Safety and Efficacy Study of VIS649 for IgA Nephropathy

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

Detailed Description
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This is a Phase 2, double-blind, randomized, placebo-controlled study in patients aged 18 years and above with biopsy confirmed diagnosis of IgAN. The study is designed to test the safety and effectiveness of multiple doses of VIS649. The main objectives are to evaluate the safety and tolerability of VIS649 and to evaluate the dose response of different doses of VIS649 by measuring proteinuria. The study is comprised of three main periods, Screening, Treatment (12 months) and Follow-Up (4 months). Approximately 144 patients will be enrolled. The findings from this study will form the basis for subsequent clinical development of VIS649. VIS649 is a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of the cytokine A PRoliferation Inducing Ligand (APRIL), a key factor in the production of aberrantly glycosylated IgA1 (a-g- IgA1), which is critical to the pathogenesis of IgAN.

Official Title
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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

Conditions
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Immunoglobulin A Nephropathy, Glomerular Disease, IgAN

Intervention / Treatment
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* Drug: Dose-Placebo
* Drug: Low Dose-VIS649
* Drug: Medium Dose-VIS649
* Drug: High Dose-VIS649


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Participant is a male or female ≥ 18 years of age at the time of signing the informed consent. Participant must have biopsy-confirmed IgAN. Participant has medical records showing they have been on stable and maximally tolerated doses of either ACEI or ARB, as per local SOC and applicable guidelines, for at least 3 months preceding screening. Participants should optimally be on at least 50% of the maximum recommended dose of these agents; however, if a participant is on their maximally tolerated dose (and this is < 50% of the maximum recommended dose) and has been on this dose for at least 3 months, they may be enrolled. Participants who are unable to tolerate ACEI/ARB therapy may be eligible for participation in the study if their overall management of IgAN, including BP control, is as per local SOC and applicable guidelines. Participants must have screening uPCR ≥ 0.75 g/g measured from a 24-hour urine or 24-hour urine protein ≥ 1.0 g/d, as measured from 24-hour urine collection. 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. Participants must have eGFR ≥ 45 mL/min/1.73 m². Participant's serum Ig values must meet specified criteria Female participants of childbearing potential must have a negative serum pregnancy test prior to the first dose. Participant is willing to adhere to contraceptive requirements. Participant or a legally authorized representative is able and is willing to give voluntary written informed consent Exclusion Criteria: Participants are excluded from the study if they meet any of the following criteria: Participant has secondary forms of IgAN as defined by the treating physician. Participant has co-existing CKD, other than IgAN. Participant has evidence of additional pathological findings in the kidney biopsy (eg, diabetic kidney disease, membranous nephropathy, or lupus nephritis). However, hypertensive vascular changes are acceptable. Participant has kidney biopsy MEST or MEST-C score as defined in the protocol. Participant has nephrotic syndrome. Participant has received a solid organ transplant, including kidney. Participant has received bone marrow or hematologic stem cell transplantation. Participant is currently receiving systemic immunosuppression (excluding topical, ophthalmic, per rectum, or inhaled corticosteroids). Participant has received treatment with systemic corticosteroid therapy within 16 weeks of initial screening. Participant has received treatment with a systemic immunosuppressive agents within 16 weeks of initial screening. Participant has any chronic infectious disease. Participant has acute infectious disease at the time of screening. Participant has Type 1 diabetes. Participant has uncontrolled Type 2 diabetes, as evidenced by a screening hemoglobin A1c value > 8%. Participant has uncontrolled BP (> 140 mm Hg systolic or > 90 mm Hg diastolic) Participant has a history of chronic autoimmune neurodegenerative disorder such as multiple sclerosis. Participant has a known allergy or intolerance to any component of the study intervention. Participant is breastfeeding. Participant has poorly compensated or controlled ischemic heart disease or cardiomyopathy, as judged by the Investigator. Participant has chronic obstructive pulmonary disease (COPD) or asthma that has required systemic steroid therapy during the prior year. 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. 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. Participant is planning or scheduled to undergo a tonsillectomy. Prior tonsillectomy is acceptable (if greater than 6 months prior to screening). Participant enrolled in another investigational drug or device study within 3 months prior to initial screening. 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. Participant is unable to comply with study protocol procedures and/or study visit schedules. Participant with known or suspected alcohol or drug abuse that would compromise their safety or study participation of the participant, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (0.9% NaCl) will be administered IV | Drug: Dose-Placebo<br>* Unit Dose Strength - 0.9%.<br>|
| Experimental: Low Dose - VIS649<br>Low dose of VIS649 administered IV | Drug: Low Dose-VIS649<br>* Dose Level = Low<br>|
| Experimental: Medium Dose - VIS649<br>Medium dose of VIS649 administered IV | Drug: Medium Dose-VIS649<br>* Dose Level = Medium<br>|
| Experimental: High Dose - VIS649<br>High dose of VIS649 administered IV | Drug: High Dose-VIS649<br>* Dose Level = High<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Assessment | Incidence of adverse events graded by severity | 12 months | 
| Efficacy Objective--effect on Proteinuria of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC | Change from baseline in uPCR (Urine protein/creatinine ratio) measured on natural log scale from 24-hour urine collection. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC plus placebo | Change from baseline in uPCR (Urine protein/creatinine ratio) | 9 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC plus placebo | Change from baseline in uPCR (Urine protein/creatinine ratio) | 16 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on protein excretion | Change from baseline in 24-hour urine protein excretion | 9 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on protein excretion | Change from baseline in 24-hour urine protein excretion | 12 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on protein excretion | Change from baseline in 24-hour urine protein excretion | 16 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in achieving ≥ 30% decline from baseline in uPCR | Number of patients with ≥ 30% decline from baseline in uPCR | 9 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in achieving ≥ 30% decline from baseline in uPCR | Number of patients with ≥ 30% decline from baseline in uPCR | 12 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in achieving ≥ 30% decline from baseline in uPCR | Number of patients with ≥ 30% decline from baseline in uPCR | 16 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on proteinuria | Number of patients meeting protocol-defined criteria for remission in 24-hour urine protein excretion for protocol-specified period | up to 16 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on kidney function. | Change from baseline in participant's eGFR (Estimated glomerular filtration rate). | 12 months | 
| Efficacy of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC on kidney function. | Change from baseline in participant's eGFR (Estimated glomerular filtration rate). | 16 months | 
| Pharmacodynamics of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in total serum IgA, IgG and IgM concentrations | Change from baseline in participant's serum Ig concentrations | 9 months | 
| Pharmacodynamics of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in total serum IgA, IgG and IgM concentrations | Change from baseline in participant's serum Ig concentrations | 12 months | 
| Pharmacodynamics of repeated doses of VIS649 added to SOC (ACEI/ARB therapy) vs. SOC in total serum IgA, IgG and IgM concentrations | Change from baseline in participant's serum Ig concentrations | 16 months | 
| Serum PK parameters | Measurement of circulating VIS649 concentrations | up to month 16 | 
| Serum anti-drug-antibody (ADA) | Measurement of circulating antibodies to VIS649 | up to 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VIS649, Kidney Diseases, Glomerulonephritis, IGA, Glomerulonephritis, Nephritis, Autoimmune Diseases, Immune System Diseases, Immunoglobulins, Antibodies, Immunoglobulin A, Immunologic Factors, Physiological Effects of Drugs, Proteinuria