Abstract
3265 Pegcetacoplan treatment effect in patients with nephrotic range proteinuria: results from the VALIANT Phase 3 study in patients with C3G or primary (idiopathic) IC-MPGN
Nephrology, dialysis, transplantation, Vol.40(Supplement_3), gfaf116012
10/21/2025
DOI: 10.1093/ndt/gfaf116.012
Abstract
Background and Aims
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. Current treatments, such as mycophenolate mofetil (MMF) and corticosteroids, are used off-label, primarily targeting inflammatory changes rather than the underlying disease mechanism. These treatments are associated with adverse effects and lack robust clinical evidence of efficacy. As a result, up to 50% of patients progress to kidney failure within 10 years.
Pegcetacoplan (PEG) binds selectively to C3 and C3b to strongly block C3 activation by classical/lectin/alternative pathways, C3/C5 convertase activity and activation of downstream effectors. PEG targets the pathogenic process in C3G/primary IC-MPGN with the aim of stopping kidney damage.
In the Phase 3 VALIANT study (NCT05067127) in pts aged ≥12 years with native or post-transplant recurrent C3G/primary IC-MPGN, PEG led to a 68.1% relative proteinuria reduction vs placebo (PBO), glomerular C3 clearance in 71% of pts and stabilization of estimated glomerular filtration rate (eGFR).
Pts with native or post-transplant recurrent C3G/primary IC-MPGN who present with nephrotic range proteinuria (urine protein-to-creatinine ratio [UPCR] ≥3 g/g) are at high risk of rapid disease progression to kidney failure, constituting a patient population with a high unmet medical need. The aim of this analysis was to evaluate the efficacy and safety of PEG vs placebo (PBO) in pts presenting with nephrotic range proteinuria at baseline.
Method
VALIANT study participants were randomized 1:1 to receive PEG (subcutaneous infusion twice weekly) or PBO for 26 weeks as add-on to their stable treatment regimen. The primary endpoint was the log-transformed ratio of UPCR at Week 26 vs baseline. Secondary endpoints included the proportion of pts achieving a reduction in C3c staining on kidney biopsy, change in eGFR from baseline vs PBO, and normalization of serum albumin.
Results
Overall, 124 pts were randomized in VALIANT (63 PEG; 61 PBO). At baseline, there were 24 (38.1%) and 16 (26.2%) pts in the PEG and PBO arm, respectively, who had UPCR ≥3 g/g. Baseline characteristics are shown in the Table.
At Week 26, PEG-treated pts with baseline UPCR ≥3 g/g achieved a significant and clinically meaningful 72.1% relative reduction in proteinuria vs PBO (p < 0.0001). 66.7% (16/24) of pts in the PEG group vs 0% (0/16) in the PBO group had a ≥50% reduction in proteinuria from baseline (p < 0.0001). Furthermore, 66.7% (10/15) of PEG-treated pts with baseline UPCR ≥3 g/g and low baseline serum albumin achieved normalization of serum albumin at Week 26 vs 0% (0/12) for PBO.
84.6% (11/13) of pts achieved a reduction in glomerular C3c staining with PEG vs 0% (0/9) with PBO (p = 0.0002). PEG-treated pts experienced a mean change of +4.7 mL/min/1.73 m2 in eGFR, showing a relative improvement of +16.2 mL/min/1.73 m2 (p = 0.0046) vs PBO.
Rates of treatment-emergent adverse events were comparable between PEG vs PBO pts with UPCR ≥3 g/g, similar to the overall study population, with no study discontinuations or deaths.
Conclusion
In the VALIANT trial, C3G/primary IC-MPGN pts presenting with nephrotic range proteinuria demonstrated robust reductions in proteinuria and glomerular C3, eGFR stabilization, and serum albumin normalization, confirming a disease-modifying effect of PEG in this severe subpopulation. PEG was well-tolerated and the safety profile was consistent with previous reports.
Details
- Title: Subtitle
- 3265 Pegcetacoplan treatment effect in patients with nephrotic range proteinuria: results from the VALIANT Phase 3 study in patients with C3G or primary (idiopathic) IC-MPGN
- Creators
- Marina Vivarelli - Bambino Gesù Children's HospitalAndrew S Bomback - Columbia University Irving Medical CenterGema Ariceta - Vall d'Hebron Hospital UniversitariAntonio Mastrangelo - Fondazione IRCCS Ca' Granda Ospedale Maggiore PoliclinicoCarla M Nester - University of IowaGiuseppe Remuzzi - Istituti di Ricovero e Cura a Carattere ScientificoNicole Van De KarZhongshen Wang - Apellis PharmaceuticalsJohan Szamosi - Swedish Orphan BiovitrumDima Decker - Apellis PharmaceuticalsLucia Quintana GallardoFadi Fakhouri - University Hospital of Lausanne
- Resource Type
- Abstract
- Publication Details
- Nephrology, dialysis, transplantation, Vol.40(Supplement_3), gfaf116012
- DOI
- 10.1093/ndt/gfaf116.012
- ISSN
- 0931-0509
- eISSN
- 1460-2385
- Publisher
- Oxford University Press
- Language
- English
- Date published
- 10/21/2025
- Academic Unit
- Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9985019028002771
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