A Study to Evaluate the Efficacy and Safety of RO7434656 in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of RO7434656, a novel Antisense Oligonucleotide (ASO) therapy in participants with primary IgA nephropathy (IgAN) who are at high risk of progressive kidney disease despite optimized supportive care.

Official Title
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A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of RO7434656, an Antisense Inhibitor of Complement Factor B, in Patients With Primary IgA Nephropathy at High Risk of Progression

Conditions
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Primary IgA Nephropathy

Intervention / Treatment
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* Drug: RO7434656
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary IgAN, as evidenced by a kidney biopsy performed within 7 years prior to or during screening, without known secondary cause Treatment with maximum tolerated doses of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) for at least 90 days immediately prior to screening Urine Protein-to-Creatinine Ratio (UPCR) ≥ 1 gram per gram (g/g) or urine protein excretion ≥ 1 gram per day (g/day) (with UPCR ≥ 0.8 g/g), all measured from a 24-hour urine collection during screening obtained no longer than 60 days prior to Day 1 eGFR ≥ 20 mL/min/1.73 m^2, as calculated by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (Inker et al. 2021a) Female participants of childbearing potential must use adequate contraception Exclusion Criteria: Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 12 weeks after the final dose of RO7434656 Histopathologic or other evidence of another autoimmune glomerular disease Presence of ≥ 50% crescents on kidney biopsy, sustained doubling of serum creatinine within 3 months prior to screening, or rapidly progressive glomerulonephritis in the opinion of the investigator Glycated Hemoglobin (HbA1c) ≥ 6.5% or a clinical diagnosis of diabetes mellitus of any type Uncontrolled blood pressure, in the investigator's assessment, for 3 months prior to screening or during screening Use of endothelin receptor antagonists, except those approved for use in IgAN Initiation of mineralocorticoid receptor antagonists or endothelin receptor antagonists within 90 days prior to screening or during screening Previous treatment with RO7434656 Use of herbal therapies within 90 days prior to or during screening Treatment with oral or intravenous (IV) corticosteroids with a dose equivalent to ≥ 7.5 milligrams per day (mg/day) of prednisone for 7 days or equivalent to ≥ 5 mg/day of prednisone for 14 days within 90 days prior to screening Treatment with other immunomodulatory agents within 6 months of randomization including, but not limited to, complement inhibitors, alkylating agents (e.g., cyclophosphamide or chlorambucil), or mycophenolate Treatment with a calcineurin inhibitor within 2 months prior to screening or during screening Treatment with anti-CD20 therapy within 9 months of screening or during screening Any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in and completion of the study Planned major procedure or major surgery during screening or the study Other protocol-defined inclusion/exclusion criteria may apply

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 |
| --- | --- |
| Experimental: RO7434656<br>Participants will receive subcutaneous (SC) doses of RO7434656 on Days 1, 15, and 29 followed by once every 4 weeks until Week 105. After Week 105, participants may continue blinded treatment or enter open-label treatment until up to 1 year after the date at which the last participant completes the Week 105 assessment, withdraws, or is discontinued from the study. | Drug: RO7434656<br>* RO7434656 will be administered subcutaneously per schedule as specified.<br>|
| Placebo Comparator: Placebo<br>Participants will receive SC doses of RO7434656 matching placebo on Days 1, 15, and 29 followed by once every 4 weeks until Week 105. After Week 105, participants may continue blinded treatment or enter open-label treatment until up to 1 year after the date at which the last participant completes the Week 105 assessment, withdraws, or is discontinued from the study. | Drug: Placebo<br>* Matching placebo will be administered subcutaneously per schedule as specified.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Urine Protein-to-Creatinine Ratio (UPCR) at Week 37 | UPCR will be assessed in urine sampled over 24 hours. | Baseline, Week 37 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Glomerular Filtration Rate (eGFR) Slope at Week 105 from Baseline | eGFR will be calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. | Baseline, Week 105 | 
| Time to the Composite Kidney Failure Endpoint | Time to the composite kidney failure endpoint is defined as receipt of kidney transplantation, need for kidney replacement therapy, or a sustained decline in eGFR of ≥ 30% or a sustained eGFR <15 mL/min/1.73m^ 2 over at least 4 weeks (both eGFR criteria requires two consecutive central laboratory eGFR values meeting criteria ≥ 4 weeks apart), whichever occurs first, without the receipt of other immunosuppressive or background therapies for the treatment of IgAN. | Up to approximately 7 years | 
| Change From Baseline in Fatigue at Week 105 | Fatigue will be assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue subscale (FACIT-F). The FACIT-F Scale is a 13-item scale used to measure self-reported fatigue. Items are assessed on a 5-point Likert scale, with responses ranging from 0 for not at all to 4 for very much. The total raw score is the sum of the values of each scored question and ranges from 0 to 52. A higher score indicates less fatigue. | Baseline, Week 105 | 
| Percentage of Participants with Treatment-Emergent Adverse Events (TEAEs) |  | Up to approximately 7 years | 
| Plasma Concentration of RO7434656 |  | Up to approximately 7 years |