The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of sefaxersen (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.
Primary IgAN, as evidenced by a kidney biopsy performed within 10 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, and without an intent to modify the dose during the study, except for interruptions due to illness (not greater than 7 consecutive days), unless the potential participant is intolerant to these medications
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
eGFR ≥ 20 mL/min/1.73 m², as calculated by the 2021 CKD-EPI creatinine equation (Inker et al. 2021a)
Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 12 weeks after the final dose of sefaxersen
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
History of kidney transplantation
Parallel
Sefaxersen (RO7434656)
DrugSefaxersen (RO7434656) will be administered as SC injection per schedule as specified.
Placebo
DrugMatching placebo will be administered as SC injection per schedule as specified.
Change From Baseline in the Urine Protein-to-Creatinine Ratio (UPCR) at Week 37
UPCR will be assessed in urine sampled over 24 hours.
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.
Percentage of Participants Achieving Hematuria Resolution at Week 37
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 milliliters/minutes/1.73m\^2 (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.
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.
Change From Baseline in Symptoms and Health-Related Quality of Life at Week 105 as Assessed Using the RAND Kidney Disease and Quality of Life 36-Item (KDQOL-36) Short Form
The RAND KDQOL-36 is an abbreviated questionnaire that combines the generic and disease-specific components to assess participant's health-related quality of life. This 36-item questionnaire includes the RAND 12, Version 1 (12 items) and 3 disease-related domains, symptoms/problems (12 items), burden of kidney disease (4 items), and effects of kidney disease (8 items). It uses a recall of 4 weeks, and items are assessed on 3- to 5-point Likert scales or with a dichotomous response option. Higher score indicates better health. The raw scores are transformed linearly to a range of 0 to 100, with higher scores indicating better health.
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