#3018 Iptacopan's rapid and sustained inhibition of overactive complement alternative pathway in C3G: Exploratory analysis from the Phase 3 APPEAR-C3G study

Abstract Background and Aims Primary C3 glomerulopathy (C3G) is an ultra-rare glomerulonephritis driven by overactivation of the alternative complement pathway (AP). Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B, thereby selectively inhibiting the AP of the complement cascade. Data from a Phase 2 study [1] showed that iptacopan significantly increased serum C3 while reducing plasma sC5b-9, serum AP activity, and urinary sC5b-9/creatinine. Similar results were observed at 6 months of APPEAR-C3G Phase 3 study [2] (NCT04817618). Here, we present the 12-month results on complement biomarkers from the APPEAR-C3G study. Method APPEAR-C3G was a randomized, double-blind, parallel-group, multicenter, placebo-controlled Phase 3 trial designed to evaluate the efficacy and safety of iptacopan 200 mg b.i.d. (twice-daily) vs placebo, alongside supportive care, in adult patients with C3G. Participants were randomized to receive either iptacopan 200 mg b.i.d. or placebo for 6 months, followed by 6-month open-label phase during which all participants received iptacopan. Changes in complement biomarkers such as serum C3, serum AP activity (measured by AP Wieslab® assay), plasma sC5b-9, and urinary sC5b-9/creatinine were assessed as exploratory endpoints during the 12-month period. Results All 74 participants randomized 1:1 to receive either iptacopan (n = 38) or placebo (n = 36) completed the 6-month double-blind period. Of these, 73 participants completed the 12-month study (double-blind then open-label period). Baseline levels of all biomarkers were comparable in the iptacopan and placebo arms. A significant increase in serum C3 was observed in the iptacopan arm, with a 185.2% increase compared to placebo at 6 months (p < 0.0001). This increase was sustained over 12 months, with similar results in the placebo arm post-iptacopan initiation. The serum C3 level increased from baseline by 211% (95% CI: 172%, 254%) for the iptacopan arm and 200% (95% CI: 162%, 244%) for the placebo arm (post-iptacopan initiation) at 12 months. At Month 6, 42.1% of participants in the iptacopan arm achieved normalized serum C3 levels (≥900 mg/L), and 44.7% at Month 12. In contrast, no participants in the placebo arm showed normalization at Month 6; however, 44.1% achieved it at Month 12 after starting iptacopan. Baseline serum AP activity values were comparable between arms, with 61.3% in the iptacopan group and 54.3% in the placebo group exhibiting serum AP activity below the lower limit of quantification, likely due to low serum C3 levels reflecting activation of the complement pathway. A 38.3% reduction in serum AP activity was noted in the iptacopan arm compared to placebo by 6 months (p < 0.0001), sustained through 12 months. At Month 12, there was a 43% (95% CI: 39%, 46%) decrease from baseline for iptacopan and 40% (95% CI: 36%, 43%) for placebo. Plasma sC5b-9 levels reduced by 66.3% in the iptacopan arm compared to placebo by 6 months (p < 0.0001) and sustained over 12 months. Plasma sC5b-9 level reduced from baseline by 66% (95% CI: 60%, 72%) for iptacopan and 66% (95% CI: 59%, 72%) for placebo at Month 12. Urinary sC5b-9/creatinine levels decreased significantly with iptacopan compared to placebo by 6 months (81.6% reduction, p < 0.0001), sustained over 12 months. The urinary sC5b-9/creatinine level decreased from baseline by 84% (95% CI: 71%, 91%) for iptacopan and 85% (95% CI: 74%, 91%) for placebo at Month 12. Conclusion Biomarker results from the APPEAR-C3G study confirmed inhibition of the AP with iptacopan, demonstrated by a rapid onset and sustained improvement of serum C3, along with a reduction in AP activity and terminal complement complex sC5b-9 over a 12-month period. Results were also replicated in the placebo arm after switch to open label iptacopan.