Targeted treatment with pegcetacoplan for adolescents with C3G or primary (idiopathic) IC-MPGN in the VALIANT phase 3 trial

Abstract

Background: C3 glomerulopathy (C3G) and primary (idiopathic) immune complex membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases where uncontrolled C3 activation results in excessive glomerular deposition of C3 breakdown products, often diagnosed in adolescence or early adulthood. Current treatments have significant side effects and approximately 20% of children progress to kidney failure within 10−15 years of diagnosis. Pegcetacoplan, a C3/C3b inhibitor, targets the central complement pathway components to directly inhibit overactivation of C3 breakdown. In the overall VALIANT (NCT05067127) population, pegcetacoplan led to significant proteinuria reduction and estimated glomerular filtration rate (eGFR) stabilization vs placebo in C3G or primary IC-MPGN patients. Here, we report results for adolescents (12–17 years). Methods: VALIANT, a randomized, double-blind, placebo-controlled Phase 3 trial, included adolescents (≥12 years) and adults with biopsy-proven C3G or primary IC-MPGN in native or post-transplant kidneys and proteinuria >1 g/day. In adolescents without a baseline biopsy, eligibility criteria included ≥1 of the following: increased plasma soluble C5b-9, decreased serum C3, presence of hematuria, or presence of C3 nephritic factor. Patients were randomized 1:1 to pegcetacoplan (subcutaneous infusion twice weekly) or placebo for 26 weeks in the RCP. Biopsies were optional for adolescents. The primary endpoint was the log-transformed ratio of urine protein-to-creatinine ratio (UPCR) at week 26 vs baseline. Key secondary endpoints included the proportion of patients achieving a composite renal endpoint criterion (≥50% UPCR reduction and ≤15% eGFR reduction), ≥50% UPCR reduction, and eGFR change from baseline. Results: In total, 28 adolescents were randomized to pegcetacoplan and 27 to placebo. Pegcetacoplan led to significant and clinically meaningful UPCR reductions at week 26, with a 74.5% relative reduction in proteinuria in the pegcetacoplan vs placebo arms (95% CI 58.5, 84.3; nominal P < .0001). A greater proportion of adolescents in the pegcetacoplan vs placebo arm achieved the composite renal endpoint (57.1% vs 3.7%; nominal P = .0016) and ≥50% UPCR reduction (71.4% vs 3.7%; nominal P = .0002). Pegcetacoplan was associated with clinically meaningful eGFR stabilization. Conclusions: In VALIANT, pegcetacoplan was well tolerated in adolescents with C3G and primary IC-MPGN and was the first treatment to induce meaningful proteinuria reduction and eGFR stabilization in this population.