Ravulizumab 300mg/3ml solution for infusion vials

Visual Abstract Key Points This phase 2, double-blind, randomized controlled trial evaluated the complement C5 inhibitor, ravulizumab, in adults with IgA nephropathy. A 30.1% (90% confidence interval, 13.7% to 43.5%) relative reduction in proteinuria for ravulizumab versus placebo was observed at approximately 6 months. Treatment with ravulizumab was well tolerated. 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: −41.9% (95% confidence interval [CI], −50.2% to −32.0%) change in urine protein with ravulizumab and −16.8% (95% CI, −31.8% to 1.6%) change with placebo (30.1% treatment effect; P = 0.005). At week 50, there was a −44.8% (95% CI, −55.1% to −32.1%) 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 −45.1% (−58.0% to −28.4%). The least squares mean change in eGFR from baseline to week 26 with ravulizumab was 0.2 (95% CI, −2.3 to 2.7) ml/min per 1.73 m2 and with placebo was −4.5 (−7.9 to −1.1) ml/min per 1.73 m2. From baseline to week 50, the least squares mean change in eGFR with ravulizumab was −3.9 (95% CI, −6.4 to−1.3) ml/min per 1.73 m2, and in patients who crossed over from placebo to ravulizumab at week 26, it was −6.3 (−9.7 to −2.9) 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. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_26_KTS_October2024.mp3

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Introduction: IgA nephropathy (IgAN) is the most prevalent primary glomerular disease, often progressing to ESKD. Complement activation leads to glomerular damage by immune complex deposition and release of proinflammatory cytokines. Terminal complement inhibition specifically targets the pathophysiology of IgAN and may provide improved renal outcomes. Methods: This primary analysis of a phase 2 RCT (NCT04564339) evaluated ravulizumab (RAV) (IV; weight-based dosing Q8W) vs placebo (PBO) in adults with primary IgAN. Eligible patients (pts) (18–75 years) with biopsy-confirmed IgAN, proteinuria ≥1g/d, on stable maximally tolerated RASi with stable blood pressure ≥3 months were enrolled. The primary endpoint was % change in proteinuria from baseline to week (wk) 26 based on 24-hour urine. Secondary endpoints included spot UPCR and change in baseline eGFR at wk 26, safety, and PK/PD. Results: 66 pts were randomized 2:1 to RAV (n=43) or PBO (n=23). Mean age was 40.1 years, 46% were female, and 21% were Asian. At 26 wks, proteinuria reduction was greater with RAV vs PBO; 40.3% vs 10.9% (treatment effect 33.1%, 90% CI, 14.7%, 47.5%; p=0.0012). In RAV-treated pts, proteinuria reduction was rapid and sustained through wk 26 and eGFR remained stable. RAV was well-tolerated with a safety profile similar to that of PBO and no new safety concerns. Conclusions: This analysis supports clinically meaningful efficacy of RAV based on rapid and sustained proteinuria reduction, providing proof-of-concept for a phase 3 trial of RAV as a potential treatment for IgAN.

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