Fakhouri, Fadi; Bomback, Andrew S; Ariceta, Gema; Delmas, Yahsou; Dixon, Bradley P; Gale, Daniel P; Greenbaum, Larry A; ... VALIANT Trial Investigators Group; + view all Fakhouri, Fadi; Bomback, Andrew S; Ariceta, Gema; Delmas, Yahsou; Dixon, Bradley P; Gale, Daniel P; Greenbaum, Larry A; Han, Seung Hyeok; Isbel, Nicole; Le Quintrec, Moglie; Licht, Christoph; Mastrangelo, Antonio; Mizuno, Masashi; Neves de Holanda, Maria Izabel; Pickering, Matthew C; Remuzzi, Giuseppe; Van De Kar, Nicole; Vivarelli, Marina; Walker, Patrick D; Wallace, Dean; Zecher, Daniel; Francois, Cedric; Deschatelets, Pascal; Li, Li; Wang, Zhongshen; Abad-Franch, Lydia; Kinnman, Nils; López-Lázaro, Luis; Szamosi, Johan; Nester, Carla M; VALIANT Trial Investigators Group; - view fewer (2025) Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN. The New England Journal of Medicine , 393 (22) pp. 2210-2220. 10.1056/NEJMoa2501510.

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Abstract

BACKGROUND: C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (MPGN) generally result in glomerular C3 deposition and irreversible kidney damage. The efficacy and safety of pegcetacoplan, a C3 and C3b inhibitor, in persons with C3 glomerulopathy or primary immune-complex MPGN are unclear. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial involving adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, including those with native kidney disease and those with disease recurrence after transplantation. Patients were randomly assigned in a 1:1 ratio to receive pegcetacoplan or placebo. The primary end point was the log-transformed ratio of the urinary protein-to-creatinine ratio at week 26 as compared with baseline. RESULTS: A total of 124 patients underwent randomization. The change in proteinuria (as measured by the log-transformed ratio to baseline in the urinary protein-to-creatinine ratio) was significantly greater with pegcetacoplan than with placebo (geometric mean of the urinary protein-to-creatinine ratio, -67.2% [95% confidence interval {CI}, -74.9 to -57.2] vs. 2.9% [95% CI, -8.6 to 15.9]). The difference represents a relative reduction of 68.1% (95% CI, 57.3 to 76.2) as compared with placebo. In hierarchical testing of five secondary end points, significantly higher percentages of patients in the pegcetacoplan group than in the placebo group met the composite renal end-point criteria (stabilization of estimated glomerular filtration rate [eGFR] and ≥50% reduction in urinary protein-to-creatinine ratio) (49% vs. 3%) and had at least a 50% reduction in the protein-to-creatinine ratio (60% vs. 5%). Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between the two groups; subsequent end points (decrease in C3 staining and change in eGFR) were not formally tested. Pegcetacoplan was not associated with more adverse events than placebo. No serious infections from encapsulated bacteria occurred; 1 patient receiving pegcetacoplan died from coronavirus disease 2019 pneumonia. No allograft rejection or loss occurred. CONCLUSIONS: Pegcetacoplan resulted in a significantly greater reduction in proteinuria than placebo among patients with C3 glomerulopathy or primary immune-complex MPGN. (Funded by Apellis Pharmaceuticals and Sobi [Swedish Orphan Biovitrum]; VALIANT ClinicalTrials.gov number, NCT05067127.).

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