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 deposition1,2. 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 preservation7,8. 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 approaches1,4. 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 20259.