately 5 months following last study drug dosing). Up to 
60 participants (approximately 15 participants in each treatment group) may have a more 
intensive PK and PD sampling schedule at Months 0-3 and 11-14 (see Current Version of 
Protocol). 
Efficacy assessments will be primarily evaluated by the reduction in uPCR from baseline. The 
 
depending on whether the uPCR are collected from the 24-hour urine collection (or an intended 
24-hour urine sample) (i.e., 24-
B Urine Collection). Schedule A Urine Collection visits include Screening, Days 270 (Month 
9), 360 (Month 12) and 485 (Month 16), where Screening would be the Baseline visit. Schedule 
B Urine Collection visits include Day 1 (pre-infusion) and Days 8, 30, 60, 90, 120, 150, 180, 
210, 240, 300 and 330, where Day 1 (pre-infusion) would be the Baseline visit. 
Safety assessments will include review of adverse events (AEs) (including hypersensitivity 
reaction, anaphylactic reaction, and injection site tolerability), physical examinations, clinical 
laboratory assessments (including biochemistry, hematology, urinalysis, and pregnancy testing), 
laboratory testing (including serum Ig levels and ADAs), vital sign measurements, and use of 
concomitant medications.  
The total study duration for each participant (from screening to end-of-study) will be up to 17 
months (assuming up to 1 month for screening, 12 months for monthly doses [including 30 days 
after the 12th dose]), and follow-up visits up to 155 days after the last dose of study intervention. 
1.2.2. 
Randomization Methodology 
Participants will be randomly assigned in a 1:1:1:1 allocation ratio to receive VIS649 at 2, 4, or 
8 mg/kg or placebo, with approximately 36 participants randomized to each treatment group.  


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Randomization will be stratified by region (Japan vs Rest of World [ROW]). A target of 12 or 
more participants are planned to be randomized at Japanese sites. Japanese participants will be 
randomized with equal allocation and without further stratification. Randomization for ROW 
will be stratified by screening uPCR (Schedule A, 
the creation of randomization schemes, and other randomization procedures, can be found in the 
Randomization Plan (Appendix 1). 
1.2.3. 
Discontinuation of Study Treatment and Withdrawal from Study 
Participants have the right to discontinue study treatment or withdraw from the study at any time 
for any reason. Participants may withdraw or be withdrawn from study-related procedures and 
interventions for the following reasons:  
 
Adverse Event 
 
Death 
 
Lost-to-Follow-up 
 
Protocol Violation 
 
Physician Decision 
 
Study Terminated by Sponsor 
 
Withdrawal by Subject 
 
Other 
Reasons of study discontinuation will be listed and summarized in the CSR. 
At the discretion of the Data Safety Monitoring Board (DSMB), in consultation with the study 
Sponsor, the participant may be discontinued from treatment or study. Furthermore, the DSMB may 
recommend the trial to be modified or cease for safety reason(s). More specific information can be 
found in the DSMB Charter. 
1.2.4. 
Study Procedures 
The schedule of assessments is presented in the latest version of the study protocol. 
1.2.5. 
Study Endpoints 
1.2.5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is measured by the change from baseline in uPCR (measured on 
the natural log scale from 24-hour urine collection or the intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days after the 12th dose is administered). 


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1.2.5.2. 
Secondary Endpoints 
Secondary endpoints include: 
 
Change from baseline in uPCR on natural log scale (from 24-hour urine collection or the 
intended 24-hour urine collection) at Months 9 and 16 
 
Change in 24-hour urine protein excretion (mg/day) from baseline to Months 9, 12, and 
16 
 
 30% decline from baseline in uPCR 
(from 24-hour urine collection or the intended 24-hour urine collection) at Months 9, 12, 
and 16 
 
Number of participants in each group achieving reduction in 24-hour urine protein 
excretion to < 300 mg/day at Months 9, 12, and 16, as well as the proportion of 
participants who have achieved reduction in 24-hour urine protein excretion to 
< 300 mg/day at (1) Month 9 and maintained the response through Month 12 and (2) at 
Month 12 and maintained the response through Month 16 
 
Linear slope eGFR (mL/min/1.73 m2) between baseline and Month 12  
 
Linear slope eGFR (mL/min/1.73 m2) between baseline and Month 16  
 
Change in eGFR (mL/min/1.73 m2) between baseline and Months 12 and 16  
 
Percent change from baseline in total serum IgA, IgG, and IgM concentrations at 
Months 9, 12, and 16 (mg/dL) 
 
Serum PK Parameters (See Section 1.2.5.4) 
 
Serum ADA levels (See Section 1.2.5.5) 
1.2.5.3. 
Exploratory Endpoints 
Exploratory endpoints include:  


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hematology, serum chemistry, urinalysis, pregnancy, serum Ig levels, ADAs, monitoring of AEs 
and concomitant medications. 
 
 


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2. 
PARTICIPANT POPULATION 
2.1. 
Population Definitions 
The following participant populations will be evaluated and used for presentation and analysis 
of the data: 
 
Intent-to-Treat (ITT) Population: All participants who are randomized. Participants will be 
categorized by treatment they were randomized to receive. 
 
Modified Intent-to-Treat (mITT) Population: All randomized participants who received at 
least 1 dose of study treatment. Participants will be categorized by treatment that they were 
randomized to receive. The mITT population will be the primary population for assessment 
of efficacy.  
 
Safety Population: All randomized participants who received any amount of study treatment. 
Participants will be categorized by treatment received. Analysis of safety parameters will be 
performed using this population.  
 
PK Population: All randomized participants who received at least 1 dose of study treatment 
and have at least 1 post-dose evaluable serum concentration. The PK population will be the 
primary population for PK analyses. 
 
Intensive PK Population: All randomized participants who received at least 1 dose of study 
treatment, and consented to participation in the Intensive PK substudy (See Current Version 
of Protocol) and have at least 1 post-dose evaluable serum concentration. 
 
PD Population: All randomized participants who received at least 1 dose of study treatment 
and have baseline and at least 1 post-dose evaluable PD measure. The PD population will be 
the primary population for PD analyses. 
 
Immunogenicity Population: All randomized participants who are administered any amount 
of study treatment and have at least 1 pre-dose evaluable ADA measure. 
 
Biomarker Population: All randomized participants who consented to participate in the 
biomarker substudy (See Current Version of Protocol). Analysis of biomarker data will be 
performed on the Biomarker population (analyses performed with Biomarker Population 
data are not included in this SAP).  
 
Per Protocol (PP) Population: All randomized participants with 
75% compliance and 
without any important protocol deviations involving inclusion/exclusion criteria, study 
treatment, or the primary efficacy analyses. Compliance (%) is calculated by 100*(number 
of doses received/12). The primary efficacy analyses will be repeated for the PP population. 
The PD and PK populations will be the population for the interim PK/Ig analyses (the interim 
PK/Ig analyses are not included in this SAP). 


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2.2. 
Protocol Deviations 
Important protocol deviations will be determined by a review of the data prior to unblinding of 
the study results. The Sponsor or designee will be responsible for producing the final 
determination (ie, major vs minor) in collaboration with Veristat, prior to final study database 
lock. 
Protocol deviations will be collected and reported at the subject level, describing the context 
and/or reasons for the deviations such as re-screening, use of alternative endpoint ascertainment 
methods, and use of alternative or rescue treatments. Additional categories related to COVID-19 
may be recorded and presented in the data listing. 
Important protocol deviations will be presented in a data listing. 
 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
The sample size for this study was calculated assuming a linear dose response (reduction of 
uPCR) of 0%, 15%, 30%, and 45% in placebo and VIS649 2, 4, and 8 mg/kg groups, 
respectively. Applying contrasts of -3, -1, 1, and 3 for the corresponding dose levels and 
analyzing uPCR on the natural log scale, the result is an expected mean change from baseline of 
0, -0.163, -0.357, and -0.593 for placebo and VIS649 groups of 2, 4, and 8 mg/kg, respectively. 
Using an analysis of variance model with contrasts of -3, -1, 1, and 3 for the corresponding 
groups, a standard deviation (SD) of 0.87, 80% power, a 2-sided type I error rate of 0.05, and 
accounting for a dropout rate of ~ 20%, the required sample size is 36 participants per group, or 
144 participants overall. 
3.2. 
General Methods 
All collected data will be included in listings that will contain a relative study day if there is an 
evaluation date. Pretreatment and on-treatment study days are numbered relative to the day of 
the first dose of study medication which is designated as Day 1. The preceding day is Day -1, 
the day before that is Day -2, etc.  
All output will be incorporated into Microsoft Word Rich Text Format files sorted and labeled 
according to the International Council on Harmonisation recommendations and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, PK, 
immunogenicity, safety, and exploratory parameters. For categorical variables, summary 
tabulations of the number and percentage of participants within each category (with a category 
for missing data) of the parameter will be presented. For continuous variables, the number of 
participants, mean, median, SD, standard error, minimum, and maximum values will be 
presented. For demographic continuous variables, the inter-quartile range (IQR) will also be 
presented. 
All summary tables will be presented by treatment, including each individual VIS649 dose 
group, a pooled VIS649 dose group and placebo. For disposition, demographics and baseline 
characteristics summaries, an overall column will be included (ie, all participants).   
Per study design, uPCR and eGFR measurements are collected up to Month 16. However, the 
treatment period is up to Month 12. Therefore, for the primary efficacy endpoint of 24-hour 
uPCR, the primary mixed model with repeated measures (MMRM) will include 24-hour uPCR 
at Months 9 and 12. For the secondary endpoint of 24-hour uPCR at 9 Months, the effect at 
Month 9 will be reported from the primary MMRM and included in the primary outputs. For the 
secondary endpoint of 24-hour uPCR at 16 Months, the same MMRM will be fitted but 24-hour 
uPCR at Months 9, 12 and 16 will be included (Section 4.3, 4.4).  


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3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4 
or higher, unless otherwise noted. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) (version 24.0 or newer). Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary 
Enhanced (March 2022 or newer). 
3.4. 
Baseline Definition and Change from Baseline 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug.  
value and baseline period value, where ti=any post baseline time point and t0 is the baseline 
result: 
 
Percent of baseline is calculated as: 
 
The percent of baseline will be analyzed for IgA, IgG, IgM, IgA1, IgA2, and Gd-IgA1 
endpoints. 
The change from baseline on the natural log scale is calculated as: 
 
The ratio change from baseline is calculated as: 
 
Where ti =any post baseline time point and t0 is the baseline result. The change from baseline on 
the natural log scale and the ratio change from baseline will be analyzed for the uPCR (both 
Schedule A and B Urine Collection) and 24-hour urine protein excretion. 
3.5. 
Methods of Pooling Data 
Data will be pooled across sites for each group. All VIS649 participants will be pooled across 
VIS649 doses in addition to a by-dose presentation.  


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3.6. 
Adjustments for Covariates 
Efficacy analyses will be adjusted for covariates including baseline measurements and strata.  
3.7. 
Multiple Comparisons/Multiplicity 
Formal statistical hypothesis testing will be performed on the primary efficacy endpoint of linear 
dose response in change from baseline in uPCR on the natural log scale at Month 12, conducted 
at the 2-sided, 0.048 level of significance to preserve the study-wide 2-sided type I error rate at 
0.05 while accounting for interim data review (Section 4.8). The inclusion of statistical tests for 
secondary endpoints is intended to yield supportive evidence related to the primary objective 
and will be descriptive in nature as no confirmatory conclusions are intended. Statistically 
significant results will be examined in sequence from high dose (8 mg/kg) to low dose 
(2 mg/kg) compared with placebo. Tests of probability are not planned for the exploratory 
endpoints so that multiplicity of statistical probability test results is not a consideration.  
3.8. 
Subgroup and Sensitivity Analyses 
Subgroup analyses for primary efficacy endpoint will be performed as described in 
Section 4.3.2. 
Sensitivity analyses will be performed as described in Section 4.3.3 for primary efficacy 
endpoint and in Section 4.4.2 for selected secondary efficacy endpoints.  
3.9. 
Withdrawals, Dropouts, Loss to Follow-up 
Participants who withdrew from the study, were discontinued, or lost to follow-up will not be 
replaced. 
3.10. 
Missing Data 
In general, there will be no imputation performed for missing data, including efficacy, safety, 
PK, PD, and ADA, unless otherwise specified. All data recorded on the case report form will be 
included in data listings that will accompany the CSR.  
Missing data due to discontinuation of treatment, withdrawal from the trial or missed endpoint 
ascertainment will be reported at the subject level with a description of the context and/or reason 
-
 
For the primary efficacy endpoint, if a result is missing or not evaluable for 24-hour uPCR, and 
there is an unscheduled visit within 30 calendar days of the nominal visit date, the unscheduled 
visit assessment will be treated as the nominal timepoint.  
For the analysis of AE, only partial dates will be imputed unless otherwise specified. The 
algorithms for imputation of partial dates depend upon the parameter, as follows:  


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 If the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as study treatment. In this case, in order to 
conservatively report the event as treatment-emergent, the onset date will be assumed to 
be the date of treatment.  
 If the onset day and month are both missing, the day and month will be assumed to be 
January 1, unless the event occurred in the same year as the study treatment. In this case, 
the event onset will be coded to the day of treatment to conservatively report the event as 
treatment-emergent.  
 A missing onset date will be coded as the day of treatment.  
Adverse events with missing relation will be considered related. Adverse events with missing 
severity will be considered severe. 
For the analysis of concomitant medication, incomplete start/stop dates will be imputed based 
on the following imputation rules:  
 If start date is completely missing, start date will not be imputed. 
 If start year is present and month and day are missing, or year and day are present and 
month is missing, set start month and day to January 1. 
 If start year and month are present and day is missing, set start day to 1st day of the 
month. 
 If end date is completely missing, end date will not be imputed. 
 If end year is present and month and day are missing, or year and day are present and 
month is missing, set end month and day to December 31. 
 If end year and month are present and day is missing, set end day to last day of the 
month. 
 The imputed dates must be logical, ensuring that no end date is after database lock or 
death or before the start date. 
3.11. 
Visit Windows 
If a participant is unable to attend a visit within 7 days of the scheduled infusion, they may still 
receive an infusion within the next 7 days; this will be recorded as a protocol deviation and will 
still be recorded for that visit. However, if there is any further delay, that dose will be skipped, 
and the participant will receive subsequent doses as per the schedule. The participant will not 
receive additional doses to make up for the missed dose(s). In data listings, all available data 
and the relative day of all dates will be presented.  
Visits will be included in the analyses as labelled on the case report form with the exception of 
the following Visit/Month labels: 
 M12/ET; where ET = Early Termination 
 W16/EOS; where EOS = End of Study 




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M14 
406 to 453 
M16 
454 to 492 
a If patient has no first dose date, Day 1 will be the randomization date. 
 
 
 


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4. 
STUDY ANALYSES 
4.1. 
Participant Disposition 
A tabulation of the disposition of participants will be presented by group. Summaries will 
include the number of participants screened, failed screening, enrolled, randomized and treated, 
participants in each stratification factor (Japan and ROW), number of participants in each study 
population and number of participants who discontinued as well as the reasons for 
discontinuation. 
A by-group, by-participant data listing of study completion information including the reason for 
premature study withdrawal, if applicable, will be presented. A data listing will also be presented 
for the inclusion/exclusion criteria not met/met, visits completed, and whether any visit was 
related to COVID-19. 
4.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics, including medical history, will be summarized and 
presented by group and overall, using the ITT population.  Age, height, weight, body mass index 
(BMI) and baseline ECG findings will be summarized using descriptive statistics (number of 
participants, mean, SD, median, minimum, and maximum). The number and percentage of 
participants in each sex, ethnicity, race and baseline ECG interpretation category will be 
presented.  
Baseline medical history tabulation will include whether the participant experienced any 
significant illnesses, pre-existing conditions or surgeries, prior tonsillectomy and prior 
 
Baseline kidney biopsy history tabulation will include time since biopsy, method used for biopsy 
interpretation, mesangial hypercellularity, endocapillary proliferation, segmental 
glomerulosclerosis tubular, tubular atrophy/interstitial fibrosis, crescents and 
immunofluorescence intensity for IgA, IgG, IgM, C3, C4 and C1q.  
Baseline ACEi/ARB history tabulation will include ACEi/ARB medication(s) information from 
the last 3 months at a minimum or previous 12 months (if known).  
Baseline Systemic Immunosuppressive Agent (SIA) history tabulation will include details of any 
previous SIA medication use. 
All demographic, baseline characteristics, medical history, kidney biopsy history, ACEi/ARB 
history, 12-lead ECG, serology, pregnancy, Hemoglobin A1c, and blood sample for 
deoxyribonucleic acid (DNA) results will be provided in data listings. 
4.3. 
Analysis of Primary Efficacy Endpoint 
Efficacy analyses will be conducted using the mITT population. The primary efficacy analyses 
will also be conducted on the PP population as a sensitivity analysis (See Section 4.3.3). 


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4.3.1. 
Primary Efficacy Analyses 
The primary endpoint of this study is the change from baseline in uPCR (Schedule A) on the 
natural log scale at Month 12 (Days 360) (See Section 3.4 for change from baseline on the 
natural log scale equation).  
A Mixed Model with Repeated Measurements (MMRM) will be used to compare the change 
from baseline in uPCR (Schedule A visits  Months 9 and 12) on the natural log scale between 
treatment groups. The response variable of the MMRM is the change from baseline in uPCR 
(Schedule A) on the natural log scale. The model includes the fixed effects of treatment group, 
categorical visit (Months 9 and 12), strata and a treatment-by-visit interaction, with a fixed effect 
covariate of baseline uPCR (Schedule A) on natural log scale. An unstructured covariance matrix 
will be used. If the model does not converge, then the Toeplitz covariance structure will be used.  
From the MMRM, the following statistics will be produced: 1) the least-square mean (LSM), its 
corresponding standard error (SE), and 95% confidence interval (CI) for each treatment group; 
2) the geometric mean ratio calculated by exponentiated (LSM) and 95% CI for each treatment 
group; 3) the least-square mean difference (LSMD) between treatment groups using placebo as 
reference, its corresponding SE and 95% CI and p-value for testing the LSMD; and 4) the 
treatment difference expressed as geometric mean reduction calculated as (1- exponentiated 
LSMD) ×100%, and 95% CI.  
The geometric mean reduction and corresponding SE estimated from the MMRM for each 
treatment group will also be presented graphically. 
The alpha value for the primary efficacy analyses (ie, p-value for the test of linear contrast at 
Month 12) will be adjusted to account for one review of the efficacy endpoint during the interim 
analyses. Although the interim efficacy data reviews will not include hypothesis testing (Section 
4.8.1), the type I error rate for the primary endpoint will be reduced by 0.002 for the interim 
efficacy review, resulting in a 2-sided type I error rate of 0.048 for the linear contrast p-value. A 
p-value < 0.048 for the linear contrast of the primary efficacy analysis will support a claim of 
efficacy. 
The primary efficacy analysis result also includes the p-value from the linear contrast statement 
of -3, -1, 1, and 3 evaluated for VIS649 dose levels 0 (placebo), 2, 4, and 8 mg/kg, respectively 
at Month 12.  
In addition to the linear contrast for the primary efficacy result, a quadratic contrast statement of 
0.56, -0.32, -0.64, and 0.40 will also be evaluated for VIS649 dose levels 0 (placebo), 2, 4, and 
8 mg/kg, respectively at Month 12 as well as a cubic contrast statement of -0.28, 0.76, -0.57 and 
0.09 for VIS649 dose levels 0 (placebo), 2, 4, and 8 mg/kg, respectively at Month 12. The 
quadratic and cubic weights are from an R orthogonal polynomial function (R, 2020).  
In addition, pairwise comparisons between the treatment groups (placebo, 2, 4, and 8 mg/kg) 
using different dose level as reference will be performed at Month 12. The geometric mean 
reduction, corresponding SEs and 95% CI for testing treatment differences will be reported. The 
percent change in uPCR from baseline (ie. -1(geometric mean ratio reduction)) and 


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corresponding SE estimated from the primary MMRM for each treatment group will be 
presented graphically. The p-values of pairwise comparisons between all treatment groups will 
also be reported. 
The baseline through Month 12 MMRM will be used to compare the change from baseline in 
uPCR (Schedule A) on the natural log scale between the pooled VIS649 and placebo. The 
outputs will be similar to those estimated from the MMRM for each individual treatment group.   
uPCR (Schedule A) on the natural log scale and changes from baseline will be summarized 
descriptively by treatment group and visit, including number and percentage of participants with 
missing or incomplete assessments at that visit. The raw uPCR (Schedule A), and the ratio 
change from baseline over time, will also be summarized over time using the geometric mean (± 
95% CI). 
uPCR (Schedule A and Schedule B) that is unable to be calculated because the total protein 
excretion is below the lower limit of quantification (LLOQ) will be reported in the statistical 
summaries as such. The LLOQ for the total protein excretion that is being used to calculate 
uPCR is 
 To account for individual differences due to creatinine values, 
values that are below the limit of quantification (BLQ) will be calculated using the imputed total 
protein excretion value of 
, divided by the 
 urine creatinine level in 
mg/24h for that visit. These imputed values will be included in the calculation of descriptive 
statistics.  
In addition, the raw spot uPCR (Schedule B), and the ratio change from baseline will be 
summarized over time using the geometric mean (± 95% CI). 
4.3.2. 
Subgroup Efficacy Analyses 
Summary statistics for the change from baseline in uPCR (Schedule A) over time will be 
reported for subpopulations of participants defined by the following baseline characteristics: 
 
 
 
Region (Japan and ROW) 
 
Baseline eGFR (30-45 and 45+ mL/min/1.73 m2) 
 
Baseline Gd-IgA1 (  50th and > 50th percentile µg/mL) 
 
Baseline BMI (< 
 30 kg/m2)  
 
Baseline 
th and > 50th percentile ug/ml) 
 
Baseline APRIL 
th and > 50th percentile pg/mL) 
The following subgroup analysis will be performed only if  10 participants fulfill 
 
category at baseline:  
 
ACEi/ARB therapy at enrollment (yes/no)  


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Use of steroid and/or any immunosuppressive therapy prior to enrollment (yes/no) 
 
Tonsillectomy prior to enrollment (yes/no) 
 
SGLT2 inhibitor use (yes/no) 
 
Prior Hypertension (yes/no) 
4.3.3. 
Sensitivity Efficacy Analyses 
There will be 3 sensitivity analyses:  
Sensitivity Analysis 1: the primary analysis (Section 4.3.1) performed on the PP population. 
Sensitivity Analysis 2: the primary analysis (Section 4.3.1) performed on uPCR from Schedule B 
collections. 
Sensitivity Analysis 3: the analysis of covariance (ANCOVA) model will be used to compare the 
treatment effects in uPCR (Schedule A) on the natural log scale between treatment groups at 
12 months as a sensitivity analysis. The ANCOVA model will be fitted with treatment group, 
strata, and baseline uPCR (Schedule A) on the natural log scale. The outputs are the same with 
those estimated from the primary efficacy model for each treatment group.  
4.4. 
Analysis of Secondary Efficacy Endpoints 
Secondary analyses will be conducted using the mITT population, unless otherwise specified.  
4.4.1. 
Secondary Efficacy Analyses 
All secondary endpoints, as well as the respective changes from baseline, for each parameter will 
be summarized descriptively over time by treatment group, including number and percentage of 
participants with missing or incomplete assessments at that visit, for the following endpoints: 
 
24-hour urine protein excretion (mg/day) 
 
eGFR (mL/min/1.73 m2) 
 
Total serum IgA, IgG, and IgM concentrations (mg/dL) in the PD population 
The uPCR (Schedule A; up to Month16), urine protein excretion (up to Month 16) will be 
summarized, at each specified time point, between placebo and VIS649 dose levels of 2, 4, and 8 
mg/kg, respectively. 
4.4.1.1. 
uPCR (from 24-hour urine collection or the intended 24-hour urine collection) at 
Months 9 and 16 
The treatment effect for each treatment group and the treatment difference at Month 9 will be 
generated from the same MMRM applied in the primary efficacy analysis (Section 4.3.1). The 


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outputs for Month 9 are included with those from the primary efficacy analyses. The Month 16 
outputs will be generated from the MMRM including Months 9, 12, and 16 (Schedule A).  
4.4.1.2. 
24-hour Urine Protein Excretion 
The MMRMs will be fitted to estimate the treatment difference for the 24-hour urine protein 
excretion at Months 9, 12, and 16, respectively. Since the distribution of 24-hour urine protein 
excretion is skewed, the response variable will be the natural log transformed ratio of 24-hour 
urine protein excretion. The models will include the treatment group, strata, categorical visit, 
treatment-by-visit, and natural log transformed baseline 24-hour urine protein excretion as 
covariates. The model for Months 9 and 12 will include Baseline, Months 9 and 12. The model 
for Month 16 will include Baseline, Months 9, 12 and 16. The treatment differences on these 
assessments  at Months 9, 12, and 16 will be estimated from their respective models by the 
differences in the geometric mean ratio reduction, along with the SEs, 95% CIs, and p-values.  
24-hour Urine Protein Excretion that is unable to be calculated because the total protein excretion 
is below the lower limit of quantification (LLOQ) will be noted in the associated listing as such. 
Statistical summary tables that include imputed values will be indicated in the footnotes. The 
LLOQ for this test is 
 Values that are below the limit of quantification 
(BLQ) will be substituted with 
 for the statistical summaries and the calculation of 
descriptive statistics.  
 
4.4.1.3. 
eGFR 
MMRMs will be fitted to estimate the treatment difference for the eGFR at Months 12 and 16, 
respectively. The models will include the treatment group, strata, categorical visit, treatment-by-
visit interaction, and baseline eGFR as covariates. The model for Month 12 will include all 
timepoints from baseline through Month 12. The model for Month 16 will include all timepoints 
from baseline through Month 16. The treatment effect on these assessments at Months 12 and 16 
will be estimated by the LS means and their differences in the LS means, along with the SEs, 
95% CIs, and p-values.  
Change from baseline eGFR (LS mean ±SE) will be displayed graphically across time by line 
chart for all visits up to Month16.  
4.4.1.4. 
eGFR Linear Slope 
The eGFR linear slope from baseline to Month 12 and 16 will be derived from the slope value of 
a linear regression of baseline through Months 12 and 16 eGFR, respectively across time (days), 
per subject, using the linear model eGFR = a + b(days) where b is the linear slope value. The 
eGFR slope, up to Months 12 and 16, will be compared between placebo and VIS649-treated 
groups using an ANCOVA model with baseline eGFR as covariate. 


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4.4.1.5. 
Total serum IgA, IgG, and IgM concentrations (mg/dL) in the PD population 
Total serum IgA, IgG, and IgM concentrations (mg/dL) percent of baseline and change on the 
natural log scale, will be summarized descriptively over time, including the geometric mean 
(± 95% CI). The total serum IgA, IgG, and IgM concentrations percent change and percent of 
baseline will be displayed graphically (mean ± SD). 
4.4.1.6. 
Other Endpoints 
The secondary efficacy analyses for the following binary endpoint will use a logistic regression 
model to compare VIS649 2, 4, and 8 mg/kg to placebo (0 mg/kg). Summary statistics, the odds 
ratio (OR), 95% CIs and p-values for each dose group (2, 4, 8 mg/kg), and pooled dose groups, 
compared to placebo, will be reported for the following outcomes:  
 
ne from baseline in 24-hour 
uPCR (Schedule A), on the log scale, at Months 9, 12, and 16. 
 
Number of participants in each group achieving reduction in 24-hour urine protein 
excretion to < 300 mg/day for at least 3 consecutive months at Months 9, 12, and 16 if 
data is available. 
An OR of 1 will indicate that the treatment (2, 4 or 8 mg/kg) does not affect the odds of the 
 30% decline from baseline in uPCR (Schedule A) or achieving 
reduction in 24-hour urine protein excretion to < 300 mg/day or < 200 mg/mg uPCR 
(Schedule A) for at least 3 consecutive months at Month 12 whereas and OR > 1 will indicate 
that the treatment is associated with a higher odds of the outcome and an OR < 1 will indicate 
that the treatment is associated with a lower odds of the outcome. 
4.4.2. 
Sensitivity Efficacy Analyses 
The annualized slope of eGFR estimated over the course of 12 months. The linear mixed effects 
model with random effects will be used to compare the annualized slope of eGFR between 
treatment groups estimated over the course of 12 months. The response variable of the model is 
the eGFR value at each post baseline visit. The model will be fitted with fixed effects of 
treatment, time (as a continuous variable), treatment-by-time interaction, strata, baseline eGFR 
and random effects of intercept and time. The unstructured covariance structure will be used. 
The annualized eGFR slope by each treatment group, together with SE and 95% CI will be 
reported. The statistical inference will be based on testing of the difference on the eGFR 
annualized slope between two treatment groups and estimation of the difference and its 95% CI. 
4.5. 
Analyses of Exploratory Endpoints 
  
All exploratory endpoints (see Section 1.2.5.3), excluding those specified to be analyzed outside 
of this SAP, as well as the respective changes from baseline, for each parameter will be 
summarized descriptively over time by treatment group, including number and percentage of 


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participants with missing or incomplete assessments at that visit. No formal statistical 
comparisons will be performed. 
4.6. 
Other Analyses 
Pharmacokinetic analyses will be conducted using the PK Population. Population PK/PD 
analysis will be analyzed outside of this SAP and will be reported separately. 
4.6.1. 
Pharmacokinetic Concentrations  
Individual and descriptive summaries of VIS649 serum concentrations by timepoint and dose 
will be provided. Figures of individual serum concentration-time profiles of VIS649 will be 
created, where the actual time will be plotted on the x-axis. 
For participants in the intensive PK population (See current version of Protocol Version for 
details of the PK substudy) at Months 0 and 11, mean and median concentration time profiles 
will be calculated by dose and plotted on linear and semi-log scales at Months 0 and 11. The 
mean profiles will include standard deviation. The number of values above the lower limit of 
quantification (LLOQ) will be reported in the statistical summaries. Values that are below the 
limit of quantification (BLQ) will be substituted with zero for the calculation of descriptive 
statistics of concentration by time point. Missing samples will be reported as no sample ("NS") 
and excluded from the statistical summaries. 
Samples with no actual date and time collected will be excluded from the analysis. No formal 
statistical comparisons will be performed.  
4.6.2. 
Pharmacokinetic Parameters  
Pharmacokinetic parameter analyses will be conducted using participants from the PK 
Population or Intensive PK Population.  
VIS649 serum concentrations for participants in the intensive PK Population will be analyzed 
using standard noncompartmental methods. Serum concentration values below the LLOQ will be 
set to 0 before the peak concentration and set to missing after the peak concentration in the PK 
evaluation. Individual and summary PK parameters (outlined in Table 4) will be listed by dose, 
visit (ie, Month 0 or Month 11) and subject. No formal statistical comparisons will be performed.  
4.6.3. 
Immunogenicity Evaluations 
Anti-VIS649 ADA analyses will be conducted using the Immunogenicity population. 
Individual ADA results will be listed by subject and the tabular summarization of ADA results 
will include the number and proportion of subjects with positive pre-dose ADA response, 
number/proportion of subjects with positive post-dose ADA response only, and 
number/proportion of subjects with positive ADA response at any time. The following 
immunogenicity endpoints will be summarized by group, dose and time point using descriptive 
statistics. 


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 Results of a confirmatory ADA assay (positive/negative) 
 ADA titers for participants with a positive confirmatory assay 
 Results of a neutralizing ADA assay (positive/negative) 
No formal statistical comparisons will be performed.  
4.7. 
Analyses of Safety Endpoints 
Safety analyses will be conducted using the Safety Population and will be summarized by the 
treatment participants receive. 
4.7.1. 
Study Drug Exposure 
The duration of drug exposure and compliance will be calculated as specified below and will be 
summarized by group using descriptive statistics. Duration of drug exposure, compliance and 
number of doses received for each participant will also be provided in a data listing, flagging 
participants who withdrew from the study early. In addition, the dose modification (eg, dose 
interruption during an infusion, missing infusions, et al.), including number of subjects with at 
least one dose interruption and reasons for interruption will be summarized. A dose is received 
 
Duration of Exposure = Last Dose Date - First Dose Date + 30 Days  
Compliance = Number of Doses Received/12 
Percent Compliance = 100*(Number of Doses Received/12) 
4.7.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system and displayed in tables and data 
listings using system organ class and preferred term (PT). Severity is assigned by the investigator 
as mild, moderate or severe. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
defined as any AE with an onset date on or after the start of study treatment, including any events 
that worsen in severity after the start of treatment. 
AEs are summarized by incidence rates; therefore, in any tabulation, a subject contributes only 
once to the count for a given AE or system organ class. For tabulations by maximum severity, 
participants will be counted only once for the most severe occurrence of the AE or system organ 
class.  
A summary of AEs will include the number and percentage of participants who experience at 
least one of the following:  
 
Treatment-Emergent Adverse Events (TEAEs) 
 
Treatment-Related TEAEs 


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Severe TEAEs 
 
Severe Treatment-Related TEAEs 
 
Serious TEAEs  
 
Serious Treatment-Related TEAEs 
 
Treatment-Related TEAEs Leading to Study Drug Interruption 
 
Treatment-Related TEAEs Leading to Study Drug Discontinuation 
 
Treatment-Related TEAEs Leading to Death  
The above categories will be presented by system organ class and PT.  In these tabulations, a 
subject contributes only once to each of the incidence rates for a given system organ class or PT, 
regardless of the number of episodes, by highest severity or closest relationship.  
Additional tabular subgroup presentations of TEAEs by System Organ Class and PT will be 
included as follows:  
 
TEAEs by concomitant 
 5% of the participant 
population during the Treatment Period 
 
Treatment-Related TEAEs 
 5% of the 
participant population during the Treatment Period 
 
Serious Adverse 
participant population during the Treatment Period 
 
TEAEs for participants with comorbidities occurring in 5% or more of overall participants by 
Treatment Group 
 
TEAEs by Maximum Severity 
 
Treatment-Related TEAEs by Maximum Severity 
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs occurring on-study (including the screening period) will be listed in by-subject data 
listings, with a flag indicating treatment emergence.  
4.7.3. 
Laboratory Data 
Clinical laboratory values will be expressed using the Conventional Units and graded using 
Common Terminology Criteria for Adverse Events (CTCAE) criteria for applicable parameters.  
The actual value and change from baseline (Day 1 Pre-infusion) to each on-study evaluation and 
to the last evaluation on study will be summarized for each clinical laboratory parameter, 


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including hematology, chemistry, and urinalysis. In the event of repeat values, the last non-
missing value per study day will be used. 
Tables presenting shift in CTCAE grade from baseline to worst and baseline to last on-study 
values may be presented for applicable hematology and clinical chemistry parameters. 
All laboratory data will be provided in data listings. A data listing will be presented for all 
abnormal laboratory values. 
4.7.4. 
Vital Signs and Physical Examination 
The actual value and change from baseline (Day 1 Pre-infusion) to each on-study evaluation will 
be summarized for vital signs. 
Vital signs will include a derived measurement of Mean Arterial Pressure (MAP): 
MAP = Diastolic Pressure+1/3(Systolic Pressure-Diastolic Pressure) 
Where pressure = blood pressure (mm Hg). 
The number and percentage of participants who experience a clinically significant vital sign 
post -baseline will be summarized. Clinically significant vital signs will be summarized as 
follows (increases and decreases are from baseline): 
 
 
 
 
 
 
 
 
 
mmHg 
 
 
 
 
Vital sign measurements will be presented for each participant in a by-group by-participant data 
listing where results meeting the above clinically significant criteria will be identified. 
4.7.5. 
Prior and Concomitant Medications 
The prior and concomitant medications or therapies will be coded using the most current 
available version of World Health Organization (WHO) Drug Dictionary Enhanced (March 2022 
or newer) by therapeutic class and drug name. 
Prior medications or therapies are defined as any medications or therapies administrated prior to 
the first dose of study treatment. Concomitant medications or therapies are defined as those 
administrated on or after the date of the first dose of study treatment.  


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Prior and concomitant medication or therapies will be summarized in each treatment group by 
each medication within each therapeutic class for the Safety population. If a subject has a 
specific medication or therapy multiple times or takes multiple medications or therapies within a 
specific therapeutic class, that subject will be counted only once for the coded drug name or 
therapeutic class. However, all prior and concomitant medications or therapies will be included 
in listings.  
A tabular presentation of concomitant medications (during the Treatment Period) will be 
 
COVID-19 vaccinations will be tabulated by group separately. 
4.8. 
Interim Analyses 
Group-unblinded summaries will be prepared for Sponsor review to inform on future study 
design, no modifications to this study protocol are planned based on results of the interim 
analyses. Individual participant treatment will be blinded in all interim outputs. The interim 
outputs will be prepared by a separate, unblinded team.  
4.8.1. 
Interim Efficacy and Safety Analyses 
The interim analyses will include disposition, efficacy and safety analysis. The interim analyses 
will be performed on the mITT population and will be performed once 50% of randomized 
participants have 9-month uPCR (Schedule A). All randomized participants will be included in 
the interim analysis.  
Both blinded and unblinded interim analysis outputs will be produced where the unblinded 
outputs will only be made available to unblinded team members.   
For the interim efficacy outputs, the uPCR (Schedule A), uPCR on the natural log scale, change 
from baseline in uPCR on the natural log scale, and ratio change from baseline in uPCR values 
will be summarized descriptively over time by treatment group, including number and 
percentage of participants with missing or incomplete assessments at that visit. The uPCR 
geometric mean (± SD) ratio change from baseline at Month 9 for VIS649 individual treatment 
groups and pooled treatment group will be also displayed graphically. In addition, the raw spot 
uPCR (Schedule B) and the ratio change from baseline over time will be presented over time 
using the geometric mean (95% CI) of the raw and ratio change values by summary and plot. 
The 24-hour uPCR (Schedule A) model at Month 9 will be an ANCOVA model for change from 
baseline on the natural logarithmic scale of uPCR at Month 9, including the covariate of baseline 
uPCR on the natural logarithmic scale, in addition to the fixed effect of strata. The exponentiated 
LSMs, SE, and 95% CI for the treatment groups will be reported at Month 9. Similar ANCOVA 
model will be applied for pooled VIS649 treatment vs. placebo.  
In the interim efficacy analyses, the hypothesis testing will not be included. Nonetheless, to 
account for the review of the efficacy endpoint, the type I error rate applied to the primary 


Visterra, Inc 
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27 Jun 2023 v5.0 
 
CONFIDENTIAL 
43 
analyses, at the end of the study, will be reduced by 0.002 for the interim efficacy review, 
resulting in a 2-sided end-of-study type I error rate of 0.048 (See Section 3.7). 
The 24-hour urine protein excretion, change from baseline and change from baseline on the 
natural log scale will be summarized descriptively over time by treatment group, including 
number and percentage of participants with missing or incomplete assessments at that visit. 
The eGFR and change from baseline will be displayed graphically over time by line chart for all 
available visits.  
The interim safety analyses will include a summary of AEs (number and percentage of 
participants) for overall who experience at least one of the following:  
 
TEAEs 
 
Treatment-Related TEAEs 
 
Serious TEAEs  
 
Serious Treatment-Related TEAEs 
 
Treatment-Related TEAEs Leading to Study Drug Interruption 
 
Treatment-Relate TEAEs Leading to Discontinuation of Study Drug  
 
Treatment-Related TEAEs Leading to Death   
 
TEAEs  
The above categories will be presented by system organ class, PT, and either maximum severity 
or maximum CTCAE grade. In these tabulations, a subject contributes only once to each of the 
incidence rates for a given system organ class or PT, regardless of the number of episodes, by 
highest severity or closest relationship.   
4.8.2. 
Interim PK/Ig Analyses 
Three interim PK/Ig analyses will be performed on the PK and PD populations, which will be 
described in a separate analysis plan. 
 
 


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44 
5. 
CHANGES TO PLANNED ANALYSES 
This document is amended after the formal efficacy interim analyses as outlined in Section 4.8. 
Sponsor was unblinded to the group summary of the efficacy interim results. 
Additional analysis populations, secondary and exploratory endpoints and time points for 
analyses are included in this SAP.  
The major change between protocol and this SAP is summarized below: 
1. There are 2 planned interim efficacy analyses in the protocol. Sponsor chose not to perform 
the interim efficacy 1 during the trial. In this SAP, Section 4.8.1 is updated to reflect the new 
scope and analysis method for the interim efficacy analysis.  
All other changes from procedures outlined in this SAP will be summarized in the study report.  


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6. 
REFERENCES 
Berthoux, F., H. Suzuki, L. Thibaudin, H. Yanagawa, N. Maillard, C. Mariat, Y. Tomino, B. A. 
Julian and J. Novak (2012). "Autoantibodies targeting galactose-deficient IgA1 associate 
with progression of IgA nephropathy." J Am Soc Nephrol 23(9): 1579-1587. 
Bossen, C., T. G. Cachero, A. Tardivel, K. Ingold, L. Willen, M. Dobles, M. L. Scott, A.  
Maquelin, E. Belnoue, C. A. Siegrist, S. Chevrier, H. Acha-Orbea, H. Leung, F. Mackay, 
J. Tschopp and P. Schneider (2008). "TACI, unlike BAFF-R, is solely activated by 
oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts." 
Blood 111(3): 1004-1012. 
Castigli, E., S. Scott, F. Dedeoglu, P. Bryce, H. Jabara, A. K. Bhan, E. Mizoguchi and R. S. Geha 
(2004). "Impaired IgA class switching in APRIL-deficient mice." Proc Natl Acad Sci U S 
A 101(11): 3903-3908. 
Endo, T., M. Nishio, T. Enzler, H. B. Cottam, T. Fukuda, D. F. James, M. Karin and T. J. Kipps 
(2007). "BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through 
activation of the canonical NF-kappaB pathway." Blood 109(2): 703-710. 
Han, S. S., S. H. Yang, M. Choi, H. R. Kim, K. Kim, S. Lee, K. C. Moon, J. Y. Kim, H. Lee, J. 
P. Lee, J. Y. Jung, S. Kim, K. W. Joo, C. S. Lim, S. W. Kang, Y. S. Kim and D. K. Kim 
(2016). "The Role of TNF Superfamily Member 13 in the Progression of IgA 
Nephropathy." J Am Soc Nephrol 27(11): 3430-3439. 
Inker, L. A., H. Mondal, T. Greene, T. Masaschi, F. Locatelli, F. P. Schena, R. Katafuchi, G. B. 
Appel, B. D. Maes, P. K. Li, M. Praga, L. Del Vecchio, S. Andrulli, C. Manno, E.  
Gutierrez, A. Mercer, K. J. Carroll, C. H. Schmid and A. S. Levey (2016). "Early Change 
in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-
Patient Meta-analysis." Am J Kidney Dis 68(3): 392-401. 
Inker, L. A., Heerspink, H. J. L., Tighioutart, H., Chaudhari, J, Miao, S., Diva, U., Mercer, A., 
Appel, G. B., Donadio, J. V., Floege, J., Li, P. K. T., Maes, B. D., Locatelli, F., Praga, 
M., Schena, F. P., Levey, A. S., Greene, T. (2021). 
Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: 
An Individual Participant Meta-analysis
Kidney Dis 78(3): 340-349.e1.  
Lai, K. N., S. C. Tang, F. P. Schena, J. Novak, Y. Tomino, A. B. Fogo and R. J. Glassock (2016). 
"IgA nephropathy." Nat Rev Dis Primers 2: 16001. 
Nam, K. H., J. H. Kie, M. J. Lee, T. I. Chang, E. W. Kang, D. W. Kim, B. J. Lim, J. T. Park, Y. 
E. Kwon, Y. L. Kim, K. S. Park, S. Y. An, H. J. Oh, T. H. Yoo, S. W. Kang, K. H. Choi, 
H. J. Jeong, D. S. Han and S. H. Han (2014). "Optimal proteinuria target for 
renoprotection in patients with IgA nephropathy." PLoS One 9(7): e101935. 
R (2020). R: A language and environment for statistical computing. R Foundation for Statistical 
Computing, Vienna, Austria. URL https://www.R-project.org/. 


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46 
Reich, H. N., S. Troyanov, J. W. Scholey and D. C. Cattran (2007). "Remission of proteinuria 
improves prognosis in IgA nephropathy." J Am Soc Nephrol 18(12): 3177-3183. 
Rodrigues, J. C., M. Haas and H. N. Reich (2017). "IgA Nephropathy." Clinical Journal of the 
American Society of Nephrology 12(4): 677-686. 
Schena, F. P. and I. Nistor (2018). "Epidemiology of IgA Nephropathy: A Global Perspective." 
Semin Nephrol 38(5): 435-442. 
Varfolomeev, E., F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. 
Tom, S. Erickson, D. French, P. Schow, I. S. Grewal and A. Ashkenazi (2004). 
"APRILdeficient mice have normal immune system development." Mol Cell Biol 24(3): 
9971006. 
Wyatt, R. J. and B. A. Julian (2013). "IgA nephropathy." N Engl J Med 368(25): 2402-2414. 
Zhai, Y. L., L. Zhu, S. F. Shi, L. J. Liu, J. C. Lv and H. Zhang (2016). "Increased APRIL 
Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy." Medicine 
(Baltimore) 95(11): e3099. 
Zhao, N., P. Hou, J. Lv, Z. Moldoveanu, Y. Li, K. Kiryluk, A. G. Gharavi, J. Novak and H. 
Zhang (2012). "The level of galactose-deficient IgA1 in the sera of patients with IgA 
nephropathy is associated with disease progression." Kidney Int 82(7): 790-796. 





Prot_001.pdf: 
 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose Study to Evaluate the 
Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy 
PROTOCOL NUMBER: 
VIS649-201 
COMPOUND 
VIS649 
STUDY PHASE 
Phase 2 
SHORT TITLE: 
Phase 2 Study of VIS649 for IgA Nephropathy 
VERSION: 
3.0 
VERSION DATE: 
27 January 2020 
SPONSOR: 
Visterra, Inc.  
275 2nd Avenue 
Waltham, MA 02451 
REGULATORY AGENCY IDENTIFIER NUMBER(S) 
IND Number: 
135,282 
EudraCT Number:  
2019-002531-29 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
2 
APPROVAL PAGE 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Multiple Dose Study to Evaluate the Efficacy and Safety of 
VIS649 in Participants with Immunoglobulin A (IgA) Nephropathy 
 
This Clinical Study Protocol has been reviewed and approved by the Sponsor in order to ensure 
compliance with Good Clinical Practice. 
 
Sponsor Signatory: 
 
 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
3 
PROTOCOL VERSION 3.0 SUMMARY OF CHANGES TABLE 
The primary reason for this protocol amendment is to address requests made by a Health 
Authority. 
The clinically relevant changes, ie, changes that affect the type or frequency of protocol 
procedures, or the addition of information to the protocol that influences clinical 
decision-making or consent, are itemized below: 
Protocol Version 3.0 (27 January 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 1.3, Table 1, Schedule of 
Assessments  
Section 7.2 Participant 
Discontinuation/Withdrawal from 
the Study 
Section 8.3.5 Pregnancy 
The End-of-Study (EOS) visit was 
changed from Month 15 (Day 450, 
approximately 120 days following 
the last dose of study intervention) 
to Month 16 (Day 485). 
This change was made so that 
safety monitoring continues 
through the end of the relevant 
systemic exposure for VIS649 
(through 5 half-lives of the 8 mg/kg 
dose, ie, 155 days following the last 
dose administration). 
Section 1.1 Synopsis 
Section 3 Objectives and Endpoints 
Section 8.5, Table 5, 
Pharmacokinetic and Serum 
Immunoglobulin Sampling 
Schedule 
All objectives and endpoints 
associated with a measurement at 
Month 15 were updated to Month 
16, to reflect the change in the EOS 
visit from Month 15 to Month 16.  
This revision was made to reflect 
the change in the timing of the EOS 
visit. 
Section 1.1 Synopsis 
Section 4.1 Overall Study Design 
The overall study duration was 
modified for each participant to 
account for the update in the timing 
of the EOS visit from Month 15 to 
Month 16. 
This revision was made to reflect 
the change in the timing of the EOS 
visit. 
Section 5.2 Exclusion Criteria 
An exclusion criterion was added, 
stipulating that female participants 
who are breastfeeding cannot be 
enrolled in the study 
Breastfeeding in this study is 
exclusionary for safety purposes, 
and at the request of a Health 
Authority. 
Section 1.3 Schedule of 
Assessments, Footnote 2 
Section 8.3.1 Time Period and 
Frequency for Collecting Adverse 
Events and Serious Adverse Event 
Information 
Section 8.3.3 Follow-up of Adverse 
Events and Serious Adverse Events 
Serious adverse events (SAEs) 
should be followed until resolution 
or for a period of 30 days after the 
EOS, whichever is longer. 
The previous protocol version 
stipulated that AEs and SAEs 
should be followed until resolution 
or for a period of 30 days after the 
EOS, whichever is shorter. 
This change was made to ensure 
adequate safety follow-up of 
participants who experience SAEs 
during the study. 
Section 8.2.1 Physical 
Examinations 
 
In addition to the complete physical 
examination to be conducted at the 
screening and Month 12/Early 
Termination visits, physical 
examinations should be conducted 
by the Investigator at the 
Month 16/EOS visit and at any time 
This change was made to increase 
the level of safety monitoring 
during the study. 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0 
4 
Protocol Version 3.0 (27 January 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
during the study if clinically 
indicated. 
Section 8.2.3 Electrocardiograms 
A mention was added that in 
addition to the electrocardiogram 
(ECG) to be conducted at 
screening, ECGs should be 
conducted by the Investigator at 
any time during the study if 
clinically indicated.  
This change was made to increase 
the level of safety monitoring 
during the study. 
Appendix 2 Table 8, 
Protocol-Required Safety 
Laboratory Assessments 
Instead of every-3-month 
collection, hematology and serum 
chemistry testing will be performed 
monthly during treatment. A 
comprehensive serum chemistry 
panel will be collected at each 
monthly visit.  
This change was made to increase 
safety monitoring of participants 
during the study. 
Appendix 4, Section 
10.4.2, Contraception 
Guidance 
Definitions for contraceptive 
requirements during the study were 
updated. For female participants, 
highly effective methods of 
contraception will be required from 
28 days before study intervention 
through at least 155 days after the 
last dose of study intervention, to 
cover the end of the relevant 
systemic exposure for VIS649. 
Highly effective methods of 
contraception for females are 
defined as methods that result in a 
failure rate of less than 1% per year 
when used consistently and 
correctly, and do not include double 
barrier methods. 
Criteria for considering vasectomy 
as a highly effective birth control 
method and a definition of sexual 
abstinence were also added. 
The type of male contraception in 
the protocol was relabeled from 
“highly effective” to “acceptable” 
per definition outlined by the 
Clinical Trial Facilitation Group. 
Contraceptive requirements were 
aligned with specifications outlined 
in the “Recommendations related to 
contraception and pregnancy 
testing” outlined by the Clinical 
Trial Facilitation Group. 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
5 
Protocol Version 2.0 (26 November 2019) 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
The original protocol (Version 1.0) 
was subjected to additional review. 
Revisions were made and a Version 
2.0 was issued. 
Version 1.0 of the protocol was not 
submitted to an IRB and no 
participants were enrolled under 
Version 1.0 of the protocol. 
Note that minor formatting changes and corrections of typographical errors are not detailed. 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
6 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1 
Synopsis ......................................................................................................................10 
1.2 
Schema ........................................................................................................................18 
1.3 
Schedule of Assessments ............................................................................................19 
2. 
INTRODUCTION ......................................................................................................22 
2.1 
Study Rationale ...........................................................................................................22 
2.2 
Background .................................................................................................................23 
2.3 
Benefit/Risk Assessment ............................................................................................25 
2.3.1 
Risk Assessment .........................................................................................................25 
2.3.2 
Benefit Assessment .....................................................................................................28 
2.3.3 
Overall Benefit: Risk Conclusion ...............................................................................29 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................30 
4. 
STUDY DESIGN .......................................................................................................33 
4.1 
Overall Design ............................................................................................................33 
4.2 
Scientific Rationale for Study Design ........................................................................35 
4.3 
Justification for Dose ..................................................................................................37 
4.4 
End-of-study Definition ..............................................................................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1 
Inclusion Criteria ........................................................................................................39 
5.2 
Exclusion Criteria .......................................................................................................40 
5.3 
Lifestyle Considerations .............................................................................................42 
5.4 
Screen Failures ............................................................................................................42 
6. 
STUDY INTERVENTION ........................................................................................43 
6.1 
Study Intervention(s) Administered ...........................................................................43 
6.2 
Preparation/Handling/Storage/Accountability ............................................................44 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................44 
6.4 
Study Intervention Compliance ..................................................................................45 
6.5 
Concomitant Therapy .................................................................................................45 
6.5.1 
Concomitant Therapy to be Avoided ..........................................................................45 
6.6 
Dosing Schedule Modification ...................................................................................46 
6.7 
Intervention after the End of the Study .......................................................................46 


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VIS649-201 Protocol Version 3.0  
 
 
7 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................47 
7.1 
Discontinuation of Study Intervention Dosing ...........................................................47 
7.1.1 
Temporary Discontinuation ........................................................................................47 
7.1.2 
Rechallenge .................................................................................................................48 
7.2 
Participant Discontinuation/Withdrawal from the Study ...........................................48 
7.3 
Lost to Follow-up .......................................................................................................48 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................49 
8.1 
Efficacy Assessments .................................................................................................49 
8.1.1 
Twenty-four-hour Urine Sample Collection ...............................................................49 
8.2 
Safety Assessments .....................................................................................................49 
8.2.1 
Physical Examinations ................................................................................................49 
8.2.2 
Vital Signs ..................................................................................................................49 
8.2.3 
Electrocardiograms .....................................................................................................50 
8.2.4 
Clinical Safety Laboratory Assessments ....................................................................50 
8.3 
Adverse Events and Serious Adverse Events .............................................................50 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................51 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...........................51 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events .......................................52 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .............................52 
8.3.5 
Pregnancy ...................................................................................................................53 
8.4 
Treatment of Overdose ...............................................................................................53 
8.5 
Pharmacokinetics ........................................................................................................53 
8.6 
Pharmacodynamics .....................................................................................................54 
8.7 
Genetics ......................................................................................................................54 
8.8 
Biomarkers ..................................................................................................................55 
8.9 
Immunogenicity Assessments ....................................................................................55 
8.10 
Medical Resource Utilization and Health Economics ................................................55 
9. 
STATISTICAL CONSIDERATIONS .......................................................................56 
9.1 
Statistical Hypothesis ..................................................................................................56 
9.2 
Sample Size Determination ........................................................................................56 
9.3 
Populations for Analyses ............................................................................................56 


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VIS649-201 Protocol Version 3.0 
8 
9.4 
Statistical Analyses .....................................................................................................57 
9.4.1 
General Considerations ................................................................................................57 
9.4.2 
Randomization and Stratification ...............................................................................57 
9.4.3 
Participant Disposition ................................................................................................57 
9.4.4 
Participant Demographics ...........................................................................................57 
9.4.5 
Efficacy Analysis ........................................................................................................57 
9.4.6 
Safety Analyses ..........................................................................................................58 
9.4.7 
Other Analyses ............................................................................................................58 
9.5 
Interim Analyses .........................................................................................................59 
9.6 
Data Safety Monitoring Board ....................................................................................60 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................61 
10.1 
Appendix 1 ..................................................................................................................61 
10.1.1 
Regulatory and Ethical Considerations ......................................................................61 
10.1.2 
Financial Disclosure ...................................................................................................61 
10.1.3 
Data Protection ...........................................................................................................62 
10.1.4 
Dissemination of Clinical Study Data ........................................................................62 
10.1.5 
Data Quality Assurance ..............................................................................................62 
10.1.6 
Source Documents ......................................................................................................63 
10.1.7 
Study and Site Start and Closure ................................................................................63 
10.1.8 
Publication Policy .......................................................................................................63 
10.2 
Appendix 2 ..................................................................................................................64 
10.3 
Appendix 3 ..................................................................................................................65 
10.3.1 
Definition of Adverse Event and Adverse Reaction ...................................................65 
10.3.2 
Definition of Serious Adverse Event ..........................................................................66 
10.3.3 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............67 
10.3.4 
Reporting of Serious Adverse Events .........................................................................68 
10.4 
Appendix 4 ..................................................................................................................69 
10.4.1 
Definitions ..................................................................................................................69 
10.4.2 
Contraception Guidance .............................................................................................69 
10.4.3 
Collection of Pregnancy Information .........................................................................70 
10.5 
Appendix 5 ..................................................................................................................72 
10.6 
Appendix 6 ..................................................................................................................74 


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VIS649-201 Protocol Version 3.0  
 
 
9 
11. 
REFERENCES ...........................................................................................................75 
 LIST OF TABLES  
Table 1:  
Schedule of Assessments ............................................................................................19 
Table 2: 
Summary of Potential Risks Associated with VIS649 ...............................................25 
Table 3: 
Study Objectives and Endpoints .................................................................................30 
Table 4: 
Study Interventions .....................................................................................................43 
Table 5: 
Pharmacokinetic and Serum Immunoglobulin Sampling Schedule ...........................54 
Table 6: 
Populations for Analysis .............................................................................................56 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews ...................................................60 
Table 8:  
Protocol-Required Safety Laboratory Assessments ...................................................64 
Table 9:  
Protocol Revision History...........................................................................................74 
LIST OF FIGURES 
Figure 1:  Study Design Schema .................................................................................................18 
Figure 2: 
Simulated Percent Baseline Immunoglobulin A by Dose ..........................................37 
  


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
10 
1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Name of Sponsor: Visterra, Inc. 
Name of Investigational Intervention:  VIS649 
Protocol Title:  
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose 
Study to Evaluate the Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy (IgAN) 
Short Title:  
Phase 2 Study of VIS649 for IgA Nephropathy 
Rationale: 
VIS649 is a humanized immunoglobulin G2 (IgG2) monoclonal antibody that 
binds to and blocks the biological actions of the cytokine A PRoliferation 
Inducing Ligand (APRIL), a key factor in the production of aberrantly 
glycosylated IgA1 (a-g IgA1), which is critical to the pathogenesis of IgAN. The 
central mechanism for the development of IgAN is the production of a-g IgA1. 
These a-g IgA1 act as autoantigens and lead to development of autoantibodies 
forming circulating immune complexes which deposit in the mesangium of the 
glomeruli and in turn, trigger an inflammatory response and complement 
activation, causing damage to the kidneys. 
In data from a single-ascending dose study (VIS649-101) of VIS649 in healthy 
participants, VIS649 reduced serum levels of IgA and a-g IgA1. The current 
study will test the hypothesis that blocking the biological actions of APRIL in 
IgAN participants leads to reduction of serum IgA (including a-g IgA1) levels 
and will reduce or halt the progression of IgAN, as measured by decrease in 
proteinuria.  
The findings from this study will form the basis for subsequent clinical 
development of VIS649. 
Objectives and 
Endpoints: 
The key objectives and endpoints of the study are: 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and 
tolerability of monthly doses of 
VIS649 at each of 3 dosing levels, 
administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
AEs graded by severity, clinical 
laboratory tests, vital sign 
measurements, and physical 
examinations 
 
 


CONFIDENTIAL 
VIS649-201 Protocol Version 3.0  
 
 
11 
 
Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of 
monthly doses of VIS649 on 
proteinuria at each of 3 dosing 
levels, administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
Change from baseline in uPCR 
(measured on natural log scale from 
24-hour urine collection or the 
intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days 
after the 12th dose is administered)  
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated 
doses of VIS649 at 3 dosing levels 
versus placebo on the following 
parameters: 
o uPCR at Month 9 and 16 (ie, 
5 months following the final 
[12th] monthly dose 
administration) 
 
o 24-hour urine protein excretion at 
Months 9, 12, and 16 
 
o ≥ 30% decline from baseline in 
uPCR at Months 9, 12, and 16 
 
 
o Clinical remission, defined as 
reduction in 24-hour urine protein 
excretion to < 300 mg/day for at 
least 3 consecutive months  
 
 
 
 
o 
Change from baseline in uPCR 
(measured on natural log scale 
from 24-hour urine collection or 
the intended 24-hour urine 
collection) at Months 9 and 16 
o 
Change in 24-hour urine protein 
excretion from baseline to 
Months 9, 12, and 16 
o 
Number of participants in each 
group achieving a ≥ 30% 
decline from baseline in uPCR 
at Months 9, 12, and 16 
o 
Number of participants in each 
group achieving clinical 
remission 
• 
eGFR at Months 12 and 16 
 
• 
To evaluate the effect of repeated 
doses of VIS649 at each dosing level 
compared with placebo on the 
following PD parameters: IgA, IgG, 
and IgM concentrations 
• 
To determine the PK profile of 
repeated dose of VIS649, at each 
dosing level 
• 
Change from baseline in eGFR at 
Months 12 and 16 
• 
Change from baseline in total serum 
IgA, IgG, and IgM concentrations at 
Months 9, 12, and 16 
 
 
• 
Serum PK parameters 
• 
To determine the PK/PD profile of 
VIS649, relating VIS649 PK 
parameters and biomarkers such as 
changes in IgA to changes in 
proteinuria and eGFR 
• 
Correlation of VIS649 PK 
parameters with changes in IgA, 
uPCR, and eGFR 
• 
To screen for ADA responses 
• 
Serum ADA levels 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = antidrug 
antibody; AE = adverse event; ARB = angiotensin receptor blocker; eGFR = estimated 
glomerular filtration rate; Ig = immunoglobulin; IgAN = immunoglobulin A 


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VIS649-201 Protocol Version 3.0  
 
 
12 
nephropathy; IV = intravenous(ly); PD = pharmacodynamic; PK = pharmacokinetic; 
SOC = standard of care; uPCR = urinary protein/creatinine ratio. 
Overall Design:  
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, 
multiple-dose study to evaluate the safety and efficacy of intravenously (IV) 
administered VIS649 over a 12-month treatment course in participants with 
IgAN. Participants will be enrolled from approximately 90 global sites in 
approximately 16 countries. 
Screening evaluations, including physical examinations, vital signs, 12-lead 
electrocardiogram (ECG), safety laboratory testing (serum chemistry, 
hematology, urinalysis, serology, hemoglobin A1c, and pregnancy), blood 
sampling for baseline Ig levels (IgA, IgG, and IgM), and 24-hour urine 
collection, will take place during the 30 days prior to the first dose of study 
intervention.  
To be eligible, participants should be on stable and maximally tolerated doses 
of either angiotensin-converting enzyme inhibitor (ACEI) or angiotensin 
receptor blocker (ARB) therapy, as per standard of care (SOC) and applicable 
guidelines, for at least 3 months. Participants must be on at least 50% of the 
maximum recommended dose of the ACEIs or ARB to be considered as having 
adequate renin-angiotensin-aldosterone system (RAAS) blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study, if their overall management of IgAN, including blood 
pressure (BP) control, is as per SOC and applicable guidelines. 
Enrolled participants must be 18 years of age or older with an IgAN diagnosis 
confirmed by biopsy.  
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have 
been interpreted using the MEST score - Mesangial cellularity, endocapillary 
proliferation, segmental sclerosis, tubular atrophy (Cattran et al, 2009) or 
MEST-C scoring system (Trimarchi, Barratt et al. 2017) from the Oxford 
classification of IgAN.  
A MEST or MEST-C score finding on kidney biopsy of T2 or C2 is 
exclusionary for this study. If the biopsy was not reported using the Oxford 
classification schema, the following findings (corresponding to these Oxford 
classifications) are exclusionary: a) > 50% tubular atrophy, and/or b) > 25% 
crescents.  
Participants must have screening urinary protein/creatinine ratio (uPCR) 
≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 24-hour urine 
collection (or an intended 24-hour urine collection).  
Participants must have estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Levey, Stevens et al. 2009).  
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. A total of 144 participants will be randomized with equal allocation 
(1:1:1:1) across the 4 intervention groups (approximately 36 participants per 
group). Randomization will be stratified first by region (Japan vs rest of world). 
A target of 12 or more participants are planned to be randomized in Japan; these 
participants will be randomized with equal allocation and without further 
stratification. The randomization for the rest-of-world will be stratified by 
screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  


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VIS649-201 Protocol Version 3.0  
 
 
13 
VIS649 or placebo will be administered as 12 monthly IV infusions starting on 
Day 1/Month 0. Participants will return to the study center on Days 8 and 18, 
then monthly through Month 14 and on Month 16 for safety, efficacy, 
pharmacokinetic (PK), and/or pharmacodynamic (PD) assessments.  
Safety assessments will include review of adverse events (AEs) (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, 
injection site tolerability (pain, irritation, and tissue damage), clinical laboratory 
assessments (including biochemistry, hematology, urinalysis, and pregnancy 
testing), laboratory testing (including serum Ig levels and antidrug antibodies 
[ADAs]) vital sign measurements and use of concomitant medications. 
Participants will return to the study center on approximately Month 16, at least 
155 days following the last dose of study intervention (Dose 12) for an 
end-of-study (EOS) visit, at which time final safety, PK, PD, and efficacy 
assessments will be performed. Participants discontinuing dosing earlier will 
attend an early termination visit at the time of dosing discontinuation and will 
be encouraged to attend the study visits as per schedule of assessments.  
A rollover, open-label extension study will be offered to enable access to 
VIS649 (there will be no placebo arm) for study participants who have 
completed this trial, provided that the Investigator believes that the participants 
might benefit, and that the site has agreed to participate in the extension study. 
Further details will be provided in a separate protocol. 
Number of 
Participants: 
Approximately 144 participants. A target of 12 or more participants are planned 
to be randomized and enrolled in Japan. The remaining participants will be 
enrolled at sites in the rest of world; there are no other country-specific 
enrollment targets.  
Intervention Groups 
and Duration: 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. VIS649 or placebo will be administered as a single, monthly IV 
infusion for 12 monthly doses.  
VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL 
infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The 
dose of study intervention for the duration of the study will be based on the 
participant’s Month 0 predose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour as a single 100 mL 
infusion, followed by a 25 mL saline flush. 
An unblinded pharmacist will prepare drug or placebo for infusion. Participants, 
the Sponsor, the Investigator, and all other site study staff will be blinded to 
study intervention.  
The total study duration for each participant (from screening to EOS) will be up 
to approximately 17 months (assuming up to 1 month for screening, 12 months 
for monthly doses [including 30 days after the 12th dose], and follow-up visits 
through at least 155 days after the last dose of study intervention).  
Target Population: 
Key inclusion criteria for eligibility into the study are the following: 
1. Participant is a male or female ≥ 18 years of age at the time of signing 
the informed consent. 
2. Participant has source-verified biopsy-confirmed IgAN. 


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VIS649-201 Protocol Version 3.0 
14 
3.
Participant has medical records showing they have been on stable and
maximally tolerated doses of either ACEI or ARB, as per SOC and
applicable guidelines, for at least 3 months preceding screening.
Participants should be on at least 50% of the maximum recommended
dose of these agents to be considered as having adequate RAAS
blockade. Participants who are unable to tolerate ACEI/ARB therapy
may be eligible for participation in the study, if their overall
management of IgAN, including BP control, is as per SOC and
applicable guidelines.
4.
Participant has screening uPCR ≥ 0.75 g/g measured from a 24-hour
urine sample (or an intended 24-hour urine sample) or 24-hour urine
protein ≥ 1.0 g/d, as measured from 24-hour urine sample (or an
intended 24-hour urine sample). The proteinuria should be stable,
defined as < 25% change when compared to values from ≥ 3 months
previously (if available). If previous values are not available or if the
change from a prior value is > 25%, a repeat measurement of
proteinuria will be done after 15 days and the participant should fulfill
the above proteinuria criteria to be eligible for randomization in the
study. The proteinuria should be assessed when the participant is
considered to be in steady state with no recent heavy exercise, fever, or
other potential issues that could impact the result.
5.
Participant has eGFR ≥ 45 mL/min/1.73 m2, calculated using the
CKD-EPI formula. The eGFR should be stable, as defined by a < 25%
change when compared to values from ≥ 3 months previously (if
available). If previous values are not available or if the change from a
prior value is > 25%, a repeat measurement of eGFR will be done after
15 days and the participant should fulfill the eGFR criteria to be eligible
for randomization in the study. The eGFR should be measured when
the participant is considered to be in a steady state without recent
changes in volume status, medications that could impact the result (eg,
nonsteroidal anti-inflammatory drugs [NSAIDs], aminoglycosides,
co-trimoxazole), or changes in dietary protein intake.
6.
Participant’s serum Ig values must meet the following criteria:
a.
IgG: ≥ 700 mg/dL
b.
IgM: ≥ 40 mg/dL
c.
IgA: ≥ 70 mg/dL
Key exclusion criteria: 
1.
Participant has secondary forms of IgAN as defined by the treating
physician (eg, Henoch-Schӧnlein purpura, minimal change disease with
IgA deposits, infection associated IgAN, or IgAN-associated with
hepatic cirrhosis).
2.
Participant has co-existing chronic kidney disease, other than IgAN.
3.
Participant has evidence of additional pathological findings in the
kidney biopsy (eg, diabetic kidney disease, membranous nephropathy,
or lupus nephritis). However, hypertensive vascular changes are
acceptable.


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VIS649-201 Protocol Version 3.0  
 
 
15 
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 
from the Oxford IgAN classification schema. If MEST-scoring was not 
performed, the presence of > 50% tubulointerstitial fibrosis, or 
crescents in >25% of glomeruli is exclusionary. 
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour 
urine protein > 3.5 g with concurrent hypoalbuminemia (serum albumin 
< 2.5 g/dL), hyperlipidemia (total cholesterol > 350 mg/dL), and 
edema. 
6. Participant has received a solid organ transplant, including kidney. 
7. Participant has received bone marrow or hematologic stem cell 
transplantation 
8. Participant is currently receiving systemic immunosuppression 
(excluding topical, ophthalmic, per rectum or inhaled corticosteroids).  
9. Participant has received systemic steroids within the 24 weeks prior to 
initial screening.  
10. Participant has received treatment with 2 or more systemic 
immunosuppressive agents within 2 years prior to initial screening. 
11. Participant has chronic infectious diseases (eg, chronic urinary tract 
infection; chronic sinusitis; bronchiectasis; active pulmonary or 
systemic tuberculosis; chronic viral hepatitis, such as hepatitis C or 
hepatitis B; or human immunodeficiency virus infection).  
12. Participant has acute infectious disease at the time of screening. 
Participants may be rescreened following resolution of acute infection 
(such as urinary tract infection or respiratory tract infection), provided 
there is no evidence of an immunosuppressive condition that 
predisposed the participant to this infection.  
13. Participant has Type 1 diabetes. 
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a 
screening hemoglobin A1c value > 8%. 
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg 
diastolic). 
16. Participant has a history of a chronic autoimmune neurodegenerative 
disorder such as multiple sclerosis. 
Data Safety 
Monitoring Board: 
An independent data safety monitoring board (DSMB) will review unblinded 
safety data. The DSMB will meet at 5 scheduled data review meetings and as 
needed on an ad hoc basis. Details regarding the content and scope of safety 
assessments, as well as the governing of the DSMB, will be described in a 
separate DSMB charter. 
Data safety monitoring board meetings will be scheduled as the following 
requirements are met: 
Scheduled DSMB Review 
Number of Participants and Treatment Exposure 
DSMB review #1 
Scheduled once 12 participants have been randomized 
and have completed at least 3 months of study dosing. 
DSMB review #2 
Scheduled once 24 participants have been randomized 
and have completed at least 3 months of study dosing. 


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VIS649-201 Protocol Version 3.0  
 
 
16 
DSMB review #3 
Scheduled once ~25% of participants have been 
randomized and have completed 3 months of study 
dosing. 
DSMB review #4 
Scheduled once ~50% of participants have been 
randomized and have completed 6 months of study 
dosing, and ~20 participants have completed 
12 months of study dosing. 
DSMB review #5 
Scheduled once ~50% of participants have been 
randomized and have completed 12 months of study 
dosing. 
Abbreviations: DSMB = data safety monitoring board. 
Statistical Methods: 
General Considerations 
All data collected will be documented using summary tables, figures, and/or 
data listings presented by intervention and dose group. For continuous 
variables, descriptive statistics (number [n]; mean; geometric mean and 
coefficient of variation [%CV], as appropriate; median; standard deviation; 
minimum; and maximum) will be presented. For categorical variables, 
frequencies and percentages will be presented. As appropriate, a 95% CI will be 
presented. Graphical displays may be presented. 
Randomization and Stratification 
Participants will be randomly assigned in a 1:1:1:1 ratio to receive VIS649 at 2, 
4, or 8 mg/kg, or placebo, with approximately 36 participants randomized per 
intervention group. Randomization will be stratified first by region (Japan vs 
rest of world). Japanese participants will be randomized with equal allocation 
and without further stratification. Randomization for the rest of world will then 
be stratified by screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
Interim Analyses 
In addition to 5 DSMB safety reviews, 3 interim PK/Ig analyses and 2 interim 
efficacy analyses are planned. The interim PK/Ig analyses will provide 
additional data for population PK/PD modeling and will advise the study 
Sponsor on future study design and planning.  
An early interim efficacy analysis may be performed when at least 
16 participants have been treated for at least 6 months and at least 50% of the 
16 (or more) participants have achieved a confirmed > 30% reduction in uPCR 
(as determined by 2 consecutive measurements) based on review of blinded 
uPCR data across all study participants. In the event that this condition is met 
and an interim analysis is triggered, group-unblinded efficacy summaries (with 
individual participant treatment blinded) will be prepared by a separate, 
unblinded team for Sponsor review to inform future study design.  
A second interim efficacy analysis will be performed at the time of the fourth 
scheduled DSMB meeting (once 50% of randomized participants have 
completed 6 months of study dosing and approximately 20 participants have 
completed 12 months of study dosing). Group-unblinded efficacy summaries 
(with individual participant treatment blinded) will be prepared for Sponsor 
review to inform future study design.  
The interim efficacy analyses will not include hypothesis testing and will be for 
the purpose of future study design and planning. The primary efficacy endpoint, 
change in proteinuria levels from baseline, will be analyzed. No modifications 






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19 
1.3 
Schedule of Assessments 
Table 1:  
Schedule of Assessments 
Procedures Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 
M12/ 
ET3 
M13 M14 
M16 
Nominal Study Day -301 
D1 Pre 
infusion 
D1 Post 
infusion D8 
D18 
D30 
D60 
D90 D120 D150 D180 D210 D240 D270 D300 D330 D360 D390 D420 
D485 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Study Visit N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of kidney biopsy4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Weight 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Vital signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention infusion7 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
AE monitoring 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Concomitant medications review 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
HBV, HCV, HIV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β-hCG (females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCG (females only) 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry8 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Hematology9 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Urinalysis (dipstick and microscopy)10  
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
24-hour urine collection11 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
Urine sample for uPCR determination 
x12 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x12 
x 
x 
x12 
 
 
x12 


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VIS649-201 Protocol Version 3.0  
 
 
20 
Procedures Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 
M12/ 
ET3 
M13 M14 
M16 
Nominal Study Day -301 
D1 Pre 
infusion 
D1 Post 
infusion D8 
D18 
D30 
D60 
D90 D120 D150 D180 D210 D240 D270 D300 D330 D360 D390 D420 
D485 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Study Visit N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Blood sample for lymphocytes  
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Serum for PK13 
 
x 
x 
x 
x 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x 
x 
x 
x 
Blood for total IgA, IgG, and IgM13 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood for IgA subtypes  
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Serum for APRIL14 
 
x 
x 
 
 
x 
x 
x14 
x 
x 
x14 
x 
x 
x14 
x 
x14 
x 
 
 
x 
Serum for a-g IgA1 and anti-IgA1 
x 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 x 
 
 
x 
 
 
x 
Serum for ADA15 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
 
 
x 
Blood sample for DNA16 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample for exploratory  
biomarker assessments17 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Blood for markers of complement activity 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
Saliva samples for IgA levels 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = antidrug antibody; AE = adverse event; a-g IgA = aberrantly glycosylated immunoglobulin A; APRIL= A 
PRoliferation Inducing Ligand; ARB = angiotensin receptor blocker; β-hCG = beta-human chorionic gonadotropin; BAFF = B-cell activating factor; BP = blood pressure; D = 
Day; ECG = electrocardiogram; eCRF = electronic case report form; EOS = end-of-study; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = 
human immunodeficiency virus; HR = heart rate; Ig = immunoglobulin; IgAN = immunoglobulin A nephropathy; M = Month; N/A = not applicable; PD = pharmacodynamics; 
PK = pharmacokinetics; RAAS = renin-angiotensin-aldosterone system; RR = respiratory rate; Scr = screening; SOC = standard of care; uACR = urinary albumin/creatinine ratio; 
uPCR = urinary protein/creatinine ratio. 
 
1 
All participants will undergo screening. To be eligible, participants should be on stable and maximally tolerated treatment with either ACEI or ARB, as per SOC and 
applicable guidelines, for at least 3 months. Participants must be on at least 50% of the maximum recommended dose of the ACEIs or ARB to be considered as having 
adequate RAAS blockade. Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in the study, if their overall management of IgAN, 
including BP control, is as per SOC and applicable guidelines. 
2 
Participants must complete EOS assessments approximately 155 days after the last dose of study intervention. Participants discontinuing early will be encouraged to attend 
study visits as per the schedule, including the EOS visit. Adverse event and concomitant medication monitoring should be performed through the EOS visit; SAEs that are 
ongoing at EOS should be monitored until resolution or 30 days after the EOS, whichever is longer; AEs that are ongoing at EOS should be monitored until resolution or 30 
days after the EOS. 
3 
Participants discontinuing early must complete ET assessments at the time of treatment discontinuation. 
4 
A biopsy diagnostic of IgAN must have been performed and source-verified documentation must be available. 




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22 
2. 
INTRODUCTION 
VIS649 is a humanized immunoglobulin G2 (IgG2) monoclonal antibody being developed for the 
treatment of immunoglobulin A nephropathy (IgAN), an autoimmune glomerulonephritis 
characterized by the deposition of immunoglobulin A (IgA)-containing immune complexes in 
the kidney. 
2.1 
Study Rationale 
Immunoglobulin A nephropathy is a chronic disease affecting the kidneys. It is clinically 
characterized by proteinuria, hematuria and progressive decline of glomerular filtration rate 
(GFR). IgAN is characterized histologically by dominant or co-dominant deposition of IgA in 
the kidney glomerulus (Rodrigues, Haas et al. 2017). The central mechanism for the 
development of IgAN is the production of aberrantly glycosylated IgA1 (a-g IgA1), which has 
been attributed to a combination of genetic and environmental factors. These a-g IgA1 act as 
autoantigens and lead to development of autoantibodies forming circulating immune complexes 
that deposit in the mesangium of glomeruli and in turn, trigger an inflammatory response and 
complement activation (Kiryluk, Moldoveanu et al. 2011, Berthoux, Suzuki et al. 2012, 
Kiryluk, Novak et al. 2013, Kiryluk, Li et al. 2014, Kiryluk and Novak 2014). This results in 
episodic and cumulative kidney damage. Natural history studies indicate that IgAN may progress 
to end-stage renal disease (ESRD) in approximately 30% of patients, over the course of 10 years 
(Lai, Tang et al. 2016).  
Proteinuria is an important marker of progression of renal disease in patients with IgAN. Patients 
with significant proteinuria (> 1.0 g/day) have a faster decline of estimated glomerular filtration 
rate (eGFR) and progression to ESRD, when compared to patients with lower degrees of 
proteinuria (< 500 mg/day). Hence, reduction in proteinuria is a crucial aspect in the 
management of IgAN (Reich, Troyanov et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 
2016). 
The cytokine A PRoliferation Inducing Ligand (APRIL), which belongs to the tumor necrosis 
factor ligand superfamily, has emerged as a key factor in the pathogenesis of IgAN through 
mediation of the Ig isotype switch during B-cell development, production of IgA, plasma-cell 
survival, and possibly specifically influencing production of a-g IgA1 as well 
(Castigli, Scott et al. 2004, Varfolomeev, Kischkel et al. 2004, Endo, Nishio et al. 2007, 
Bossen, Cachero et al. 2008). Studies in IgAN patients have shown that elevated APRIL levels 
correlate with poor kidney outcomes, when compared with patients with lower APRIL levels 
(Han, Yang et al. 2016, Zhai, Zhu et al. 2016). A similar trend is also seen with a-g IgA1 levels, 
with higher levels associated with faster and more frequent progression to kidney failure when 
compared to patients with lower a-g IgA1 levels (Castigli, Scott et al. 2004, Berthoux, Suzuki 
et al. 2012, Zhao, Hou et al. 2012). 
VIS649 is a humanized IgG2 monoclonal antibody (mAb) that binds to and blocks the biological 
actions of APRIL, preventing its binding to its receptors, transmembrane activator and CAML 
interactor (TACI), and B-cell maturation antigen (BCMA). Blocking the biological actions of 
APRIL reduces the production of IgA. The hypothesis to be tested in this study is that a decrease 
in the production of IgA and a-g IgA1 will diminish the formation of circulating immune 


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23 
complexes and their deposition in the glomeruli, allowing injury repair and clinical 
improvement, as measured by reduction in proteinuria. 
In data from a single-ascending dose study (VIS649-101) of VIS649 in healthy participants, 
VIS649 reduced serum levels of IgA and a-g IgA1. The current study will test the hypothesis that 
blocking the biological actions of APRIL in IgAN participants leads to reduction of serum IgA 
(including a-g IgA1) levels and will reduce or halt the progression of IgAN as measured by 
reduction in proteinuria (the study’s primary efficacy endpoint). The current study will also 
assess the safety of VIS649 in participants with IgAN and collect extensive data on 
pharmacokinetics (PK) and pharmacodynamics (PD).  
The findings from this study will form the basis for subsequent clinical development of VIS649. 
2.2 
Background 
Immunoglobulin A nephropathy is one of the most common primary glomerular diseases and 
affects patients globally, with some geographical variation in incidence and prevalence 
(Wyatt and Julian 2013, Rodrigues, Haas et al. 2017, Schena and Nistor 2018). Clinical 
presentation varies from incidentally detected asymptomatic hematuria and proteinuria to rapidly 
progressive glomerulonephritis requiring dialysis. Immunoglobulin A nephropathy is a 
significant cause of chronic kidney disease (CKD) and ESRD, with 30–40% of patients reaching 
ESRD 20–30 years after the first clinical presentation. Immunoglobulin A nephropathy can occur 
in either sporadic (90–95%) or familial (5%–10%) patterns. Patients with familial IgAN might 
have poorer prognoses than those with sporadic disease, with an increased risk of progression to 
renal failure (Lai, Tang et al. 2016). 
Immunoglobulin A nephropathy is diagnosed by kidney biopsy, which shows dominant or 
co-dominant IgA deposition on immunofluorescence. The pathogenesis of IgAN is currently 
thought to be a multi-hit process, the “first hit” being the production of a-g IgA1. The primary 
defect is the deficiency of galactose in the hinge region of IgA1. As a consequence, the 
N-acetylgalactosamine in the truncated IgA1 hinge region glycan is exposed and acts as an 
autoantigen. Multiple cohort studies have shown the relationship between elevated a-g IgA1 and 
IgAN, with higher a-g IgA1 levels resulting in more rapid disease progression. The “second hit” 
consists of IgA and IgG autoantibody production against these a-g IgA1. The “third hit” consists 
of formation of circulating immune complexes consisting of the IgG/IgA auto antibody and 
a-g IgA1 antigen complex. The “fourth hit” consists of deposition of these circulating immune 
complexes in the mesangium of the glomeruli. These antigen-antibody complexes are 
nephritogenic and trigger an inflammatory response leading to infiltration of macrophages, 
monocytes and T cells, local release of cytokines, complement activation, and activation of the 
renin-angiotensin cascade. This leads to glomerular injury and tubulointerstitial fibrosis, 
clinically manifesting as proteinuria, hematuria, hypertension, and reduced GFR 
(Berthoux, Suzuki et al. 2012, Floege, Moura et al. 2014, Knoppova, Reily et al. 2016, 
Mestecky, Novak et al. 2016). 
While proteinuria is a common manifestation of IgAN, the degree of proteinuria correlates with 
disease progression, with faster decline of eGFR, and progression to ESRD in patients with high-
grade proteinuria (> 1.0 g/d) when compared to patients with low-grade proteinuria (< 0.5 g/d) 
(Reich, Troyanov et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016, 
Thompson, Carroll et al. 2019). Control of proteinuria is a key therapeutic target in patients with 


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IgAN. Measures to control proteinuria often consist of renin-angiotensin-aldosterone system 
(RAAS) blockade in the form of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin 
receptor blocker (ARB) therapy, blood pressure (BP) control, statins to control cholesterol, 
smoking cessation, low-salt diet, low-protein diet, and avoidance of nephrotoxic drugs. If 
patients continue to have significant proteinuria despite these measures, they are usually treated 
with nonspecific immunosuppressive agents such as steroids, azathioprine, mycophenolate 
mofetil, or cyclophosphamide (Boyd, Cheung et al. 2012, KDIGO 2012, Radhakrishnan and 
Cattran 2012, Barbour and Feehally 2017, Rodrigues, Haas et al. 2017). These drugs, especially 
steroids (Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 2015, Tesar, Troyanov et al. 2015, 
Lv, Zhang et al. 2017), have been shown to be beneficial from a renal perspective in some 
studies, but their use is often complicated by significant adverse effects such as increased risk of 
infections, metabolic derangements, cosmetic changes, weight gain, fractures, and 
neuropsychiatric manifestations. Some of these agents have other significant risks such as 
increased risk of malignancies with prolonged administration. The significant side effects of 
these drugs preclude chronic use of these agents and limit their benefits in a chronic disease such 
as IgAN. 
APRIL is a member of the tumor necrosis factor superfamily of ligands and is emerging as a key 
mediator in IgAN pathogenesis and disease progression based on convergence of genetic, 
biochemical, and clinical data. APRIL is produced by myeloid and mucosal epithelial cells. 
APRIL regulates B cell-mediated immune responses through several mechanisms, including 
class-switch recombination, principally through its 2 receptors: TACI and BCMA. APRIL is also 
important for plasmablast differentiation in secondary lymphoid organs. In addition, myeloid-
derived APRIL mediates plasma cell survival by promoting the formation of so-called “survival 
niches” within the bone marrow microenvironment and mucosal compartments, leading to the 
establishment of a reservoir for long-lived antibody-secreting cells (Bossen, Cachero et al. 2008). 
Evidence of the critical role of APRIL in IgAN includes the following: (a) serum a-g IgA1 
(autoantigen) levels are elevated in patients with IgAN and correlate with APRIL levels and 
disease severity; (b) genome-wide association studies link APRIL to the disease; (c) serum 
APRIL is elevated in patients with IgAN and higher APRIL levels among IgAN patients are 
associated with more rapid progression to kidney failure (Mestecky, Raska et al. 2013, 
Han, Yang et al. 2016, Muto, Manfroi et al. 2017). 
In a mouse model of IgAN, administration of an anti-APRIL antibody similar to VIS649 led to 
lower IgA deposits in the kidney, lower proteinuria, and less glomerular sclerosis compared with 
animals administered a control antibody that does not bind APRIL. These data suggest that 
APRIL plays a key role in the pathogenesis of IgAN and that blocking APRIL could be an 
attractive approach for the treatment of IgAN (Myette, Kano et al. 2019).  
VIS649 is a humanized IgG2 mAb against the biologically active form of APRIL. VIS649 was 
tested in healthy human participants in a Phase 1, randomized, placebo-controlled, 
single-ascending dose, first-in-human study to assess the safety, tolerability, PK, and PD of 
VIS649 (VIS649-101). The study enrolled 51 participants in 5 sequential dosing cohorts. 
Participants in Cohorts 1 to 4 received 4 different dose levels of VIS649 (0.5, 2, 6, and 12 mg/kg, 
respectively), enrolling 9 participants per cohort (7 participants receiving VIS649 and 
2 participants receiving placebo). Cohort 5 had 15 participants with 10 receiving VIS649 and 
5 participants receiving placebo. Participants in Cohort 5 received 6 mg/kg of VIS649 on Day 1 


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and subsequently received a tetanus and diphtheria (Td) vaccine on Day 28. Blinded group data 
are available, including IgA levels. Preliminary data show that the total serum IgA declined by 
up to ~60% from normalized baseline values in these healthy participants. The vaccine response 
in Cohort 5 was intact, with a comparable IgG response to Td vaccine in participants receiving 
VIS649 and participants receiving placebo. Mean serum IgG levels declined by up to ~35% 
below normalized baseline values and mean IgM levels showed a marked decline of up to ~70% 
below the normalized baseline values. These declines in the Ig levels were reversible and the 
time taken to restoration of Ig levels to baseline was dependent on the dose of VIS649, with 
higher doses requiring a longer time period. VIS649 was very well tolerated across all dose 
levels and there were no serious adverse events (SAEs) attributed to VIS649. Further details can 
be found in the Investigator’s Brochure.  
The adverse risk-benefit ratio of nonspecific immunosuppressive agents precludes the chronic 
use of such agents and highlights the need for the development of an effective alternative that 
acts specifically on relevant pathophysiological factors in IgAN and is safe for chronic use. 
2.3 
Benefit/Risk Assessment 
2.3.1 Risk Assessment 
Table 2 summarizes the important potential risks that have been recognized during the conduct 
of VIS649 nonclinical and clinical development programs. At present, all are considered 
potential risks.  
More detailed information about the risks and reasonably expected adverse events (AEs) of 
VIS649 may be found in the Investigator’s Brochure. 
Table 2: 
Summary of Potential Risks Associated with VIS649 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
IgA suppression risk 
 
Based on the mechanism of action of 
VIS649, preclinical studies, and human data 
from healthy participants, total serum IgA 
levels are expected to be suppressed to nadir 
levels 
. 
There is increasing recognition that selective 
IgA deficiency, which has typically been 
associated with IgA levels below the lower 
limit of detection 
 
, may be associated with recurrent 
sinopulmonary infection, allergy, 
autoimmunity, and gastrointestinal 
microbiome perturbation (Yazdani, Azizi et 
al. 2017, Fadlallah, El Kafsi et al. 2018).  
VIS649 is expected to reduce but not ablate 
IgA expression. Additionally, the syndrome 
of selective IgA deficiency is often associated 
with additional immunologic impairments, 
including T-cell disorders which are not 
expected to occur with VIS649 dosing. 
• 
Serum IgA, IgG, and IgM will 
be measured on a monthly 
basis as blinded data, to be 
made available for routine 
DSMB review. The DSMB 
will assess unblinded safety 
data on a scheduled and as 
needed ad hoc basis, including 
AEs, laboratory data, and Ig 
data. The DSMB charter calls 
for assessment of the 
relationship of AEs to 
observed Ig levels (IgA, IgG 
and IgM) in study participants. 
• 
If needed, the DSMB charter 
also calls for specific 
risk-mitigation strategies 
including, but not limited to, 
change in inclusion/exclusion 
criteria, establishing criteria 




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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Most patients with selective IgM deficiency 
are asymptomatic, but a few patients develop 
chronic and recurrent infections and 
increased risk of autoimmune diseases 
(Yel, Ramanuja et al. 2009, Louis and Gupta 
2014, Louis, Agrawal et al. 2016, Janssen, 
Macken et al. 2018). Selective IgM 
deficiency is usually associated with other 
defects such as decreased T-helper cell 
activity, increased isotype specific suppressor 
T cells, increased CD8 Treg cells, and 
intrinsic B cell defects.  
VIS649 is not expected to have effects such 
as these on cellular immunity. 
Additional information can be found in the 
Investigator’s Brochure. 
Nonspecific 
immunosuppression risk 
There is the possibility of nonspecific 
immunodeficiency with potential risk of 
exacerbation of pre-existing latent infection 
or poor response to new infection. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
Participants with acute or 
chronic infections at the time 
of screening are prohibited 
from enrollment.  
• 
Participants with underlying 
iatrogenic or primary 
immunodeficiency syndromes 
are prohibited from 
enrollment.  
• 
DSMB monitoring will 
include careful attention to 
infection-related AEs. 
• 
Concurrent treatment with 
systemic corticosteroids or 
other immunosuppressive 
therapy is prohibited during 
study conduct. 
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) 
There were no SAEs among participants in 
the Phase 1 VIS649-101 study at dose levels 
up to 12 mg/kg. 
Severe infusion reactions such as anaphylaxis 
have not been observed with VIS649 in 
humans.  
There was no effect of VIS649 on measured 
plasma cytokine concentrations in the 
monkey toxicology studies, and VIS649 did 
not stimulate significant cytokine release in 
an in vitro human peripheral blood 
lymphocyte cytokine release assay. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for the occurrence 
of infusion reactions.  
Delayed allergic reactions 
(SSLR [ie, urticaria, 
Delayed allergic reactions to a mAb such as 
serum sickness (ie, urticaria, fever, general 
glandular enlargement, joint pains) have been 
• 
Participants will be monitored 
for AEs throughout the 
duration of the study. 


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
fever, general glandular 
enlargement, joint pains]) 
reported with other mAbs and may not 
appear until several days or weeks after the 
infusion. 
Additional information can be found in the 
Investigator’s Brochure. 
Injection site reactions 
Injection site reactions may occur following 
administration of any intravenous therapy.  
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for injection site 
reactions. 
Abbreviations: AE = adverse event; APRIL= A Proliferation Inducing Ligand; CVID = common variable immunodeficiency; 
DSMB = data safety monitoring board; Ig = immunoglobulin; IgA = immunoglobulin A; IgG = immunoglobulin G; 
IgM = immunoglobulin M; IV = intravenous; LLN = lower limit of normal; mAb = monoclonal antibody; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); SAE = serious adverse event; SSLR = serum-sickness like reaction. 
2.3.2 Benefit Assessment 
Immunoglobulin A nephropathy is a chronic disease with periodic flares. IgAN is a significant 
cause of CKD and ESRD, the clinical progression varies, with 30 – 40% of patients reaching 
ESRD 20 to 30 years after the first clinical presentation (Lai, Tang et al. 2016). These patients 
have significantly increased mortality and morbidity, with life expectancy reduced by 6 to 
10 years when compared to healthy individuals. (Hastings, Bursac et al. 2017, Jarrick, Lundberg 
et al. 2019). There are currently no approved therapies for IgAN, and the current treatment 
strategies consist of 2 main approaches: nonspecific supportive treatments consisting of BP 
control, treatment with ACEI/ARB, smoking cessation, lipid reduction, low-salt diet, or fish oil, 
and immunosuppressive therapies such as steroids, cyclophosphamide, or azathioprine. The 
immunosuppressive therapies are usually employed in patients with a high risk of progression, as 
characterized by proteinuria > 1.0 g/d and declining GFR (Cheng, Zhang et al. 2009, 
Boyd, Cheung et al. 2012, KDIGO 2012, Radhakrishnan and Cattran 2012, Barbour and Feehally 
2017, Rodrigues, Haas et al. 2017). Recent trials have shown some benefit in proteinuria 
reduction with steroids in these patients, thought they are at high risk for developing significant 
complications like infections, metabolic derangements, osteoporosis, and diabetes mellitus with 
these immunosuppressive agents, thus limiting the duration for which these drugs can be given to 
patients despite benefit from a renal perspective (Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 
2015, Tesar, Troyanov et al. 2015, Lv, Zhang et al. 2017). Hence, there is a critical need for a 
safe and specific treatment for IgAN. 
VIS649 has the potential to provide a significant advancement in the therapeutic approach to 
IgAN. It has a very specific mechanism of action in the form of APRIL inhibition, which plays a 
critical pathophysiological role in the production of a-g IgA1 in patients with IgAN.  
VIS649 has an attractive safety profile based on currently available data, including data from the 
first-in-human study (VIS649-101), in which no SAEs attributable to VIS649 were observed. It 
is anticipated that VIS649 will be used as chronic therapy and will significantly improve the 
outcomes in patients with IgAN when compared to intermittent therapies like steroids that are 
currently used to treat these patients. 


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2.3.3 Overall Benefit: Risk Conclusion 
Given the mechanism of action of VIS649 and data from a Phase 1 single-ascending dose study 
(VIS649-101) in healthy participants, it is expected that participants receiving VIS649 will have 
a decline in Ig levels 
. To mitigate the risk of IgG reduction, serum IgG 
thresholds for enrollment have been established so as to prevent the development of clinically 
significant hypogammaglobulinemia. In addition, studies in both healthy human participants and 
nonhuman primates have demonstrated that the ability to develop an IgG response to novel 
antigens and recall T-cell dependent antigen challenge is not significantly impaired. As 
mentioned earlier, there were no SAEs considered attributable to VIS649 in the Phase 1 
single-ascending dose study (VIS649-101), and in the nonhuman primate 6-month toxicology 
study, the no-adverse effect level for the antibody was the highest dose evaluated.  
An independent data safety monitoring board (DSMB) for this study will be reviewing all 
available safety data, including unblinded Ig data and AEs on a periodic and, as needed, on an ad 
hoc basis.  
Given these encouraging preliminary data and the precautions built into the protocol, evaluation 
of the potential benefit of VIS649 in slowing or halting CKD progression in IgAN participants is 
warranted. 


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3. 
OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints are outlined in Table 3. 
Table 3: 
Study Objectives and Endpoints 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and tolerability of 
monthly doses of VIS649 at each of 3 dosing 
levels, administered IV to IgAN participants 
over the course of 12 months as an add-on to 
SOC treatment with ACEI/ARB therapy, 
compared with saline placebo infusions as an 
add-on to SOC treatment with ACEI/ARB 
therapy 
• 
AEs graded by severity, clinical laboratory 
tests, vital sign measurements, and physical 
examinations  
Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of monthly 
doses of VIS649 on proteinuria at each of 
3 dosing levels, administered IV to IgAN 
participants over the course of 12 months as 
an add-on to SOC treatment with ACEI/ARB 
therapy, compared with saline placebo 
infusions as an add-on to SOC treatment with 
ACEI/ARB therapy 
• 
Change from baseline in uPCR (measured on 
natural log scale from 24-hour urine collection 
or the intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days after the 
12th dose is administered) 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated doses of 
VIS649 at 3 dosing levels versus placebo on 
the following parameters: 
 
o uPCR at Months 9 and 16 (ie, 5 months 
following the final [12th] monthly dose 
administration) 
o Change from baseline in uPCR (measured 
on natural log scale from 24-hour urine 
collection or the intended 24-hour urine 
collection) at Months 9 and 16 
o 24-hour urine protein excretion at Months 
9, 12, and 16 
o Change in 24-hour urine protein excretion 
from baseline to Months 9, 12, and 16 
o ≥ 30% decline from baseline in uPCR at 
Months 9, 12, and 16  
o Number of participants in each group 
achieving a ≥ 30% decline from baseline 
in uPCR at Months 9, 12, and 16 
o Clinical remission, defined as reduction in 
24-hour urine protein excretion to 
< 300 mg/day for at least 3 consecutive 
months  
o Number of participants in each group 
achieving clinical remission 
• 
eGFR at Months 12 and 16 
• 
Change from baseline in eGFR at Months 12 
and 16 
 






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4. 
STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, multiple-dose study 
to evaluate the safety and efficacy of intravenously (IV) administered VIS649 over a 12-month 
treatment course in participants with IgAN.  
Participants will be enrolled from approximately 90 global sites in approximately 16 countries. 
Screening evaluations (including physical examinations, vital signs, 12-lead electrocardiogram 
[ECG], safety laboratory testing [serum chemistry, hematology, urinalysis, serology, hemoglobin 
A1c, and pregnancy], blood sampling for baseline Ig levels [IgA, IgG, and IgM], and 24-hour 
urine collection) will take place during the 30 days prior to the first dose of study intervention.  
To be eligible, participants should be on stable and maximally tolerated doses of either ACEI or 
ARB therapy, as per standard of care (SOC) and applicable guidelines, for at least 3 months. 
Participants must be on at least 50% of the recommended maximum dose of the ACEI or ARB to 
be considered as having adequate RAAS blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in 
the study if their overall management of IgAN, including BP control, is as per SOC and 
applicable guidelines. 
Participant education regarding temporary cessation of ACEIs/ARBs during acute illness and 
resumption of these drugs after resolution of the acute illness will be as per local practice and 
SOC and this therapy will be resumed at the dose closest to the level at the time of 
randomization. During the course of the study, the doses of ACEIs or ARBs should not change; 
however, minor changes are allowed depending on the clinical situation. Control of BP should be 
as per SOC and applicable guidelines. Although additional antihypertensives can be used to 
control BP as per the Investigator’s preference and local practice, combination of ACEIs and 
ARBs (or direct renin inhibitors) is prohibited and addition of mineralocorticoid receptor 
antagonists such as spironolactone or eplerenone should be avoided. 
Enrolled participants must be 18 years of age or older with an IgAN diagnosis confirmed by 
biopsy. 
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have been interpreted 
using the MEST score - mesangial cellularity, endocapillary proliferation, segmental sclerosis, 
tubular atrophy (Cattran et al, 2009) or MEST-C scoring system (Trimarchi, Barratt et al. 2017) 
from the Oxford classification of IgAN. Components of the MEST-C score include:  
• 
M – Mesangial hypercellularity, defined as more than 3 mesangial cells in any mesangial 
area of a glomerulus; a score of M0 indicates hypercellularity in < 50% of glomeruli and 
a score of M1 is for hypercellularity noted in ≥ 50% of glomeruli. 
• 
E – Endocapillary proliferation, defined as hypercellularity due to an increased number of 
cells within glomerular capillary lumina causing narrowing. E0 represents absence of 
hypercellularity; E1 is hypercellularity in any glomeruli. 
• 
S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of 
capillary lumina by matrix) in part of but not the whole glomerular tuft; S0 represents 


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absence of segmental glomerulosclerosis; S1 is presence of segmental glomerulosclerosis 
in any glomerulus. 
• 
T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical 
area showing tubular atrophy or interstitial fibrosis, whichever is greater; T0 is 0-25%; 
T1 is 25-50%; T2 is > 50% atrophy/interstitial fibrosis. 
• 
C – Crescents: C0 (no crescents), C1 (crescents in < 25% of glomeruli), and C2 
(crescents in ≥ 25% of glomeruli). 
A MEST-C score finding on kidney biopsy of T2 or C2 is exclusionary for this study. If the 
biopsy was not reported using the Oxford classification schema, the following findings 
(corresponding to these Oxford classifications) are exclusionary: a) > 50% tubular atrophy and/or 
b) > 25% crescents.  
Eligible participants must have sufficient proteinuria at screening, defined as urine protein to 
creatinine ratio (uPCR) ≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 
24-hour urine collection (or an intended 24-hour urine collection). The proteinuria should be 
stable, as defined by a < 25% change when compared to values from ≥ 3 months ago (if 
available). If previous values are not available, or if the change from a prior value is > 25%, a 
repeat measurement of proteinuria will be done after 15 days and the patient should fulfill the 
above proteinuria criteria to be eligible for randomization in the trial.  
Eligible participants must have an eGFR ≥ 45 mL/min/1.73 m2, calculated using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey, Stevens et al. 2009), 
before dosing on Day 1. The eGFR should be stable, as defined by a < 25% change when 
compared to values from ≥ 3 months ago (if available). If previous values are not available or if 
the change from a prior value is > 25%, a repeat measurement of eGFR will be done after 
15 days and the patient should fulfill the eGFR criteria to be eligible for randomization in the 
trial.  
If the patient fulfills the proteinuria and eGFR criteria based on 2 measurements performed for 
each during the screening period, the second measurement (for each) will be considered as the 
baseline for analysis.  
Participants known to have chronic infectious diseases (eg, chronic sinusitis, chronic urinary 
tract infections, bronchiectasis) will be excluded. Participants in countries with high prevalence 
of tuberculosis may undergo appropriate investigations such as chest X-ray or interferon 
gamma-release assay, as deemed appropriate by the Investigator, to rule out tuberculosis. 
Participants will be excluded from the study if they test positive for the screening serology 
markers listed in Table 8. Participants with a positive Hepatitis C virus (HCV) antibody test must 
undergo testing for HCV RNA; if HCV RNA is undetectable, the participant can be included in 
the study. Participants with positive HbSAg and/or positive Anti HbC antibody will be excluded. 
Participants must be vaccinated as per respective national guidelines and other relevant 
guidelines. Participants should continue to receive annual influenza vaccine and pneumococcal 
vaccine, as per local guidelines. 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus placebo. A total of 
144 participants will be randomized with equal allocation (1:1:1:1) across the 4 intervention 
groups (approximately 36 participants per group). Randomization will be stratified first by 


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region (Japan vs rest-of-world). A target of 12 or more participants are planned to be randomized 
in Japan; these participants will be randomized with equal allocation and without further 
stratification. The randomization for the rest-of-world will be stratified by screening uPCR 
(≤ 2.0 g/g vs > 2.0 g/g).  
VIS649 or placebo will be administered as 12 monthly IV infusions starting on Day 1/Month 0. 
Participants will return to the study center on Days 8 and 18, then monthly through Month 14 
and on Month 16 for safety, efficacy, PK, and/or PD assessments. Participants will be 
encouraged to follow the schedule of visits for their monthly infusions as close to the prescribed 
interval as possible. If under special circumstances, a participant is unable to visit the study 
center within 7 days of the scheduled infusion, they will still be able to receive the infusion 
within the next 7 days, and this will be recorded as a protocol deviation. However, if there is any 
further delay, that dose should be skipped, and the participant should receive subsequent doses as 
per the schedule. The participant will not receive additional doses to make up for the missed 
dose(s). 
Safety assessments will include review of AEs (including hypersensitivity reaction and 
anaphylactic reaction), physical examinations, injection site tolerability (pain, irritation, and 
tissue damage), clinical laboratory assessments (including biochemistry, hematology, urinalysis, 
and pregnancy testing), laboratory testing (including serum Ig levels and antidrug antibodies 
[ADAs]), vital sign measurements, and use of concomitant medications. 
Participants will return to the study center on Month 16, 155 days following the last dose of 
study intervention (Dose 12) for an end-of-study (EOS) visit, at which time final safety, PK, PD, 
and efficacy assessments will be performed. Participants discontinuing dosing prior to Dose 12 
will attend an early termination visit at the time of dosing discontinuation and will be encouraged 
to attend the study visits as per schedule of assessments (Table 1).  
An independent DSMB will review safety data at regular intervals (see Section 9.6). 
A rollover, open-label extension study will be offered to enable access to VIS649 (there will be 
no placebo arm) for study participants who have completed this trial, provided that the 
Investigator believes that the participants might benefit, and that the site has agreed to participate 
in the extension study. Further details will be provided in a separate protocol. 
The total study duration for each participant (from screening to EOS) will be up to 17 months 
(assuming up to 1 month for screening, 12 months for monthly doses [including 30 days after the 
12th dose], and follow-up visits up to 155 days after the last dose of study intervention.  
4.2 
Scientific Rationale for Study Design 
This study is designed as a randomized, double-blind, placebo-controlled, multiple-dose study to 
evaluate the safety and efficacy of IV administered VIS649 in IgAN participants over a 
12-month intervention course.  
Immunoglobulin A nephropathy is a chronic, slowly progressing disease. The underlying 
pathogenic factor in IgAN is the formation of a-g IgA1, which is attributed to a culmination of 
genetic and environmental factors in susceptible individuals. The hypoglycosylated hinge region 
of a-g IgA1 presents as a novel antigen, against which IgG and IgA autoantibodies may be 
generated. This leads to formation of circulating IgG/a-g IgA1 immune complexes that are 


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deposited (in part) in the mesangium of the glomerulus, inciting an inflammatory, nephritogenic 
response (Boyd, Cheung et al. 2012, Mestecky, Raska et al. 2013, Lv, Zhang et al. 2017). This 
manifests clinically as proteinuria, hematuria, and decline in eGFR. High grade proteinuria 
(> 1.0 g/d) is a critical marker of progressive IgAN and remission of proteinuria is a crucial 
therapeutic target in the management of IgAN (Donadio, Bergstralh et al. 2002, Reich, Troyanov 
et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016, Thompson, Carroll et al. 2019). 
VIS649 inhibits the biological actions of APRIL and reduces the levels of IgA, a-g IgA1 and 
other Ig. In patients with IgAN, it is hypothesized that this reduction in APRIL and a-g IgA1 will 
reduce the deposition of circulating immunocomplexes in the glomerulus. This should lead to 
cessation of ongoing renal damage and lead to recovery of the damaged glomeruli, as reflected 
by a reduction in proteinuria. 
Based on the PK/PD data from the Phase 1 single-ascending dose study (VIS649-101) and on 
simulation models, full therapeutic suppression of IgA through APRIL signaling inhibition will 
be achieved at 12 weeks, with the selected doses administered monthly. Considering the 
time-dependent and indirect effect of VIS649, a 12-month study intervention duration is deemed 
necessary to achieve therapeutic effect and assess for clinically relevant benefit of VIS649, as 
measured by reduction in proteinuria. 
The primary efficacy endpoint will be the change from baseline in uPCR, at Month 12 (30 days 
after the 12th dose of study intervention), as measured from a 24-hour urine collection. Studies 
have shown that in patients with IgAN, reduction of proteinuria leads to clinically relevant 
improvements like reduction in the rate of decline of eGFR and progression to ESRD.  
In an analysis of data from the Toronto Glomerulonephritis Registry of 542 patients followed for 
a mean of 6.5 years (61% males, 50% whites, 23% Asians, with mean initial proteinuria 2.4 g/d 
and creatinine clearance of 77 mL/min/1.73 m2), time-averaged proteinuria (defined as an 
average of the mean of the proteinuria measurements for every 6-month period) was the most 
important predictor of kidney function decline and risk of ESRD, independently of BP and use of 
renin-angiotensin blockers. If time-averaged proteinuria was maintained < 1 g/d, the 10-year risk 
of ESRD was 5%, versus 20% with a time-averaged proteinuria of 1–2 g/d, 40% with a 
time-averaged proteinuria of 2 to 3 g/d, and 60% with > 3 g/d (Reich, Troyanov et al. 2007). 
This study highlights the primary importance of proteinuria reduction as a therapeutic target in 
the management of IgAN.  
A comprehensive series of safety evaluations, including review of AEs (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, injection site 
tolerability (pain, irritation, and tissue damage), clinical laboratory assessments (including 
biochemistry, hematology, urinalysis, and pregnancy testing), laboratory testing (including 
serum Ig levels and ADAs), vital sign measurements, and use of concomitant medications will be 
conducted to evaluate the safety profile of VIS649. 
It is expected that VIS649 will result in obvious reductions in serum IgA, IgG, and IgM, which, 
if visible to the site or Sponsor, would effectively unblind treatment. Therefore, unblinded Ig 
data will only be available to designated unblinded personnel.  
The DSMB will have access to the unblinded Ig data and will be responsible for monitoring Ig 
and AE data periodically (see Section 9.6). 




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4.4 
End-of-study Definition 
A participant is considered to have completed the study if he/she has completed the intervention 
period and EOS visit.  
The end of the study is defined as the date of the last visit of the last participant in the study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. Rescreening is typically not permitted; possible 
exceptions include re-testing of samples due to issues arising during shipping/storage/handling of 
samples. Rescreening of a participant may also be permitted if initial participation in the study 
was precluded due to an acute infection or an acute illness that subsequently resolved 
completely, and the participant then is able to fulfill all study eligibility criteria.  
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant is a male or female ≥ 18 years of age at the time of signing the informed 
consent. 
2. Participant has biopsy-confirmed IgAN.  
3. Participant has medical records showing they have been on stable and maximally 
tolerated doses of either ACEI or ARB, as per SOC and applicable guidelines, for at least 
3 months preceding screening. Participants should be on at least 50% of the maximum 
recommended dose of these agents to be considered as having adequate RAAS blockade. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study if their overall management of IgAN, including BP control, is as 
per SOC and applicable guidelines. 
4. Participant has screening uPCR ≥ 0.75 g/g measured from a 24-hour urine (or an intended 
24-hour urine sample) or 24-hour urine protein ≥ 1.0 g/d, as measured from 24-hour urine 
collection (or an intended 24-hour urine sample). The proteinuria should be stable, 
defined as < 25% change when compared to values from ≥ 3 months previously (if 
available).  
• If previous values are not available or if the change from a prior value is > 25%, a 
repeat measurement of proteinuria will be done after 15 days and the participant 
should fulfill the above proteinuria criteria to be eligible for randomization in the 
study.  
• The proteinuria should be assessed when the participant is considered to be in a 
steady state with no recent heavy exercise, fever, or other potential issues that 
could impact the result. 
5. Participant has eGFR ≥ 45 mL/min/1.73 m2, calculated using the CKD-EPI formula. The 
eGFR should be stable, as defined by a < 25% change when compared to values from ≥ 3 
months previously (if available).  
• If previous values are not available or if the change from a prior value is > 25%, a 
repeat measurement of eGFR will be done after 15 days and the participant should 
fulfill the eGFR criteria to be eligible for randomization in the study.  
• The eGFR should be measured when the participant is considered to be in a 
steady state without recent changes in volume status, medications that could 


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impact the result (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], 
aminoglycosides, co-trimoxazole), or changes in dietary protein intake. 
6. Participant’s serum Ig values must meet the following criteria:
•
IgG: ≥ 700 mg/dL
•
IgM: ≥ 40 mg/dL
•
IgA: ≥ 70 mg/dL
7. Female participants of childbearing potential must have a negative serum pregnancy test
prior to the first dose.
8. Participant is willing to adhere to contraceptive requirements outlined in Appendix 4.
9. Participant or a legally authorized representative is able to understand the purpose and
risks of the study and is willing to give voluntary written informed consent as described
in Appendix 1.
5.2 
Exclusion Criteria 
Participants are excluded from the study if they meet any of the following criteria: 
1. Participant has secondary forms of IgAN as defined by the treating physician (eg,
Henoch-Schӧnlein purpura, minimal change disease with IgA deposits, infection
associated IgAN, or IgAN-associated with hepatic cirrhosis).
2. Participant has co-existing CKD, other than IgAN.
3. Participant has evidence of additional pathological findings in the kidney biopsy (eg,
diabetic kidney disease, membranous nephropathy, or lupus nephritis). However,
hypertensive vascular changes are acceptable.
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 from the Oxford
IgAN classification schema. If MEST-scoring was not performed, the presence of > 50%
tubulo-interstitial fibrosis or crescents in > 25% of glomeruli is exclusionary.
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour urine protein
> 3.5 g with concurrent hypoalbuminemia (serum albumin < 2.5 g/dL), hyperlipidemia
(total cholesterol > 350 mg/dL), and edema.
6. Participant has received a solid organ transplant, including kidney.
7. Participant has received bone marrow or hematologic stem cell transplantation.
8. Participant is currently receiving systemic immunosuppression (excluding topical,
ophthalmic, per rectum, or inhaled corticosteroids).
9. Participant has received systemic steroids within the 24 weeks prior to initial screening.
10. Participant has received treatment with 2 or more systemic immunosuppressive agents
within 2 years prior to initial screening.
11. Participant has chronic infectious diseases (eg, chronic urinary tract infection; chronic
sinusitis; bronchiectasis; active pulmonary or systemic tuberculosis; chronic viral
hepatitis, such as hepatitis C or hepatitis B; or human immunodeficiency virus infection).


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12. Participant has acute infectious disease at the time of screening. Participants may be 
rescreened following resolution of acute infection (such as urinary tract infection or 
respiratory tract infection), provided there is no evidence of an immunosuppressive 
condition that predisposed the participant to this infection.  
13. Participant has Type 1 diabetes. 
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin 
A1c value > 8%. 
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg diastolic), 
Systolic and diastolic BP should be assessed while the participant is seated or supine for 
at least 5 minutes in a quiet room without distractions. BP should be measured with a 
completely automated device. At least 3 readings should be taken and average values 
from these 3 readings should be calculated. 
16. Participant has a history of chronic autoimmune neurodegenerative disorder such as 
multiple sclerosis. 
17. Participant has a known allergy or intolerance to any component of the study 
intervention. 
18. Participant is breastfeeding. 
19. Participant has poorly compensated or controlled ischemic heart disease or 
cardiomyopathy, as judged by the Investigator. 
20. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has 
required systemic steroid therapy during the prior year. If COPD is present, severity must 
not exceed Global Initiative for Chronic Obstructive Lung Disease 1 (mild), defined as a 
forced 1-second expiratory volume (FEV1) > 80% of predicted. 
21. Participant has known cirrhosis or liver dysfunction, defined as presence of 
coagulopathy, platelet count < 100,000/µL or alanine aminotransferase > 3× upper limit 
of normal. 
22. Participant has active malignancy or is receiving chemotherapy for malignancy, except 
for nonmelanoma skin cancers and cervical carcinoma in situ. Participants with prior 
malignancy who have been documented to be cancer-free for ≥ 5 years may be enrolled. 
23. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is 
acceptable (if greater than 6 months prior to screening). 
24. Participant enrolled in another investigational drug or device study within 3 months prior 
to initial screening. 
25. Participant with a pre-existing illness other than those listed above that, in the opinion of 
the Investigator, would place the participant at increased risk through participation in this 
study. 
26. Participant is unable to comply with study protocol procedures and/or study visit 
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27. Participant with known or suspected alcohol or drug abuse that would compromise their 
safety or study participation, in the opinion of the Investigator. 
5.3 
Lifestyle Considerations 
Lifestyle recommendations applicable to IgAN patients such as, but not limited to, BP control, 
low-salt diet, low-protein diet, smoking cessation, weight reduction, and avoidance of 
nephrotoxic drugs (eg, NSAIDs) will be followed as per local practice and guidelines. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 


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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1 
Study Intervention(s) Administered 
The study interventions to be administered under this protocol are detailed in Table 4. 
VIS649 is for investigational use only and should only be used within the context of this study.  
VIS649 will be administered as a mg/kg dosage determined by dose assigned at time of 
randomization. VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL 
infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The dose of study 
intervention will be based on the Month 0 predose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour as a single 100 mL infusion, followed 
by a 25 mL saline flush. 
Infusions should preferentially be administered to the participant’s dominant arm. 
Table 4: 
Study Interventions 
Study Arm 
VIS649 
Placebo 
Intervention Name 
VIS649 
Placebo 
Intervention Type 
Drug (IMP) 
Placebo (NIMP) 
Dose Formulation 
Solution 
NaCl (normal saline solution) 
Unit Dose Strength 
VIS649 is formulated at a 
concentration of 25 mg/mL 
0.9% 
Dosage Levels 
2, 4, and 8 mg/kg 
as a single, final volume of 100 mL 
N/A 
Dosing Frequency 
Monthly for 12 months 
Monthly for 12 months 
Route of Administration 
1-hour IV infusion, followed by a 
25-mL saline flush 
1-hour IV infusion, followed by a 
25-mL saline flush 
Use 
Experimental 
Placebo-comparator 
Sourcing 
Provided centrally by the Sponsor 
Supplies will be obtained locally  
Packaging and Labeling 
VIS649 will be supplied in vials 
containing a nominal volume of 10 mL 
and will be labeled according to local 
regulations 
Per local supplies 
Storage Conditions 
VIS649 must be stored at a 
temperature between ≥ 2°C and ≤ 8°C 
and protected from light. Must be 
infused within 4 hours of 
reconstitution 
Per package insert 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; IMP = investigational 
medicinal product; IV = intravenous(ly); N/A = not applicable; NIMP = noninvestigational medicinal product; SOC = standard of 
care. 


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6.2 
Preparation/Handling/Storage/Accountability 
The required amount of VIS649 to be dosed will be diluted in normal saline up to a maximum 
total volume of 100 mL; for placebo participants, 100 mL of normal saline will be prepared. The 
length of the IV line will be set to a maximum volume of 25 mL, so that the 25-mL saline flush 
following administration will ensure all VIS649/placebo has been administered. 
The VIS649/placebo infusion will be administered IV using a 0.20-µm in-line filter and will be 
controlled by a volumetric pump. Standard, uniform-length infusion lines will be used. 
In addition: 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained for study intervention during transit to and storage in the investigational 
pharmacy. Any deviations from Pharmacy Manual guidance are to be reported and 
resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply and administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions, with access limited to 
the Investigator and authorized site staff. 
3. The Investigator, institution, or head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This study is double-blinded. An unblinded pharmacist will prepare study intervention doses for 
infusion. Participants, the Sponsor, the Investigator, and all other site study staff will be blinded 
to study intervention.  
All eligible participants will be centrally assigned to randomized study intervention using an 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the 
telephone number and call-in directions for the IVRS and/or the log-in information and 
directions for the IWRS will be provided to each site. 
Participants will be randomly assigned in a 1:1:1:1 allocation ratio to receive VIS649 at 2, 4, or 
8 mg/kg or placebo, with approximately 36 participants randomized to each intervention group. 
Randomization will be stratified first by region (Japan vs rest of world). A target of 12 or 
more participants are planned to be randomized at Japanese sites. Japanese participants will be 
randomized with equal allocation and without further stratification. Randomization for the rest of 
world will then be stratified by screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
Each assignment will have a unique randomization number, assigned to eligible participants after 
the screening. Once a randomization number has been assigned via the IVRS/IWRS, it may not 
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In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is required for participant safety, the Investigator should make every effort to contact 
the Sponsor prior to unblinding a participant’s intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s intervention assignment is unblinded, 
the Sponsor must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and electronic case report 
form (eCRF), as applicable. 
Local laboratory testing such as Ig concentrations, albumin:globulin ratio (often tested as part of 
routine liver function panel), or serum protein electrophoresis may reveal obvious reduction in 
the total globulin levels in participants receiving study intervention and could effectively unblind 
the participant. Performing such investigations is prohibited, unless this has been discussed with 
the Sponsor and such investigations have been deemed necessary for clinical management of the 
participant. 
6.4 
Study Intervention Compliance 
Preparation of individual doses of study intervention will be verified by a second (unblinded) 
member of the study site pharmacy staff.  
Participants will receive study intervention at the study center directly from the Investigator or 
designee under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and eCRF. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.  
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter and prescription medicines, vitamins, 
herbal supplements, fish oil, and NSAIDs) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with the following: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 Concomitant Therapy to be Avoided 
Participants should avoid using drugs that are contraindicated in IgAN (eg, NSAIDs, 
aminoglycosides, co-trimoxazole) during the study, per local practice. 
During conduct of the study, administration of systemic corticosteroids or other 
immunosuppressive therapy (for IgAN or other conditions) is prohibited due to the risk of over 
immune suppression due to overlapping actions of VIS649 and other immunosuppressive agents. 
If the Investigator believes that treatment with such therapy is required, and the potential benefits 


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outweigh the possible risks, the Medical Monitor must be notified, as continued dosing with 
study intervention may, in this circumstance, be discontinued.  
6.6 
Dosing Schedule Modification 
Participants will be encouraged to follow the schedule of visits for their monthly infusions as 
close to the prescribed interval as possible. If under special circumstances, a participant is unable 
to visit the study center within 7 days of the scheduled infusion, they will still be able to receive 
the infusion within the next 7 days, and this will be recorded as a protocol deviation. However, if 
there is any further delay, that dose should be skipped, and the participant should receive 
subsequent doses as per the schedule. The participant will not receive additional doses to make 
up for the missed dose(s). 
There will be no other alterations from the dosing schedule outlined in Section 6.1.  
6.7 
Intervention after the End of the Study 
A rollover, open-label extension study will be offered to enable access to VIS649 (there will be 
no placebo arm) for study participants who have completed this trial, provided that the 
Investigator believes that the participants might benefit, and that the site has agreed to participate 
in the extension study. Further details will be provided in a separate protocol. 


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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1 
Discontinuation of Study Intervention Dosing
Participants have the right to discontinue study intervention or withdraw from the study at any 
time for any reason. Participants may withdraw or be withdrawn from study-related procedures 
and intervention for the following reasons: 
•
Withdrawal of consent
•
Adverse event
•
Protocol deviation
•
Investigator decision
•
Pregnancy (Appendix 4)
•
Sponsor decision to terminate the study
•
Lost to follow-up
In particular, study intervention should be discontinued if participants experience the following: 
•
Grade ≥ 3 infusion reaction such as severe anaphylaxis or cytokine release syndrome
•
At the discretion of the Investigator, study intervention may be stopped if the participant
has an unexplained decline in eGFR of > 30% sustained over 3 months that is not
reversed after correction of all reversible factors such as volume depletion, NSAID,
ACEI/ARB, other nephrotoxic drug use, or resolution of acute illness or infection.
Adverse events that are ongoing at the EOS should be monitored until resolution, stabilization, 
until the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS.  
Serious AEs that are ongoing at the EOS should be monitored until resolution, stabilization, until 
the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS, 
whichever is longer (Section 8.3.1). If the participant withdraws because of an AE, every effort 
must be made to perform protocol-specified safety follow-up procedures. 
If study intervention dosing is definitively discontinued, participants are encouraged to continue 
with assessments as per the schedule of assessments. At a minimum, if study participation is 
terminated by the participant or Investigator, the participant should complete all early 
termination assessments and will be encouraged to return for the EOS assessments outlined in 
Table 1. The primary reason for discontinuation should be recorded in the appropriate section of 
the eCRF. 
7.1.1 Temporary Discontinuation 
Study intervention may be interrupted for up to 2 doses in participants who experience the 
following:  
•
Severe or intractable infection
•
Acute severe illness or injury requiring hospitalization


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7.1.2 Rechallenge 
VIS649 doses may be re-initiated (at the same dose) under the following conditions: 
•
If study intervention was interrupted due to acute illness or infection, study intervention
can be re-initiated if the participant has recovered from the acute illness or infection, as
determined by the Investigator.
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, the participant should complete all early 
termination (ET) assessments outlined in Table 1. The participant will be encouraged to attend 
an EOS visit 155 days following the last dose of study intervention. The participant will be 
permanently discontinued both from the study intervention and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule. The site also should ascertain whether or not the participant wishes to and/or
should continue in the study.
•
Before a participant is deemed lost to follow up, the Investigator or designee must make
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record.
•
Should the participant continue to be unreachable, he/she will be considered to have
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 


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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are outlined in Table 1. Protocol waivers or exemptions are 
not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements is essential for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. A pathology report that confirms the IgAN diagnosis will be submitted with eCRFs. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Efficacy Assessments 
8.1.1 Twenty-four-hour Urine Sample Collection 
Twenty-four-hour urine collection for derivation of 24-hour urine volume, protein, albumin, 
creatinine, uPCR, and uACR will be performed at the time points outlined in Table 1.  
Participants will discard the first morning void and begin a 24-hour urine collection the day prior 
to the clinic visit. Care should be taken to avoid over-collection or under-collection of urine, 
however, if this occurs, the sample may still be used to calculate the proteinuria and uPCR. On 
days of 24-hour urine collection (or the intended 24-hour urine collection), the uPCR sample will 
be collected from the 24-hour urine collection and routine urinalysis will be performed on a 
sample freshly voided during the clinic visit. 
8.2 
Safety Assessments 
8.2.1 Physical Examinations 
A complete physical examination, including assessments of the cardiovascular, respiratory, 
gastrointestinal, and neurological systems will be completed at the screening, at the 
Month 12/ET visit, and at the Month 16/EOS visit. In addition, physical examinations may be 
conducted at any other time if considered clinically indicated by the Investigator. 
8.2.2 Vital Signs 
Vital sign measurements will be performed at the visits outlined in Table 1 and will include 
weight, temperature, pulse rate, respiratory rate, and systolic and diastolic BP. Height will be 
measured and recorded during screening.  
Vital signs measurements on dosing days will be recorded within 15 (±5) minutes prior to the 
start of the infusion, every 15 minutes until the infusion is complete, and postinfusion at 
60 minutes and 2 hours. 
Systolic and diastolic BP and pulse measurements will be assessed while the participant is seated 
or supine with a completely automated device. Manual techniques will be used only if an 


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automated device is not available. Blood pressure and pulse measurements should be preceded 
by at least 5 minutes of rest for the participant in a quiet setting without distractions (no 
television, cell phone, etc). 
Whenever possible, vital signs should be collected before blood collection for laboratory tests 
and before dosing with study intervention. 
8.2.3 Electrocardiograms 
A single 12-lead ECG, heart rate, and measures of PR, QRS, QT, and QTc intervals will be 
obtained at the screening visit. Twelve-lead ECGs should also be conducted at other times during 
the study if considered clinically indicated by the Investigator. 
Twelve-lead ECGs should be conducted after 5 minutes in recumbence or semi-recumbency. 
8.2.4 Clinical Safety Laboratory Assessments 
Clinical laboratory evaluations for safety will be performed by a central laboratory whenever 
possible, however, local laboratory tests may be utilized for more urgent safety monitoring. 
Before starting the study, the Investigator will provide the Sponsor (or its designee) copies of all 
laboratory certifications and normal ranges for all laboratory assessments to be performed by that 
laboratory. Local laboratory assessments to make intervention-related decisions may be 
performed at all visits. 
A list of clinical safety laboratory tests to be performed is provided in Appendix 2 and the timing 
for these assessments is provided in Table 1. All protocol-required laboratory assessments must 
be conducted in accordance with the laboratory manual. Details of laboratory tests to be 
conducted for assessment of VIS649 PK, PD, exploratory biomarkers, and immunogenicity are 
provided in Sections 8.5, 8.6, 8.8, and 8.9, respectively.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal, with the exception 
of disease defining abnormalities such as eGFR and proteinuria considered to be a part of the 
natural history of IgAN, during the study or within 30 days after the last dose of study 
intervention should be repeated until the values return to normal, baseline, or are no longer 
considered clinically significant by the Investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
8.3 
Adverse Events and Serious Adverse Events 
Adverse event and SAE definitions are provided in Appendix 3. 
All AEs (serious and nonserious) reported by the participant must be recorded on the source 
documents and eCRF provided by the Sponsor. Medical terminology should be used for AE 


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reporting. Adverse events should be reported as a single unifying diagnosis whenever possible 
or, in the absence of a unifying diagnosis, as individual signs or symptoms. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
Adverse events that are ongoing at the EOS should be monitored until resolution, stabilization, 
until the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS.  
Serious AEs that are ongoing at the EOS should be monitored until resolution, stabilization, until 
the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS, 
whichever is longer (see Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information about AEs or SAEs after conclusion 
of study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. For example, participants should be asked the nonleading question: “How have 
you felt since your last visit?”  
Exacerbation or disease progression should be reported as an AE only if there are unusual or 
severe clinical features that were not present, or experienced earlier, or not expected based on the 
course of the condition. 
In addition, the Sponsor must be notified immediately by telephone, fax, or e-mail of any 
immediately reportable events. Immediately reportable events (IRE) include the following:  
• SAEs 
• Pregnancies. Although normal pregnancy is not an AE, it will mandate study intervention 
discontinuation and must be reported on an IRE form and the Pregnancy Surveillance 
Form(s) to the Sponsor. Pregnancy will only be documented on the AE eCRF if there is 


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an abnormality or complication. This includes pregnancy of the participant or the 
participant’s partner 
Adverse event, start date, end date, seriousness, severity, relationship to study intervention, 
action taken with study treatment, and outcome will be recorded on the source documents and in 
the eCRF. Special attention should be paid to recording hospitalization and concomitant 
medications. 
8.3.3 Follow-up of Adverse Events and Serious Adverse Events 
Nonserious AEs that are identified at any time during the study must be recorded on the AE 
eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious events (that 
are not IREs) that are ongoing at the last scheduled contact will be recorded as ongoing on the 
eCRF. For any AE having been identified throughout the study, additional relevant medical 
history information may be requested by the Sponsor during analysis to further ascertain 
causality (including, but not limited to, information such as risk-related behavior, family history, 
and occupation). 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be collected from the signing of 
the ICF until the EOS. Adverse events that are ongoing at the EOS should be monitored until 
resolution, stabilization, until the event is otherwise explained, the participant is lost to 
follow-up, or 30 days after EOS. Serious AEs that are ongoing at the EOS should be monitored 
until resolution, stabilization, until the event is otherwise explained, the participant is lost to 
follow-up, or 30 days after EOS, whichever is longer (see Section 1.3).   
Resolution means that the participant has returned to the baseline state of health and stabilized 
means that the Investigator does not expect any further improvement or worsening of the 
participant’s condition. The Investigator will continue to report any significant follow-up 
information to the Sponsor up to the point the event has resolved or stabilized, or the participant 
is lost to follow-up or has died. 
Further information on follow-up procedures is provided in Appendix 3. 
8.3.4 Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
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An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 155 days after the last dose of study 
intervention. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4 
Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. No antidotes are available. 
8.5 
Pharmacokinetics 
For all participants, serial blood samples will be drawn prior to each VIS649/placebo IV infusion 
and at the end of each infusion in order to determine circulating serum concentrations of VIS649, 
as specified in Table 1 and Table 5. Up to 60 participants (approximately 15 participants in each 
cohort) may have a more intensive PK and PD sampling schedule, as described in Table 5. Study 
participants who agree to participate in this more intensive PK and PD sample collection 
sub-study will sign an additional informed consent for this activity.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate laboratory manual. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for analyses of serum VIS649 concentrations may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 






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9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypothesis 
The primary efficacy objective of this study is to evaluate the effect of VIS649 on proteinuria. 
The hypothesis that there is a VIS649-related dose response in the change from baseline in 
natural log uPCR at Month 12 versus placebo will be formally tested.   
9.2 
Sample Size Determination 
The sample size for this study was calculated assuming a linear dose response in reduction of 
uPCR in placebo and VIS649 2, 4, and 8 mg/kg dose levels of 0%, 15%, 30%, and 45%, 
respectively.  Applying contrasts of -3, -1, 1, and 3 for the corresponding dose levels and 
analyzing uPCR on the natural log scale, the result is an expected mean change from baseline of 
0, -0.163, -0.357, and -0.593 for placebo and VIS649 dose levels of 2, 4, and 8 mg/kg, 
respectively.  Using an analysis of variance model with contrasts of -3, -1, 1, and 3 for the 
corresponding dose levels, a standard deviation of 0.87, 80% power, a 2-sided type I error rate of 
0.05, and accounting for a dropout rate of ~ 20%, the required sample size is 36 participants per 
group, or 144 participants overall.   
9.3 
Populations for Analyses 
Populations for analysis in this study are defined in Table 6. 
Table 6: 
Populations for Analysis 
Population 
Description 
ITT 
All participants who are randomized. Participants will be categorized by the 
intervention and dose they were randomized to receive.  
mITT 
All randomized participants who receive at least 1 dose of study intervention. 
Participants will be categorized by the intervention and dose that they were 
randomized to receive. 
Safety 
All randomized participants who receive any amount of study intervention. 
Participants will be analyzed according to the intervention and dose they actually 
received. 
PK/PD 
All randomized participants who have at least 1 set of PK/PD measures taken. 
Biomarker 
All randomized participants who consented to participation in the biomarker 
substudy. A separate consent process is required, as described in Section 8.8. 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s). 
Analysis of safety parameters will be performed on the Safety population. The modified 
intent-to-treat (mITT) population will be the primary population for assessment of efficacy. The 
PK/PD population will be the primary population for PK/PD summaries. Analysis of biomarker 
data will be performed on the Biomarker population. 






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PK/PD modeling and simulation may be utilized to measure the dynamic relationship between 
drug concentration, drug effect, and drug safety. 
9.4.7.2 
Antidrug Antibodies 
Presence vs absence of anti-VIS649 antibodies, anti-VIS649 antibody titers (including 
neutralizing antibody titers, if available), will be summarized by intervention group and time 
point using descriptive statistics. 
9.5 
Interim Analyses 
In addition to 5 DSMB safety reviews (Section 9.6), 3 interim PK/Ig analyses and 2 interim 
efficacy analyses (completed to inform future study design) are planned: 
•
The first PK/Ig analysis will be performed once ~25% of participants have been
randomized and have completed 3 months of study dosing. All the PK/Ig assessments
will be performed by a separate, unblinded team. Summarized results will be made
available to the Sponsor to inform future study design.
•
The second PK/Ig analysis will be performed once ~20 participants have been
randomized and have completed 9 months of study dosing. This analysis will be used to
update previously developed population PK/PD models. Summarized results will be
made available to the Sponsor to inform future study design.
•
The third PK/Ig analysis will be performed once ~50% of study participants have been
randomized and have completed 6 months of study dosing and ~20 participants have
completed 12 months of study dosing. Summarized results will be made available to the
Sponsor to inform future study design.
•
An early interim efficacy analysis may be performed when at least 16 participants have
been treated for at least 6 months and at least 50% of the 16 (or more) participants have
achieved a confirmed > 30% reduction in uPCR (as determined by 2 consecutive
measurements) based on review of blinded uPCR data across all study participants. In the
event that this condition is met and an interim analysis is triggered, group-unblinded
efficacy summaries (with individual participant treatment blinded) will be prepared by a
separate, unblinded team for Sponsor review to inform future study design.
•
A second interim efficacy analysis will be performed at the time of the fourth scheduled
DSMB meeting (once 50% of randomized participants have completed 6 months of study
dosing and approximately 20 participants have completed 12 months of study dosing).
Group-unblinded efficacy summaries (with individual participant treatment blinded) will
be prepared for Sponsor review to inform future study design.
•
The interim efficacy analyses will not include hypothesis testing and will be for the
purpose of future study design and planning. The primary efficacy endpoint, change in
proteinuria levels from baseline, will be analyzed. No modifications to this study protocol
are planned based on results of the interim analyses. Nonetheless, to account for multiple
reviews of the efficacy endpoint, the type I error rate applied at the end of the study will
be reduced by 0.002 for each interim efficacy review, resulting in a 2-sided end-of-study
type I error rate of 0.046.
Additional details will be provided in the SAP. 


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9.6 
Data Safety Monitoring Board 
An independent DSMB will review unblinded safety data. The DSMB will meet at 5 scheduled 
data review meetings and on an ad hoc basis as needed. Details regarding the content and scope 
of safety assessments, as well as the governing of the DSMB, will be described in a separate 
DSMB charter. Data safety monitoring board meetings will be scheduled as the requirements in 
Table 7 are met. 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews 
Scheduled DSMB Review Number of Participants and Treatment Exposure 
DSMB review #1 
The first scheduled meeting will occur after 12 participants have been 
randomized and have completed at least 3 months of study dosing. 
DSMB review #2 
The second scheduled meeting will occur after 24 participants have been 
randomized and have completed at least 3 months of study dosing. 
DSMB review #3 
The third scheduled meeting will occur after ~25% of participants have been 
randomized and have completed 3 months of study dosing.  
DSMB review #4 
The fourth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 6 months of study dosing, and ~20 participants 
have completed 12 months of study dosing.  
DSMB review #5 
The fifth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 12 months of study dosing. 
Abbreviations: DSMB = data safety monitoring board. 
 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2 Financial Disclosure 
All required information regarding financial certification or disclosure will be provided to the 
Sponsor for all investigators and subinvestigators in accordance with the terms of the relevant 
regional regulation(s). 
Informed consent will be freely obtained from all participants (or their guardian or legally 
acceptable representative, as applicable per local laws).  
Each ICF will comply with ICH GCP: Consolidated Guideline E61 and local regulatory 
requirements. The Investigator will ensure that the Sponsor reviews and authorizes any written 
site-specific ICF used in the study before submission to the IRB/IEC. 


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Investigators may discuss study availability and the possibility for entry with a potential 
participant without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose of 
determining eligibility for this study, including withdrawal from current medication(s).  
Potential participants are free to refuse entry into the study, or withdraw from the study at any 
time, without justification, and there will be no consequences to their further care. 
A separate and similar consent process will be followed for the optional blood samples for 
pharmacogenomic testing and future biospecimen research. Consent must be obtained before the 
blood sample is collected. 
10.1.3 Data Protection 
All information generated in this study will be considered confidential and will not be disclosed 
to anyone not directly concerned with the study without the Sponsor’s prior written permission. 
Participant confidentiality requirements of the region(s) where the study is conducted will be 
met. However, authorized regulatory officials and Sponsor personnel (or their representatives) 
may be allowed full access to inspect and copy the records, consistent with local requirements. 
All investigational medicinal products, participant bodily fluids, and/or other materials collected 
shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
Sponsor. 
Participants will be identified only by unique participant ID in eCRF. If further participant 
identification is required, participants’ full names may be made known to a regulatory agency or 
other authorized officials if necessary, subject to local regulations. 
10.1.4 Dissemination of Clinical Study Data 
This study will comply with the Clinical Trials Registration and Results Information Submission 
rule. As such, this study will be registered at ClinicalTrials.gov, and results information from this 
study will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish 
results in peer-reviewed journals.  
10.1.5 
Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and periodic monitoring visits by the Sponsor or 
designee. 
Written instructions will be provided for the collection, preparation, and shipment of samples. 
The Sponsor or its designee will review the electronic data capture system for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; any 
discrepancies will be resolved with the Investigator or designee, as appropriate. After uploading 
the data into the clinical study database, they will be verified for accuracy. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 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 a national GCP compliance 


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program or to review the results of this study in support of a regulatory submission. The 
Investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. 
10.1.6 Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include but are not limited to medical records, electronic 
data, screening logs, and recorded data from automated instruments. All source documents 
pertaining to this study will be maintained by the Investigators and made available for direct 
inspection by authorized persons. 
Investigator(s)/institution(s) will permit study-related monitoring, audits, [IRB/IEC] review, and 
regulatory inspection(s) by providing direct access to source data/documents by authorized 
persons as defined in the ICF. In all cases, participant confidentiality must be maintained in 
accordance with local regulatory requirements. 
10.1.7 Study and Site Start and Closure 
Study site participation may be discontinued if the Sponsor or its designee, the Investigator, or 
the ethical review board of the study site judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 10.3.2.  
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
10.1.8 Publication Policy 
The publication policy for the study will be documented in the agreement between the Sponsor 
and the Investigator. Authorship for any Visterra-sponsored publications resulting from the 
conduct of this study will be based on International Committee of Medical Journal Editors 
authorship criteria (http://www.icmje.org/recommendations). According to these guidelines, one 
may be considered an author only if the following criteria are met: 
1. Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
2. Drafting the work or revising it critically for important intellectual content; AND 
3. Final approval of the version to be published; AND 
4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet the above criteria, and all who qualify for authorship based on the above 
criteria should be listed as authors. 


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10.2 
Appendix 2  
Clinical Laboratory Tests 
Table 8 provides a list of laboratory tests to be evaluated by the Investigator. 
The tests detailed in Table 8 will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF. Local lab 
results will not be acceptable for qualifying a participant for the study. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8:  
Protocol-Required Safety Laboratory Assessments 
Serology (screening only) 
HBsAg, anti-HBc (IgG and IgM) antibody, anti-HCV antibody, HIV. 
Hematology 
Hemoglobin, RBC, WBC with differential (including absolute 
neutrophil count), platelet count. 
Serum chemistry 
Comprehensive serum analyte testing will include sodium, potassium, 
BUN, bicarbonate (venous), creatinine, calcium, chloride, magnesium, 
phosphorus, albumin, glucose, AST, ALT, ALP, total bilirubin (direct 
bilirubin if total > ULN), total cholesterol and triglycerides. This panel 
of tests will be collected as described in Table 1.  
Urinalysis  
Color and appearance; pH, specific gravity, ketones, protein, glucose, 
bilirubin, nitrite, urobilinogen, blood by dipstick. 
Pregnancy (females only) 
Serum β-hCG (screening only); urine β-hCG (all other visits). 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
β-hCG = β -human chorionic gonadotropin; eGFR = estimated glomerular filtration rate; HBc = hepatitis B core; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = red 
blood cell; ULN = upper limit of normal; WBC = white blood cell. 
Note: eGFR will be calculated from serum creatinine by the Chronic Kidney Disease Epidemiology Collaboration 
formula, which is as follows: 
eGFR =141 x min (SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black] 
κ = 0.7 (females) or 0.9 (males), α = -0.329 (females) or -0.411 (males), min = indicates the minimum of SCr/κ or 1, 
max = indicates the maximum of SCr/κ or 1. Additional adjustment for ethnicity or race may be incorporated as 
warranted. 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study (eg, Ig) will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 










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10.4 
Appendix 4  
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1 Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from site personnel review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.2 Contraception Guidance 
Women of childbearing potential must use highly effective methods of contraception for at least 
28 days prior to first study intervention through 155 days after the last dose of study intervention. 
Highly effective methods of contraception are defined as methods that can achieve a failure rate 
of less than 1% per year when used consistently and correctly, and include:  


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• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:  
o oral 
o intravaginal  
o transdermal  
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral  
o injectable  
o implantable   
• intrauterine device   
• intrauterine hormone-releasing system    
• bilateral tubal occlusion  
• vasectomized partner; note: a vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the WOCBP study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success  
• sexual abstinence; sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant  
Women of childbearing potential must also have a negative serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test at screening and a negative urine β-hCG pregnancy test 
prior to the first study intervention on Day 1. Female participants must also agree not to donate 
eggs/bank eggs for the duration of their participation in the study. 
Male participants and/or his partner must use an acceptable form of contraception (ie, 
double-barrier, have had a vasectomy, or have a female partner of nonchildbearing potential) 
from date of first study dose through 155 days after the last dose of study intervention. Following 
the first dose of study intervention, male participants must also agree to not donate sperm 
through 155 days after the last dose of study intervention. 
10.4.3 Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 


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pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• Any poststudy pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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10.5 
Appendix 5 
Abbreviations 
Abbreviation 
Definition 
ACEI 
Angiotensin-converting enzyme inhibitor 
ADA 
Antidrug antibody 
AE 
Adverse event 
a-g 
Aberrantly glycosylated 
APRIL 
A proliferation inducing ligand 
ARB 
Angiotensin receptor blocker 
β-hCG 
Beta human chorionic gonadotropin 
BCMA 
B-cell maturation antigen 
BP 
Blood pressure 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COPD 
Chronic obstructive pulmonary disease 
%CV 
Coefficient of variation 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-study 
ESRD 
End-stage renal disease 
ET 
Early termination 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCV 
Hepatitis C virus 
HRT 
Hormone-replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgA/G/M 
Immunoglobulin A/G/M 
IgAN 
Immunoglobulin A nephropathy 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRE 
Immediately reportable event 
IV 
Intravenous 
IVRS/IWRS 
Interactive voice/web response system 
MEST-C 
Mesangial cellularity, Endocapillary proliferation, Segmental sclerosis, 
Tubular atrophy, Crescents 
mITT 
Modified intent-to-treat 
MMRM 
Mixed Model Repeated Measurement 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
TACI 
Transmembrane activator and CAML interactor 
Td 
Tetanus and diphtheria 
uPCR 
Urine protein to creatinine ratio 
WOCBP 
Woman of childbearing potential 


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10.6 
Appendix 6 
Table 9:  
Protocol Revision History 
Document 
Date 
Protocol Version 3.0   
27 January 2020 
Protocol Version 2.0 
26 November 2019 
Protocol Version 1.0 
28 August 2019 
 


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11. 
REFERENCES
Ballow, M. (2002). "Primary immunodeficiency disorders: antibody deficiency." J Allergy Clin 
Immunol 109(4): 581-591. 
Barbour, S. and J. Feehally (2017). "An update on the treatment of IgA nephropathy." Curr 
Opin Nephrol Hypertens 26(4): 319-326. 
Berthoux, F., H. Suzuki, L. Thibaudin, H. Yanagawa, N. Maillard, C. Mariat, Y. Tomino, B. A. 
Julian and J. Novak (2012). "Autoantibodies targeting galactose-deficient IgA1 associate with 
progression of IgA nephropathy." J Am Soc Nephrol 23(9): 1579-1587. 
Bossen, C., T. G. Cachero, A. Tardivel, K. Ingold, L. Willen, M. Dobles, M. L. Scott, A. 
Maquelin, E. Belnoue, C. A. Siegrist, S. Chevrier, H. Acha-Orbea, H. Leung, F. Mackay, J. 
Tschopp and P. Schneider (2008). "TACI, unlike BAFF-R, is solely activated by oligomeric 
BAFF and APRIL to support survival of activated B cells and plasmablasts." Blood 111(3): 
1004-1012. 
Boyd, J. K., C. K. Cheung, K. Molyneux, J. Feehally and J. Barratt (2012). "An update on the 
pathogenesis and treatment of IgA nephropathy." Kidney Int 81(9): 833-843. 
Castigli, E., S. Scott, F. Dedeoglu, P. Bryce, H. Jabara, A. K. Bhan, E. Mizoguchi and R. S. 
Geha (2004). "Impaired IgA class switching in APRIL-deficient mice." Proc Natl Acad Sci U S 
A 101(11): 3903-3908. 
Cheng, J., W. Zhang, X. H. Zhang, Q. He, X. J. Tao and J. H. Chen (2009). "ACEI/ARB 
therapy for IgA nephropathy: a meta analysis of randomised controlled trials." Int J Clin Pract 
63(6): 880-888.
Donadio, J. V., E. J. Bergstralh, J. P. Grande and D. M. Rademcher (2002). "Proteinuria patterns 
and their association with subsequent end‐stage renal disease in IgA nephropathy." Nephrology 
Dialysis Transplantation 17(7): 1197-1203. 
Endo, T., M. Nishio, T. Enzler, H. B. Cottam, T. Fukuda, D. F. James, M. Karin and T. J. Kipps 
(2007). "BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through 
activation of the canonical NF-kappaB pathway." Blood 109(2): 703-710. 
Fadlallah, J., H. El Kafsi, D. Sterlin, C. Juste, C. Parizot, K. Dorgham, G. Autaa, D. Gouas, M. 
Almeida, P. Lepage, N. Pons, E. Le Chatelier, F. Levenez, S. Kennedy, N. Galleron, J. P. de 
Barros, M. Malphettes, L. Galicier, D. Boutboul, A. Mathian, M. Miyara, E. Oksenhendler, Z. 
Amoura, J. Dore, C. Fieschi, S. D. Ehrlich, M. Larsen and G. Gorochov (2018). "Microbial 
ecology perturbation in human IgA deficiency." Sci Transl Med 10(439). 
Floege, J., I. C. Moura and M. R. Daha (2014). "New insights into the pathogenesis of IgA 
nephropathy." Semin Immunopathol 36(4): 431-442. 
Furst, D. E. (2009). "Serum immunoglobulins and risk of infection: how low can you go?" 
Semin Arthritis Rheum 39(1): 18-29. 


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Han, S. S., S. H. Yang, M. Choi, H. R. Kim, K. Kim, S. Lee, K. C. Moon, J. Y. Kim, H. Lee, J. P. 
Lee, J. Y. Jung, S. Kim, K. W. Joo, C. S. Lim, S. W. Kang, Y. S. Kim and D. K. Kim (2016). 
"The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy." J Am Soc 
Nephrol 27(11): 3430-3439.
Hastings, M. C., Z. Bursac, B. A. Julian, E. Villa Baca, J. Featherston, S. Y. Woodford, L. Bailey 
and R. J. Wyatt (2017). "Life Expectancy for Patients From the Southeastern United States With 
IgA Nephropathy." Kidney international reports 3(1): 99-104. 
Inker, L. A., H. Mondal, T. Greene, T. Masaschi, F. Locatelli, F. P. Schena, R. Katafuchi, G. B. 
Appel, B. D. Maes, P. K. Li, M. Praga, L. Del Vecchio, S. Andrulli, C. Manno, E. Gutierrez, A. 
Mercer, K. J. Carroll, C. H. Schmid and A. S. Levey (2016). "Early Change in Urine Protein as a 
Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis." Am J 
Kidney Dis 68(3): 392-401. 
Janssen, L. M. A., T. Macken, M. C. W. Creemers, J. F. M. Pruijt, J. J. J. Eijk and E. de Vries 
(2018). "Truly selective primary IgM deficiency is probably very rare." Clin Exp Immunol 
191(2): 203-211. 
Jarrick, S., S. Lundberg, A. Welander, J. J. Carrero, J. Hoijer, M. Bottai and J. F. Ludvigsson 
(2019). "Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study." J Am 
Soc Nephrol 30(5): 866-876. 
KDIGO (2012). "KDIGO Clinical Practice Guideline for Glomerulonephritis." Kidney 
International Supplements 2(2): 139-274. 
Kiryluk, K., Y. Li, F. Scolari, S. Sanna-Cherchi, M. Choi, M. Verbitsky, D. Fasel, S. Lata, S. 
Prakash, S. Shapiro, C. Fischman, H. J. Snyder, G. Appel, C. Izzi, B. F. Viola, N. Dallera, L. Del 
Vecchio, C. Barlassina, E. Salvi, F. E. Bertinetto, A. Amoroso, S. Savoldi, M. Rocchietti, A. 
Amore, L. Peruzzi, R. Coppo, M. Salvadori, P. Ravani, R. Magistroni, G. M. Ghiggeri, G. Caridi, 
M. Bodria, F. Lugani, L. Allegri, M. Delsante, M. Maiorana, A. Magnano, G. Frasca, E. Boer, G. 
Boscutti, C. Ponticelli, R. Mignani, C. Marcantoni, D. Di Landro, D. Santoro, A. Pani, R. Polci, 
S. Feriozzi, S. Chicca, M. Galliani, M. Gigante, L. Gesualdo, P. Zamboli, G. G. Battaglia, M. 
Garozzo, D. Maixnerova, V. Tesar, F. Eitner, T. Rauen, J. Floege, T. Kovacs, J. Nagy, K. Mucha, 
L. Paczek, M. Zaniew, M. Mizerska-Wasiak, M. Roszkowska-Blaim, K. Pawlaczyk, D. Gale, J. 
Barratt, L. Thibaudin, F. Berthoux, G. Canaud, A. Boland, M. Metzger, U. Panzer, H. Suzuki, S. 
Goto, I. Narita, Y. Caliskan, J. Xie, P. Hou, N. Chen, H. Zhang, R. J. Wyatt, J. Novak, B. A. 
Julian, J. Feehally, B. Stengel, D. Cusi, R. P. Lifton and A. G. Gharavi (2014). "Discovery of new 
risk loci for IgA nephropathy implicates genes involved in immunity against intestinal 
pathogens." Nat Genet 46(11): 1187-1196.
Kiryluk, K., Z. Moldoveanu, J. T. Sanders, T. M. Eison, H. Suzuki, B. A. Julian, J. Novak, A. G. 
Gharavi and R. J. Wyatt (2011). "Aberrant glycosylation of IgA1 is inherited in both pediatric 
IgA nephropathy and Henoch-Schonlein purpura nephritis." Kidney Int 80(1): 79-87. 
Kiryluk, K. and J. Novak (2014). "The genetics and immunobiology of IgA nephropathy." The 
Journal of Clinical Investigation 124(6): 2325-2332. 




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78 
Pozzi, C., S. Andrulli, L. Del Vecchio, P. Melis, G. B. Fogazzi, P. Altieri, C. Ponticelli and F. 
Locatelli (2004). "Corticosteroid effectiveness in IgA nephropathy: long-term results of a 
randomized, controlled trial." J Am Soc Nephrol 15(1): 157-163. 
Radhakrishnan, J. and D. C. Cattran (2012). "The KDIGO practice guideline on 
glomerulonephritis: reading between the (guide)lines--application to the individual patient." 
Kidney Int 82(8): 840-856. 
Rauen, T., F. Eitner, C. Fitzner, C. Sommerer, M. Zeier, B. Otte, U. Panzer, H. Peters, U. Benck, 
P. R. Mertens, U. Kuhlmann, O. Witzke, O. Gross, V. Vielhauer, J. F. Mann, R. D. Hilgers and J. 
Floege (2015). "Intensive Supportive Care plus Immunosuppression in IgA Nephropathy." N 
Engl J Med 373(23): 2225-2236. 
Reich, H. N., S. Troyanov, J. W. Scholey and D. C. Cattran (2007). "Remission of proteinuria 
improves prognosis in IgA nephropathy." J Am Soc Nephrol 18(12): 3177-3183. 
Rodrigues, J. C., M. Haas and H. N. Reich (2017). "IgA Nephropathy." Clinical Journal of the 
American Society of Nephrology 12(4): 677-686. 
Schena, F. P. and I. Nistor (2018). "Epidemiology of IgA Nephropathy: A Global Perspective." 
Semin Nephrol 38(5): 435-442. 
Tesar, V., S. Troyanov, S. Bellur, J. C. Verhave, H. T. Cook, J. Feehally, I. S. Roberts, D. Cattran 
and R. Coppo (2015). "Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the 
VALIGA Study." J Am Soc Nephrol 26(9): 2248-2258. 
Thompson, A., K. Carroll, L. A. Inker, J. Floege, V. Perkovic, S. Boyer-Suavet, R. W. Major, J. 
I. Schimpf, J. Barratt, D. C. Cattran, B. S. Gillespie, A. Kausz, A. W. Mercer, H. N. Reich, B. H. 
Rovin, M. West and P. H. Nachman (2019). "Proteinuria Reduction as a Surrogate End Point in 
Trials of IgA Nephropathy." Clinical Journal of the American Society of Nephrology 14(3): 
469-481.
Trimarchi, H., J. Barratt, D. C. Cattran, H. T. Cook, R. Coppo, M. Haas, Z. H. Liu, I. S. Roberts, 
Y. Yuzawa, H. Zhang and J. Feehally (2017). "Oxford Classification of IgA nephropathy 2016: 
an update from the IgA Nephropathy Classification Working Group." Kidney Int 91(5): 
1014-1021.
Varfolomeev, E., F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. 
Tom, S. Erickson, D. French, P. Schow, I. S. Grewal and A. Ashkenazi (2004). "APRIL-deficient 
mice have normal immune system development." Mol Cell Biol 24(3): 997-1006. 
Working Group of the International Ig, A. N. N., S. the Renal Pathology, D. C. Cattran, R. 
Coppo, H. T. Cook, J. Feehally, I. S. Roberts, S. Troyanov, C. E. Alpers, A. Amore, J. Barratt, F. 
Berthoux, S. Bonsib, J. A. Bruijn, V. D'Agati, G. D'Amico, S. Emancipator, F. Emma, F. 
Ferrario, F. C. Fervenza, S. Florquin, A. Fogo, C. C. Geddes, H. J. Groene, M. Haas, A. M. 
Herzenberg, P. A. Hill, R. J. Hogg, S. I. Hsu, J. C. Jennette, K. Joh, B. A. Julian, T. Kawamura, 
F. M. Lai, C. B. Leung, L. S. Li, P. K. Li, Z. H. Liu, B. Mackinnon, S. Mezzano, F. P. Schena, Y. 
Tomino, P. D. Walker, H. Wang, J. J. Weening, N. Yoshikawa and H. Zhang (2009). "The


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Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and 
classification." Kidney Int 76(5): 534-545. 
Wyatt, R. J. and B. A. Julian (2013). "IgA nephropathy." N Engl J Med 368(25): 2402-2414. 
Yazdani, R., G. Azizi, H. Abolhassani and A. Aghamohammadi (2017). "Selective IgA 
Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and 
Management." Scand J Immunol 85(1): 3-12. 
Yel, L., S. Ramanuja and S. Gupta (2009). "Clinical and immunological features in IgM 
deficiency." Int Arch Allergy Immunol 150(3): 291-298. 
Zhai, Y. L., L. Zhu, S. F. Shi, L. J. Liu, J. C. Lv and H. Zhang (2016). "Increased APRIL 
Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy." Medicine 
(Baltimore) 95(11): e3099. 
Zhao, N., P. Hou, J. Lv, Z. Moldoveanu, Y. Li, K. Kiryluk, A. G. Gharavi, J. Novak and H. 
Zhang (2012). "The level of galactose-deficient IgA1 in the sera of patients with IgA 
nephropathy is associated with disease progression." Kidney Int 82(7): 790-796. 

Prot_000.pdf: 
CONFIDENTIAL 
VIS649-201 Protocol Version 4.0 
1 
 
PROTOCOL TITLE: 
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled, Multiple Dose Study to Evaluate the 
Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy 
PROTOCOL NUMBER: 
VIS649-201 
COMPOUND 
VIS649 
STUDY PHASE 
Phase 2 
SHORT TITLE: 
Phase 2 Study of VIS649 for IgA Nephropathy 
VERSION: 
4.0 
VERSION DATE: 
08 December 2020 
SPONSOR: 
Visterra, Inc.  
275 2nd Avenue 
Waltham, MA 02451 
REGULATORY AGENCY IDENTIFIER NUMBER(S) 
IND Number: 
135,282 
EudraCT Number: 
2019-002531-29 




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VIS649-201 Protocol Version 4.0 
3 
PROTOCOL VERSION 4.0 SUMMARY OF CHANGES TABLE 
The primary reason for this protocol amendment is to modify participant eligibility criteria for 
clarity and to ensure enrollment of the intended patient population. 
The clinically relevant changes, ie, changes that affect the type or frequency of protocol 
procedures, or the addition of information to the protocol that influences clinical 
decision-making or consent, are itemized below:  
Protocol Version 4.0 (08 December 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 4.1 Overall Design  
Section 9.4.2 Randomization and 
Stratification 
The number of global sites where 
participants will be enrolled was 
changed from approximately 90 to 
approximately 100 global sites. 
Additional sites were added to meet 
enrollment goals. 
Section 1.1 Synopsis 
Section 4.1 Overall Design 
Section 5.1 Inclusion Criteria 
The inclusion requirement for 
participants to be on at least 50% of 
the maximum recommended dose 
of ACEI or ARB was modified to 
allow participants to be on < 50% 
dose, as long as that is the 
maximum tolerated dose for the 
participant and he/she has been on 
this dose for at least 3 months. 
The doses of ACEIs/ARBs vary 
considerably across countries, 
depending on the local clinical 
practice, ethnic differences in body 
mass, and patient tolerability to 
higher doses. Hence, this 
requirement was modified, and 
participants are now required to be 
on maximum tolerated dose, rather 
than on a minimum dose 
requirement of at least 50% of the 
maximum recommended dose.  
Section 1.1 Synopsis 
Section 1.2, Figure 1 Study Design 
Schema 
Section 4.1 Overall Design 
Section 5.1 Inclusion Criteria 
An inclusion criterion was added, 
stipulating that participants with an 
eGFR ≥ 30 mL/min/1.73 m2 and 
< 45 mL/min/1.73 m2 may also 
undergo screening, if they have 
undergone a kidney biopsy within 
12 months of the date of initial 
screening and do not have ≥ 50% 
tubulo-interstitial fibrosis (T2 if 
using MEST-C score) or crescents 
in ≥ 25% of glomeruli (C2 if using 
MEST-C score). 
The inclusion criterion for 
participants to have stable eGFR or 
to repeat eGFR measurements after 
15 days if previous values are not 
available or if eGFR is not stable 
was removed. 
Participants with eGFR 
≥ 30 mL/min/1.73m2 and 
< 45 mL/min/1.73m2 have a high 
unmet need for novel therapeutic 
options; however, they may also 
have significant kidney fibrosis, 
which would limit potential benefit 
from VIS649. Hence, this criterion 
was expanded to this eGFR range 
only if these patients have recent 
biopsy evidence of absent advanced 
fibrosis or crescents. 
eGFR is generally stable over 
shorter periods of time (e.g., 
weeks/months). Hence, the first 
eGFR can be considered as baseline 
and thus avoid the inconvenience to 
participants of requiring a repeat 
laboratory measurement in 15 days’ 
time. 


CONFIDENTIAL 
VIS649-201 Protocol Version 4.0  
 
 
4 
Protocol Version 4.0 (08 December 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
The inclusion criterion for 
participants to have stable 
proteinuria or to repeat proteinuria 
measurements after 15 days if 
previous values are not available or 
if proteinuria is not stable was 
removed. 
 
 
 
 
Inclusion criteria stipulating that 
participants should be on stable and 
maximally tolerated doses of 
ACEIs/ARBs for at least 3 months 
with uPCR > 0.75g/g or 24-hour 
protein ≥ 1.0 g/d and eGFR > 
45 mL/min/1.73m2 were removed 
from Figure 1. 
Patients with persistent proteinuria 
above the stated threshold comprise 
the target population for VIS649 
therapy, irrespective of the 
day-to-day variability typically 
described at this range of 
proteinuria. Hence, the first 
proteinuria can be considered as 
baseline and thus avoid the 
inconvenience to participants of 
requiring a repeat measurement in 
15 days’ time. 
For simplification of the schema, 
inclusion criteria were modified. 
Section 1.1 Synopsis 
Section 5.2 Exclusion Criteria 
 
An exclusion criteria specification 
was added, stipulating that 
participants with isolated nephrotic 
range proteinuria (> 3.5 g/day) will 
be eligible. 
The exclusion criteria due to 
previous immunosuppressive 
therapies were changed from 
2 years (for combined 
immunosuppressive therapy) and 
6 months (for systemic steroids) to 
16 weeks from the time of 
screening. 
Additional language added to 
clarify these criteria. 
 
 
Systemic steroids and other 
immunosuppressive therapies 
typically do not have significant 
immunosuppressive potential 
beyond 12 weeks following 
discontinuation. As a safety buffer, 
4 weeks were added for a total of 
16 weeks. Hence, the exclusion 
criterion was updated to exclude 
participants who have received 
these therapies in the previous 
16 weeks. 
Section 1.1 Synopsis 
Section 5.1 Inclusion Criteria 
 
Minimum requirement for IgM was 
updated to 37 mg/dL. 
Normal Ig levels vary significantly 
across the Globe and are affected 
by race and ethnicity. The IgM was 
updated to reflect emerging and 
recent data on IgM levels. The level 
of 37 mg/dL has been cited in the 
literature as the lower limit of 
normal in adults as listed below: 
1) Guha Krishnaswamy. Selective 
IgM deficiency. In: UpToDate, 
Post, Luigi D Notarangelo (Ed), 
UpToDate, Waltham, MA, 2020.  


CONFIDENTIAL 
VIS649-201 Protocol Version 4.0  
 
 
5 
Protocol Version 4.0 (08 December 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
2) Gonzalez-Quintela A et al., 
Serum levels of immunoglobulins 
(IgG, IgA, IgM) in a general adult 
population and their relationship 
with alcohol consumption, smoking 
and common metabolic 
abnormalities. Clin Exp Immunol. 
2008 Jan;151(1):42-50.  
3) https://www.mayocliniclabs.com
/test-catalog/Overview/8156 
(Accessed on 12/4/2020) 
Section 1.1 Synopsis 
Section 1.3, Table 1 Schedule of 
Assessments, Footnote 1, 6, and 10 
Section 4.1 Overall Design 
Section 5.1 Inclusion Criteria  
Section 8.2.2 Vital Signs 
Section 10.2 Appendix 2 
The schedule of assessment was 
updated to reflect the continuous 
AE monitoring and concomitant 
medications review through 
Day 485.  
Blood sample for total IgA, IgG, 
and IgM13 was removed from D1 
postinfusion. 
Footnote 1 and Sections 1.1, 4, and 
5 were updated to reflect the 
ACEI/ARB therapy eligibility 
criteria. 
Footnote 6 and Section 8.2.2 were 
updated to specify that vital signs 
measurements will be recorded 
postinfusion at 60 (±10) minutes 
and 2 hours. 
Footnote 10 and Section 10.2 were 
updated to specify that dipstick will 
be performed locally and that local 
laboratory results will be permitted 
for the urine dipstick and 
microscopy. 
Administrative updates for clarity.  
Section 1.1 Synopsis 
Section 9.5 Interim Analyses 
Additional specifications were 
added to the 3 interim PK/Ig 
analyses, including group-
unblinded PK/Ig summaries (with 
individual participant treatment 
blinded). 
The first of the 2 early interim 
efficacy analyses, which may be 
performed when at least 
16 participants have been treated, 
was changed from at least 6 months 
to at least 2 months, optimally 
when at least 50% of the 16 (or 
more) participants have achieved > 
30% reduction in uPCR based on 
The time required to see reduction 
in proteinuria after treatment with 
VIS649 is currently unknown. It is 
possible that the reduction in 
proteinuria may occur earlier than 
6 months. This amendment gives 
the flexibility to perform a blinded 
assessment of proteinuria response 
as early as 2 months after treatment 
with VIS649. As the analysis will 
be performed on blinded uPCR 
data, and only if the aforementioned 
criteria are met, there is no 
statistical cost. These data and 
analyses will be prepared by a 
separate, unblinded team for 




CONFIDENTIAL 
VIS649-201 Protocol Version 4.0  
 
 
7 
Protocol Version 4.0 (08 December 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.3 Lost to Follow-up 
A lost-to-follow up action was 
added, stipulating that the 
participant, if reached, should be 
invited to attend EOS visits, which 
can also be done via phone call, 
medical record review, etc. if the 
participant is unwilling to visit the 
clinic. 
This was added to allow data 
collection remotely. 
Section 8 Study Assessments and 
Procedures 
Submission of pathology report that 
confirms IgAN diagnosis was 
removed as part of eCRF collection. 
Actual report not required.  
Section 8.5, Table 5 
Pharmacokinetic and Serum 
Immunoglobulin Sampling 
Schedule 
Preinfusion time was updated from 
-30 min alone to a range of -180 
min to -1 min. 
This was added to increase 
flexibility in collecting pre-infusion 
samples. 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; AE = adverse event; ARB = angiotensin receptor 
blocker; eGFR = estimated glomerular filtration rate; EOS = end-of-study; ; Ig = immunoglobulin; 
IgA/G/M = immunoglobin A/G/M; IgAN = immunoglobulin A nephropathy; MEST-C = mesangial cellularity, 
endocapillary proliferation, segmental sclerosis, tubular atrophy-Crescents; MRAs = mineralcorticoid receptor 
antagonists; NS = normal saline; NSAID = nonsteroidal anti-inflammatory drug; PK = pharmacokinetic(s); RAAS = 
renin-angiotensin-aldosterone system; uPCR = urine protein to creatinine ratio.  
 
Protocol Version 3.0 (27 January 2020) 
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Version 4.0  
Simplified various inclusion and 
exclusion criteria and provided 
general clarifications after feedback 
from global clinical sites.  
Note that minor formatting changes and corrections of typographical errors are not detailed. 


CONFIDENTIAL 
VIS649-201 Protocol Version 4.0  
 
 
8 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
1.1 
Synopsis ......................................................................................................................12 
1.2 
Schema ........................................................................................................................20 
1.3 
Schedule of Assessments ............................................................................................21 
2. 
INTRODUCTION ......................................................................................................24 
2.1 
Study Rationale ...........................................................................................................24 
2.2 
Background .................................................................................................................25 
2.3 
Benefit/Risk Assessment ............................................................................................27 
2.3.1 
Risk Assessment .........................................................................................................27 
2.3.2 
Benefit Assessment .....................................................................................................30 
2.3.3 
Overall Benefit: Risk Conclusion ...............................................................................31 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
4. 
STUDY DESIGN .......................................................................................................35 
4.1 
Overall Design ............................................................................................................35 
4.2 
Scientific Rationale for Study Design ........................................................................37 
4.3 
Justification for Dose ..................................................................................................39 
4.4 
End-of-study Definition ..............................................................................................40 
5. 
STUDY POPULATION .............................................................................................41 
5.1 
Inclusion Criteria ........................................................................................................41 
5.2 
Exclusion Criteria .......................................................................................................42 
5.3 
Lifestyle Considerations .............................................................................................44 
5.4 
Screen Failures ............................................................................................................44 
6. 
STUDY INTERVENTION ........................................................................................45 
6.1 
Study Intervention(s) Administered ...........................................................................45 
6.2 
Preparation/Handling/Storage/Accountability ............................................................46 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................46 
6.4 
Study Intervention Compliance ..................................................................................47 
6.5 
Concomitant Therapy .................................................................................................47 
6.5.1 
Concomitant Therapy to be Avoided ..........................................................................48 
6.6 
Dosing Schedule Modification ...................................................................................48 
6.7 
Intervention after the End of the Study .......................................................................48 


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VIS649-201 Protocol Version 4.0  
 
 
9 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................49 
7.1 
Discontinuation of Study Intervention Dosing ...........................................................49 
7.1.1 
Temporary Discontinuation ........................................................................................49 
7.1.2 
Rechallenge .................................................................................................................50 
7.2 
Participant Discontinuation/Withdrawal from the Study ...........................................50 
7.3 
Lost to Follow-up .......................................................................................................50 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
8.1 
Efficacy Assessments .................................................................................................51 
8.1.1 
Twenty-four-hour Urine Sample Collection ...............................................................51 
8.2 
Safety Assessments .....................................................................................................51 
8.2.1 
Physical Examinations ................................................................................................51 
8.2.2 
Vital Signs ..................................................................................................................51 
8.2.3 
Electrocardiograms .....................................................................................................52 
8.2.4 
Clinical Safety Laboratory Assessments ....................................................................52 
8.3 
Adverse Events and Serious Adverse Events .............................................................52 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................53 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...........................53 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events .......................................54 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .............................54 
8.3.5 
Pregnancy ...................................................................................................................55 
8.4 
Treatment of Overdose ...............................................................................................55 
8.5 
Pharmacokinetics ........................................................................................................55 
8.6 
Pharmacodynamics .....................................................................................................56 
8.7 
Genetics ......................................................................................................................56 
8.8 
Biomarkers ..................................................................................................................57 
8.9 
Immunogenicity Assessments ....................................................................................57 
8.10 
Medical Resource Utilization and Health Economics ................................................57 
9. 
STATISTICAL CONSIDERATIONS .......................................................................58 
9.1 
Statistical Hypothesis ..................................................................................................58 
9.2 
Sample Size Determination ........................................................................................58 
9.3 
Populations for Analyses ............................................................................................58 


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VIS649-201 Protocol Version 4.0  
 
 
10 
9.4 
Statistical Analyses .....................................................................................................59 
9.4.1 
General considerations ................................................................................................59 
9.4.2 
Randomization and Stratification ...............................................................................59 
9.4.3 
Participant Disposition ................................................................................................59 
9.4.4 
Participant Demographics ...........................................................................................59 
9.4.5 
Efficacy Analysis ........................................................................................................59 
9.4.6 
Safety Analyses ..........................................................................................................60 
9.4.7 
Other Analyses ............................................................................................................60 
9.5 
Interim Analyses .........................................................................................................61 
9.6 
Data Safety Monitoring Board ....................................................................................62 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................63 
10.1 
Appendix 1 ..................................................................................................................63 
10.1.1 
Regulatory and Ethical Considerations ......................................................................63 
10.1.2 
Financial Disclosure ...................................................................................................63 
10.1.3 
Data Protection ...........................................................................................................64 
10.1.4 
Dissemination of Clinical Study Data ........................................................................64 
10.1.5 
Data Quality Assurance ..............................................................................................64 
10.1.6 
Source Documents ......................................................................................................65 
10.1.7 
Study and Site Start and Closure ................................................................................65 
10.1.8 
Publication Policy .......................................................................................................65 
10.2 
Appendix 2 ..................................................................................................................67 
10.3 
Appendix 3 ..................................................................................................................68 
10.3.1 
Definition of Adverse Event and Adverse Reaction ...................................................68 
10.3.2 
Definition of Serious Adverse Event ..........................................................................69 
10.3.3 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............70 
10.3.4 
Reporting of Serious Adverse Events .........................................................................71 
10.4 
Appendix 4 ..................................................................................................................73 
10.4.1 
Definitions ..................................................................................................................73 
10.4.2 
Contraception Guidance .............................................................................................73 
10.4.3 
Collection of Pregnancy Information .........................................................................74 
10.5 
Appendix 5 ..................................................................................................................76 
10.6 
Appendix 6 ..................................................................................................................78 


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11. 
REFERENCES ...........................................................................................................79 
 LIST OF TABLES  
Table 1:  
Schedule of Assessments ............................................................................................21 
Table 2: 
Summary of Potential Risks Associated with VIS649 ...............................................27 
Table 3: 
Study Objectives and Endpoints .................................................................................32 
Table 4: 
Study Interventions .....................................................................................................45 
Table 5: 
Pharmacokinetic and Serum Immunoglobulin Sampling Schedule ...........................56 
Table 6: 
Populations for Analysis .............................................................................................58 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews ...................................................62 
Table 8:  
Protocol-Required Safety Laboratory Assessments ...................................................67 
Table 9:  
Protocol Revision History...........................................................................................78 
LIST OF FIGURES 
Figure 1:  Study Design Schema .................................................................................................20 
Figure 2: 
Simulated Percent Baseline Immunoglobulin A by Dose ..........................................39 
  


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1. PROTOCOL SUMMARY 
1.1 Synopsis 
Name of Sponsor: Visterra, Inc. 
Name of Investigational Intervention:  VIS649 
Protocol Title:  
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose 
Study to Evaluate the Efficacy and Safety of VIS649 in Participants with 
Immunoglobulin A (IgA) Nephropathy (IgAN) 
Short Title:  
Phase 2 Study of VIS649 for IgA Nephropathy 
Rationale: 
VIS649 is a humanized immunoglobulin G2 (IgG2) monoclonal antibody that 
binds to and blocks the biological actions of the cytokine A PRoliferation 
Inducing Ligand (APRIL), a key factor in the production of aberrantly 
glycosylated IgA1 (a-g IgA1), which is critical to the pathogenesis of IgAN. The 
central mechanism for the development of IgAN is the production of a-g IgA1. 
These a-g IgA1 act as autoantigens and lead to development of autoantibodies 
forming circulating immune complexes which deposit in the mesangium of the 
glomeruli and in turn, trigger an inflammatory response and complement 
activation, causing damage to the kidneys. 
In data from a single-ascending dose study (VIS649-101) of VIS649 in healthy 
participants, VIS649 reduced serum levels of IgA and a-g IgA1. The current 
study will test the hypothesis that blocking the biological actions of APRIL in 
IgAN participants leads to reduction of serum IgA (including a-g IgA1) levels 
and will reduce or halt the progression of IgAN, as measured by decrease in 
proteinuria.  
The findings from this study will form the basis for subsequent clinical 
development of VIS649. 
Objectives and 
Endpoints: 
The key objectives and endpoints of the study are: 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and 
tolerability of monthly doses of 
VIS649 at each of 3 dosing levels, 
administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
AEs graded by severity, clinical 
laboratory tests, vital sign 
measurements, and physical 
examinations 
 
 


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VIS649-201 Protocol Version 4.0  
 
 
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Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of 
monthly doses of VIS649 on 
proteinuria at each of 3 dosing 
levels, administered IV to IgAN 
participants over the course of 
12 months as an add-on to SOC 
treatment with ACEI/ARB therapy, 
compared with saline placebo 
infusions as an add-on to SOC 
treatment with ACEI/ARB therapy 
• 
Change from baseline in uPCR 
(measured on natural log scale from 
24-hour urine collection or the 
intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days 
after the 12th dose is administered)  
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated 
doses of VIS649 at 3 dosing levels 
versus placebo on the following 
parameters: 
o uPCR at Month 9 and 16 (ie, 
5 months following the final 
[12th] monthly dose 
administration) 
 
o 24-hour urine protein excretion at 
Months 9, 12, and 16 
 
o ≥ 30% decline from baseline in 
uPCR at Months 9, 12, and 16 
 
 
o Clinical remission, defined as 
reduction in 24-hour urine protein 
excretion to < 300 mg/day for at 
least 3 consecutive months  
 
 
 
 
o 
Change from baseline in uPCR 
(measured on natural log scale 
from 24-hour urine collection or 
the intended 24-hour urine 
collection) at Months 9 and 16 
o 
Change in 24-hour urine protein 
excretion from baseline to 
Months 9, 12, and 16 
o 
Number of participants in each 
group achieving a ≥ 30% 
decline from baseline in uPCR 
at Months 9, 12, and 16 
o 
Number of participants in each 
group achieving clinical 
remission 
• 
eGFR at Months 12 and 16 
 
• 
To evaluate the effect of repeated 
doses of VIS649 at each dosing level 
compared with placebo on the 
following PD parameters: IgA, IgG, 
and IgM concentrations 
• 
To determine the PK profile of 
repeated dose of VIS649, at each 
dosing level 
• 
Change from baseline in eGFR at 
Months 12 and 16 
• 
Change from baseline in total serum 
IgA, IgG, and IgM concentrations at 
Months 9, 12, and 16 
 
 
• 
Serum PK parameters 
• 
To determine the PK/PD profile of 
VIS649, relating VIS649 PK 
parameters and biomarkers such as 
changes in IgA to changes in 
proteinuria and eGFR 
• 
Correlation of VIS649 PK 
parameters with changes in IgA, 
uPCR, and eGFR 
• 
To screen for ADA responses 
• 
Serum ADA levels 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = antidrug 
antibody; AE = adverse event; ARB = angiotensin receptor blocker; eGFR = estimated 
glomerular filtration rate; Ig = immunoglobulin; Ig A/G/M = immunoglobulin A/G/M;  


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VIS649-201 Protocol Version 4.0  
 
 
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IgAN = immunoglobulin A nephropathy; IV = intravenous(ly); 
PD = pharmacodynamic; PK = pharmacokinetic(s); SOC = standard of care; 
uPCR = urinary protein/creatinine ratio. 
Overall Design:  
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, 
multiple-dose study to evaluate the safety and efficacy of intravenously (IV) 
administered VIS649 over a 12-month treatment course in participants with 
IgAN. Participants will be enrolled from approximately 100 global sites in 
approximately 16 countries. 
Screening evaluations, including physical examinations, vital signs, 12-lead 
electrocardiogram, safety laboratory testing (serum chemistry, hematology, 
urinalysis, serology, hemoglobin A1c, and pregnancy), blood sampling for 
baseline Ig levels (IgA, IgG, and IgM), and 24-hour urine collection, will take 
place during the 30 days prior to the first dose of study intervention.  
To be eligible, participants should be on stable and maximally tolerated doses 
of either angiotensin-converting enzyme inhibitor (ACEI) or angiotensin 
receptor blocker (ARB) therapy, as per standard of care (SOC) and applicable 
guidelines, for at least 3 months. Participants should optimally be on at least 
50% of the maximum recommended dose  of these agents; however, if a 
participant is on their maximally tolerated dose (and this is < 50% of the 
maximum recommended dose) and has been on this dose for at least 3 months, 
they may be enrolled. 
Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study, if their overall management of IgAN, including blood 
pressure (BP) control, is as per local SOC and applicable guidelines. 
Enrolled participants must be 18 years of age or older with an IgAN diagnosis 
confirmed by biopsy.  
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have 
been interpreted using the MEST score - Mesangial cellularity, endocapillary 
proliferation, segmental sclerosis, tubular atrophy (Cattran et al, 2009) or 
MEST-Crescents (C) scoring system (Trimarchi, Barratt et al. 2017) from the 
Oxford classification of IgAN.  
A MEST or MEST-C score finding on kidney biopsy of T2 or C2 is 
exclusionary for this study. If the biopsy was not reported using the Oxford 
classification schema, the following findings (corresponding to these Oxford 
classifications) are exclusionary: a) > 50% tubular atrophy, and/or b) > 25% 
crescents.  
Participants must have screening urinary protein/creatinine ratio 
(uPCR) ≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 
24-hour urine collection (or an intended 24-hour urine collection).  
Participants must have estimated glomerular filtration rate 
(eGFR) ≥ 45 mL/min/1.73 m2, calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Levey, Stevens et al. 2009). 
Participants with eGFR ≥ 30 mL/min/1.73 m2 and < 45 mL/min/1.73 m2 may 
also undergo screening, if they have undergone a kidney biopsy within 12 
months of the date of initial screening and do not have ≥ 50% tubulo-interstitial 
fibrosis (T2 if using MEST-C score) or crescents in  ≥ 25% of glomeruli (C2 if 
using MEST-C score). 
 


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VIS649-201 Protocol Version 4.0  
 
 
15 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. A total of 144 participants will be randomized with equal allocation 
(1:1:1:1) across the 4 intervention groups (approximately 36 participants per 
group). Randomization will be stratified first by region (Japan vs rest of world). 
A target of 12 or more participants are planned to be randomized in Japan; these 
participants will be randomized with equal allocation and without further 
stratification. The randomization for the rest-of-world will be stratified by 
screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
VIS649 or placebo will be administered as 12 monthly IV infusions starting on 
Day 1/Month 0. Participants will return to the study center on Days 8 and 18, 
then monthly through Month 14 and on Month 16 for safety, efficacy, 
pharmacokinetic (PK), and/or pharmacodynamic (PD) assessments.  
Safety assessments will include review of adverse events (AEs) (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, 
injection site tolerability (pain, irritation, and tissue damage), clinical laboratory 
assessments (including biochemistry, hematology, urinalysis, and pregnancy 
testing), laboratory testing (including serum Ig levels and antidrug antibodies 
[ADAs]) vital sign measurements and use of concomitant medications. 
Participants will return to the study center on approximately Month 16, at least 
155 days following the last dose of study intervention (Dose 12) for an 
end -of -study (EOS) visit, at which time final safety, PK, PD, and efficacy 
assessments will be performed. Participants discontinuing dosing earlier will 
attend an early termination visit at the time of dosing discontinuation and will 
be encouraged to attend the study visits as per schedule of assessments.  
A rollover, open-label extension study will be offered to enable access to 
VIS649 (there will be no placebo arm) for study participants who have 
completed this trial, provided that the Investigator believes that the participants 
might benefit, and that the site has agreed to participate in the extension study. 
Further details will be provided in a separate protocol. 
Number of 
Participants: 
Approximately 144 participants. A target of 12 or more participants are planned 
to be randomized and enrolled in Japan. The remaining participants will be 
enrolled at sites in the rest of world; there are no other country-specific 
enrollment targets.  
Intervention Groups 
and Duration: 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus 
placebo. VIS649 or placebo will be administered as a single, monthly IV 
infusion for 12 monthly doses.  
VIS649 will be administered IV over 1 hour, in a single, final volume 100 mL 
infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The 
dose of study intervention for the duration of the study will be based on the 
participant’s Month 0 pre-dose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour as a single 100-mL 
infusion, followed by a 25 mL saline flush. 
An unblinded pharmacist (or other unblinded designee) will prepare drug or 
placebo for infusion. Participants, the Sponsor, the Investigator, and all other 
site study staff will be blinded to study intervention.  
 


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The total study duration for each participant (from screening to EOS) will be up 
to approximately 17 months (assuming up to 1 month for screening, 12 months 
for monthly doses [including 30 days after the 12th dose], and follow-up visits 
through at least 155 days after the last dose of study intervention).  
Target Population: 
Key inclusion criteria for eligibility into the study are the following: 
1. Participant is a male or female ≥ 18 years of age at the time of signing 
the informed consent. 
2. Participant has source-verified biopsy-confirmed IgAN. 
3. Participant has medical records showing they have been on stable and 
maximally tolerated doses of either ACEI or ARB, as per local SOC 
and applicable guidelines, for at least 3 months preceding screening. 
Participants should optimally be on at least 50% of the maximum 
recommended dose of these agents; however, if a participant is on their 
maximally tolerated dose (and this is < 50% of the maximum 
recommended dose) and has been on this dose for at least 3 months, 
they may be enrolled. Participants who are unable to tolerate 
ACEI/ARB therapy may be eligible for participation in the study, if 
their overall management of IgAN, including BP control, is as per local 
SOC and applicable guidelines. 
4. Participant has screening uPCR ≥ 0.75 g/g measured from a 24-hour 
urine sample (or an intended 24-hour urine sample) or 24-hour urine 
protein ≥ 1.0 g/d, as measured from 24-hour urine sample (or an 
intended 24-hour urine sample). The proteinuria should be assessed 
when the participant is considered to be in steady state with no recent 
heavy exercise, fever, or other potential issues that could impact the 
result.  
5. Participant has eGFR ≥ 45 mL/min/1.73 m2, calculated using the 
CKD-EPI formula. Participants with eGFR ≥ 30 mL/min/1.73 m2 and 
< 45 mL/min/1.73 m2 may also undergo screening, if they have 
undergone a kidney biopsy within 12 months of the date of initial 
screening and do not have ≥ 50% tubulo-interstitial fibrosis (T2 if using 
MEST-C score) or crescents in ≥ 25% of glomeruli (C2 if using 
MEST-C score). The eGFR should be measured when the participant is 
considered to be in a steady state without recent changes in volume 
status, medications that could impact the result (eg, nonsteroidal 
anti-inflammatory drugs [NSAIDs], aminoglycosides, co-trimoxazole), 
or changes in dietary protein intake. 
6. Participant’s serum Ig values must meet the following criteria: 
a. IgG: ≥ 700 mg/dL 
b. IgM: ≥ 37 mg/dL 
c. IgA: ≥ 70 mg/dL 
Key exclusion criteria:  
1. Participant has secondary forms of IgAN as defined by the treating 
physician (eg, Henoch-Schӧnlein purpura (IgA vasculitis), infection-
associated IgAN, or IgAN associated with hepatic cirrhosis). 
2. Participant has co-existing chronic kidney disease, other than IgAN. 


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3. Participant has evidence of additional pathological findings in the 
kidney biopsy (eg, diabetic kidney disease, membranous nephropathy, 
or lupus nephritis). However, hypertensive vascular changes are 
acceptable. 
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 
from the Oxford IgAN classification schema. If MEST-scoring was not 
performed, the presence of > 50% tubulo-interstitial fibrosis, or 
crescents in > 25% of glomeruli is exclusionary. 
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour 
urine protein > 3.5 g with concurrent hypoalbuminemia (serum albumin 
< 2.5 g/dL), hyperlipidemia (total cholesterol > 350 mg/dL), and 
edema. Participants with isolated nephrotic range proteinuria 
(> 3.5 g/day) will be eligible. 
6. Participant has received a solid organ transplant, including kidney. 
7. Participant has received bone marrow or hematologic stem cell 
transplantation. 
8. Participant is currently receiving systemic immunosuppression 
(excluding topical, ophthalmic, per rectum, or inhaled corticosteroids).  
9. Participant has received treatment with systemic corticosteroid therapy 
(excluding topical, ophthalmic, per rectum, or inhaled corticosteroids) 
within 16 weeks of initial screening. 
10. Participant has received treatment with a systemic immunosuppressive 
agent (e.g., mycophenolate mofetil, azathioprine, calcineurin inhibitors, 
cyclophosphamide/cytotoxic agents) within 16 weeks of initial 
screening.  
11. Participant has any chronic infectious disease (eg, chronic urinary tract 
infection; chronic sinusitis; bronchiectasis; active pulmonary or 
systemic tuberculosis; chronic viral hepatitis, such as hepatitis C or 
hepatitis B; or human immunodeficiency virus infection).  
12. Participant has acute infectious disease at the time of screening. 
Participants may be rescreened following resolution of acute infection 
(such as urinary tract infection or respiratory tract infection), provided 
there is no evidence of an immunosuppressive condition that 
predisposed the participant to this infection.  
13. Participant has Type 1 diabetes. 
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a 
screening hemoglobin A1c value > 8%. 
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg 
diastolic). 
16. Participant has a history of a chronic autoimmune neurodegenerative 
disorder such as multiple sclerosis. 
Data Safety 
Monitoring Board: 
An independent data safety monitoring board (DSMB) will review unblinded 
safety data. The DSMB will meet at 5 scheduled data review meetings and as 
needed on an ad hoc basis. Details regarding the content and scope of safety 
assessments, as well as the governing of the DSMB, will be described in a 
separate DSMB charter. 


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VIS649-201 Protocol Version 4.0  
 
 
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Data safety monitoring board meetings will be scheduled as the following 
requirements are met: 
Scheduled DSMB Review 
Number of Participants and Treatment Exposure 
DSMB review #1 
Scheduled once 12 participants have been randomized 
and have completed at least 3 months of study dosing. 
DSMB review #2 
Scheduled once 24 participants have been randomized 
and have completed at least 3 months of study dosing. 
DSMB review #3 
Scheduled once ~25% of participants have been 
randomized and have completed 3 months of study 
dosing. 
DSMB review #4 
Scheduled once ~50% of participants have been 
randomized and have completed 6 months of study 
dosing, and ~20 participants have completed 
12 months of study dosing. 
DSMB review #5 
Scheduled once ~50% of participants have been 
randomized and have completed 12 months of study 
dosing. 
Abbreviations: DSMB = data safety monitoring board. 
Statistical Methods: 
General Considerations 
All data collected will be documented using summary tables, figures, and/or 
data listings presented by intervention and dose group. For continuous 
variables, descriptive statistics (number [n]; mean; geometric mean and 
coefficient of variation [%CV], as appropriate; median; standard deviation; 
minimum; and maximum) will be presented. For categorical variables, 
frequencies and percentages will be presented. As appropriate, a 95% CI will be 
presented. Graphical displays may be presented. 
Randomization and Stratification 
Participants will be randomly assigned in a 1:1:1:1 ratio to receive VIS649 at 2, 
4, or 8 mg/kg, or placebo, with approximately 36 participants randomized per 
intervention group. Randomization will be stratified first by region (Japan vs 
rest of world). Japanese participants will be randomized with equal allocation 
and without further stratification. Randomization for the rest of world will then 
be stratified by screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
Interim Analyses 
In addition to 5 DSMB safety reviews, 3 interim PK/Ig analyses and 2 interim 
efficacy analyses are planned. The interim PK/Ig analyses will provide 
additional data for population PK/PD modeling and will advise the study 
Sponsor on future study design and planning.  
An early interim efficacy analysis may be performed when at least 
16 participants have been treated for at least 2 months, optimally when at least 
50% of the 16 (or more) participants have achieved  > 30% reduction in uPCR  
based on review of blinded uPCR data across all study participants. The interim 
analysis will present group-unblinded efficacy summaries (with individual 
participant treatment blinded) and will be prepared by a separate, unblinded 
team for Sponsor review to inform future study design.  
 


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A second interim efficacy analysis will be performed at the time of the fourth 
scheduled DSMB meeting (once 50% of randomized participants have 
completed 6 months of study dosing and approximately 20 participants have 
completed 12 months of study dosing). Group-unblinded efficacy summaries 
(with individual participant treatment blinded) will be prepared for Sponsor 
review to inform future study design.  
The interim efficacy analyses will not include hypothesis testing and will be for 
the purpose of future study design and planning. The primary efficacy endpoint, 
change in proteinuria levels from baseline, will be analyzed. No modifications 
to this study protocol are planned based on results of the interim analyses. 
Nonetheless, to account for multiple reviews of the efficacy endpoint, the type I 
error rate applied at the end of the study will be reduced by 0.002 for each 
interim efficacy review, resulting in a 2-sided end-of-study type I error rate of 
0.046. 
Planned analyses 
The primary efficacy outcome for this study is the change from baseline in 
uPCR on the natural log scale at Month 12. Dose response will be explored 
using orthogonal contrasts. Sensitivity analysis will follow using dose as a 
continuous covariate. 
In addition, to assess the dose response over time, a Mixed Model with 
Repeated Measurements (MMRM), which includes fixed class-effects of 
treatment (intervention), visit, randomization strata, and treatment -by -visit 
interaction, with a fixed effect covariate of baseline uPCR on the natural log 
scale will be used. 
Secondary efficacy endpoints will be summarized using descriptive statistics.  
In addition, comparisons between dose groups against placebo will be 
performed using an Analysis of Covariance or MMRM for continuous measures 
and logistic regression or generalized estimating equations for categorical 
variables. 
Safety will be assessed by evaluation of AEs (including hypersensitivity 
reaction and anaphylactic reaction), physical examinations, injection site 
tolerability (pain, irritation, and tissue damage), clinical laboratory assessments 
(including biochemistry, hematology, urinalysis, and pregnancy testing), 
laboratory testing (including serum Ig levels and ADAs), vital sign 
measurements, and use of concomitant medications. 
Analysis of PK parameters will include participant data-listings of serum 
concentrations and summary statistics by intervention group, including mean, 
geometric mean, standard deviation, %CV, median, and range, as appropriate. 
Summary graphs including mean concentration-time profiles by group will also 
be presented. For the subset of participants in whom intensive PK samples are 
collected, serum concentration data will be analyzed by noncompartmental 
analysis and population PK methods using nonlinear mixed -effects modeling, 
as implemented in NONMEM or equivalent software. Additional analyses and 
summaries may be generated, as appropriate. 




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1.3 Schedule of Assessments 
Table 1:  
Schedule of Assessments 
Procedures Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 
M12/ 
ET3 
M13 M14 
M16 
Nominal Study Day -301 
D1 Pre 
infusion 
D1 Post 
infusion D8 
D18 
D30 
D60 
D90 D120 D150 D180 D210 D240 D270 D300 D330 D360 D390 D420 
D485 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Study Visit N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Informed consent  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of kidney biopsy4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination5 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Weight 
x 
x 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Vital signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention infusion7 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
AE monitoring 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV, HCV, HIV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β-hCG (females only) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-hCG (females only) 
 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Hemoglobin A1c 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry8 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Hematology9 
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
Urinalysis (dipstick and microscopy)10  
x 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
24-hour urine collection11 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
 
x 
Urine sample for uPCR determination 
x12 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x12 
x 
x 
x12 
 
 
x12 


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Procedures Scr1 
Intervention Period (Study Month) 
EOS2 
Study Month 
N/A 
M0 
M1 
M2 
M3 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 
M12/ 
ET3 
M13 M14 
M16 
Nominal Study Day -301 
D1 Pre 
infusion 
D1 Post 
infusion D8 
D18 
D30 
D60 
D90 D120 D150 D180 D210 D240 D270 D300 D330 D360 D390 D420 
D485 
Visit allowance (±days) 
 
N/A 
N/A 
±3 
±5 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
+7 
Study Visit N/A 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Blood sample for lymphocytes  
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
Serum for PK13 
 
x 
x 
x 
x 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x14 
x 
x 
x 
x 
Blood for total IgA, IgG, and IgM13 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood for IgA subtypes  
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Serum for APRIL 
 
x 
x 
 
 
x 
x 
x14 
x 
x 
x14 
x 
x 
x14 
x 
x14 
x 
 
 
x 
Serum for a-g IgA1 and anti-IgA1 
x 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 x 
 
 
x 
 
 
x 
Serum for ADA15 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
 
 
x 
Blood sample for DNA16 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample for exploratory  
biomarker assessments17 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
Blood for markers of complement activity 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
Saliva samples for IgA levels 
 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ADA = antidrug antibody; AE = adverse event; a-g IgA = aberrantly glycosylated immunoglobulin A; APRIL= A 
PRoliferation Inducing Ligand; ARB = angiotensin receptor blocker; β-hCG = beta-human chorionic gonadotropin; BAFF = B-cell activating factor; BP = blood pressure; 
D = Day; ECG = electrocardiogram; eCRF = electronic case report form; EOS = end-of-study; ET = early termination; HBV = hepatitis B virus; HCV = hepatitis C virus; 
HIV = human immunodeficiency virus; HR = heart rate; Ig = immunoglobulin; IgAN = immunoglobulin A nephropathy; M = Month; N/A = not applicable; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); RR = respiratory rate; SAE = serious adverse event; Scr = screening; SOC = standard of care; uACR = urinary 
albumin/creatinine ratio; uPCR = urinary protein/creatinine ratio. 
 
1 
All participants will undergo screening. To be eligible, participants should be on stable and maximally tolerated treatment with either ACEI or ARB, as per SOC and 
applicable guidelines, for at least 3 months. Participants should be on ACEI/ARB therapies as described in the eligibility criteria. If re-testing of samples is required, it must 
be completed within an additional 15 days beyond the 30-day screening period.  
2 
Participants must complete EOS assessments approximately 155 days after the last dose of study intervention. Participants discontinuing early will be encouraged to attend 
study visits as per the schedule, including the EOS visit. Adverse event and concomitant medication monitoring should be performed through the EOS visit; SAEs that are 
ongoing at EOS should be monitored until resolution or 30 days after the EOS, whichever is longer; AEs that are ongoing at EOS should be monitored until resolution or 30 
days after the EOS. 
3 
Participants discontinuing early must complete ET assessments at the time of treatment discontinuation. 
4 
A biopsy diagnostic of IgAN must have been performed and source-verified documentation must be available. 
5 
A complete physical examination, including assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems will be completed at the screening, 
Month 12/ET visit, and Month 16/EOS visits.  


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6 
Vital sign measurements include BP, HR, RR, and temperature. Vital sign measurements on dosing days will be recorded within 15 (±5) minutes prior to the start of the 
infusion, every 15 minutes until the infusion is complete, and postinfusion at 60 (±10) minutes and 2 hours. 
7 
The dose of study intervention will be based on the M0 pre-dose weight. 
8 
The comprehensive list of serum chemistry tests to be performed is provided in Appendix 2. A full serum chemistry panel will be obtained at screening and monthly. Local 
laboratory assessments may be performed at the Investigator’s discretion throughout the study in the course of participant care (but not assessments that would potentially 
unblind treatment status, such as measurement of Ig levels). Any clinically significant abnormalities should be recorded in the eCRF.  
9 
The comprehensive list of hematology tests to be performed is provided in Appendix 2.  
10 
The comprehensive list of urinalysis tests to be performed is provided in Appendix 2. On days of 24-hour urine collections, the uPCR sample will be collected from the 
24-hour urine collection and routine urinalysis will be performed on a sample freshly voided during the clinic visit. Dipstick will be done locally. 
11 
Participants will discard the first void and begin a 24-hour urine collection the day prior to the clinic visit. For all 24-hour urine collection, the following parameters will be 
obtained or derived: 24-hour urine volume, protein, albumin, creatinine, uPCR, and uACR. 
12 
Samples should be taken from the 24-hour urine sample. 
13 
Up to 60 participants (approximately 15 per cohort) may have a more intensive PK and PD sampling schedule, as described in Table 5. Study participants agreeing to 
participate in this more intensive PK and PD sample collection sub-study will sign an additional informed consent for this activity.  
14 
Blood samples to be collected before and after study intervention infusion at all visits.  
15 
Samples for ADA assessment will be collected before the start of infusion. 
16 
Samples for evaluation of host genetic markers related to IgAN susceptibility loci, the APRIL/BAFF pathway, and/or immunity will be collected before the start of infusion. 
Participation in genetics research is optional; a separate informed consent form must be completed. 
17 
On days of 24-hour urine collection, urine samples for exploratory biomarker analysis will be collected and stored from a sample freshly voided during the clinic visit. 
Participation in biomarker research is optional; a separate informed consent form must be completed. 


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2. INTRODUCTION 
VIS649 is a humanized immunoglobulin G2 (IgG2) monoclonal antibody being developed for the 
treatment of immunoglobulin A nephropathy (IgAN), an autoimmune glomerulonephritis 
characterized by the deposition of immunoglobulin A (IgA)-containing immune complexes in 
the kidney. 
2.1 Study Rationale 
Immunoglobulin A nephropathy is a chronic disease affecting the kidneys. It is clinically 
characterized by proteinuria, hematuria and progressive decline of glomerular filtration rate 
(GFR). IgAN is characterized histologically by dominant or co-dominant deposition of IgA in 
the kidney glomerulus (Rodrigues, Haas et al. 2017). The central mechanism for the 
development of IgAN is the production of aberrantly glycosylated IgA1 (a-g IgA1), which has 
been attributed to a combination of genetic and environmental factors. These a-g IgA1 act as 
autoantigens and lead to development of autoantibodies forming circulating immune complexes 
that deposit in the mesangium of glomeruli and in turn, trigger an inflammatory response and 
complement activation (Kiryluk, Moldoveanu et al. 2011, Berthoux, Suzuki et al. 2012, Kiryluk, 
Novak et al. 2013, Kiryluk, Li et al. 2014, Kiryluk and Novak 2014). This results in episodic and 
cumulative kidney damage. Natural history studies indicate that IgAN may progress to end-stage 
renal disease (ESRD) in approximately 30% of patients, over the course of 10 years (Lai, Tang et 
al. 2016).  
Proteinuria is an important marker of progression of renal disease in patients with IgAN. Patients 
with significant proteinuria (> 1.0 g/day) have a faster decline of estimated glomerular filtration 
rate (eGFR) and progression to ESRD, when compared to patients with lower degrees of 
proteinuria (< 500 mg/day). Hence, reduction in proteinuria is a crucial aspect in the 
management of IgAN (Reich, Troyanov et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 
2016). 
The cytokine A PRoliferation Inducing Ligand (APRIL), which belongs to the tumor necrosis 
factor ligand superfamily, has emerged as a key factor in the pathogenesis of IgAN through 
mediation of the Ig isotype switch during B-cell development, production of IgA, plasma-cell 
survival, and possibly specifically influencing production of a-g IgA1 as well (Castigli, Scott et 
al. 2004, Varfolomeev, Kischkel et al. 2004, Endo, Nishio et al. 2007, Bossen, Cachero et al. 
2008). Studies in IgAN patients have shown that elevated APRIL levels correlate with poor 
kidney outcomes, when compared with patients with lower APRIL levels (Han, Yang et al. 2016, 
Zhai, Zhu et al. 2016). A similar trend is also seen with a-g IgA1 levels, with higher levels 
associated with faster and more frequent progression to kidney failure when compared to patients 
with lower a-g IgA1 levels (Castigli, Scott et al. 2004, Berthoux, Suzuki et al. 2012, Zhao, Hou et 
al. 2012). 
VIS649 is a humanized IgG2 monoclonal antibody (mAb) that binds to and blocks the biological 
actions of APRIL, preventing its binding to its receptors, transmembrane activator and calcium-
modulator and cyclophilin ligand (CAML) interactor (TACI), and B-cell maturation antigen 


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(BCMA). Blocking the biological actions of APRIL reduces the production of IgA. The 
hypothesis to be tested in this study is that a decrease in the production of IgA and a-g IgA1 will 
diminish the formation of circulating immune complexes and their deposition in the glomeruli, 
allowing injury repair and clinical improvement, as measured by reduction in proteinuria. 
In data from a single-ascending dose study (VIS649-101) of VIS649 in healthy participants, 
VIS649 reduced serum levels of IgA and a-g IgA1. The current study will test the hypothesis that 
blocking the biological actions of APRIL in IgAN participants leads to reduction of serum IgA 
(including a-g IgA1) levels and will reduce or halt the progression of IgAN as measured by 
reduction in proteinuria (the study’s primary efficacy endpoint). The current study will also 
assess the safety of VIS649 in participants with IgAN and collect extensive data on 
pharmacokinetics (PK) and pharmacodynamics (PD).  
The findings from this study will form the basis for subsequent clinical development of VIS649. 
2.2 Background 
Immunoglobulin A nephropathy is one of the most common primary glomerular diseases and 
affects patients globally, with some geographical variation in incidence and prevalence (Wyatt 
and Julian 2013, Rodrigues, Haas et al. 2017, Schena and Nistor 2018). Clinical presentation 
varies from incidentally detected asymptomatic hematuria and proteinuria to rapidly progressive 
glomerulonephritis requiring dialysis. Immunoglobulin A nephropathy is a significant cause of 
chronic kidney disease (CKD) and ESRD, with 30-40% of patients reaching ESRD 20-30 years 
after the first clinical presentation. Immunoglobulin A nephropathy can occur in either sporadic 
(90-95%) or familial (5%-10%) patterns. Patients with familial IgAN might have poorer 
prognoses than those with sporadic disease, with an increased risk of progression to renal failure 
(Lai, Tang et al. 2016). 
Immunoglobulin A nephropathy is diagnosed by kidney biopsy, which shows dominant or 
co-dominant IgA deposition on immunofluorescence. The pathogenesis of IgAN is currently 
thought to be a multi-hit process, the “first hit” being the production of a-g IgA1. The primary 
defect is the deficiency of galactose in the hinge region of IgA1. As a consequence, the 
N-acetylgalactosamine in the truncated IgA1 hinge region glycan is exposed and acts as an 
autoantigen. Multiple cohort studies have shown the relationship between elevated a-g IgA1 and 
IgAN, with higher a-g IgA1 levels resulting in more rapid disease progression. The “second hit” 
consists of IgA and IgG autoantibody production against these a-g IgA1. The “third hit” consists 
of formation of circulating immune complexes consisting of the IgG/IgA auto antibody and 
a-g IgA1 antigen complex. The “fourth hit” consists of deposition of these circulating immune 
complexes in the mesangium of the glomeruli. These antigen-antibody complexes are 
nephritogenic and trigger an inflammatory response leading to infiltration of macrophages, 
monocytes and T cells, local release of cytokines, complement activation, and activation of the 
renin-angiotensin cascade. This leads to glomerular injury and tubulo-interstitial fibrosis, 
clinically manifesting as proteinuria, hematuria, hypertension, and reduced GFR (Berthoux, 
Suzuki et al. 2012, Floege, Moura et al. 2014, Knoppova, Reily et al. 2016, Mestecky, Novak et 
al. 2016). 


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While proteinuria is a common manifestation of IgAN, the degree of proteinuria correlates with 
disease progression, with faster decline of eGFR, and progression to ESRD in patients with high-
grade proteinuria (> 1.0 g/d) when compared to patients with low-grade proteinuria (< 0.5 g/d) 
(Reich, Troyanov et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016, Thompson, 
Carroll et al. 2019). Control of proteinuria is a key therapeutic target in patients with IgAN. 
Measures to control proteinuria often consist of renin-angiotensin-aldosterone system (RAAS) 
blockade in the form of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor 
blocker (ARB) therapy, blood pressure (BP) control, statins to control cholesterol, smoking 
cessation, low-salt diet, low-protein diet, and avoidance of nephrotoxic drugs. If patients 
continue to have significant proteinuria despite these measures, they are usually treated with 
nonspecific immunosuppressive agents such as steroids, azathioprine, mycophenolate mofetil, or 
cyclophosphamide (Boyd, Cheung et al. 2012, KDIGO 2012, Radhakrishnan and Cattran 2012, 
Barbour and Feehally 2017, Rodrigues, Haas et al. 2017). These drugs, especially steroids 
(Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 2015, Tesar, Troyanov et al. 2015, Lv, Zhang et 
al. 2017), have been shown to be beneficial from a renal perspective in some studies, but their 
use is often complicated by significant adverse effects such as increased risk of infections, 
metabolic derangements, cosmetic changes, weight gain, fractures, and neuropsychiatric 
manifestations. Some of these agents have other significant risks such as increased risk of 
malignancies with prolonged administration. The significant side effects of these drugs preclude 
chronic use of these agents and limit their benefits in a chronic disease such as IgAN. 
APRIL is a member of the tumor necrosis factor superfamily of ligands and is emerging as a key 
mediator in IgAN pathogenesis and disease progression based on convergence of genetic, 
biochemical, and clinical data. APRIL is produced by myeloid and mucosal epithelial cells. 
APRIL regulates B cell-mediated immune responses through several mechanisms, including 
class-switch recombination, principally through its 2 receptors: TACI and BCMA. APRIL is also 
important for plasmablast differentiation in secondary lymphoid organs. In addition, myeloid-
derived APRIL mediates plasma cell survival by promoting the formation of so-called “survival 
niches” within the bone marrow microenvironment and mucosal compartments, leading to the 
establishment of a reservoir for long-lived antibody-secreting cells (Bossen, Cachero et al. 2008). 
Evidence of the critical role of APRIL in IgAN includes the following: (a) serum a-g IgA1 
(autoantigen) levels are elevated in patients with IgAN and correlate with APRIL levels and 
disease severity; (b) genome-wide association studies link APRIL to the disease; (c) serum 
APRIL is elevated in patients with IgAN and higher APRIL levels among IgAN patients are 
associated with more rapid progression to kidney failure (Mestecky, Raska et al. 2013, Han, 
Yang et al. 2016, Muto, Manfroi et al. 2017). 
In a mouse model of IgAN, administration of an anti-APRIL antibody similar to VIS649 led to 
lower IgA deposits in the kidney, lower proteinuria, and less glomerular sclerosis compared with 
animals administered a control antibody that does not bind APRIL. These data suggest that 
APRIL plays a key role in the pathogenesis of IgAN and that blocking APRIL could be an 
attractive approach for the treatment of IgAN (Myette, Kano et al. 2019).  
VIS649 is a humanized IgG2 mAb against the biologically active form of APRIL. VIS649 was 
tested in healthy human participants in a Phase 1, randomized, placebo-controlled, 


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single-ascending dose, first-in-human study to assess the safety, tolerability, PK, and PD of 
VIS649 (VIS649-101). The study enrolled 51 participants in 5 sequential dosing cohorts. 
Participants in Cohorts 1 to 4 received 4 different dose levels of VIS649 (0.5, 2, 6, and 12 mg/kg, 
respectively), enrolling 9 participants per cohort (7 participants receiving VIS649 and 
2 participants receiving placebo). Cohort 5 had 15 participants with 10 receiving VIS649 and 
5 participants receiving placebo. Participants in Cohort 5 received 6 mg/kg of VIS649 on Day 1 
and subsequently received a tetanus and diphtheria (Td) vaccine on Day 28. Blinded group data 
are available, including IgA levels. Preliminary data show that the total serum IgA declined by 
up to ~60% from normalized baseline values in these healthy participants. The vaccine response 
in Cohort 5 was intact, with a comparable IgG response to Td vaccine in participants receiving 
VIS649 and participants receiving placebo. Mean serum IgG levels declined by up to ~35% 
below normalized baseline values and mean IgM levels showed a marked decline of up to ~70% 
below the normalized baseline values. These declines in the Ig levels were reversible and the 
time taken to restoration of Ig levels to baseline was dependent on the dose of VIS649, with 
higher doses requiring a longer time period. VIS649 was very well tolerated across all dose 
levels and there were no serious adverse events (SAEs) attributed to VIS649. Further details can 
be found in the Investigator’s Brochure.  
The adverse risk-benefit ratio of nonspecific immunosuppressive agents precludes the chronic 
use of such agents and highlights the need for the development of an effective alternative that 
acts specifically on relevant pathophysiological factors in IgAN and is safe for chronic use. 
2.3 Benefit/Risk Assessment 
2.3.1 Risk Assessment 
Table 2 summarizes the important potential risks that have been recognized during the conduct 
of VIS649 nonclinical and clinical development programs. At present, all are considered 
potential risks.  
More detailed information about the risks and reasonably expected adverse events (AEs) of 
VIS649 may be found in the Investigator’s Brochure. 
Table 2: 
Summary of Potential Risks Associated with VIS649 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
IgA suppression risk 
 
Based on the mechanism of action of 
VIS649, preclinical studies, and human data 
from healthy participants, total serum IgA 
levels are expected to be suppressed to nadir 
levels 
. 
There is increasing recognition that selective 
IgA deficiency, which has typically been 
associated with IgA levels below the lower 
limit of detection 
 
), may be associated with recurrent 
sinopulmonary infection, allergy, 
• 
Serum IgA, IgG, and IgM will 
be measured on a monthly 
basis as blinded data, to be 
made available for routine 
DSMB review. The DSMB 
will assess unblinded safety 
data on a scheduled and as 
needed ad hoc basis, including 
AEs, laboratory data, and Ig 
data. The DSMB charter calls 
for assessment of the 




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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
was not suppressed by 
VIS649, and peripheral blood 
myeloid cell line populations 
were unaffected.  
IgM suppression risk 
 
Based on the mechanism of action of 
VIS649, preclinical studies, and human data 
from healthy volunteers, total serum IgM is 
expected to be suppressed to levels 
approximately 
below baseline.  
Most patients with selective IgM deficiency 
are asymptomatic, but a few patients develop 
chronic and recurrent infections and 
increased risk of autoimmune diseases (Yel, 
Ramanuja et al. 2009, Louis and Gupta 2014, 
Louis, Agrawal et al. 2016, Janssen, Macken 
et al. 2018). Selective IgM deficiency is 
usually associated with other defects such as 
decreased T-helper cell activity, increased 
isotype specific suppressor T cells, increased 
CD8 Treg cells, and intrinsic B cell defects.  
VIS649 is not expected to have effects such 
as these on cellular immunity. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
Please see above regarding Ig 
and AE data monitoring under 
DSMB review.  
Nonspecific 
immunosuppression risk 
There is the possibility of nonspecific 
immunodeficiency with potential risk of 
exacerbation of pre-existing latent infection 
or poor response to new infection. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
Participants with acute or 
chronic infections at the time 
of screening are prohibited 
from enrollment.  
• 
Participants with underlying 
iatrogenic or primary 
immunodeficiency syndromes 
are prohibited from 
enrollment.  
• 
DSMB monitoring will 
include careful attention to 
infection-related AEs. 
• 
Concurrent treatment with 
systemic corticosteroids or 
other immunosuppressive 
therapy is prohibited during 
study conduct. 
Infusion reactions 
(anaphylaxis, fever, chills, 
rigors, nausea, vomiting, 
pain, headache, dizziness, 
shortness of breath, 
bronchospasm, 
hypotension, 
There were no SAEs among participants in 
the Phase 1 VIS649-101 study at dose levels 
up to 12 mg/kg. 
Severe infusion reactions such as anaphylaxis 
have not been observed with VIS649 in 
humans.  
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for the occurrence 
of infusion reactions.  


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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
hypertension, pruritus, 
rash, urticaria, 
angioedema, diarrhea, 
tachycardia, and chest 
pain) 
There was no effect of VIS649 on measured 
plasma cytokine concentrations in the 
monkey toxicology studies, and VIS649 did 
not stimulate significant cytokine release in 
an in vitro human peripheral blood 
lymphocyte cytokine release assay. 
Additional information can be found in the 
Investigator’s Brochure. 
Delayed allergic reactions 
(SSLR [ie, urticaria, 
fever, general glandular 
enlargement, joint pains]) 
Delayed allergic reactions to a mAb such as 
serum sickness (ie, urticaria, fever, general 
glandular enlargement, joint pains) have been 
reported with other mAbs and may not 
appear until several days or weeks after the 
infusion. 
Additional information can be found in the 
Investigator’s Brochure. 
• 
Participants will be monitored 
for AEs throughout the 
duration of the study. 
Injection site reactions 
Injection site reactions may occur following 
administration of any intravenous therapy.  
• 
All VIS649 doses will be 
administered at the clinical site 
by trained personnel, and 
participants will be closely 
monitored for injection site 
reactions. 
Abbreviations: AE = adverse event; CVID = common variable immunodeficiency; DSMB = data safety monitoring board; 
Ig = immunoglobulin; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; IV = intravenous(ly); 
LLN = lower limit of normal; mAb = monoclonal antibody; PD = pharmacodynamic(s); PK = pharmacokinetic(s); SAE = serious 
adverse event; SSLR = serum-sickness like reaction. 
2.3.2 Benefit Assessment 
Immunoglobulin A nephropathy is a chronic disease with periodic flares. IgAN is a significant 
cause of CKD and ESRD, the clinical progression varies, with 30 – 40% of patients reaching 
ESRD 20 to 30 years after the first clinical presentation (Lai, Tang et al. 2016). These patients 
have significantly increased mortality and morbidity, with life expectancy reduced by 6 to 
10 years when compared to healthy individuals. (Hastings, Bursac et al. 2017, Jarrick, Lundberg 
et al. 2019). There are currently no approved therapies for IgAN, and the current treatment 
strategies consist of 2 main approaches: nonspecific supportive treatments consisting of BP 
control, treatment with ACEI/ARB, smoking cessation, lipid reduction, low-salt diet, or fish oil, 
and immunosuppressive therapies such as steroids, cyclophosphamide, or azathioprine. The 
immunosuppressive therapies are usually employed in patients with a high risk of progression, as 
characterized by proteinuria > 1.0 g/d and declining GFR (Cheng, Zhang et al. 2009, Boyd, 
Cheung et al. 2012, KDIGO 2012, Radhakrishnan and Cattran 2012, Barbour and Feehally 2017, 
Rodrigues, Haas et al. 2017). Recent trials have shown some benefit in proteinuria reduction 
with steroids in these patients, thought they are at high risk for developing significant 
complications like infections, metabolic derangements, osteoporosis, and diabetes mellitus with 
these immunosuppressive agents, thus limiting the duration for which these drugs can be given to 
patients despite benefit from a renal perspective (Pozzi, Andrulli et al. 2004, Rauen, Eitner et al. 


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2015, Tesar, Troyanov et al. 2015, Lv, Zhang et al. 2017). Hence, there is a critical need for a 
safe and specific treatment for IgAN. 
VIS649 has the potential to provide a significant advancement in the therapeutic approach to 
IgAN. It has a very specific mechanism of action in the form of APRIL inhibition, which plays a 
critical pathophysiological role in the production of a-g IgA1 in patients with IgAN.  
VIS649 has an attractive safety profile based on currently available data, including data from the 
first-in-human study (VIS649-101), in which no SAEs attributable to VIS649 were observed. It 
is anticipated that VIS649 will be used as chronic therapy and will significantly improve the 
outcomes in patients with IgAN when compared to intermittent therapies like steroids that are 
currently used to treat these patients. 
2.3.3 Overall Benefit: Risk Conclusion 
Given the mechanism of action of VIS649 and data from a Phase 1 single-ascending dose study 
(VIS649-101) in healthy participants, it is expected that participants receiving VIS649 will have 
a decline in Ig levels 
. To mitigate the risk of IgG reduction, serum IgG 
thresholds for enrollment have been established so as to prevent the development of clinically 
significant hypogammaglobulinemia. In addition, studies in both healthy human participants and 
nonhuman primates have demonstrated that the ability to develop an IgG response to novel 
antigens and recall T-cell dependent antigen challenge is not significantly impaired. As 
mentioned earlier, there were no SAEs considered attributable to VIS649 in the Phase 1 
single-ascending dose study (VIS649-101), and in the nonhuman primate 6-month toxicology 
study, the no-adverse effect level for the antibody was the highest dose evaluated.  
An independent data safety monitoring board (DSMB) for this study will be reviewing all 
available safety data, including unblinded Ig data and AEs on a periodic and, as needed, on an ad 
hoc basis.  
Given these encouraging preliminary data and the precautions built into the protocol, evaluation 
of the potential benefit of VIS649 in slowing or halting CKD progression in IgAN participants is 
warranted. 


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3. OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints are outlined in Table 3. 
Table 3: 
Study Objectives and Endpoints 
Primary Safety Objective 
Primary Safety Endpoint 
• 
To evaluate the safety and tolerability of 
monthly doses of VIS649 at each of 3 dosing 
levels, administered IV to IgAN participants 
over the course of 12 months as an add-on to 
SOC treatment with ACEI/ARB therapy, 
compared with saline placebo infusions as an 
add-on to SOC treatment with ACEI/ARB 
therapy 
• 
AEs graded by severity, clinical laboratory 
tests, vital sign measurements, and physical 
examinations  
Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the dose response of monthly 
doses of VIS649 on proteinuria at each of 
3 dosing levels, administered IV to IgAN 
participants over the course of 12 months as 
an add-on to SOC treatment with ACEI/ARB 
therapy, compared with saline placebo 
infusions as an add-on to SOC treatment with 
ACEI/ARB therapy 
• 
Change from baseline in uPCR (measured on 
natural log scale from 24-hour urine collection 
or the intended 24-hour urine collection) at 
Month 12 (ie, approximately 30 days after the 
12th dose is administered) 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate the effect of repeated doses of 
VIS649 at 3 dosing levels versus placebo on 
the following parameters: 
 
o uPCR at Months 9 and 16 (ie, 5 months 
following the final [12th] monthly dose 
administration) 
o Change from baseline in uPCR (measured 
on natural log scale from 24-hour urine 
collection or the intended 24-hour urine 
collection) at Months 9 and 16 
o 24-hour urine protein excretion at Months 
9, 12, and 16 
o Change in 24-hour urine protein excretion 
from baseline to Months 9, 12, and 16 
o ≥ 30% decline from baseline in uPCR at 
Months 9, 12, and 16  
o Number of participants in each group 
achieving a ≥ 30% decline from baseline 
in uPCR at Months 9, 12, and 16 
o Clinical remission, defined as reduction in 
24-hour urine protein excretion to 
< 300 mg/day for at least 3 consecutive 
months  
o Number of participants in each group 
achieving clinical remission 
• 
eGFR at Months 12 and 16 
• 
Change from baseline in eGFR at Months 12 
and 16 
 






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4. STUDY DESIGN 
4.1 Overall Design 
This is a Phase 2 multicenter, randomized, double-blind, placebo-controlled, multiple-dose study 
to evaluate the safety and efficacy of intravenously (IV) administered VIS649 over a 12-month 
treatment course in participants with IgAN.  
Participants will be enrolled from approximately 100 global sites in approximately 16 countries. 
Screening evaluations (including physical examinations, vital signs, 12-lead electrocardiogram 
[ECG], safety laboratory testing [serum chemistry, hematology, urinalysis, serology, hemoglobin 
A1c, and pregnancy], blood sampling for baseline Ig levels [IgA, IgG, and IgM], and 24-hour 
urine collection) will take place during the 30 days prior to the first dose of study intervention.  
To be eligible, participants should be on stable and maximally tolerated doses of either ACEI or 
ARB therapy, as per standard of care (SOC) and applicable guidelines, for at least 3 months. 
Participants should optimally be on at least 50% of the maximum recommended dose of these 
agents; however, if a participant is on their maximally tolerated dose (and this is < 50% of the 
maximum recommended dose) and has been on this dose for at least 3 months, they may be 
enrolled. Participants who are unable to tolerate ACEI/ARB therapy may be eligible for 
participation in the study if their overall management of IgAN, including BP control, is as per 
SOC and applicable guidelines. 
Participant education regarding temporary cessation of ACEIs/ARBs during acute illness and 
resumption of these drugs after resolution of the acute illness will be as per local practice and 
SOC and this therapy will be resumed at the dose closest to the level at the time of 
randomization. During the course of the study, the doses of ACEIs or ARBs should not change; 
however, minor changes are allowed depending on the clinical situation. Control of BP should be 
as per SOC and applicable guidelines. Additional antihypertensives can be used to control BP as 
per the Investigator’s preference and local practice.  
Enrolled participants must be 18 years of age or older with an IgAN diagnosis confirmed by 
biopsy. 
It is anticipated that most biopsies resulting in a diagnosis of IgAN will have been interpreted 
using the MEST score–mesangial cellularity, endocapillary proliferation, segmental sclerosis, 
tubular atrophy (Cattran et al, 2009) or MEST-Crescents (C) scoring system (Trimarchi, Barratt 
et al. 2017) from the Oxford classification of IgAN. Components of the MEST-C score include:  
• 
M – Mesangial hypercellularity, defined as more than 3 mesangial cells in any mesangial 
area of a glomerulus; a score of M0 indicates hypercellularity in < 50% of glomeruli and 
a score of M1 is for hypercellularity noted in ≥ 50% of glomeruli. 
• 
E – Endocapillary proliferation, defined as hypercellularity due to an increased number of 
cells within glomerular capillary lumina causing narrowing. E0 represents absence of 
hypercellularity; E1 is hypercellularity in any glomeruli. 
 


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• 
S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of 
capillary lumina by matrix) in part of but not the whole glomerular tuft; S0 represents 
absence of segmental glomerulosclerosis; S1 is presence of segmental glomerulosclerosis 
in any glomerulus. 
• 
T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical 
area showing tubular atrophy or interstitial fibrosis, whichever is greater; T0 is 0-25%; 
T1 is 25-50%; T2 is > 50% atrophy/interstitial fibrosis. 
• 
C – Crescents: C0 (no crescents), C1 (crescents in < 25% of glomeruli), and C2 
(crescents in ≥ 25% of glomeruli). 
A MEST-C score finding on kidney biopsy of T2 or C2 is exclusionary for this study. If the 
biopsy was not reported using the Oxford classification schema, the following findings 
(corresponding to these Oxford classifications) are exclusionary: a) > 50% tubular atrophy and/or 
b) > 25% crescents.  
Eligible participants must have sufficient proteinuria at screening, defined as urine protein to 
creatinine ratio (uPCR) ≥ 0.75 g/g or 24-hour urine protein ≥ 1.0 g/d, as measured from a 
24-hour urine collection (or an intended 24-hour urine collection).  
Eligible participants must have an eGFR ≥ 45 mL/min/1.73 m2, calculated using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (Levey, Stevens et al. 2009), 
before dosing on Day 1. Participants with an eGFR ≥ 30 mL/min/1.73 m2 and < 45 mL/min/1.73 
m2 may also undergo screening, if they have undergone a kidney biopsy within 12 months of the 
date of initial screening and do not have ≥ 50% tubulo-interstitial fibrosis (T2 if using MEST-C 
score) or crescents in > 25% of glomeruli (C2 if using MEST-C score).  
Participants known to have chronic infectious diseases (eg, chronic sinusitis, chronic urinary 
tract infections, bronchiectasis) will be excluded. Participants in countries with high prevalence 
of tuberculosis may undergo appropriate investigations such as chest X-ray or interferon 
gamma-release assay, as deemed appropriate by the Investigator, to rule out tuberculosis. 
Participants will be excluded from the study if they test positive for the screening serology 
markers listed in Table 8. Participants with a positive Hepatitis C virus (HCV) antibody test must 
undergo testing for HCV RNA; if HCV RNA is undetectable, the participant can be included in 
the study. Participants with positive HbSAg and/or positive Anti HbC antibody will be excluded. 
Participants must be vaccinated as per respective national guidelines and other relevant 
guidelines. Participants should continue to receive annual influenza vaccine and pneumococcal 
vaccine, as per local guidelines. 
The study will evaluate 3 dose levels of VIS649 (2, 4, and 8 mg/kg) versus placebo. A total of 
144 participants will be randomized with equal allocation (1:1:1:1) across the 4 intervention 
groups (approximately 36 participants per group). Randomization will be stratified first by 
region (Japan vs rest-of-world). A target of 12 or more participants are planned to be randomized 
in Japan; these participants will be randomized with equal allocation and without further 
stratification. The randomization for the rest-of-world will be stratified by screening uPCR 
(≤ 2.0 g/g vs > 2.0 g/g).  


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VIS649 or placebo will be administered as 12 monthly IV infusions starting on Day 1/Month 0. 
Participants will return to the study center on Days 8 and 18, then monthly through Month 14 
and on Month 16 for safety, efficacy, PK, and/or PD assessments. Participants will be 
encouraged to follow the schedule of visits for their monthly infusions as close to the prescribed 
interval as possible. If under special circumstances, a participant is unable to visit the study 
center within 7 days of the scheduled infusion, they will still be able to receive the infusion 
within the next 7 days, and this will be recorded as a protocol deviation. However, if there is any 
further delay, that dose should be skipped, and the participant should receive subsequent doses as 
per the schedule. The participant will not receive additional doses to make up for the missed 
dose(s).Safety assessments will include review of AEs (including hypersensitivity reaction and 
anaphylactic reaction), physical examinations, injection site tolerability (pain, irritation, and 
tissue damage), clinical laboratory assessments (including biochemistry, hematology, urinalysis, 
and pregnancy testing), laboratory testing (including serum Ig levels and antidrug antibodies 
[ADAs]), vital sign measurements, and use of concomitant medications. 
Participants will return to the study center on Month 16, 155 days following the last dose of 
study intervention (Dose 12) for an end-of-study (EOS) visit, at which time final safety, PK, PD, 
and efficacy assessments will be performed. Participants discontinuing dosing prior to Dose 12 
will attend an early termination visit at the time of dosing discontinuation and will be encouraged 
to attend the study visits as per schedule of assessments (Table 1).  
An independent DSMB will review safety data at regular intervals (see Section 9.6). 
A rollover, open-label extension study will be offered to enable access to VIS649 (there will be 
no placebo arm) for study participants who have completed this trial, provided that the 
Investigator believes that the participants might benefit, and that the site has agreed to participate 
in the extension study. Further details will be provided in a separate protocol. 
The total study duration for each participant (from screening to EOS) will be up to 17 months 
(assuming up to 1 month for screening, 12 months for monthly doses [including 30 days after the 
12th dose], and follow-up visits up to 155 days after the last dose of study intervention.  
In response to the Coronavirus Disease 2019 (COVID-19) pandemic and to prepare for possible 
quarantines, site closures, travel limitations etc., Visterra, in consultation with clinical 
investigators and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), 
may determine that the protection of a participant’s safety, welfare, and rights is best served by 
home health visits, telemedicine, or other remote support. Local regulations will be followed.  
4.2 Scientific Rationale for Study Design 
This study is designed as a randomized, double-blind, placebo-controlled, multiple-dose study to 
evaluate the safety and efficacy of IV administered VIS649 in IgAN participants over a 
12-month intervention course.  
Immunoglobulin A nephropathy is a chronic, slowly progressing disease. The underlying 
pathogenic factor in IgAN is the formation of a-g IgA1, which is attributed to a culmination of 
genetic and environmental factors in susceptible individuals. The hypoglycosylated hinge region 
of a-g IgA1 presents as a novel antigen, against which IgG and IgA autoantibodies may be 


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generated. This leads to formation of circulating IgG/a-g IgA1 immune complexes that are 
deposited (in part) in the mesangium of the glomerulus, inciting an inflammatory, nephritogenic 
response (Boyd, Cheung et al. 2012, Mestecky, Raska et al. 2013, Lv, Zhang et al. 2017). This 
manifests clinically as proteinuria, hematuria, and decline in eGFR. High grade proteinuria 
(> 1.0 g/d) is a critical marker of progressive IgAN and remission of proteinuria is a crucial 
therapeutic target in the management of IgAN (Donadio, Bergstralh et al. 2002, Reich, Troyanov 
et al. 2007, Nam, Kie et al. 2014, Inker, Mondal et al. 2016, Thompson, Carroll et al. 2019). 
VIS649 inhibits the biological actions of APRIL and reduces the levels of IgA, a-g IgA1 and 
other Ig. In patients with IgAN, it is hypothesized that this reduction in APRIL and a-g IgA1 will 
reduce the deposition of circulating immunocomplexes in the glomerulus. This should lead to 
cessation of ongoing renal damage and lead to recovery of the damaged glomeruli, as reflected 
by a reduction in proteinuria. 
Based on the PK/PD data from the Phase 1 single-ascending dose study (VIS649-101) and on 
simulation models, full therapeutic suppression of IgA through APRIL signaling inhibition will 
be achieved at 12 weeks, with the selected doses administered monthly. Considering the 
time-dependent and indirect effect of VIS649, a 12-month study intervention duration is deemed 
necessary to achieve therapeutic effect and assess for clinically relevant benefit of VIS649, as 
measured by reduction in proteinuria. 
The primary efficacy endpoint will be the change from baseline in uPCR, at Month 12 (30 days 
after the 12th dose of study intervention), as measured from a 24-hour urine collection. Studies 
have shown that in patients with IgAN, reduction of proteinuria leads to clinically relevant 
improvements like reduction in the rate of decline of eGFR and progression to ESRD.  
In an analysis of data from the Toronto Glomerulonephritis Registry of 542 patients followed for 
a mean of 6.5 years (61% males, 50% whites, 23% Asians, with mean initial proteinuria 2.4 g/d 
and creatinine clearance of 77 mL/min/1.73 m2), time-averaged proteinuria (defined as an 
average of the mean of the proteinuria measurements for every 6-month period) was the most 
important predictor of kidney function decline and risk of ESRD, independently of BP and use of 
renin-angiotensin blockers. If time-averaged proteinuria was maintained < 1 g/d, the 10-year risk 
of ESRD was 5%, versus 20% with a time-averaged proteinuria of 1–2 g/d, 40% with a 
time-averaged proteinuria of 2 to 3 g/d, and 60% with > 3 g/d (Reich, Troyanov et al. 2007). 
This study highlights the primary importance of proteinuria reduction as a therapeutic target in 
the management of IgAN.  
A comprehensive series of safety evaluations, including review of AEs (including 
hypersensitivity reaction and anaphylactic reaction), physical examinations, injection site 
tolerability (pain, irritation, and tissue damage), clinical laboratory assessments (including 
biochemistry, hematology, urinalysis, and pregnancy testing), laboratory testing (including 
serum Ig levels and ADAs), vital sign measurements, and use of concomitant medications will be 
conducted to evaluate the safety profile of VIS649. 
It is expected that VIS649 will result in obvious reductions in serum IgA, IgG, and IgM, which, 
if visible to the site or Sponsor, would effectively unblind treatment. Therefore, unblinded Ig 
data will only be available to designated unblinded personnel.  




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The results of VIS649-101 and PK/PD model simulations and the safety coverage from the 
6-month toxicology study all support the planned dosing strategy for the current study.  
4.4 End-of-study Definition 
A participant is considered to have completed the study if he/she has completed the intervention 
period and EOS visit.  
The end of the study is defined as the date of the last visit of the last participant in the study. 


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5. STUDY POPULATION 
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, is not permitted. Rescreening is permitted if a previous participant was a 
Screen Fail under Protocol Version 3.0. The medical monitor must be consulted prior to 
rescreening. Rescreening or retesting may also be permitted due to issues arising during 
shipping/storage/handling/collection/processing of samples. Rescreening of a participant may 
also be permitted if initial participation in the study was precluded due to an acute infection or an 
acute illness that subsequently resolved completely, and the participant then is able to fulfill all 
study eligibility criteria. 
5.1 Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant is a male or female ≥ 18 years of age at the time of signing the informed 
consent. 
2. Participant has biopsy-confirmed IgAN. 
3. Participant has medical records showing they have been on stable and maximally 
tolerated doses of either ACEI or ARB, as per local SOC and applicable guidelines, for at 
least 3 months preceding screening. Participants should optimally be on at least 50% of 
the maximum recommended dose of these agents; however, if a participant is on their 
maximally tolerated dose (and this is < 50% of the maximum recommended dose) and 
has been on this dose for at least 3 months, they may be enrolled. Participants who are 
unable to tolerate ACEI/ARB therapy may be eligible for participation in the study if 
their overall management of IgAN, including BP control, is as per local SOC and 
applicable guidelines. 
4. Participant has screening uPCR ≥ 0.75 g/g measured from a 24-hour urine (or an intended 
24-hour urine sample) or 24-hour urine protein ≥ 1.0 g/d, as measured from 24-hour urine 
collection (or an intended 24-hour urine sample).  
• The proteinuria should be assessed when the participant is considered to be in a 
steady state with no recent heavy exercise, fever, or other potential issues that 
could impact the result. Re-testing may be allowed if it is determined that the 
participant was not in steady state after consultation with the medical monitor. 
5. Participant has eGFR ≥ 45 mL/min/1.73 m2, calculated using the CKD-EPI formula.  
• Retesting may be allowed if it is determined that the participant was not in steady 
state after consultation with the medical monitor. 
• Participants with eGFR ≥ 30 mL/min/1.73 m2 and < 45 mL/min/1.73 m2 may also 
undergo screening, if they have undergone a kidney biopsy within 12 months of 
the date of initial screening and do not have ≥ 50% tubulo-interstitial fibrosis (T2 
if using MEST-C score) or crescents in > 25% of glomeruli (C2 if using MEST-C 
score).The eGFR should be measured when the participant is considered to be in a 
steady state without recent changes in volume status, medications that could 


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impact the result (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], 
aminoglycosides, co-trimoxazole), or changes in dietary protein intake. 
6. Participant’s serum Ig values must meet the following criteria:
•
IgG: ≥ 700 mg/dL
•
IgM: ≥ 37 mg/dL
•
IgA: ≥ 70 mg/dL
7. Female participants of childbearing potential must have a negative serum pregnancy test
prior to the first dose.
8. Participant is willing to adhere to contraceptive requirements outlined in Appendix 4.
9. Participant or a legally authorized representative is able to understand the purpose and
risks of the study and is willing to give voluntary written informed consent as described
in Appendix 1.
5.2 Exclusion Criteria 
Participants are excluded from the study if they meet any of the following criteria: 
1. Participant has secondary forms of IgAN as defined by the treating physician (eg,
Henoch-Schӧnlein purpura (IgA vasculitis), infection-associated IgAN, or IgAN
associated with hepatic cirrhosis).
2. Participant has co-existing CKD, other than IgAN.
3. Participant has evidence of additional pathological findings in the kidney biopsy (eg,
diabetic kidney disease, membranous nephropathy, or lupus nephritis). However,
hypertensive vascular changes are acceptable.
4. Participant has kidney biopsy MEST or MEST-C score of T2 or C2 from the Oxford
IgAN classification schema. If MEST-scoring was not performed, the presence of > 50%
tubulo-interstitial fibrosis or crescents in > 25% of glomeruli is exclusionary.
5. Participant has nephrotic syndrome, defined for this purpose as 24-hour urine protein
> 3.5 g with concurrent hypoalbuminemia (serum albumin < 2.5 g/dL), hyperlipidemia
(total cholesterol > 350 mg/dL), and edema. Participants with isolated nephrotic range
proteinuria (>3.5 g/d) will be eligible.
6. Participant has received a solid organ transplant, including kidney.
7. Participant has received bone marrow or hematologic stem cell transplantation.
8. Participant is currently receiving systemic immunosuppression (excluding topical,
ophthalmic, per rectum, or inhaled corticosteroids).
9. Participant has received treatment with systemic corticosteroid therapy (excluding
topical, ophthalmic, per rectum, or inhaled corticosteroids) within 16 weeks of initial
screening.


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10. Participant has received treatment with a systemic immunosuppressive agent (e.g., 
mycophenolate mofetil, azathioprine, calcineurin inhibitors, cyclophosphamide/cytotoxic 
agents) within 16 weeks of initial screening.  
11. Participant has any chronic infectious disease (eg, chronic urinary tract infection; chronic 
sinusitis; bronchiectasis; active pulmonary or systemic tuberculosis; chronic viral 
hepatitis, such as hepatitis C or hepatitis B; or human immunodeficiency virus 
infection). See Section 4.1 Study Design for further details. 
12. Participant has acute infectious disease at the time of screening. Participants may be 
rescreened following resolution of acute infection (such as urinary tract infection or 
respiratory tract infection), provided there is no evidence of an immunosuppressive 
condition that predisposed the participant to this infection.  
13. Participant has Type 1 diabetes. 
14. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin 
A1c value > 8%. 
15. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg diastolic), 
Systolic and diastolic BP should be assessed while the participant is seated or supine for 
at least 5 minutes in a quiet room without distractions. BP should be measured with a 
completely automated device. At least 3 readings should be taken and average values 
from these 3 readings should be calculated. 
16. Participant has a history of chronic autoimmune neurodegenerative disorder such as 
multiple sclerosis. 
17. Participant has a known allergy or intolerance to any component of the study 
intervention. 
18. Participant is breastfeeding. 
19. Participant has poorly compensated or controlled ischemic heart disease or 
cardiomyopathy, as judged by the Investigator. 
20. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has 
required systemic steroid therapy during the prior year. If COPD is present, severity must 
not exceed Global Initiative for Chronic Obstructive Lung Disease 1 (mild), defined as a 
forced 1-second expiratory volume (FEV1) > 80% of predicted. 
21. Participant has known cirrhosis or liver dysfunction, defined as presence of 
coagulopathy, platelet count < 100,000/µL or alanine aminotransferase > 3× upper limit 
of normal. 
22. Participant has active malignancy or is receiving chemotherapy for malignancy, except 
for nonmelanoma skin cancers and cervical carcinoma in situ. Participants with prior 
malignancy who have been documented to be cancer-free for ≥ 5 years may be enrolled. 
23. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is 
acceptable (if greater than 6 months prior to screening). 


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24. Participant enrolled in another investigational drug or device study within 3 months prior 
to initial screening. 
25. Participant with a pre-existing illness other than those listed above that, in the opinion of 
the Investigator, would place the participant at increased risk through participation in this 
study. 
26. Participant is unable to comply with study protocol procedures and/or study visit 
schedules. 
27. Participant with known or suspected alcohol or drug abuse that would compromise their 
safety or study participation, in the opinion of the Investigator. 
5.3 Lifestyle Considerations 
Lifestyle recommendations applicable to IgAN patients such as, but not limited to, BP control, 
low-salt diet, low-protein diet, smoking cessation, weight reduction, and avoidance of 
nephrotoxic drugs (eg, NSAIDs) will be followed as per local practice and guidelines. 
5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered into the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 


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6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1 Study Intervention(s) Administered 
The study interventions to be administered under this protocol are detailed in Table 4. 
VIS649 is for investigational use only and should only be used within the context of this study.  
VIS649 will be administered as a mg/kg dosage determined by dose assigned at time of 
randomization. VIS649 will be administered IV over 1 hour*, in a single, final volume of 
100-mL infusion in normal saline (0.9% NaCl), followed by a 25-mL saline flush. The dose of 
study intervention will be based on the Month 0 predose weight. 
Placebo (0.9% NaCl) will be administered IV over 1 hour* as a single 100 mL infusion, followed 
by a 25-mL saline flush. 
Infusions should preferentially be administered to the participant’s dominant arm. 
Table 4: 
Study Interventions 
Study Arm 
VIS649 
Placebo 
Intervention Name 
VIS649 
Placebo 
Intervention Type 
Drug (IMP) 
Placebo (NIMP) 
Dose Formulation 
Solution 
NaCl (normal saline solution) 
Unit Dose Strength 
VIS649 is formulated at a 
concentration of 25 mg/mL 
0.9% 
Dosage Levels 
2, 4, and 8 mg/kg 
as a single, final volume of 100 mL 
N/A 
Dosing Frequency 
Monthly for 12 months 
Monthly for 12 months 
Route of Administration 
1-hour* IV infusion, followed by a 
25-mL saline flush 
1-hour* IV infusion, followed by a 
25-mL saline flush 
Use 
Experimental 
Placebo-comparator 
Sourcing 
Provided centrally by the Sponsor 
Supplies will be obtained locally  
Packaging and Labeling 
VIS649 will be supplied in vials 
containing a nominal volume of 10 mL 
and will be labeled according to local 
regulations 
Per local supplies 
Storage Conditions 
VIS649 must be stored at a 
temperature between ≥ 2°C and ≤ 8°C 
and protected from light. Must be 
infused within 4 hours of 
reconstitution 
Per package insert 


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Abbreviations: IMP = investigational medicinal product; IV = intravenous(ly); N/A = not applicable; NIMP = noninvestigational 
medicinal product. * Occasionally pre-filled saline bags have some additional fluid as overage, in such scenarios dispense the 
entire contents of the bag during the infusion (may be over 60 minutes). 
6.2 Preparation/Handling/Storage/Accountability 
The required amount of VIS649 to be dosed will be diluted in normal saline up to a maximum 
total volume of 100 mL; for placebo participants, 100 mL of normal saline will be prepared. The 
length of the IV line will be set to a maximum volume of 25 mL, so that the 25-mL saline flush 
following administration will ensure all VIS649/placebo has been administered. 
The VIS649/placebo infusion will be administered IV using a 0.20- or 0.22-µm in-line filter and 
will be controlled by a volumetric pump. Standard, uniform-length infusion lines will be used. 
In addition: 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained for study intervention during transit to and storage in the investigational 
pharmacy. Any deviations from Pharmacy Manual guidance are to be reported and 
resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply and administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions, with access limited to 
the Investigator and authorized site staff. 
3. The Investigator, institution, or head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
This study is double-blinded. An unblinded pharmacist (or other unblinded designee) will 
prepare study intervention doses for infusion. Participants, the Sponsor, the Investigator, and all 
other site study staff will be blinded to study intervention.  
All eligible participants will be centrally assigned to randomized study intervention using an 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is initiated, the 
telephone number and call-in directions for the IVRS and/or the log-in information and 
directions for the IWRS will be provided to each site. 
Participants will be randomly assigned in a 1:1:1:1 allocation ratio to receive VIS649 at 2, 4, or 
8 mg/kg or placebo, with approximately 36 participants randomized to each intervention group. 
Randomization will be stratified first by region (Japan vs rest of world). A target of 12 or 
more participants are planned to be randomized at Japanese sites. Japanese participants will be 


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randomized with equal allocation and without further stratification. Randomization for the rest of 
world will then be stratified by screening uPCR (≤ 2.0 g/g vs > 2.0 g/g).  
Each assignment will have a unique randomization number, assigned to eligible participants after 
the screening. Once a randomization number has been assigned via the IVRS/IWRS, it may not 
be reassigned. 
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides that 
unblinding is required for participant safety, the Investigator should make every effort to contact 
the Sponsor prior to unblinding a participant’s intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s intervention assignment is unblinded, 
the Sponsor must be notified within 24 hours after breaking the blind. The date and reason that 
the blind was broken must be recorded in the source documentation and electronic case report 
form (eCRF), as applicable. 
Local laboratory testing such as Ig concentrations, albumin:globulin ratio (often tested as part of 
routine liver function panel), or serum protein electrophoresis may reveal obvious reduction in 
the total globulin levels in participants receiving study intervention and could effectively unblind 
the participant. Performing such investigations is prohibited, unless this has been discussed with 
the Sponsor and such investigations have been deemed necessary for clinical management of the 
participant. 
6.4 Study Intervention Compliance 
Preparation of individual doses of study intervention will be verified by a second (unblinded) 
member of the study site pharmacy staff.  
Participants will receive study intervention at the study center directly from the Investigator or 
designee under medical supervision. The date and time of each dose administered in the clinic 
will be recorded in the source documents and eCRF. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.  
6.5 Concomitant Therapy 
Any medication or vaccine (including over-the-counter and prescription medicines, vitamins, 
herbal supplements, fish oil, and NSAIDs) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with the following: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information, including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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6.5.1 Concomitant Therapy to be Avoided 
Participants should avoid using drugs that are contraindicated in IgAN (eg, NSAIDs, 
aminoglycosides, co-trimoxazole) during the study, per local practice. 
During conduct of the study, administration of systemic corticosteroids or other 
immunosuppressive therapy (for IgAN or other conditions) is prohibited due to the risk of over 
immune suppression due to overlapping actions of VIS649 and other immunosuppressive agents. 
If the Investigator believes that treatment with such therapy is required, and the potential benefits 
outweigh the possible risks, the Medical Monitor must be notified, as continued dosing with 
study intervention may, in this circumstance, be discontinued.  
6.6 Dosing Schedule Modification 
Participants will be encouraged to follow the schedule of visits for their monthly infusions as 
close to the prescribed interval as possible. If under special circumstances, a participant is unable 
to visit the study center within 7 days of the scheduled infusion, they will still be able to receive 
the infusion within the next 7 days, and this will be recorded as a protocol deviation. However, if 
there is any further delay, that dose should be skipped, and the participant should receive 
subsequent doses as per the schedule. The participant will not receive additional doses to make 
up for the missed dose(s). 
There will be no other alterations from the dosing schedule outlined in Section 6.1.  
6.7 Intervention after the End of the Study 
A rollover, open-label extension study will be offered to enable access to VIS649 (there will be 
no placebo arm) for study participants who have completed this trial, provided that the 
Investigator believes that the participants might benefit, and that the site has agreed to participate 
in the extension study. Further details will be provided in a separate protocol. 


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7. DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Study Intervention Dosing 
Participants have the right to discontinue study intervention or withdraw from the study at any 
time for any reason. Participants may withdraw or be withdrawn from study-related procedures 
and intervention for the following reasons: 
• Withdrawal of consent 
• Adverse event 
• Protocol deviation 
• Investigator decision 
• Pregnancy (Appendix 4) 
• Sponsor decision to terminate the study 
• Lost to follow-up 
In particular, study intervention should be discontinued if participants experience the following:  
• Grade ≥ 3 infusion reaction such as severe anaphylaxis or cytokine release syndrome 
• At the discretion of the Investigator, study intervention may be stopped if the participant 
has an unexplained decline in eGFR of > 30% sustained over 3 months that is not 
reversed after correction of all reversible factors such as volume depletion, NSAID, 
ACEI/ARB, other nephrotoxic drug use, or resolution of acute illness or infection. 
Adverse events that are ongoing at the EOS should be monitored until resolution, stabilization, 
until the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS.  
Serious AEs that are ongoing at the EOS should be monitored until resolution, stabilization, until 
the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS, 
whichever is longer (Section 8.3.1). If the participant withdraws because of an AE, every effort 
must be made to perform protocol-specified safety follow-up procedures. 
If study intervention dosing is definitively discontinued, participants are encouraged to continue 
with assessments as per the schedule of assessments. At a minimum, if study participation is 
terminated by the participant or Investigator, the participant should complete all early 
termination assessments and will be encouraged to return for the EOS assessments outlined in 
Table 1. The primary reason for discontinuation should be recorded in the appropriate section of 
the eCRF. 
7.1.1 Temporary Discontinuation 
Study intervention may be interrupted for up to 2 doses in participants who experience the 
following:  
• Severe or intractable infection  
• Acute severe illness or injury requiring hospitalization 


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7.1.2 Rechallenge 
VIS649 doses may be re-initiated (at the same dose) under the following conditions: 
• If study intervention was interrupted due to acute illness or infection, study intervention 
can be re-initiated if the participant has recovered from the acute illness or infection, as 
determined by the Investigator. 
7.2 Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, the participant should complete all early 
termination (ET) assessments outlined in Table 1. The participant will be encouraged to attend 
an EOS visit 155 days following the last dose of study intervention. The participant will be 
permanently discontinued both from the study intervention and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
7.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule. The site also should ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• The participant, if reached, should be invited to attend EOS visits, which can also be done 
via phone call, medical record review, etc. if the participant is unwilling to visit the 
clinic. 
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8. STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are outlined in Table 1. Protocol waivers or exemptions are 
not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements is essential for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 Efficacy Assessments 
8.1.1 Twenty-four-hour Urine Sample Collection 
Twenty-four-hour urine collection for derivation of 24-hour urine volume, protein, albumin, 
creatinine, uPCR, and uACR will be performed at the time points outlined in Table 1.  
Participants will discard the first morning void and begin a 24-hour urine collection the day prior 
to the clinic visit. Care should be taken to avoid over-collection or under-collection of urine, 
however, if this occurs, the sample may still be used to calculate the proteinuria and uPCR. On 
days of 24-hour urine collection (or the intended 24-hour urine collection), the uPCR sample will 
be collected from the 24-hour urine collection and routine urinalysis will be performed on a 
sample freshly voided during the clinic visit. 
8.2 Safety Assessments 
8.2.1 Physical Examinations 
A complete physical examination, including assessments of the cardiovascular, respiratory, 
gastrointestinal, and neurological systems will be completed at the screening, at the 
Month 12/ET visit, and at the Month 16/EOS visit. In addition, physical examinations may be 
conducted at any other time if considered clinically indicated by the Investigator. 
8.2.2 Vital Signs 
Vital sign measurements will be performed at the visits outlined in Table 1 and will include 
weight, temperature, pulse rate, respiratory rate, and systolic and diastolic BP. Height will be 
measured and recorded during screening.  
Vital signs measurements on dosing days will be recorded within 15 (±5) minutes prior to the 
start of the infusion, every 15 minutes until the infusion is complete, and postinfusion at 
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Systolic and diastolic BP and pulse measurements will be assessed while the participant is seated 
or supine with a completely automated device. Manual techniques will be used only if an 
automated device is not available. Blood pressure and pulse measurements should be preceded 
by at least 5 minutes of rest for the participant in a quiet setting without distractions (no 
television, cell phone, etc). 
Whenever possible, vital signs should be collected before blood collection for laboratory tests 
and before dosing with study intervention. 
8.2.3 Electrocardiograms 
A single 12-lead ECG, heart rate, and measures of PR, QRS, QT, and QTc intervals will be 
obtained at the screening visit. Twelve-lead ECGs should also be conducted at other times during 
the study if considered clinically indicated by the Investigator. 
Twelve-lead ECGs should be conducted after 5 minutes in recumbence or semi-recumbency.  
8.2.4 Clinical Safety Laboratory Assessments 
Clinical laboratory evaluations for safety will be performed by a central laboratory whenever 
possible, however, local laboratory tests may be utilized for more urgent safety monitoring. 
Before starting the study, the Investigator will provide the Sponsor (or its designee) copies of all 
laboratory certifications and normal ranges for all laboratory assessments to be performed by that 
laboratory. Local laboratory assessments to make intervention-related decisions may be 
performed at all visits. 
A list of clinical safety laboratory tests to be performed is provided in Appendix 2 and the timing 
for these assessments is provided in Table 1. All protocol-required laboratory assessments must 
be conducted in accordance with the laboratory manual. Details of laboratory tests to be 
conducted for assessment of VIS649 PK, PD, exploratory biomarkers, and immunogenicity are 
provided in Sections 8.5, 8.6, 8.8, and 8.9, respectively.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal, with the exception 
of disease defining abnormalities such as eGFR and proteinuria considered to be a part of the 
natural history of IgAN, during the study or within 30 days after the last dose of study 
intervention should be repeated until the values return to normal, baseline, or are no longer 
considered clinically significant by the Investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 


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8.3 Adverse Events and Serious Adverse Events 
Adverse event and SAE definitions are provided in Appendix 3. 
All AEs (serious and nonserious) reported by the participant must be recorded on the source 
documents and eCRF provided by the Sponsor. Medical terminology should be used for AE 
reporting. Adverse events should be reported as a single unifying diagnosis whenever possible 
or, in the absence of a unifying diagnosis, as individual signs or symptoms. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
Adverse events that are ongoing at the EOS should be monitored until resolution, stabilization, 
until the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS.  
Serious AEs that are ongoing at the EOS should be monitored until resolution, stabilization, until 
the event is otherwise explained, the participant is lost to follow-up, or 30 days after EOS, 
whichever is longer (see Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information about AEs or SAEs after conclusion 
of study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of Detecting Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. For example, participants should be asked the nonleading question: “How have 
you felt since your last visit?”  
Exacerbation or disease progression should be reported as an AE only if there are unusual or 
severe clinical features that were not present, or experienced earlier, or not expected based on the 
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In addition, the Sponsor must be notified immediately by telephone, fax, or e-mail of any 
immediately reportable events. Immediately reportable events (IRE) include the following:  
• SAEs 
• Pregnancies. Although normal pregnancy is not an AE, it will mandate study intervention 
discontinuation and must be reported on an IRE form and the Pregnancy Surveillance 
Form(s) to the Sponsor. Pregnancy will only be documented on the AE eCRF if there is 
an abnormality or complication. This includes pregnancy of the participant or the 
participant’s partner 
Adverse event, start date, end date, seriousness, severity, relationship to study intervention, 
action taken with study treatment, and outcome will be recorded on the source documents and in 
the eCRF. Special attention should be paid to recording hospitalization and concomitant 
medications. 
8.3.3 Follow-up of Adverse Events and Serious Adverse Events 
Nonserious AEs that are identified at any time during the study must be recorded on the AE 
eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious events (that 
are not IREs) that are ongoing at the last scheduled contact will be recorded as ongoing on the 
eCRF. For any AE having been identified throughout the study, additional relevant medical 
history information may be requested by the Sponsor during analysis to further ascertain 
causality (including, but not limited to, information such as risk-related behavior, family history, 
and occupation). 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be collected from the signing of 
the informed consent form (ICF) until the EOS. Adverse events that are ongoing at the EOS 
should be monitored until resolution, stabilization, until the event is otherwise explained, the 
participant is lost to follow-up, or 30 days after EOS. Serious AEs that are ongoing at the EOS 
should be monitored until resolution, stabilization, until the event is otherwise explained, the 
participant is lost to follow-up, or 30 days after EOS, whichever is longer (see Section 1.3).   
Resolution means that the participant has returned to the baseline state of health and stabilized 
means that the Investigator does not expect any further improvement or worsening of the 
participant’s condition. The Investigator will continue to report any significant follow-up 
information to the Sponsor up to the point the event has resolved or stabilized, or the participant 
is lost to follow-up or has died. 
Further information on follow-up procedures is provided in Appendix 3. 
8.3.4 Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 


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Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5 Pregnancy 
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until 155 days after the last dose of study 
intervention. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4 Treatment of Overdose 
Standard symptomatic support measures should be used in the case of excessive pharmacological 
effects or overdose. No antidotes are available. 
8.5 Pharmacokinetics 
For all participants, serial blood samples will be drawn prior to each VIS649/placebo IV infusion 
and at the end of each infusion in order to determine circulating serum concentrations of VIS649, 
as specified in Table 1 and Table 5. Up to 60 participants (approximately 15 participants in each 
cohort) may have a more intensive PK and PD sampling schedule, as described in Table 5. Study 
participants who agree to participate in this more intensive PK and PD sample collection 
sub-study will sign an additional informed consent for this activity.  
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate laboratory manual. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
Samples collected for analyses of serum VIS649 concentrations may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 






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9. STATISTICAL CONSIDERATIONS 
9.1 Statistical Hypothesis 
The primary efficacy objective of this study is to evaluate the effect of VIS649 on proteinuria. 
The hypothesis that there is a VIS649-related dose response in the change from baseline in 
natural log uPCR at Month 12 versus placebo will be formally tested.   
9.2 Sample Size Determination 
The sample size for this study was calculated assuming a linear dose response in reduction of 
uPCR in placebo and VIS649 2, 4, and 8 mg/kg dose levels of 0%, 15%, 30%, and 45%, 
respectively. Applying contrasts of -3, -1, 1, and 3 for the corresponding dose levels and 
analyzing uPCR on the natural log scale, the result is an expected mean change from baseline of 
0, -0.163, -0.357, and -0.593 for placebo and VIS649 dose levels of 2, 4, and 8 mg/kg, 
respectively.  Using an analysis of variance model with contrasts of -3, -1, 1, and 3 for the 
corresponding dose levels, a standard deviation of 0.87, 80% power, a 2-sided type I error rate of 
0.05, and accounting for a dropout rate of ~ 20%, the required sample size is 36 participants per 
group, or 144 participants overall.   
9.3 Populations for Analyses 
Populations for analysis in this study are defined in Table 6. 
Table 6: 
Populations for Analysis 
Population 
Description 
ITT 
All participants who are randomized. Participants will be categorized by the 
intervention and dose they were randomized to receive.  
mITT 
All randomized participants who receive at least 1 dose of study intervention. 
Participants will be categorized by the intervention and dose that they were 
randomized to receive. 
Safety 
All randomized participants who receive any amount of study intervention. 
Participants will be analyzed according to the intervention and dose they actually 
received. 
PK/PD 
All randomized participants who have at least 1 set of postdose PK/PD measures 
taken. 
Biomarker 
All randomized participants who consented to participation in the biomarker 
substudy. A separate consent process is required, as described in Section 8.8. 
Abbreviations: ITT = intent-to-treat; mITT = modified intent-to-treat; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s). 
Analysis of safety parameters will be performed on the Safety population. The modified 
intent-to-treat (mITT) population will be the primary population for assessment of efficacy. The 
PK/PD population will be the primary population for PK/PD summaries. Analysis of biomarker 
data will be performed on the Biomarker population. 






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methods. If appropriate, continuous independent variables will be evaluated as such and as 
categorical variables with participants grouped by exposure categories. Additionally, population 
PK/PD modeling and simulation may be utilized to measure the dynamic relationship between 
drug concentration, drug effect, and drug safety. 
9.4.7.2 Antidrug Antibodies 
Presence vs absence of anti-VIS649 antibodies, anti-VIS649 antibody titers (including 
neutralizing antibody titers, if available), will be summarized by intervention group and time 
point using descriptive statistics. 
9.5 Interim Analyses 
In addition to 5 DSMB safety reviews (Section 9.6), 3 interim PK/Ig analyses and 2 interim 
efficacy analyses (completed to inform future study design) are planned: 
• Three PK/Ig analyses will be performed; each will be conducted in parallel with a key 
milestone event (DSMB meetings, early interim analysis, or the formal interim analysis).  
APRIL levels may also be analyzed along with PK and Ig. Anti-drug antibody may be 
assessed if warranted based on the PK data. These PK/Ig assessments will be performed 
by a separate, unblinded team which will include group-unblinded PK/Ig summaries 
(with individual participant treatment blinded). Summarized results will be made 
available to the Sponsor to inform future study design. These analyses may be used to 
update a previously developed population PK/PD model. 
• An early interim efficacy analysis may be performed when at least 16 participants have 
been treated for at least 2 months, optimally when at least 50% of the 16 (or more) 
participants have achieved > 30% reduction in uPCR based on review of blinded uPCR 
data across all study participants. Blinded uPCR monitoring will be conducted to 
determine the timing of this early interim efficacy analysis. Monitoring will include 
plotting blinded uPCR data over time per participant. The interim analysis will present 
group-unblinded efficacy summaries (with individual participant treatment blinded) and 
will be prepared by a separate, unblinded team for Sponsor review to inform future study 
design.  
• A second interim efficacy analysis will be performed at the time of the fourth scheduled 
DSMB meeting (once 50% of randomized participants have completed 6 months of study 
dosing and approximately 20 participants have completed 12 months of study dosing). 
Group-unblinded efficacy summaries (with individual participant treatment blinded) will 
be prepared for Sponsor review to inform future study design.  
• The interim efficacy analyses will not include hypothesis testing and will be for the 
purpose of future study design and planning. The primary efficacy endpoint, change in 
proteinuria levels from baseline, will be analyzed. No modifications to this study protocol 
are planned based on results of the interim analyses. Nonetheless, to account for multiple 
reviews of the efficacy endpoint, the type I error rate applied at the end of the study will 
be reduced by 0.002 for each interim efficacy review, resulting in a 2-sided end-of-study 
type I error rate of 0.046. 


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Additional details will be provided in the SAP. 
9.6 Data Safety Monitoring Board 
An independent DSMB will review unblinded safety data. The DSMB will meet at 5 scheduled 
data review meetings and on an ad hoc basis as needed. Details regarding the content and scope 
of safety assessments, as well as the governing of the DSMB, will be described in a separate 
DSMB charter. Data safety monitoring board meetings will be scheduled as the requirements in 
Table 7 are met. 
Table 7: 
Scheduled Data Safety Monitoring Board Reviews 
Scheduled DSMB Review Number of Participants and Treatment Exposure 
DSMB review #1 
The first scheduled meeting will occur after 12 participants have been 
randomized and have completed at least 3 months of study dosing. 
DSMB review #2 
The second scheduled meeting will occur after 24 participants have been 
randomized and have completed at least 3 months of study dosing. 
DSMB review #3 
The third scheduled meeting will occur after ~25% of participants have been 
randomized and have completed 3 months of study dosing.  
DSMB review #4 
The fourth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 6 months of study dosing, and ~20 participants 
have completed 12 months of study dosing.  
DSMB review #5 
The fifth scheduled meeting will occur after ~50% of participants have been 
randomized and have completed 12 months of study dosing. 
Abbreviations: DSMB = data safety monitoring board. 
 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
•
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical Sciences
International Ethical Guidelines
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
Guidelines
•
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
•
Providing written summaries of the status of the study to the IRB/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established by
the IRB/IEC
•
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
•
Providing oversight of the conduct of the study at the site and adherence to requirements
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical
studies (if applicable), and all other applicable local regulations
10.1.2 Financial Disclosure 
All required information regarding financial certification or disclosure will be provided to the 
Sponsor for all investigators and subinvestigators in accordance with the terms of the relevant 
regional regulation(s). 
Informed consent will be freely obtained from all participants (or their guardian or legally 
acceptable representative, as applicable per local laws).  


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Each ICF will comply with ICH GCP: Consolidated Guideline E61 and local regulatory 
requirements. The Investigator will ensure that the Sponsor reviews and authorizes any written 
site-specific ICF used in the study before submission to the IRB/IEC. 
Investigators may discuss study availability and the possibility for entry with a potential 
participant without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose of 
determining eligibility for this study, including withdrawal from current medication(s).  
Potential participants are free to refuse entry into the study, or withdraw from the study at any 
time, without justification, and there will be no consequences to their further care. 
A separate and similar consent process will be followed for the optional blood samples for 
pharmacogenomic testing and future biospecimen research. Consent must be obtained before the 
blood sample is collected. 
10.1.3 Data Protection 
All information generated in this study will be considered confidential and will not be disclosed 
to anyone not directly concerned with the study without the Sponsor’s prior written permission. 
Participant confidentiality requirements of the region(s) where the study is conducted will be 
met. However, authorized regulatory officials and Sponsor personnel (or their representatives) 
may be allowed full access to inspect and copy the records, consistent with local requirements. 
All investigational medicinal products, participant bodily fluids, and/or other materials collected 
shall be used solely in accordance with this protocol, unless otherwise agreed to in writing by the 
Sponsor. 
Participants will be identified only by unique participant ID in eCRF. If further participant 
identification is required, participants’ full names may be made known to a regulatory agency or 
other authorized officials if necessary, subject to local regulations. 
10.1.4 Dissemination of Clinical Study Data 
This study will comply with the Clinical Trials Registration and Results Information Submission 
rule. As such, this study will be registered at ClinicalTrials.gov, and results information from this 
study will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish 
results in peer-reviewed journals.  
10.1.5 Data Quality Assurance 
The accuracy and reliability of the study data will be assured by the selection of qualified 
Investigators and appropriate study centers, review of protocol procedures with the Investigator 
and associated personnel prior to the study, and periodic monitoring visits by the Sponsor or 
designee. 
Written instructions will be provided for the collection, preparation, and shipment of samples. 
The Sponsor or its designee will review the electronic data capture system for accuracy and 
completeness during (on-site) monitoring visits and after transmission to the Sponsor; any 


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discrepancies will be resolved with the Investigator or designee, as appropriate. After uploading 
the data into the clinical study database, they will be verified for accuracy. 
In accordance with Good Clinical Research Practice Guidelines and Recommendations, 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 a national GCP compliance 
program or to review the results of this study in support of a regulatory submission. The 
Investigator should immediately notify the Sponsor if they have been contacted by a regulatory 
agency concerning an upcoming inspection. 
10.1.6 Source Documents 
Source documents are defined as the results of original observations and activities of a clinical 
investigation. Source documents will include but are not limited to medical records, electronic 
data, screening logs, and recorded data from automated instruments. All source documents 
pertaining to this study will be maintained by the Investigators and made available for direct 
inspection by authorized persons. 
Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s) by providing direct access to source data/documents by authorized 
persons as defined in the ICF. In all cases, participant confidentiality must be maintained in 
accordance with local regulatory requirements. 
10.1.7 Study and Site Start and Closure 
Study site participation may be discontinued if the Sponsor or its designee, the Investigator, or 
the ethical review board of the study site judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 10.3.2.  
The study will be discontinued if the Sponsor or its designee judges it necessary for medical, 
safety, regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 
10.1.8 Publication Policy 
The publication policy for the study will be documented in the agreement between the Sponsor 
and the Investigator. Authorship for any Visterra-sponsored publications resulting from the 
conduct of this study will be based on International Committee of Medical Journal Editors 
authorship criteria (http://www.icmje.org/recommendations). According to these guidelines, one 
may be considered an author only if the following criteria are met: 
1. Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work; AND 
2. Drafting the work or revising it critically for important intellectual content; AND 
3. Final approval of the version to be published; AND 


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4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved. 
All authors must meet the above criteria, and all who qualify for authorship based on the above 
criteria should be listed as authors. 


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10.2 Appendix 2 
Clinical Laboratory Tests 
Table 8 provides a list of laboratory tests to be evaluated by the Investigator. 
The tests detailed in Table 8 will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a 
local sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the eCRF. Local 
laboratory results will not be acceptable for qualifying a participant for the study (except for the 
urine dipstick and microscopy). 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 8: 
Protocol-Required Safety Laboratory Assessments 
Serology (screening only) 
HBsAg, anti-HBc (IgG and IgM) antibody, anti-HCV antibody, HIV. 
Hematology 
Hemoglobin, RBC, WBC with differential (including absolute 
neutrophil count), platelet count. 
Serum chemistry 
Comprehensive serum analyte testing will include sodium, potassium, 
BUN, bicarbonate (venous), creatinine, calcium, chloride, magnesium, 
phosphorus, albumin, glucose, AST, ALT, ALP, total bilirubin (direct 
bilirubin if total > ULN), total cholesterol and triglycerides. This panel 
of tests will be collected as described in Table 1.  
Urinalysis 
Color and appearance; pH, specific gravity, ketones, protein, glucose, 
bilirubin, nitrite, urobilinogen, blood by dipstick. Dipstick performed 
locally. 
Pregnancy (females only) 
Serum β-hCG (screening only); urine β-hCG (all other visits). 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
β-hCG = β-human chorionic gonadotropin; eGFR = estimated glomerular filtration rate; HBc = hepatitis B core; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = red 
blood cell; ULN = upper limit of normal; WBC = white blood cell. 
Note: eGFR will be calculated from serum creatinine by the Chronic Kidney Disease Epidemiology Collaboration 
formula, which is as follows: 
eGFR =141 x min (SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black] 
κ = 0.7 (females) or 0.9 (males), α = -0.329 (females) or -0.411 (males), min = indicates the minimum of SCr/κ or 1, 
max = indicates the maximum of SCr/κ or 1. Additional adjustment for ethnicity or race may be incorporated as 
warranted. 
Investigators must document their review of each laboratory safety report. 
Laboratory results that could unblind the study (eg, Ig) will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 










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the site can report this information on a paper SAE form or to the Medical Monitor by 
telephone. 
• 
Contact information for SAE reporting: email 
 or telephone:  
o North America   
 
 
o Asia Pacific  
 
 
 
o Europe/Middle East/Africa  
 
o Latin America   
 
 
 


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10.4 Appendix 4  
Contraceptive Guidance and Collection of Pregnancy Information 
10.4.1 Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from site personnel review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required.  
o Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
10.4.2 Contraception Guidance 
Women of childbearing potential must use highly effective methods of contraception for at least 
28 days prior to first study intervention through 155 days after the last dose of study intervention. 


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Highly effective methods of contraception are defined as methods that can achieve a failure rate 
of less than 1% per year when used consistently and correctly, and include:  
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:  
o oral 
o intravaginal  
o transdermal  
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
o oral  
o injectable  
o implantable   
• intrauterine device   
• intrauterine hormone-releasing system    
• bilateral tubal occlusion  
• vasectomized partner; note: a vasectomized partner is a highly effective birth control 
method provided that the partner is the sole sexual partner of the WOCBP study 
participant and that the vasectomized partner has received medical assessment of the 
surgical success  
• sexual abstinence; sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the participant  
Women of childbearing potential must also have a negative serum beta human chorionic 
gonadotropin (β-hCG) pregnancy test at screening and a negative urine β-hCG pregnancy test 
prior to the first study intervention on Day 1. Female participants must also agree not to donate 
eggs/bank eggs for the duration of their participation in the study. 
Male participants and/or his partner must use an acceptable form of contraception (ie, 
double-barrier, have had a vasectomy, or have a female partner of nonchildbearing potential) 
from date of first study dose through 155 days after the last dose of study intervention. Following 
the first dose of study intervention, male participants must also agree to not donate sperm 
through 155 days after the last dose of study intervention. 
10.4.3 Collection of Pregnancy Information 
Male participants with partners who become pregnant 


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• The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to the Sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the Sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) is always considered to be an SAE and will 
be reported as such.  
• Any poststudy pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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10.5 Appendix 5 
Abbreviations 
Abbreviation 
Definition 
ACEI 
Angiotensin-converting enzyme inhibitor 
ADA 
Antidrug antibody 
AE 
Adverse event 
a-g 
Aberrantly glycosylated 
APRIL 
A proliferation inducing ligand 
ARB 
Angiotensin receptor blocker 
β-hCG 
Beta human chorionic gonadotropin 
BCMA 
B-cell maturation antigen 
BP 
Blood pressure 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COPD 
Chronic obstructive pulmonary disease 
%CV 
Coefficient of variation 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End-of-study 
ESRD 
End-stage renal disease 
ET 
Early termination 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCV 
Hepatitis C virus 
HRT 
Hormone-replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IgA/G/M 
Immunoglobulin A/G/M 


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Abbreviation 
Definition 
IgAN 
Immunoglobulin A nephropathy 
IRB 
Institutional Review Board 
IRE 
Immediately reportable event 
IV 
Intravenous(ly) 
IVRS/IWRS 
Interactive voice/web response system 
MEST-C 
Mesangial cellularity, Endocapillary proliferation, Segmental sclerosis, 
Tubular atrophy-Crescents 
mITT 
Modified intent-to-treat 
MMRM 
Mixed Model Repeated Measurement 
NSAID 
Nonsteroidal anti-inflammatory drug 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
TACI 
Transmembrane activator and calcium-modulator and cyclophilin ligand 
(CAML) interactor 
Td 
Tetanus and diphtheria 
uPCR 
Urine protein to creatinine ratio 
WOCBP 
Woman of childbearing potential 


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10.6 Appendix 6 
Table 9: 
Protocol Revision History 
Document 
Date 
Protocol Version 4.0 
08 December 2020 
Protocol Version 3.0 
27 January 2020 
Protocol Version 2.0 
26 November 2019 
Protocol Version 1.0 
28 August 2019 


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11. REFERENCES 
Ballow, M. (2002). "Primary immunodeficiency disorders: antibody deficiency." J Allergy Clin 
Immunol 109(4): 581-591. 
Barbour, S. and J. Feehally (2017). "An update on the treatment of IgA nephropathy." Curr Opin 
Nephrol Hypertens 26(4): 319-326. 
Berthoux, F., H. Suzuki, L. Thibaudin, H. Yanagawa, N. Maillard, C. Mariat, Y. Tomino, B. A. 
Julian and J. Novak (2012). "Autoantibodies targeting galactose-deficient IgA1 associate with 
progression of IgA nephropathy." J Am Soc Nephrol 23(9): 1579-1587. 
Bossen, C., T. G. Cachero, A. Tardivel, K. Ingold, L. Willen, M. Dobles, M. L. Scott, A. 
Maquelin, E. Belnoue, C. A. Siegrist, S. Chevrier, H. Acha-Orbea, H. Leung, F. Mackay, J. 
Tschopp and P. Schneider (2008). "TACI, unlike BAFF-R, is solely activated by oligomeric 
BAFF and APRIL to support survival of activated B cells and plasmablasts." Blood 111(3): 
1004-1012. 
Boyd, J. K., C. K. Cheung, K. Molyneux, J. Feehally and J. Barratt (2012). "An update on the 
pathogenesis and treatment of IgA nephropathy." Kidney Int 81(9): 833-843. 
Castigli, E., S. Scott, F. Dedeoglu, P. Bryce, H. Jabara, A. K. Bhan, E. Mizoguchi and R. S. 
Geha (2004). "Impaired IgA class switching in APRIL-deficient mice." Proc Natl Acad Sci U S 
A 101(11): 3903-3908. 
Cheng, J., W. Zhang, X. H. Zhang, Q. He, X. J. Tao and J. H. Chen (2009). "ACEI/ARB therapy 
for IgA nephropathy: a meta analysis of randomised controlled trials." Int J Clin Pract 63(6): 
880-888. 
Donadio, J. V., E. J. Bergstralh, J. P. Grande and D. M. Rademcher (2002). "Proteinuria patterns 
and their association with subsequent end‐stage renal disease in IgA nephropathy." Nephrology 
Dialysis Transplantation 17(7): 1197-1203. 
Endo, T., M. Nishio, T. Enzler, H. B. Cottam, T. Fukuda, D. F. James, M. Karin and T. J. Kipps 
(2007). "BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through 
activation of the canonical NF-kappaB pathway." Blood 109(2): 703-710. 
Fadlallah, J., H. El Kafsi, D. Sterlin, C. Juste, C. Parizot, K. Dorgham, G. Autaa, D. Gouas, M. 
Almeida, P. Lepage, N. Pons, E. Le Chatelier, F. Levenez, S. Kennedy, N. Galleron, J. P. de 
Barros, M. Malphettes, L. Galicier, D. Boutboul, A. Mathian, M. Miyara, E. Oksenhendler, Z. 
Amoura, J. Dore, C. Fieschi, S. D. Ehrlich, M. Larsen and G. Gorochov (2018). "Microbial 
ecology perturbation in human IgA deficiency." Sci Transl Med 10(439). 
Floege, J., I. C. Moura and M. R. Daha (2014). "New insights into the pathogenesis of IgA 
nephropathy." Semin Immunopathol 36(4): 431-442. 
Furst, D. E. (2009). "Serum immunoglobulins and risk of infection: how low can you go?" 
Semin Arthritis Rheum 39(1): 18-29. 


CONFIDENTIAL 
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80 
 
 
Han, S. S., S. H. Yang, M. Choi, H. R. Kim, K. Kim, S. Lee, K. C. Moon, J. Y. Kim, H. Lee, J. 
P. Lee, J. Y. Jung, S. Kim, K. W. Joo, C. S. Lim, S. W. Kang, Y. S. Kim and D. K. Kim (2016). 
"The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy." J Am Soc 
Nephrol 27(11): 3430-3439. 
Hastings, M. C., Z. Bursac, B. A. Julian, E. Villa Baca, J. Featherston, S. Y. Woodford, L. Bailey 
and R. J. Wyatt (2017). "Life Expectancy for Patients From the Southeastern United States With 
IgA Nephropathy." Kidney international reports 3(1): 99-104. 
Inker, L. A., H. Mondal, T. Greene, T. Masaschi, F. Locatelli, F. P. Schena, R. Katafuchi, G. B. 
Appel, B. D. Maes, P. K. Li, M. Praga, L. Del Vecchio, S. Andrulli, C. Manno, E. Gutierrez, A. 
Mercer, K. J. Carroll, C. H. Schmid and A. S. Levey (2016). "Early Change in Urine Protein as a 
Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis." Am J 
Kidney Dis 68(3): 392-401. 
Janssen, L. M. A., T. Macken, M. C. W. Creemers, J. F. M. Pruijt, J. J. J. Eijk and E. de Vries 
(2018). "Truly selective primary IgM deficiency is probably very rare." Clin Exp Immunol 
191(2): 203-211. 
Jarrick, S., S. Lundberg, A. Welander, J. J. Carrero, J. Hoijer, M. Bottai and J. F. Ludvigsson 
(2019). "Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study." J Am 
Soc Nephrol 30(5): 866-876. 
KDIGO (2012). "KDIGO Clinical Practice Guideline for Glomerulonephritis." Kidney 
International Supplements 2(2): 139-274. 
Kiryluk, K., Y. Li, F. Scolari, S. Sanna-Cherchi, M. Choi, M. Verbitsky, D. Fasel, S. Lata, S. 
Prakash, S. Shapiro, C. Fischman, H. J. Snyder, G. Appel, C. Izzi, B. F. Viola, N. Dallera, L. Del 
Vecchio, C. Barlassina, E. Salvi, F. E. Bertinetto, A. Amoroso, S. Savoldi, M. Rocchietti, A. 
Amore, L. Peruzzi, R. Coppo, M. Salvadori, P. Ravani, R. Magistroni, G. M. Ghiggeri, G. 
Caridi, M. Bodria, F. Lugani, L. Allegri, M. Delsante, M. Maiorana, A. Magnano, G. Frasca, E. 
Boer, G. Boscutti, C. Ponticelli, R. Mignani, C. Marcantoni, D. Di Landro, D. Santoro, A. Pani, 
R. Polci, S. Feriozzi, S. Chicca, M. Galliani, M. Gigante, L. Gesualdo, P. Zamboli, G. G. 
Battaglia, M. Garozzo, D. Maixnerova, V. Tesar, F. Eitner, T. Rauen, J. Floege, T. Kovacs, J. 
Nagy, K. Mucha, L. Paczek, M. Zaniew, M. Mizerska-Wasiak, M. Roszkowska-Blaim, K. 
Pawlaczyk, D. Gale, J. Barratt, L. Thibaudin, F. Berthoux, G. Canaud, A. Boland, M. Metzger, 
U. Panzer, H. Suzuki, S. Goto, I. Narita, Y. Caliskan, J. Xie, P. Hou, N. Chen, H. Zhang, R. J. 
Wyatt, J. Novak, B. A. Julian, J. Feehally, B. Stengel, D. Cusi, R. P. Lifton and A. G. Gharavi 
(2014). "Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity 
against intestinal pathogens." Nat Genet 46(11): 1187-1196. 
Kiryluk, K., Z. Moldoveanu, J. T. Sanders, T. M. Eison, H. Suzuki, B. A. Julian, J. Novak, A. G. 
Gharavi and R. J. Wyatt (2011). "Aberrant glycosylation of IgA1 is inherited in both pediatric 
IgA nephropathy and Henoch-Schonlein purpura nephritis." Kidney Int 80(1): 79-87. 
Kiryluk, K. and J. Novak (2014). "The genetics and immunobiology of IgA nephropathy." The 
Journal of Clinical Investigation 124(6): 2325-2332. 


CONFIDENTIAL 
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81 
 
 
Kiryluk, K., J. Novak and A. G. Gharavi (2013). "Pathogenesis of immunoglobulin A 
nephropathy: recent insight from genetic studies." Annual review of medicine 64: 339-356. 
Knoppova, B., C. Reily, N. Maillard, D. V. Rizk, Z. Moldoveanu, J. Mestecky, M. Raska, M. B. 
Renfrow, B. A. Julian and J. Novak (2016). "The Origin and Activities of IgA1-Containing 
Immune Complexes in IgA Nephropathy." Front Immunol 7: 117. 
Lai, K. N., S. C. Tang, F. P. Schena, J. Novak, Y. Tomino, A. B. Fogo and R. J. Glassock 
(2016). "IgA nephropathy." Nat Rev Dis Primers 2: 16001. 
Levey, A. S., L. A. Stevens, C. H. Schmid, Y. L. Zhang, A. F. Castro, 3rd, H. I. Feldman, J. W. 
Kusek, P. Eggers, F. Van Lente, T. Greene, J. Coresh and E. P. I. Ckd (2009). "A new equation 
to estimate glomerular filtration rate." Ann Intern Med 150(9): 604-612. 
Louis, A. G., S. Agrawal and S. Gupta (2016). "Analysis of subsets of B cells, Breg, CD4Treg 
and CD8Treg cells in adult patients with primary selective IgM deficiency." Am J Clin Exp 
Immunol 5(1): 21-32. 
Louis, A. G. and S. Gupta (2014). "Primary selective IgM deficiency: an ignored 
immunodeficiency." Clin Rev Allergy Immunol 46(2): 104-111. 
Lv, J., H. Zhang, M. G. Wong, M. J. Jardine, M. Hladunewich, V. Jha, H. Monaghan, M. Zhao, 
S. Barbour, H. Reich, D. Cattran, R. Glassock, A. Levin, D. Wheeler, M. Woodward, L. Billot, 
T. M. Chan, Z. H. Liu, D. W. Johnson, A. Cass, J. Feehally, J. Floege, G. Remuzzi, Y. Wu, R. 
Agarwal, H. Y. Wang and V. Perkovic (2017). "Effect of Oral Methylprednisolone on Clinical 
Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial." Jama 
318(5): 432-442. 
Mestecky, J., J. Novak, Z. Moldoveanu and M. Raska (2016). "IgA nephropathy enigma." Clin 
Immunol 172: 72-77. 
Mestecky, J., M. Raska, B. A. Julian, A. G. Gharavi, M. B. Renfrow, Z. Moldoveanu, L. Novak, 
K. Matousovic and J. Novak (2013). "IgA nephropathy: molecular mechanisms of the disease." 
Annu Rev Pathol 8: 217-240. 
Muto, M., B. Manfroi, H. Suzuki, K. Joh, M. Nagai, S. Wakai, C. Righini, M. Maiguma, S. Izui, 
Y. Tomino, B. Huard and Y. Suzuki (2017). "Toll-Like Receptor 9 Stimulation Induces Aberrant 
Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA 
Nephropathy." J Am Soc Nephrol 28(4): 1227-1238. 
Myette, J. R., T. Kano, H. Suzuki, S. E. Sloan, K. J. Szretter, B. Ramakrishnan, H. Adari, K. D. 
Deotale, F. Engler, Z. Shriver, A. M. Wollacott, Y. Suzuki and B. J. G. Pereira (2019). "A 
Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of 
murine IgA nephropathy." Kidney International 96(1): 104-116. 
Nam, K. H., J. H. Kie, M. J. Lee, T. I. Chang, E. W. Kang, D. W. Kim, B. J. Lim, J. T. Park, Y. 
E. Kwon, Y. L. Kim, K. S. Park, S. Y. An, H. J. Oh, T. H. Yoo, S. W. Kang, K. H. Choi, H. J. 


CONFIDENTIAL 
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82 
 
 
Jeong, D. S. Han and S. H. Han (2014). "Optimal proteinuria target for renoprotection in patients 
with IgA nephropathy." PLoS One 9(7): e101935. 
Pozzi, C., S. Andrulli, L. Del Vecchio, P. Melis, G. B. Fogazzi, P. Altieri, C. Ponticelli and F. 
Locatelli (2004). "Corticosteroid effectiveness in IgA nephropathy: long-term results of a 
randomized, controlled trial." J Am Soc Nephrol 15(1): 157-163. 
Radhakrishnan, J. and D. C. Cattran (2012). "The KDIGO practice guideline on 
glomerulonephritis: reading between the (guide)lines--application to the individual patient." 
Kidney Int 82(8): 840-856. 
Rauen, T., F. Eitner, C. Fitzner, C. Sommerer, M. Zeier, B. Otte, U. Panzer, H. Peters, U. Benck, 
P. R. Mertens, U. Kuhlmann, O. Witzke, O. Gross, V. Vielhauer, J. F. Mann, R. D. Hilgers and J. 
Floege (2015). "Intensive Supportive Care plus Immunosuppression in IgA Nephropathy." N 
Engl J Med 373(23): 2225-2236. 
Reich, H. N., S. Troyanov, J. W. Scholey and D. C. Cattran (2007). "Remission of proteinuria 
improves prognosis in IgA nephropathy." J Am Soc Nephrol 18(12): 3177-3183. 
Rodrigues, J. C., M. Haas and H. N. Reich (2017). "IgA Nephropathy." Clinical Journal of the 
American Society of Nephrology 12(4): 677-686. 
Schena, F. P. and I. Nistor (2018). "Epidemiology of IgA Nephropathy: A Global Perspective." 
Semin Nephrol 38(5): 435-442. 
Tesar, V., S. Troyanov, S. Bellur, J. C. Verhave, H. T. Cook, J. Feehally, I. S. Roberts, D. 
Cattran and R. Coppo (2015). "Corticosteroids in IgA Nephropathy: A Retrospective Analysis 
from the VALIGA Study." J Am Soc Nephrol 26(9): 2248-2258. 
Thompson, A., K. Carroll, L. A. Inker, J. Floege, V. Perkovic, S. Boyer-Suavet, R. W. Major, J. 
I. Schimpf, J. Barratt, D. C. Cattran, B. S. Gillespie, A. Kausz, A. W. Mercer, H. N. Reich, B. H. 
Rovin, M. West and P. H. Nachman (2019). "Proteinuria Reduction as a Surrogate End Point in 
Trials of IgA Nephropathy." Clinical Journal of the American Society of Nephrology 14(3): 469-
481. 
Trimarchi, H., J. Barratt, D. C. Cattran, H. T. Cook, R. Coppo, M. Haas, Z. H. Liu, I. S. Roberts, 
Y. Yuzawa, H. Zhang and J. Feehally (2017). "Oxford Classification of IgA nephropathy 2016: 
an update from the IgA Nephropathy Classification Working Group." Kidney Int 91(5): 1014-
1021. 
Varfolomeev, E., F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. 
Tom, S. Erickson, D. French, P. Schow, I. S. Grewal and A. Ashkenazi (2004). "APRIL-
deficient mice have normal immune system development." Mol Cell Biol 24(3): 997-1006. 
Working Group of the International Ig, A. N. N., S. the Renal Pathology, D. C. Cattran, R. 
Coppo, H. T. Cook, J. Feehally, I. S. Roberts, S. Troyanov, C. E. Alpers, A. Amore, J. Barratt, F. 
Berthoux, S. Bonsib, J. A. Bruijn, V. D'Agati, G. D'Amico, S. Emancipator, F. Emma, F. 


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Ferrario, F. C. Fervenza, S. Florquin, A. Fogo, C. C. Geddes, H. J. Groene, M. Haas, A. M. 
Herzenberg, P. A. Hill, R. J. Hogg, S. I. Hsu, J. C. Jennette, K. Joh, B. A. Julian, T. Kawamura, 
F. M. Lai, C. B. Leung, L. S. Li, P. K. Li, Z. H. Liu, B. Mackinnon, S. Mezzano, F. P. Schena, 
Y. Tomino, P. D. Walker, H. Wang, J. J. Weening, N. Yoshikawa and H. Zhang (2009). "The 
Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and 
classification." Kidney Int 76(5): 534-545. 
Wyatt, R. J. and B. A. Julian (2013). "IgA nephropathy." N Engl J Med 368(25): 2402-2414. 
Yazdani, R., G. Azizi, H. Abolhassani and A. Aghamohammadi (2017). "Selective IgA 
Deficiency: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and 
Management." Scand J Immunol 85(1): 3-12. 
Yel, L., S. Ramanuja and S. Gupta (2009). "Clinical and immunological features in IgM 
deficiency." Int Arch Allergy Immunol 150(3): 291-298. 
Zhai, Y. L., L. Zhu, S. F. Shi, L. J. Liu, J. C. Lv and H. Zhang (2016). "Increased APRIL 
Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy." Medicine (Baltimore) 
95(11): e3099. 
Zhao, N., P. Hou, J. Lv, Z. Moldoveanu, Y. Li, K. Kiryluk, A. G. Gharavi, J. Novak and H. 
Zhang (2012). "The level of galactose-deficient IgA1 in the sera of patients with IgA 
nephropathy is associated with disease progression." Kidney Int 82(7): 790-796.