Efficacy and Safety of Ravulizumab in a Phase 2 Randomized Controlled Trial in IgA Nephropathy

Background: 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 (Figure 1) and eGFR remained stable. RAV was well-tolerated with a safety profile similar to that of PBO and no new safety concerns (Table 1). Table 1: - Treatment-emergent adverse events up to 26wks Ravulizumab N=43 Placebo N=23 Any adverse event, n (%) 32 (74.4) 19 (82.6) Investigator-assessed as related to study drug 9 (20.9) 6 (26.1) Serious adverse event, n (%) 1 (2.3)* 0 (0.0) *COVID occurred in one patient as an SAE that led to hospitalization and was investigator-assessed as unrelated to study drug and resolved during the study. AEs of special interest included meningococcal infections; there were no AEs of special interest. No AEs or SAEs leading to withdrawal from the study occurred and no deaths were reported. Conclusions: This analysis supports clinically meaningful efficacy of RAV based on rapid and sustained proteinuria reduction, providing pro of-of-concept for a phase 3 trial of RAV as a potential treatment for IgAN. Funding: Commercial Support - Alexion, AstraZeneca Rare Disease