Abstract
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
Immunobiology (1979), Vol.230(4), 153039
07/2025
DOI: 10.1016/j.imbio.2025.153039
Abstract
C3 glomerulopathy (C3G) and primary immune complex-membranoproliferative glomerulonephritis (IC-MPGN) are complement-mediated diseases driven by C3 dysregulation with excessive accumulation of C3 breakdown products in the kidney. Pegcetacoplan (PEG) a C3/C3b inhibitor, targets the central components of the complement pathway, directly inhibiting C3 overactivation and preventing further deposition of C3 breakdown products in the glomeruli. VALIANT (NCT05067127) is the first Phase 3 trial investigating PEG in a broad cohort, including adolescents (≥12 yrs) and adults with native or post-transplant recurrent C3G or primary IC-MPGN.
VALIANT is a randomized, multicenter, double-blind, placebo (PBO)-controlled trial evaluating PEG efficacy and safety. 124 pts were randomized to PEG (n = 63) (twice weekly subcutaneous infusion) or PBO (n = 61) for 26 weeks (wks). The primary endpoint was log-transformed UPCR ratio at wk 26 vs baseline, assessing proteinuria reduction vs PBO. Key secondary endpoints at wk 26 were a composite renal endpoint (proportion of pts achieving ≥50% UPCR and ≤15% eGFR decline), 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/1.73 m2. Safety was assessed by treatment-emergent adverse events (TEAE) frequency and severity.
The primary endpoint was met, with PEG demonstrating a 68.1% (95% CI: –76.2, –57.3) mean UPCR reduction vs. PBO at wk 26 (p < 0.0001). Results were consistent across disease type, age, and transplant status subgroups. PEG also led to robust reductions in C3c staining and clinically meaningful eGFR stabilization vs PBO. Treatment-emergent AE frequency and severity were similar between arms. None of the 4 serious infections (3 PEG; 1 PBO) were attributed to encapsulated bacteria.
PEG is the first therapy to achieve significant and clinically meaningful reductions in proteinuria (68.1% vs. PBO), C3c staining and eGFR stabilization in pts ≥12 yrs with C3G or primary IC-MPGN. PEG was well tolerated with no new safety signals observed.
Details
- Title: Subtitle
- 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
- Creators
- Carla M. Nester - University of IowaAndrew S. Bomback - Columbia University Irving Medical CenterGema Ariceta - Vall d'Hebron Hospital UniversitariYahsou Delmas - Hôpital PellegrinBradley P. Dixon - University of Colorado Anschutz Medical CampusDaniel P. Gale - University College LondonLarry A. Greenbaum - Emory and Henry CollegeSeung Hyeok Han - Yonsei UniversityNicole Isbel - Princess Alexandra HospitalChristoph Licht - Hospital for Sick ChildrenAntonio Mastrangelo - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMasashi Mizuno - Nagoya UniversityMaria Izabel Neves de Holanda - Hospital Geral de BonsucessoMatthew C. Pickering - Imperial College LondonGiuseppe Remuzzi - Mario Negri Institute for Pharmacological ResearchNicole Van De Kar - Radboud University Medical CenterMarina Vivarelli - Bambino Gesù Children's HospitalPatrick D. Walker - Arkana LaboratoriesDean Wallace - Royal Manchester Children's HospitalDaniel Zecher - University Hospital RegensburgLi Li - Apellis PharmaceuticalsZhongshen Wang - Apellis PharmaceuticalsLuis López Lázaro - Swedish Orphan BiovitrumJohan Szamosi - Swedish Orphan BiovitrumFadi Fakhouri - University of Lausanne
- Resource Type
- Abstract
- Publication Details
- Immunobiology (1979), Vol.230(4), 153039
- DOI
- 10.1016/j.imbio.2025.153039
- ISSN
- 0171-2985
- eISSN
- 1878-3279
- Publisher
- Elsevier GmbH
- Language
- English
- Date published
- 07/2025
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984946701302771
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