Efficacy and Safety of Ravulizumab in IgA Nephropathy A Phase 2 Randomized Double-Blind Placebo-Controlled Trial

Abstract

Background The complement system plays a central role in the pathogenesis of IgA nephropathy. We present findings from a phase 2 trial of ravulizumab, a complement C5 inhibitor. Methods The Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy (NCT04564339) was a randomized, double-blind, placebo-controlled trial of ravulizumab in addition to standard of care. Adults with IgA nephropathy, proteinuria $1 g/d, and eGFR $30 ml/min per 1.73 m2, and on stable renin-angiotensin blockade were randomized 2:1 to ravulizumab (intravenous every 8 weeks) or placebo for 26 weeks. From week 26–50, all participants received open-label ravulizumab. The primary end point was percentage change in proteinuria from baseline to week 26. Secondary end points included change in proteinuria at week 50 and eGFR. Safety, pharmacokinetics, and pharmacodynamics were evaluated. Results Forty-three patients were randomized to ravulizumab and 23 to placebo. At week 26, a statistically significant reduction in proteinuria was observed with ravulizumab versus placebo: 241.9% (95% confidence interval [CI], 250.2% to 232.0%) change in urine protein with ravulizumab and 216.8% (95% CI, 231.8% to 1.6%) change with placebo (30.1% treatment effect; P 5 0.005). At week 50, there was a 244.8% (95% CI, 255.1% to 232.1%) change from baseline in urine protein with ravulizumab, and in patients who crossed over from placebo to ravulizumab at week 26, the change from baseline (week 0) to week 50 was 245.1% (258.0% to 228.4%). The least squares mean change in eGFR from baseline to week 26 with ravulizumab was 0.2 (95% CI, 22.3 to 2.7) ml/min per 1.73 m2 and with placebo was 24.5 (27.9 to 21.1) ml/min per 1.73 m2. From baseline to week 50, the least squares mean change in eGFR with ravulizumab was 23.9 (95% CI, 26.4 to21.3) ml/min per 1.73 m2, and in patients who crossed over from placebo to ravulizumab at week 26, it was 26.3 (29.7 to 22.9) ml/min per 1.73 m2. Ravulizumab was well tolerated, with an adverse event profile similar to that for placebo. Conclusions An early, sustained, and clinically meaningful reduction in proteinuria and trend toward stabilization of eGFR were observed with ravulizumab versus placebo. A phase 3 trial (NCT06291376) is enrolling. Clinical Trial registry name and registration number: Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy, NCT04564339.