VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN, With Carla Nester, MD

New findings show pegcetacoplan maintained a 70% reduction in proteinuria over 52 weeks in adolescents with C3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), with many patients achieving remission (≤0.5 g/g) or normalization (≤0.2 g/g).1

Data from a 26-week open-label extension of the phase 3 VALIANT trial, presented at the American Society of Nephrology (ASN) Kidney Week 2025 by Carla Nester, MD, a professor of pediatrics-nephrology at the University of Iowa, highlighted sustained proteinuria reductions and stable estimated glomerular filtration rate (eGFR) in the pegcetacoplan-treated patient population.

“For the first time ever, we can offer targeted therapy specifically for adolescents. It’s a major step forward for clinicians and patients,” said Nester in an interview with HCPLive.

Natural history studies of disease progression in C3G and IC-MPGN connected proteinuria <0.88 or 1 g/g or proteinuria reduction ≥50% with improved patient outcomes, including stabilization of the eGFR slope and a significantly lower lifetime risk of kidney failure.2

Pegcetacoplan is a PEGylated cyclic peptide aimed to selectively bind to C3 and C3b, inhibiting C3 activation and the formation of the alternative pathway C3 convertase. The US Food and Drug Administration (FDA) approved pegcetacoplan in patients with C3G and IC-MPGN in July 2025. The FDA’s decision was based on the 26-week results from the phase 3 VALIANT trial, the largest clinical trial conducted in this patient population, and the first to include adolescent and adult patients with native and post-transplant kidneys.2,3

The 52-week extension of VALIANT included pegcetacoplan-to-pegcetacoplan (n = 59) and placebo-to-pegcetacoplan (n = 55) groups. The primary endpoint was proteinuria change from baseline.

Patients receiving pegcetacoplan demonstrated sustained proteinuria reduction through 52 weeks, with a mean change of –67.2% at week 26 (95% confidence interval [CI], -74.9 to –57.2) and -67.2% at week 52 (95% CI, -75.8 to -55.4).

At week 26, 20 pegcetacoplan-treated patients (31.8%) achieved complete remission (≤0.5 g/g) and 11 (17.5%) reached normalization (≤0.2 g/g). These responses were maintained through week 52. By week 52, 34 patients (54.0%) had achieved a ≥50% reduction in proteinuria compared to 4.9% receiving placebo. Similar proportions of placebo-to-pegcetacoplan patients achieved remission and normalization during the open-label period, and 25 patients (41.0%) reached a ≥50% reduction.

“Many of these patients already have chronic kidney disease, so some degree of fixed proteinuria is expected. Getting them down to 0.5 g/g is remarkable, and it’s not something we’ve routinely been able to achieve in this population. Of course, the best outcome is getting patients into the normal range,” said Nester. “More than 70% of patients had a complete loss of C3 deposition on biopsy, and 17.5% achieved normalization of urine protein. That combination is a home run for this group of patients and is a tremendously satisfying outcome for clinicians treating glomerular disease.”

At 52 weeks, pegcetacoplan-treated patients saw stabilized eGFR in both adolescents and adults, signaling the therapy’s potential to change disease trajectory.

Editors’ note: Nester reports relevant disclosures with Apellis, Biocryst, Kira, Novartis, Silence Therapeutics, and Biocryst.

References

1. Nester CM, Fakhouri F, Gale DP, et al. Pegcetacoplan for 52 Weeks Results in Sustained Proteinuria Reduction to Remission (≤0.5 g/g) and Normalization (≤0.2 g/g): Phase 3 VALIANT Trial. Journal of the American Society of Nephrology. 2025;36(10S). doi:https://doi.org/10.1681/asn.2025da4gcc32

2. Kavanagh D, Ariceta G, Vivarelli M, et al. Current and Emerging Therapies for C3 Glomerulopathy and Primary (Idiopathic) Immune Complex Membranoproliferative Glomerulonephritis. Kidney International Reports. Published online November 5, 2025. doi:https://doi.org/10.1016/j.ekir.2025.10.020

3. ‌Brooks A. FDA Approves Pegcetacoplan (Empaveli) for C3 Glomerulopathy, IC-MPGN. Hcplive.com. Published July 28, 2025. https://www.hcplive.com/view/fda-approves-pegcetacoplan-empaveli-for-c3-glomerulopathy-ic-mpgn