In this study, researchers will learn more about the use of felzartamab in participants with immunoglobulin A nephropathy (IgAN). IgAN is a kidney disease caused by the buildup of an antibody called IgA in the kidneys over time. In people with IgAN, abnormal IgA and other antibodies form clusters that build up in the small filters of the kidneys, which leads to inflammation and damage. Felzartamab is designed to target certain immune cells that produce these abnormal antibodies. This study will focus on participants who have protein in their urine (proteinuria) as a result of damaged kidneys.

The main goal of the study is to learn about the effect felzartamab has on proteinuria. The main question that researchers want to answer is:

• How much does the amount of protein in the urine change from the start of the study to Week 36?

Researchers will learn about the effect felzartamab has on the kidneys' ability to filter blood. They will also learn more about the safety of felzartamab and how it is processed by the body.

The study will be done as follows:

• Participants will be screened to check if they can join the study.
• Participants will be randomized to receive either felzartamab or a placebo. A placebo looks like the study drug but contains no real medicine.
• Neither the researchers nor the participants will know what the participants will receive.
• Participants will receive felzartamab or placebo as intravenous (IV) infusions. The treatment period will last 24 weeks.
• Afterwards, participants will enter a follow-up period which will last 80 weeks.
• In total, participants will have 17 study visits. Participants will stay in the study for about 2 years.

The primary objective of the study is to evaluate the efficacy of felzartamab compared to placebo on proteinuria in participants with Immunoglobulin A nephropathy (IgAN). The main secondary objective of the study is to evaluate the efficacy of felzartamab compared to placebo on kidney functions in participants with IgAN. The additional secondary objectives are to evaluate the efficacy of felzartamab compared to placebo on additional clinical endpoints and to assess the pharmacokinetics (PK) and immunogenicity of felzartamab.

Key Inclusion Criteria:

• Biopsy-confirmed diagnosis of IgAN within the past 10 years prior to signature of the informed consent form (ICF). For participants with diabetes mellitus type 2, an IgAN diagnostic biopsy within the past 24 months prior to signing the ICF.
• An eGFR ≥ 30 mL/min/1.73 m^2 at Screening as calculated using the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine formula. An eGFR of ≥ 20 and < 30 mL/min/1.73 m^2 is acceptable for the cohorts 3 and 4.
• Proteinuria of ≥ 1.0 gram per day (g/day) or UPCR ≥0.8 gram per gram (g/g) as assessed by an adequate 24-hour urine collection.
• Clinically stable on a maximally tolerated dose or maximally approved dose of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for at least 12 weeks prior to Screening. Participants may also be using sodium-glucose cotransporter-2 inhibitors (SGLT2is); endothelin receptor antagonists (ERAs) or dual endothelin angiotensin receptor antagonist (DEARAs) approved for the treatment of IgAN; and/or mineralocorticoid receptor antagonists (MRAs) as long as the dose is stable for at least 12 weeks prior to Screening. Participants should remain on stable doses of these background medications for the duration of the study. Once the ICF is signed and thereafter, the doses cannot be changed during the study nor the drugs discontinued except if deemed related to an AE. Participants using a DEARA (e.g., sparsentan) will not be permitted to use simultaneous ACEI or ARB medication.

Key Exclusion Criteria:

• Any history of secondary forms of IgAN, indicated by the presence of any other systemic disease potentially leading to IgA deposits as determined by the Investigator.
• History of rapidly progressive variant of IgAN, defined as eGFR loss by > 50% per 3 months and not explained by changes in renin-angiotensin system (RAS) blockade or other factors.
• IgAN-(MCD) variant.
• Concomitant other progressive glomerulonephritis or non-immunologic glomerular disease such as diabetic nephropathy.
• Type 2 diabetes mellitus with Hemoglobin A1c (HbA1c) > 8% at Screening, or evidence of diabetic nephropathy on biopsy, history of diabetic microvascular or macrovascular disease (eg, diabetic retinopathy, peripheral neuropathy).
• Any diagnosed or suspected immunosuppressed or immunodeficient state such as asplenia, human immunodeficiency virus (HIV), primary immunodeficiencies, organ or bone marrow transplantation, with the exception of corneal transplants.
• Previously treated with immunosuppressive or other immunomodulatory agents such as but not limited to cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus, sirolimus, everolimus, or systemic glucocorticoid exposure (> 7.5 milligrams per day [mg/d] prednisone-equivalent for indications other than IgAN or any dose if given for the treatment of IgAN) within 4 months prior to Screening. Use of hydroxychloroquine in Mainland China is allowed if the candidate has been on this for at least 6 months prior to Screening with a stable dose for at least 12 weeks prior to Screening. If a potential participant requires systemic glucocorticoids at any dose for IgAN during Screening, this will result in a screen fail. If a potential participant requires systemic glucocorticoids > 7.5 mg/day prednisone-equivalent for indications other than IgAN during Screening, this will result in a screen fail.
• Participants currently treated with oral budesonide. Participants who have stopped this therapy ≥ 4 months prior to Screening may be eligible.
• Active clinically significant infections, known history of recurrent clinically significant infection, or Screening laboratory evidence consistent with an active infection, or non-prophylactic treatment with IV anti-infectives (antibacterials, antiviral or antifungals). Participants with a history of opportunistic infections are excluded.
• Hypogammaglobulinemia: serum Immunoglobin G (IgG) < 6.0 gram per litre (g/L), at Screening.

Note: Other protocol-defined Inclusion/Exclusion criteria may apply.

In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/