ORAL IPTACOPAN THERAPY IN C3 GLOMERULOPATHY SHOWS CONSISTENT STABILIZATION OF eGFR SLOPE ACROSS PATIENT SUBGROUPS

C3 glomerulopathy (C3G) is an ultra-rare and severe form of primary chronic glomerulonephritis caused by overactivation of the alternative complement pathway (AP). Iptacopan is a proximal complement inhibitor that targets factor B to specifically inhibit the AP and was recently approved for the treatment of adult patients with C3G, representing the first oral targeted treatment approved for C3G. The APPEAR-C3G Phase 3 trial (NCT04817618) met its primary endpoint, demonstrating a statistically significant (p=0.0014) relative reduction in 24-hour urine protein–creatinine ratio (UPCR) of 35.1% (95% CI: 13.8% to 51.1%) with iptacopan treatment at 6 months vs placebo. The iptacopan arm had a baseline to 12 month sustained reduction of 40% in 24-hour UPCR, showing durability of the treatment effect. Iptacopan treatment in the APPEAR-C3G trial stabilized patients estimated glomerular filtration rate (eGFR) slope trajectory compared to pre-treatment decline. This analysis compares eGFR slope changes after iptacopan initiation to pre-treatment slopes across multiple C3G participant subgroups in the APPEAR-C3G study.

The APPEAR-C3G trial was a Phase 3, randomized, double-blind, placebo-controlled, multicenter study. It assessed the efficacy and safety of iptacopan, alongside supportive care, in adult participants with C3G​. The study comprised a 6-month randomized double-blind treatment with iptacopan 200 mg twice daily vs. placebo, followed by 6 months of open-label iptacopan treatment​. Pre-enrolment eGFR measurements (up to 2.5 years pre-randomization in the placebo arm, up to 2 years in the iptacopan arm) and post-iptacopan treatment values (6 months in the placebo arm, 12 months in the iptacopan arm) were assessed for changes in eGFR slope. Pre-enrolment eGFR values were based on historical source data verified serum creatinine collected prior to the study.  The patient subgroups analyzed were i) baseline UPCR ≥3 g/g vs. <3 g/g, ii) baseline eGFR <90 vs. ≥90 mL/min/1.73 m2, and iii) with or without corticosteroid and/or mycophenolic acid treatment at randomization.

74 adult participants were randomized 1:1 to receive either iptacopan (n=38) or placebo (n=36), with 73 participants completing the 12-month study. Iptacopan reduced the rate of kidney function decline and stabilized eGFR slopes in all subgroups during the study treatment. In all subgroups evaluated, except those with eGFR ≥ 90ml/min/1.73m2, pre-treatment slopes were steeply negative, indicating a rapid loss of kidney function prior to iptacopan treatment. Iptacopan initiation resulted in an annualized eGFR slope between −1.75 and + 3.99 mL/min/1.73 m2/year (Table 1). These improvements in eGFR slope reflect consistent eGFR stabilization and suggest preservation of kidney function in participants with C3G following iptacopan treatment.

Iptacopan demonstrated clinical benefits in a broad set of adult participants with C3G, stabilizing the eGFR slope across all evaluated subgroups consistently, including those at high risk of disease progression. These findings support iptacopan as a disease-modifying therapy, targeting the underlying pathophysiology of C3G.