#2613 Reduction of hematuria and albuminuria with iptacopan in C3G: findings from APPEAR-C3G study

Abstract Background and Aims C3 glomerulopathy (C3G), is an ultra-rare primary glomerulonephritis caused by overactivation of the alternative complement pathway (AP). Hematuria is a common manifestation of kidney damage in patients with active C3G; while albuminuria is a prognostic biomarker for many types of glomerulonephritis, including C3G. Iptacopan (LNP023) is an oral, proximal complement inhibitor that targets Factor B to selectively inhibit the AP of the complement cascade. We previously reported data from the Phase 3 APPEAR-C3G study (NCT04817618) showing iptacopan treatment for up to 12 months resulted in a statistically significant and clinically meaningful proteinuria reduction, estimated glomerular filtration rate stabilization and a reduction in C3 deposition within the glomeruli. Here, we report the efficacy of iptacopan 200 mg twice daily (b.i.d.) in reducing hematuria and albuminuria compared to baseline in participants with C3G over 12 months in the APPEAR-C3G study. Method APPEAR-C3G was a multicenter, randomized, double-blind, parallel-group, placebo (PBO)-controlled, pivotal Phase 3 study that treated adult patients with biopsy confirmed C3G. The study comprised a 6-month randomized double-blind treatment with iptacopan vs PBO followed by 6-month open-label iptacopan treatment, as previously described. Two of the key exploratory endpoints were to evaluate reduction of urine albumin-creatinine ratio (UACR) and incidence of hematuria with iptacopan and PBO at 6 and 12 months compared to baseline. The proportion of participants without hematuria (≤5 red blood cell [rbc]/ high power field [HPF] using central laboratory data), mixed model for repeated measures analysis of the log-transformed ratio to baseline (BL) in 24-hour (h) UACR (g/g) and change from BL in first morning void (FMV) UACR (g/g), at both 6 and 12 months are reported here. Results Seventy-four participants were randomized 1:1 to either iptacopan (n = 38) or PBO (n = 36). At BL, the proportion of participants without hematuria were notably lower in the iptacopan arm vs PBO (13/38 [34.2%] vs 18/34 [52.9%]). The proportion of participants without hematuria at Month 6 increased in the iptacopan arm (22/36 [61.1%]; 95% CI: 45%, 77%) in comparison to no improvement in the PBO arm (18/32 [56.3%]; 95% CI: 39%, 73%) compared to baseline. The proportion of participants without hematuria increased further at Month 12 in the iptacopan arm to 28/36 (77.8%; 95% CI: 64%, 91%). A similar effect was observed in PBO arm after switching to iptacopan with an increase to 29/34 (85.3%; 95% CI: 74%, 97%) after 6 months of iptacopan treatment (Fig. 1). A clinically meaningful reduction in 24h UACR for iptacopan vs PBO was observed at Month 6 (42.5%; 95% CI: 21.1%, 58.1%, 1-sided P = 0.0004) consistent with the primary endpoint analysis of 24 h urine protein-creatinine ratio. At Month 12, the 24 h UACR (g/g) showed a 44.0% (95% CI: 25.5%, 57.9%) reduction in the iptacopan arm and 29.3% (95% CI: 7.6%, 46.0%) in the PBO arm, following 6 months of iptacopan treatment in the open-label period (Fig. 2). The results of FMV UACR were consistent with those assessed as 24 h UACR. Compared to PBO, the iptacopan arm showed a 14.0% (95% CI: −8.7%, 32.0%) and 37.9% (95% CI: 15.3%, 54.5%) reduction in FMV UACR at Day 14 and 30, respectively, which further reduced to 42.0% (95% CI: 9.3%, 62.9%, 1-sided P = 0.0089) at Month 6 demonstrating rapid onset of action. Additionally, at Month 12, the analysis of log-transformed ratio of FMV UACR (g/g) indicated a reduction of 41.5% (95% CI: 20.9%, 56.7%) in the iptacopan arm and 30.8% (95% CI: 5.7%, 49.3%) in the PBO arm, following switch and 6 months of iptacopan treatment in the open-label period. Conclusion The results demonstrate that iptacopan effectively reduces the levels of active disease biomarkers such as hematuria and albuminuria associated with C3G which was sustained over 12 months of treatment. Beneficial effects were observed in patients receiving placebo after switching to iptacopan treatment. These data continue to support iptacopan as an important treatment option that targets the root cause of C3G.