A Study of the Efficacy and Safety of Zigakibart + Atrasentan in Adult Patients With Primary IgA Nephropathy

The study includes a 52-week double-blind treatment period and a 52-week open-label extension (OLE):

* Double-blind treatment period: Participants will receive zigakibart and either atrasentan or matching placebo. The purpose is to evaluate if zigakibart + atrasentan demonstrates increased efficacy in reducing proteinuria and delaying progression of disease compared to zigakibart + placebo. It also aims to evaluate the safety and tolerability of zigakibart + atrasentan.
* OLE: Participants will receive zigakibart and atrasentan. The purpose is to provide study participants with the opportunity to continue to receive zigakibart and atrasentan, while enabling continued collection of long-term efficacy, safety, and tolerability data.

• zigakibart (Biological), also known as BION-1301, FUB523: Solution for injection via PFS-NSD
• atrasentan (Drug), also known as CHK01, EXV811: Tablet
• Placebo (Drug): Tablet

Primary outcomes

• Change in proteinuria from Baseline to Week 36, based on 24 hour urine collection [Baseline, Week 36]: Relative difference between treatment groups in mean change of natural log 24-hour UPCR from Baseline to Week 36, expressed as percent reduction

Secondary outcomes

• Rate of patients achieving proteinuria remission at Week 52 [Week 52]: Difference between the treatment groups in the rate of patients achieving proteinuria remission, defined as 24-hour UPCR < 0.5 g/g
• Rate of proteinuria remission [Week 52]: Difference between the treatment groups in the rate of proteinuria remission, defined as 24-hour UPCR of < 0.3 g/g
• Proportion of participants with AEs, SAEs and AESIs [128 Weeks]: Proportion of participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of special interest (AESIs)
• Change from baseline in Glomerular Filtration rate (GFR) [Baseline and up to 104 weeks]: Change from baseline in GFR (safety laboratory parameters)
• Change from baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [Baseline and up to 104 weeks]: Change from baseline in SBP and DBP (vital signs)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Aged ≥ 18 years at the time of signing the informed consent, prior to initiation of any study specific activities/procedures
* Biopsy-proven IgAN diagnosed within the past 10 years prior to Screening, that, in the opinion of the Investigator, is not due to secondary causes. If a biopsy report within 10 years is not available, re-biopsy may be performed locally during Screening.
* eGFR ≥ 30 mL/min/1.73m2 by a central laboratory at Screening, calculated using serum creatinine based on the 2021 CKD-EPI equation (Inker et al 2021)
* UPCR ≥ 0.7 g/g (700 mg/g), as measured from a 24 hour urine collection by a central laboratory at Screening
* Stable on a maximally tolerated dose of ACEi and/or ARB for at least 12 weeks prior to Screening unless intolerant to ACEi and ARB. May also be on a stable and well tolerated dose of SGLT2i, MRA, and/or GLP-1A if stable for at least 12 weeks prior to Screening. Participants are expected to stay on a stable dose of ACEi, ARB, SGLT2i, MRA and/or GLP-1A for the duration of the study.

Exclusion Criteria:

* Chronic Kidney Disease (CKD), either clinically suspected or based on biopsy, resulting from any condition or another glomerulopathy/podocytopathy other than IgAN
* Secondary forms of IgAN as determined by the Investigator, in the setting of systemic disorders, infections, autoimmune disorders or neoplasia
* Diagnosis of active IgA vasculitis
* Clinical suspicion of IgAN with rapidly progressive glomerulonephritis (RPGN) based on Kidney Disease: Improving Global Outcomes (KDIGO) guidelines (2025)
* Current clinical diagnosis of nephrotic syndrome
* Known history of heart failure or conditions relating to fluid overload such as pulmonary edema, uncontrolled peripheral edema, pleural effusion, or ascites
* Current severe infection requiring antimicrobials, or history of recurrent, severe infections as determined by the Investigator

Other protocol-defined inclusion/exclusion criteria may apply

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals