Pegcetacoplan Versus Iptacopan for the Treatment of Patients with C3 Glomerulopathy: Indirect Treatment Comparisons.

introductionC3 glomerulopathy (C3G) is a rare complement-mediated kidney disease. Pegcetacoplan [targeted complement 3 (C3)/C3b inhibitor] and iptacopan (factor B inhibitor) target the complement system and are approved for treatment of C3G in adults and adolescents (pegcetacoplan) or adults only (iptacopan). Currently, no head-to-head randomized controlled trials (RCTs) have assessed their relative efficacy.

methodsIndirect treatment comparisons (ITCs) were conducted using the Bucher (primary analysis-preserves randomization) and matching-adjusted indirect comparison (MAIC; supportive analyses-adjusts for trial differences) methodologies and data from two similarly designed, placebo-controlled, Phase III RCTs in C3G/primary immune-complex membranoproliferative glomerulonephritis [VALIANT (NCT05067127)] and C3G only [APPEAR-C3G (NCT04817618)]. Relative efficacy was assessed at 6 months (anchored Bucher and MAIC) and 12 months (anchored Bucher/MAIC plus unanchored MAIC).

resultsAt 6 months, the Bucher analysis demonstrated pegcetacoplan was associated with a significantly greater reduction in urine protein-creatinine ratio (UPCR) relative to baseline versus iptacopan [mean difference -50.90% (95% confidence interval: - 67.34, - 26.18); p < 0.001]; also a significantly greater proportion of patients achieved UPCR reduction to < 1 g/g, UPCR reduction by ≥ 50%, and the composite renal endpoint [≥ 50% reduction in UPCR and ≤ 15% reduction in estimated glomerular filtration rate (eGFR)]. The between-trial difference in mean eGFR change from baseline was not statistically different between treatments. Results from the anchored MAIC were generally consistent with the Bucher analysis. At 12 months, pegcetacoplan was associated with a significantly greater reduction in UPCR from baseline versus iptacopan but not for eGFR.

conclusionThese ITCs indicate that, in patients with C3G, pegcetacoplan is associated with greater reductions in proteinuria levels, and more patients achieved the composite renal endpoint compared with iptacopan. The relative efficacy benefits for pegcetacoplan observed at 6 months were sustained at 12 months. These comparative effectiveness findings may help clinicians and payers better understand the utility of new therapies to treat patients with C3G.