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, except for interruptions due to illness (not greaterthan 7 consecutive days), unless the potential participant is intolerant to thesemedications

• 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 Chronic Kidney DiseaseEpidemiology Collaboration (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 SGLT2 inhibitors within 16 weeks prior to screening or duringscreening

• 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 GLP-1-based therapy (i.e., GLP-1 mono-agonists, GLP-1/GIP dual agonists,etc.) within 90 days prior to screening or during screening, or intent to initiateduring the study period