What is the Efficacy and Safety of Sibeprenlimab Administered Subcutaneously in Subjects with Immunoglobulin A Nephropathy (IgAN)?

Study Sites • Sri Jayewardenepura General Hospital • National Hospital of Sri Lanka • National Hospital, Kandy • Kurunegala Teaching Hospital • Karapitiya Teaching Hospital

Randomization: Subjects will be randomized with equal allocation (1:1) to sibeprenlimab or placebo. Randomization will be stratified by screening urine protein/creatinine ratio (uPCR; <2.0 g/g versus > 2.0 g/g), screening estimated glomerular filtration rate (eGFR; 30 - 44 mL/min versus >45 mL/min), and sodium-glucose cotransporter-2 inhibitor (SGLT2i) use at the time of randomization (yes or no). Approximately 450 subjects will be randomized with equal allocation (1:1) to sibeprenlimab or placebo (approximately 225 subjects per treatment) in a blinded manner.

Subjects will be randomly assigned to a treatment group. The randomization code will be created by the sponsor following the standard operating procedures.

Intervention: This trial will evaluate a dose of 400 mg sibeprenlimab compared with placebo. The Investigational Medicinal Product (IMP) (sibeprenlimab or placebo) will be administered Sub Cutaneously (SC) once every 4 weeks (total of 26 doses) by trained, qualified personnel designated by the investigator or sponsor. The IMP administration will be in the abdomen, thigh, or upper arm based on assignment at randomization. For all subjects, Dose 1 (Day 1), Dose 2 (Week 4), Dose 3 (Week 8), Dose 4 (Week 12), Dose 5 (Week 16), and Dose 7 (Week 24) will be injected SC in the abdomen. Dose 6 (Week 20) and Dose 8 (Week 28) will be rotated to either the thigh or upper arm based on assignment at randomization so that each subject has at least one IMP administration in each of the SC injection sites. From Dose 9 (Week 32) and onwards, subjects will be allowed to select which injection site they prefer for the IMP administration. The date and time of IMP administration, the volume of IMP administered, and the injection site location will be recorded for each IMP administration. The details of the placebo is given below: 25 mM histidine, 100 mM sorbitol, 50 mM arginine, 50 mM glutamic acid, 0.02% (w/v) PS-80, pH 6.2

Blinding: subjects, investigators, trial staff and sponsor, will remain blinded to treatment assignment until the final analysis of the key secondary endpoint of eGFR

• Male and female patients >18 years of age. • Biopsy-confirmed IgA Nephropathy (IgAN). (Patients with an eGFR of 30 to 45 mL/min/1.73m2 must have had a kidney biopsy performed within 36 months of the screening visit). • Stable and maximally tolerated dose of ACEI (Angiotensin-converting enzyme inhibitor) and/or ARB (Angiotensin receptor blocker) for at least 3 months prior to screening. Patients who are on a stable dose of SGLT2i may participate if treatment was initiated >3 months prior to screening. Patients who are unable to take an ACEI or ARB may participate if their overall management conforms with standards of care and other protocol requirements. • Screening urine protein/creatinine ratio (uPCR) >0.75 g/g or urine protein >1.0 g/day • eGFR >30 mL/min/1.73 m2, (for the exploratory cohort* only: eGFR 20- <30 mL/min/1.73 m2), calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.

*The Exploratory cohort is up to 20 subjects with IgAN and an eGFR of 20 to 30 mL/min/1.73 m2. These subjects will also randomized with equal allocation (1:1) to sibeprenlimab or placebo in this cohort.

• Secondary forms of IgAN or IgA vasculitis. • Coexisting chronic kidney disease other than IgAN. • Kidney biopsy findings in addition to IgAN including those of diabetic nephropathy, membranous nephropathy, or lupus nephritis. Hypertensive vascular changes are acceptable. • Kidney biopsy MEST (Mesangial cellularity, endocapillary proliferation, segmental sclerosis, tubular atrophy) or MEST-C (MEST-Crescents) score of T2 or C2 (Oxford IgAN classification). If MEST-scoring was not performed, the presence of > 50% tubulo-interstitial fibrosis, or crescents in > 25% of glomeruli is exclusionary. This does not apply to the exploratory cohort*. • Nephrotic syndrome • Serum IgG < 600 mg/dL at screening. • Chronic systemic immunosuppression, including glucocorticoids, within 16 weeks of randomization • Participation in another interventional clinical trial and receipt of another investigational drug within 30 days prior to the administration of IMP or 5 half-lives from last investigational drug administration, whichever is longer. • Chronic infectious disease, or acute infectious disease at time of screening. • Type 1 diabetes, or poorly controlled Type 2 diabetes • Uncontrolled hypertension

*The Exploratory cohort is up to 20 subjects with IgAN and an eGFR of 20 to 30 mL/min/1.73 m2. These subjects will also randomized with equal allocation (1:1) to sibeprenlimab or placebo in this cohort.