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
Phase: PHASE2
Conditions: Immunoglobulin A Nephropathy, Glomerular Disease, IgAN
Sponsor: Visterra, Inc.

 
 
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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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: 
 
 
 
 

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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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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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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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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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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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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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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 
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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 
local requirements. 

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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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