VALIANT: Randomized, multicenter, double-blind, placebo-controlled, phase 3 trial of pegcetacoplan for patients with native or post-transplant recurrent C3G or primary (idiopathic) IC-MPGN

Abstract

Objective: C3 glomerulopathy (C3G) and primary immune complexmembranoproliferative glomerulonephritis (IC-MPGN) are complement- mediated diseases driven by C3 dysregulation with excessive accumulation of C3 breakdown products in the kidney. Pegcetacoplan is a C3/C3b inhibitor targeting the central components of the complement pathway, thereby directly inhibiting C3 overactivation, preventing further deposition of C3 breakdown products in the glomeruli. VALIANT (NCT05067127) is a double-blind, placebo-controlled trial investigating the efficacy and safety of pegcetacoplan, a C3/C3b inhibitor, in adolescents (≥ 12 years) and adults with native or post-transplant recurrent C3G or primary IC-MPGN. Method: VALIANT (NCT05067127) is a randomized, multicenter, double-blind, placebo-controlled trial to investigate pegcetacoplan safety and efficacy and the only Phase 3 study to investigate treatment in a wide cohort including adults and adolescents (≥ 12 years), with native or posttransplant recurrent C3G and IC-MPGN. 124 patients were randomized to pegcetacoplan (n = 63) (twice weekly subcutaneous infusion) or placebo (n = 61) for 26 weeks. The primary endpoint was log-transformed ratio of uPCR at week 26 vs. baseline to measure proteinuria reduction vs. placebo. Key secondary endpoints at week 26 were a composite renal endpoint (proportion of patients achieving ≥ 50% uPCR and ≤ 15% eGFR reductions), proportion of patients achieving ≥ 50% uPCR reduction, C3G histologic index activity score change (adjusted LS mean change), reduced C3c renal biopsy staining of ≥ 2 OOM, eGFR change, (LS mean change), mL/ min/1.73m2. Safety was assessed by treatment-emergent adverse events (TEAE) frequency and severity. Results: The primary endpoint was met, with 68.1% (95% CI-76.2, .57.3) mean reduction of uPCR in pegcetacoplan vs. placebo arms at week 26 (p < 0.0001) (Table 1). Results were consistent across all subgroups (disease type, age, and transplant status). Robust reductions in C3c staining and clinically meaningful eGFR stabilization were observed with pegcetacoplan vs. placebo (Table 1). Treatment-emergent AE frequency and severity were similar between arms. None of the 4 serious infections (3 pegcetacoplan; 1 placebo) were attributed to encapsulated bacteria. Conclusion: Pegcetacoplan, a C3/C3b inhibitor, is the first therapy to achieve significant and clinically meaningful reductions in proteinuria (68.1% vs. placebo), C3c staining and eGFR stabilization, compared with placebo in patients ≥ 12 years with C3G or primary IC-MPGN. Pegcetacoplan was well tolerated with no new safety signals observed.