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January 06, 2026
2 min read
Key takeaways:
- Pegcetacoplan reduced proteinuria in patients with rare complement-mediated glomerular diseases vs. placebo.
- Results were derived from a phase 3, double-blind, placebo-controlled trial.
Pegcetacoplan significantly reduces proteinuria in patients with recurrent C3 glomerulopathy, or primary immune-complex membranoproliferative glomerulonephritis, compared with placebo, according to data.
“Pegcetacoplan is a targeted C3 and C3b inhibitor that directly blocks both C3 and C5 activation through the classical, lectin and alternative complement pathways, which inhibits downstream effectors,” Fadi Fakhouri, MD, PhD, professor of nephrology at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues wrote in the New England Journal of Medicine. “Consequently, pegcetacoplan is predicted to halt glomerular C3 and C5 activation in C3 glomerulopathy and primary immune-complex MPGN, which could prevent glomerular complement deposition and kidney failure.”
Data were derived from Fakhouri F, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2501510.
To assess the efficacy and safety of pegcetacoplan (Syfovre, Appelis Pharmaceuticals) for patients with recurrent C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis (MPGN), including patients with native kidney disease and disease recurrence after transplantation, Fakhouri and colleagues from the VALIANT trial investigators group conducted a phase 3, double-blind, placebo-controlled trial.
The researchers randomly assigned 124 adult and adolescent patients to receive either subcutaneous pegcetacoplan or placebo. The primary outcome measure was change in the urinary protein-to-creatinine ratio (UPCR) from baseline to 26-week follow-up. At 26 weeks, 59 patients (94%) in the pegcetacoplan group and 57 patients (93%) in the placebo group completed the trial.
According to the researchers, the geometric mean of UPCR was –67.2% (95% CI, 74.9 to 57.2) in the pegcetacoplan group vs 2.9% (95% CI, 8.6 to 15.9) in the placebo group, representing a 68.1% (95% CI, 57.3-76.2) relative reduction in proteinuria for pegcetacoplan vs. placebo.
Fakhouri and colleagues found 60% of the pegcetacoplan group, vs. 5% of the placebo group, had at least a 50% reduction in UPCR. In addition, 49% of the pegcetacoplan group, vs. 3% of the placebo group, met composite renal end-point criteria. The researchers concluded patients receiving pegcetacoplan were more likely to achieve meaningful renal responses.
Regarding safety, the pegcetacoplan group demonstrated an 84% rate of adverse events, while the placebo group had a 93% rate. Both groups demonstrated a 10% rate of serious adverse events. One patient in the pegcetacoplan group died from respiratory failure associated with COVID-19-related pneumonia.
“A reduction in proteinuria has disease-specific relevance for prognosis and treatment,” Fakhouri and colleagues wrote. “Although we did not perform formal testing, our findings with respect to complement activation and glomerular C3 staining provide support for the hypothesis that the significant benefit of pegcetacoplan with respect to the primary end point is due to its stopping of the pathophysiological drivers of disease.”
Sources/Disclosures
Source:
Fakhouri F, et al. N Engl J Med. 2025;doi:10.1056/NEJMoa2501510.
Disclosures:
Fakhouri reports receiving consulting fees from Alexion Pharmaceuticals, Apellis Pharmaceuticals, AstraZeneca, F. Hoffmann-La Roche, Novartis and Sobi. The authors report receiving financial support from Apellis Pharmaceuticals and Sobi for the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.
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