#4333 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF BION-1301 IN ADULTS WITH IGA NEPHROPATHY

Abstract

Abstract Background and Aims IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis and has limited treatment options, especially for high-risk patients. Approximately 30-45% of IgAN patients progress to end-stage kidney disease over a period of 20-25 years and proteinuria is the strongest predictor of disease progression [1]. BION-1301 is a novel, humanized monoclonal antibody that blocks a proliferation-inducing ligand (APRIL), a cytokine that is elevated in patients with IgAN. APRIL promotes the production of pathogenic galactose-deficient IgA1 (Gd-IgA1), resulting in immune complex formation and subsequent glomerular deposition, leading to inflammation and kidney injury. Blocking APRIL with BION-1301 is a potential disease-modifying approach to treating IgAN. Interim results from a Phase 1/2 trial of BION-1301 in patients with IgAN (NCT03945318) demonstrate rapid and durable reductions in Gd-IgA1 and sustained, clinically meaningful reductions in proteinuria with an acceptable safety profile [2]. Methods CHK02-02 is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the effect of BION-1301 in adults with primary IgAN at risk of progressive kidney function loss. Approximately 272 patients will be enrolled across North America, South America, Europe and Asia-Pacific. Key eligibility criteria include biopsy-proven IgAN within the past 10 years (not due to secondary causes), eGFR ≥ 30 ml/min/1.73 m2 (CKD-EPI) and total urine protein ≥ 1.0 g/day at screening. Patients must be stable on a maximally tolerated dose of angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) for at least 12 weeks prior to screening or intolerant to ACEi/ARB. Patients may also be on a stable dose of SGLT2i, mineralocorticoid receptor antagonists, and/or endothelin receptor antagonists for at least 12 weeks prior to screening. The study will be comprised of a screening period (6 weeks), a double-blind treatment period (104 weeks), and a safety follow-up period (24 weeks). Patients will be randomized 1:1 to receive subcutaneous 600 mg BION-1301 Q2W or placebo for 104 weeks. Randomization will be stratified by region (Asia vs. Rest of World), baseline proteinuria (≥ 2 g/day vs. < 2 g/day) and eGFR (≤ 45 ml/min/1.73 m2 vs. > 45 ml/min/1.73 m2). An additional ∼20 patients with eGFR 20 to < 30 mL/min/1.73 m2 will be enrolled into an exploratory cohort not included in the primary or secondary analyses. Results The primary endpoint is change in proteinuria (UPCR from a 24-hour urine collection) from baseline to week 36. The key secondary endpoint is change in eGFR from baseline to week 104. Additional secondary endpoints will evaluate the effect of BION-1301 vs. placebo on composite clinical outcomes including patients experiencing at least one of the following: 30% or 40% reduction in eGFR, eGFR < 15 mL/min/1.73 m2, dialysis, kidney transplantation or all-cause mortality. Safety endpoints include type, incidence, severity, and relatedness of adverse events (AEs) and serious AEs. Exploratory endpoints include impact of BION-1301 on disease biomarkers and health-related quality of life as well as analysis of BION-1301 pharmacokinetics and immunogenicity. Conclusion BION-1301 provides a potentially disease-modifying approach for the treatment of IgAN by directly targeting the disease pathogenesis. Interim results of the Phase 1/2 open-label trial demonstrated proof-of-concept for BION-1301 to reduce pathogenic Gd-IgA1 and provide sustained, clinically meaningful reductions in proteinuria while supporting SC dosing at 600 mg Q2W [2]. The Phase 3 trial will evaluate the effect of BION-1301 vs. placebo on proteinuria, eGFR and composite clinical endpoints and key safety measures in adult patients with IgAN at risk of progressive kidney function loss.