WCN25-726 NELL1-ASSOCIATED MEMBRANOUS NEPHROPATHY: A DETAILED CASE SERIES WITH CLINICAL, PATHOLOGICAL, AND IMMUNOLOGICAL INSIGHTS

Introduction:The alternative complement pathway (AP) plays a key role in IgAN pathogenesis and there is an unmet need for targeted disease-modifying treatments.In IgAN, the AP is often activated in urine but not in plasma, indicating renal complement activity.Iptacopan binds to Factor B and specifically inhibits the AP.In a Phase 2 study, iptacopan decreased plasma Bb and Wieslab activity, and urinary sC5b-9 decreased to almost healthy volunteer range.The APPLAUSE-IgAN trial is evaluating iptacopan vs placebo on top of optimized stable supportive therapy.In the pre-specified interim analysis (IA), iptacopan was superior to placebo in reducing proteinuria at Month 9 relative to baseline (24h urine protein-creatinine ratio reduction 38.3%; P<0.0001).Here, we present complement biomarker exploratory results from the IA.Methods: APPLAUSE-IgAN (NCT04578834), a Phase 3, randomized, double-blind, placebo-controlled trial, enrolled adults with biopsyconfirmed IgAN with proteinuria $1 g/g despite stable supportive therapy.Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on supportive therapy.IA was performed when 250 patients reached Month 9 or discontinued the study.Change from baseline in biomarkers of complement activity was assessed: C3 and C4 in all patients; Bb, sC5b-9, and Wieslab were only assessed in a subset of patients.Results: Iptacopan selectively inhibited the AP, with reductions in serum Wieslab activity, plasma Bb and sC5b-9, and increases in serum C3, while serum C4 was unchanged (Figure).Median decrease in urinary sC5b-9 was 97.6% (IQR 86.1-99.2) in the iptacopan arm; the Month 9 value was within the range observed in healthy individuals.Conclusions: Iptacopan inhibited systemic and intrarenal activation of the AP in patients with IgAN at Month 9, supported by reductions in serum Wieslab, plasma Bb and sC5b-9, and urinary sC5b-9.