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A PRoliferation-Inducing Ligand (APRIL) is a key driver in the immune-related pathogenesis of immunoglobulin A nephropathy (IgAN). Sibeprenlimab, a humanized IgG2 monoclonal antibody that blocks APRIL, demonstrated acceptable safety with robust urine protein creatinine ratio (uPCR) reduction and eGFR stability at 12 months in a Phase 2 study of patients with IgAN.1 Defined criteria for remission in IgAN are varied and include reduction of proteinuria below certain thresholds (<1.0 g/d, <500 mg/d and <300 mg/day) as well as remission in hematuria (reduction in red blood cell [RBC] count to <5 RBC/high power field [HPF]).2–4 We report the effect of sibeprenlimab on hematuria resolution and remission of proteinuria.
VIS649-201 (NCT04287985; ENVISION) is a global multicenter, randomized (1:1:1:1) study evaluating monthly intravenous sibeprenlimab (2, 4, or 8 mg/kg) vs placebo for 12 months (with 4 months of follow-up) in adults with IgAN on optimized supportive treatment who have eGFR ≥30 mL/min/1.73m2 and proteinuria ≥1.0 g/d or uPCR ≥0.75 g/g. Efficacy endpoints include change from baseline in 24-hour uPCR at Month 12 (primary) and eGFR at Months 12 and 16, change in 24-hour proteinuria over time (key secondary), and change in microscopic hematuria (RBC/HPF) over time (exploratory). Hematuria was assessed by validated automated urine microscopy in a central laboratory.
A total of 155 patients were randomized and treated (sibeprenlimab 2 mg/kg n=38; 4 mg/kg n=41; 8 mg/kg n=38; placebo n=38); 146/155 (94.2%) received all 12 treatment doses. Baseline characteristics were generally balanced between groups. Median follow-up was 16.0 months. Key results including impact of sibeprenlimab on proteinuria and eGFR were recently published.1 Sibeprenlimab recipients showed marked reduction in microscopic hematuria at Months 9, 12, and 16 vs placebo (Figure 1). At Month 12, 21 patients had proteinuria ≤300 mg/day, and 10 (47.6%) of these patients also had ≤5 RBC/HPF (1, 2, 6 and 1 in the 2, 4, 8 mg/kg cohorts and placebo, respectively). Hematuria response corresponded to proteinuria response, with proteinuria reductions showing dose-dependent sibeprenlimab activity.1
Figure 1: Change From Baseline in Hematuria (RBC/HPF) Over Time
Box plots show median, 25%–75%, and minimum and maximum values. RBC/HBF, red blood cells per high power field.
This Phase 2 study of patients with IgAN demonstrated robust hematuria resolution by sibeprenlimab at all study doses from Months 9 through 16, while in the placebo group hematuria persisted throughout the study. Observed resolution in hematuria, proteinuria, and eGFR profiles over time indicate that APRIL blockade with sibeprenlimab may stabilize kidney function, likely through reduction of glomerular inflammation. These results suggest a favorable efficacy and safety profile of sibeprenlimab as a disease-modifying agent in IgAN and support its further evaluation in an ongoing global Phase 3 trial (NCT05248646).
1 Mathur M, et al. NEJM in press; 2 Suzuki Y, et al. Clin Exp Nephrol 18, 481–486 (2014); 3 Reich HN, et al. J Am Soc Nephro 18, 3177–3183 (2007); 4 Canney M, et al. J Am Soc Nephro 32, 436–447 (2021)