#456 Efficacy and safety of iptacopan in patients with primary IgA nephropathy: interim analysis results of the Phase 3 APPLAUSE-IgAN study

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. An unmet need for targeted disease-modifying treatments addressing its pathophysiology remains. There is compelling evidence for involvement of the alternative complement pathway (AP) in IgAN. Iptacopan binds to Factor B and specifically inhibits the AP. The APPLAUSE-IgAN trial is evaluating the efficacy and safety of iptacopan vs placebo, on top of optimized supportive therapy, in patients with IgAN. Here we present the results of the pre-specified interim analysis (IA) with a focus on the results for key subgroups. Method APPLAUSE-IgAN (NCT04578834), a Phase 3, multicentre, randomised, double-blind, placebo-controlled trial, enrolled adults with biopsy-confirmed IgAN with proteinuria ≥1 g/g by urine−protein creatinine ratio from 24-hour urine collection (UPCR-24h) despite being on a stable dose of maximally tolerated renin-angiotensin-system inhibition (RASi) for 3 months, with or without other background therapy such as sodium-glucose transport protein 2 inhibition (SGLT2i). Patients were randomized 1:1 to iptacopan 200 mg or placebo twice daily for 24 months while remaining on stable supportive therapy. The primary objective of the prespecified IA was to demonstrate superiority of iptacopan vs placebo in reducing UPCR-24h at Month 9 (M9) in the main study population (estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2 at baseline). Subgroup analyses included baseline age, sex, Asia vs non-Asia region, proteinuria, eGFR, and SGLT2i use. Efficacy analyses were performed on the first 250 patients (n = 125 each for iptacopan and placebo) who reached the M9 visit or discontinued from the study. Safety analyses included all patients of the main population who had received treatment by the time of the IA (iptacopan, n = 222; placebo, n = 221). Results Baseline demographics and disease characteristics were similar between the two arms (Table) and indicative of patients at high risk of IgAN disease progression. Iptacopan was superior to placebo in reducing proteinuria, with reduction in UPCR-24h at M9 relative to baseline of 38.3% (95% CI: 26.0%, 48.6%; 1-sided p < 0.0001) vs placebo (Figure). Subgroup analyses showed that treatment effect consistently favoured iptacopan regardless of baseline age, sex, Asia vs non-Asia region, UPCR-24h or eGFR levels, or SGLT2i use as part of the supportive care (Figure). Treatment-emergent adverse events (TEAEs) occurred in 138 (62.2%) iptacopan vs 153 (69.2%) placebo patients, with the majority being of mild to moderate severity. Treatment-emergent serious AEs were reported in 18 (8.1%) and 11 (5.0%) patients in the iptacopan and placebo arms, respectively. TEAEs leading to treatment discontinuation occurred in 6 patients (2.7%) in each arm. No deaths were reported. Iptacopan treatment did not lead to clinically relevant differences in total cholesterol, low-density lipoprotein cholesterol, and serum triglycerides compared with placebo. Conclusion APPLAUSE-IgAN, the first Phase 3 study confirming the relevance of the AP in IgAN, demonstrated superiority of iptacopan vs placebo, with a significant reduction in proteinuria at M9 (38.3%) that was consistent across key subgroups evaluated. Iptacopan was well tolerated with a favourable safety profile.