Pegcetacoplan as a targeted C3 inhibitor in C3 glomerulopathy and immune-complex MPGN

To the Editor, C3 glomerulopathy (C3G) and immune-complex membranoproliferative glomerulonephritis (IC-MPGN) are rare complement-mediated kidney diseases that have historically defied effective treatment. C3G is characterized by the deposition of complement by-products due to dysregulation of the alternative pathway, while IC-MPGN involves glomerular deposition of both immunoglobulins and complement fragments, often secondary to infection, autoimmunity, or monoclonal immunoglobulin deposition[1,2]. Both conditions confer a high risk of progression to end-stage kidney disease and recurrence after transplantation [3]. Conventional therapies, such as mycophenolate mofetil, have shown partial remission but high relapse rates, while C5 inhibitors (eculizumab and avacopan) have demonstrated limited response [4,5]. Pegcetacoplan, a C3 and C3b inhibitor, blocks all three complement pathways (alternative, classical, and lectin), thereby preventing the generation of C3a and downstream inflammatory fragments. In the recently published phase 3, double-blind, placebo-controlled trial by Fakhouri et al in The New England Journal of Medicine, pegcetacoplan, administered subcutaneously twice weekly in 124 patients with C3G or IC-MPGN, achieved a 68.1% reduction in proteinuria at 26 weeks compared to placebo, with stabilization of the estimated glomerular filtration rate (eGFR)[6]. Notably, reductions in proteinuria were observed as early as 4 weeks, despite 72% of participants already receiving immunosuppressive therapy at baseline. Repeat biopsies demonstrated decreased C3 staining in 74% of pegcetacoplan-treated patients versus 12% of placebo, underscoring its mechanistic efficacy. These findings build upon earlier reports of pegcetacoplan’s efficacy in paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and age-related macular degeneration, where targeted C3 inhibition improved hemolysis, renal outcomes, and retinal preservation[7,8]. Together, these data suggest that effective treatment of C3G and IC-MPGN requires upstream complement blockade beyond C5, addressing both C3a-mediated inflammation and tissue-level deposition of C3 fragments. However, challenges remain. Some pegcetacoplan-treated patients continued to lose kidney function, highlighting variability in response. Long-term safety data are limited, particularly regarding infection risk due to broad complement inhibition. The high cost of therapy may restrict accessibility, especially in low-resource settings. Moreover, heterogeneity in disease drivers – autoantibodies, nephritic factors, or genetic variants – may influence therapeutic outcomes, necessitating personalized approaches[1,4]. In conclusion, pegcetacoplan represents a major advance in the management of C3G and IC-MPGN, offering targeted inhibition of complement activation with clinically meaningful renal protection. Future directions should include long-term follow-up to assess the sustainability of proteinuria and eGFR responses, multicenter trials across diverse populations, and cost-effectiveness analyses. For young patients with progressive nephropathy or recurrence after transplantation, pegcetacoplan provides a promising therapeutic option. This letter adheres to the Transparency in the Reporting of Artificial Intelligence (TITAN) guidelines 2025[9].