Pegcetacoplan reduces proteinuria, stabilizes kidney function in adolescents with C3G and IC-MPGN

C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) frequently take hold before adulthood, and a newly published adolescent subgroup analysis suggests pegcetacoplan (EMPAVELI) can meaningfully slow that early trajectory. Results from a prespecified analysis of the phase 3 VALIANT trial, published in the Clinical Journal of the American Society of Nephrology (CJASN), showed that adolescents treated with pegcetacoplan achieved a 75% relative reduction in proteinuria compared with placebo by week 26, with effects emerging as early as week 4.¹

“C3G and primary IC-MPGN are often diagnosed early in life, when preventing progressive kidney damage can have a meaningful long-term impact,” said Bradley Dixon, MD, section chief of pediatric nephrology and professor of pediatrics at the University of Colorado School of Medicine and Children's Hospital Colorado. “The VALIANT results show substantial reductions in proteinuria and stabilization of kidney function in adolescents, consistent with what we observed in the broader population.”

VALIANT trial design and adolescent subgroup findings

VALIANT (NCT05067127) was a randomized, double-blind, placebo-controlled phase 3 trial that enrolled 124 patients aged 12 years and older with biopsy-confirmed C3G or primary IC-MPGN, including both native-kidney and post-transplant recurrent disease. Participants received subcutaneous pegcetacoplan or placebo twice weekly for 26 weeks, followed by a 26-week open-label extension in which all patients received active treatment. The primary endpoint was the change in urine protein-to-creatinine ratio (UPCR) at week 26.^1,2

Adolescents made up 44% of the trial population (n=55), one of the largest randomized cohorts assembled for this age group in these diseases. Among adolescents, pegcetacoplan produced a 75% relative reduction in proteinuria versus placebo (95% CI, 59%-84%; nominal P<.001). Seventy-one percent of treated adolescents achieved at least a 50% proteinuria reduction, compared with 4% on placebo, and 57% met a composite endpoint of stable kidney function plus at least 50% proteinuria reduction, versus 4% with placebo (nominal P=.002). Safety in adolescents was consistent with the overall trial population, with no new signals identified.

Disease burden and unmet need in pediatric C3G and IC-MPGN

C3G and primary IC-MPGN are rare, complement-mediated kidney diseases that damage the glomeruli and can progress to kidney failure. Roughly half of C3G cases are diagnosed before age 18, and the median age at diagnosis for primary IC-MPGN is approximately 21 years, placing many patients squarely in pediatric and adolescent care. Despite standard-of-care management, about 20% of children with these conditions progress to kidney failure within 10 to 15 years of diagnosis, often culminating in dialysis or transplant. Until pegcetacoplan's 2025 approval, no targeted therapy existed for this population.

Mechanism and regulatory history of pegcetacoplan

Pegcetacoplan is a pegylated cyclic peptide that binds complement protein C3 and its activation fragment C3b, blocking amplification of the complement cascade upstream of the terminal pathway. It was first approved for paroxysmal nocturnal hemoglobinuria before the FDA granted approval in July 2025 for C3G and primary IC-MPGN in patients 12 years and older, based on 26-week VALIANT data showing reduced proteinuria, stabilized eGFR, and clearance of glomerular C3 deposits. The label was subsequently expanded to include reducing the loss of kidney function, based on 52-week efficacy and safety data, making pegcetacoplan the first and only therapy approved for both endpoints in this population.³

Interpreting the adolescent-specific data

The consistency between the adolescent subgroup and the overall VALIANT population is reassuring, but the adolescent cohort remains small (n=55), and the subgroup analysis — while prespecified — was not powered as an independent pivotal endpoint. The reported P values are nominal rather than adjusted for multiplicity, a common feature of subgroup reporting that warrants some caution in interpretation. Daniel Jones, PhD, vice president and head of global medical affairs for EMPAVELI at Biogen, framed the publication as reinforcing rather than establishing efficacy: “These findings reinforce the potential for EMPAVELI to help protect patients' kidney health.”

Limitations and open questions

The VALIANT trial's randomized period was limited to 26 weeks, and while open-label extension data through 52 weeks have been presented separately, the CJASN publication centers on the earlier window. Biopsies were optional for adolescents who met alternative eligibility criteria, which may introduce some diagnostic heterogeneity within the pediatric cohort. Long-term outcomes — particularly durability of kidney function stabilization into adulthood and effects on progression to kidney failure — will require extended follow-up. Pegcetacoplan also carries a boxed warning for serious infections from encapsulated bacteria, requiring vaccination and REMS enrollment, considerations that are especially relevant when treating adolescents.

References

1. Biogen. Phase 3 pediatric EMPAVELI data published in Clinical Journal of the American Society of Nephrology show reduction in proteinuria and stabilized kidney function in adolescents with C3G or primary IC-MPGN. Biogen. September 17, 2026. Accessed September 17, 2026. https://investors.biogen.com/news-releases/news-release-details/phase-3-pediatric-empaveli-data-published-clinical-journal

2. Fakhouri F, Bomback AS, Ariceta G, et al; VALIANT Trial Investigators Group. Trial of pegcetacoplan in C3 glomerulopathy and immune-complex MPGN. N Engl J Med. 2025;393(22):2210-2220. doi:10.1056/NEJMoa2501510

3. US Food and Drug Administration. FDA approves EMPAVELI (pegcetacoplan) as first treatment for C3G and primary IC-MPGN in patients 12 and older. July 28, 2025. Accessed September 17, 2026. https://www.biospace.com/press-releases/fda-approves-apellis-empaveli-pegcetacoplan-as-the-first-c3g-and-primary-ic-mpgn-treatment-for-patients-12-and-older