Pivotal Clinical Trials in C3 Glomerulopathy: answers and remaining uncertainties

Complement 3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare glomerular diseases driven by dysregulation of the complement system, most commonly involving the alternative pathway. Recent advances in the understanding of disease pathogenesis have enabled the development of targeted complement therapies. The publication of pivotal phase 3 trials evaluating proximal complement inhibitors -iptacopan, a selective factor B inhibitor, and pegcetacoplan, a C3 inhibitor- marks a turning point in the management of C3G and IC-MPGN. Both agents demonstrated clinically meaningful reductions in proteinuria and stabilization of kidney function, establishing proof of efficacy. Despite these advances, important uncertainties remain. Key unresolved issues include optimal patient selection, timing and duration of therapy, treatment sequencing, monitoring strategies, and long-term kidney outcomes. Conventional immunosuppressive approaches provide inconsistent benefit and do not directly address complement dysregulation, while validated biomarkers to guide complement blockade are lacking. Additional challenges relate to treatment discontinuation, management of special populations, and health-system implementation. This review critically appraises the evidence from recent pivotal trials, highlighting both their transformative impact and the questions they raise. We emphasize the need for long-term outcome studies, precision-based therapeutic strategies, and pragmatic real-world data. Ultimately, the challenge ahead is not whether complement inhibition is effective but how best to deploy these therapies to maximize durable benefit, minimize risk, and ensure equitable access.