A phase 3, randomized, double-blind, placebo-controlled study of bion-1301 in adults with iga nephropathy
Nephrology Dialysis Transplantation(2023)
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.
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Key words
double-blind,placebo-controlled
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