Evaluating Sibeprenlimab in IgA Nephropathy - Rationale and Baseline Data from the VISIONARY Trial

Introduction Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis and a leading cause of kidney failure worldwide. Treatments that target the underlying immune drivers of the disease to improve long-term patient outcomes are needed. Sibeprenlimab, a selective A Proliferation-Inducing Ligand (APRIL) inhibitor that significantly decreases pathogenic galactose-deficient IgA1 production and immune complex formation, is being investigated in the ongoing Phase 3 VISIONARY trial. Here, we summarize the overall study design and report on the baseline characteristics of patients enrolled in the trial. Methods VISIONARY is a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier, NCT05248646; study date of registration: 2022-02-18). Adults with biopsy-confirmed IgA nephropathy were randomized 1:1 to receive subcutaneous sibeprenlimab 400 mg or placebo once every 4 weeks for 26 doses. The primary endpoint is the 24-hour urine protein-to-creatinine ratio (uPCR-24h) at 9 months compared with the baseline. Results Of 510 enrolled patients across 31 countries, 58.8% were male, 59.0% were Asian, and 57.3% lived in East or South/Southeast Asia. The median age was 42.0 (range, 18.0-83.0) years; 97.8% of patients were using renin-angiotensin system inhibitors, and 45.1% were using sodium-glucose cotransporter 2 inhibitors. The mean (SD) baseline uPCR-24h was 1.54 (0.92) g/g. The mean (SD) baseline urine protein was 2.1 (1.3) g/day, and the mean (SD) baseline eGFR was 64.2 (25.3) mL/min/1.73 m 2 . Conclusion VISIONARY, the largest IgA nephropathy trial to date, is evaluating the efficacy and safety of subcutaneous sibeprenlimab in a broadly representative population with IgA nephropathy at high risk of disease progression.