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

Inclusion Criteria:

• Primary IgAN, as evidenced by a kidney biopsy performed within 10 years prior to orduring 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 daysimmediately prior to screening, and without an intent to modify the dose during thestudy, except for interruptions due to illness (not greater than 7 consecutivedays), unless the potential participant is intolerant to these medications

• Urine Protein-to-Creatinine Ratio (UPCR) ≥ 1 gram per gram (g/g) or urine proteinexcretion ≥ 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 m^2, as calculated by the 2021 CKD-EPI creatinine equation (Inker et al. 2021a)

• Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilusinfluenzae according to national vaccination recommendations

• Female participants of childbearing potential must use adequate contraception

Exclusion Criteria:

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study orwithin 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 creatininewithin 3 months prior to screening, or rapidly progressive glomerulonephritis in theopinion of the investigator

• History of kidney transplantation

• Glycated Hemoglobin (HbA1c) ≥ 6.5% or a clinical diagnosis of diabetes mellitus ofany type

• Systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg from theaverage of two measurements performed at least 1 minute apart during screening

• Initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors within 16 weeksprior to screening or during screening

• Initiation of endothelin receptor antagonists within 90 days prior to screening orduring screening

• Initiation of mineralocorticoid receptor antagonists or non-dihydropyridine calciumchannel blockers within 90 days prior to screening or during screening

• Use of herbal therapies within 90 days prior to or during screening

• Treatment with investigational therapy within 28 days prior to screening or 5.5drug-elimination half-lives of that investigational product prior to screening

• Treatment with an investigational therapy planned during the treatment period

• Previous treatment with sefaxersen

• 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/dayof prednisone for 14 days within 90 days prior to screening

• Treatment with corticosteroids with systemic effects during screening

• Treatment with a systemic calcineurin inhibitor within 2 months prior to screeningor during screening

• Treatment with anti-CD20 therapy within 9 months of screening or during screening

• Treatment with other systemic immunosuppressive agents within 6 months ofrandomization including, but not limited to, complement inhibitors, alkylatingagents (e.g., cyclophosphamide or chlorambucil), azathioprine, or mycophenolate

• Planned major procedure or major surgery during screening or the study

• Substance abuse within 12 months prior to screening or during screening

• Any serious medical condition or abnormality in clinical laboratory tests thatprecludes an individual's safe participation in and completion of the study

• History of malignancy within < 5 years prior to screening, with the exception ofmalignancies with a negligible risk of metastasis or death

• Usage of Glucagon-like Peptide-1 (GLP-1)-based therapy (i.e., GLP-1 mono-agonists,GLP-1/GIP dual agonists, etc.) within 90 days prior to screening or duringscreening, or intent to initiate during the study period