INTRODUCTION Iptacopan, a factor B inhibitor, targets alternative complement pathway overactivation, a key driver of glomerular inflammation in IgA nephropathy. In the phase 3 APPLAUSE-IgAN trial (NCT04578834), iptacopan significantly slowed kidney function decline versus placebo over 24 months (difference in total estimated glomerular filtration rate [eGFR] slope: 3.02 ml/min per 1.73 m2 per year [95% confidence interval (CI) 2.02, 4.01; P < 0.001]). METHODS Patients who completed APPLAUSE-IgAN or the phase 2 iptacopan trial (NCT03373461) could enter an open-label rollover extension program (REP) (NCT04557462). Patients in this REP receive oral iptacopan 200 mg twice daily alongside supportive care. Patients from the phase 2 trial were not included in efficacy analyses. RESULTS Overall, 194 and 174 patients from the APPLAUSE-IgAN iptacopan and placebo arms, respectively, entered the REP. In patients who received iptacopan for up to 48 months, the total annualized eGFR slope was -3.49 ml/min per 1.73 m2 per year (95% CI -4.17, -2.80). Urine protein-to-creatinine ratio from first morning void (UPCR-FMV) reduction was sustained through 48 months with iptacopan (geometric mean ratio to baseline: 0.61 [95% CI 0.50, 0.75]). Before receiving iptacopan, the total eGFR slope over 24 months in APPLAUSE-IgAN placebo arm patients who entered the REP was -5.29 ml/min per 1.73 m2 per year (95% CI -6.09, -4.49). After switching to iptacopan, the total eGFR slope improved to -2.11 ml/min per 1.73 m2 per year (95% CI -3.08, -1.13) over the next 24 months. UPCR-FMV decreased after switching (geometric mean ratio to baseline at month 48: 0.74 [95% CI 0.59, 0.91]). Long-term safety up to 5 years (median treatment duration: 29.9 months) was consistent with the known profile of iptacopan. CONCLUSIONS Long-term treatment with iptacopan led to sustained slowing in eGFR decline and proteinuria reduction that were also observed after switching from placebo. No new safety signals were observed. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study numbers NCT04578834 (APPLAUSE-IgAN), NCT03373461 (phase 2 trial of iptacopan in IgAN), and NCT04557462 (rollover extension program).
