Sibeprenlimab in Patients with IgA Nephropathy: A Phase 2 Trial

Background: A Proliferation-Inducing Ligand (APRIL) is implicated in the pathogenesis of immunoglobulin A nephropathy (IgAN). Sibeprenlimab is a humanized IgG2 monoclonal antibody that blocks APRIL signaling. Methods: VIS649-201 (NCT04287985) is a global, multicenter, randomized, double-blind, placebo-controlled study evaluating monthly intravenous (IV) sibeprenlimab 2, 4 or 8 mg/kg added to background optimized renin-angiotensin-aldosterone system blockade for 12 months in adults with IgAN. Patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, and proteinuria ≥1.0 g/d or urine protein creatinine ratio (uPCR) ≥0.75 g/g, were included. Results: 155 participants were randomized: 56.8% male; 74.2% Asian; median age 39 years. At Month 12, compared with placebo, sibeprenlimab groups demonstrated significant reductions in 24-hour uPCR (Figure, Table) and clinically relevant smaller changes in eGFR (sibeprenlimab, -2.7 to +0.2 mL/min/1.73 m2; placebo, -7.4 mL/min/1.73 m2; Table). The incidence of treatment-emergent adverse events (TEAEs) was 78.6% (sibeprenlimab pooled) and 71.1% (placebo), with comparable distribution of serious, severe, and drug-related TEAEs.Percentage Change in 24-Hour uPCR From Baseline Over Time - Efficacy and Safety Data Parameter Sibeprenlimab 2 mg/kg (n = 38) Sibeprenlimab 4 mg/kg (n = 41) Sibeprenlimab 8 mg/kg (n = 38) Placebu (n = 38) Median baseline urine protein excretion, g/day (range) 1.47 (0.67-6.92) 1.93 (0.33-8.00) 1.90 (0.76-12.44) 2.13 (0.76-8.48) Genmetric mean ratio reduction in 24-h uPCR from baseline at Month 12, % (standard error) 47.2 (8.2) 58.8 (6.1) 62.0 (5.7) 20.0 (12.6) Genmetric mean uPCR reduction at Month 12 relative to placebu, % (standard error) 53.96 (13.7) P = 0.048 48.45 (10.3) P = 0.0013 52.53 (9.7) P = 0.0004 - Median baseline eGFR, mL/min/1.73 m2 (range) 58.0 (35.0-154.0) 64.0 (35.0-133.0) 56.0 (34.0-109.0) 68.5 (33.0-416.0) Least squares mean eGFR change from baseline at Month 12, mL/min/1.73 m2 (standard error) -2.7 (1.8) -0.2 (1.7) -1.5 (1.8) -7.4 (4.8) Least squares mean difference in eGFR at Month 12 relative to placebo, mt/min/1.73 m2 (standard error) +4.6 (2.5) P = 0.065 +7.6 (2.4) P = 0.002 +5.8 (2.5) P = 0.020 - Any TEAE, n (%)* 28 (73.7) 32 (80.5) 31 (81.6) 27 (71.1) Serious TEAE, n (%) 2 (5.3) 2 (4.9) 1 (2.6) 2 (5.3) *Lower incidence of infections in pooled sibeprenlimab group vs placebo. Conclusions: These results suggest that IV sibeprenlimab may provide an effective and well-tolerated treatment option to slow disease progression of IgAN, and support the ongoing Phase 3 VISIONARY trial of subcutaneous sibeprenlimab in patients with IgAN (NCT05248646). Funding: Commercial Support - Visterra, Inc. (Waltham, MA), a member of the Otsuka family of companies.