Highlight
– Pegcetacoplan achieved a 67% geometric mean reduction in urinary protein-to-creatinine ratio at 26 weeks versus no meaningful change with placebo (relative reduction 68.1%; 95% CI, 57.3–76.2).
– Nearly half of treated patients met a composite endpoint of eGFR stabilization plus ≥50% proteinuria reduction (49% vs. 3% with placebo), and 60% had ≥50% proteinuria reduction (5% with placebo).
– Histologic activity scores did not differ in the biopsy subgroup at week 26; safety signals were comparable between groups with no confirmed serious infections from encapsulated bacteria reported.
Background and Clinical Context
C3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC‑MPGN) are rare, often progressive glomerular diseases characterized by dominant C3 deposition in the glomerulus and dysregulation of the complement alternative pathway. Clinical manifestations commonly include nephrotic-range or subnephrotic proteinuria, hematuria, and progressive loss of kidney function. Long-term outcomes are poor for many patients: a substantial proportion progress to end-stage kidney disease (ESKD) or require kidney transplantation, with disease recurrence after transplant common in C3G.
There has been an unmet need for targeted, disease-modifying therapies in these conditions. Complement inhibition offers a mechanistic approach: pegcetacoplan is a pegylated compstatin analog that inhibits C3 and C3b, blocking activation upstream of C5 and the terminal membrane attack complex. Upstream blockade differs mechanistically from C5 inhibitors (e.g., eculizumab) and could plausibly prevent formation of C3 fragments and subsequent glomerular deposition more effectively. The VALIANT (phase 3) trial was designed to test whether pegcetacoplan improves clinically meaningful endpoints in patients with C3G or IC‑MPGN.
Study Design
VALIANT was a randomized, double-blind, placebo-controlled phase 3 trial (NCT05067127) enrolling adolescents and adults with either C3 glomerulopathy or primary immune-complex MPGN. The trial included patients with native kidney disease and those with disease recurrence after kidney transplantation. A total of 124 patients were randomized 1:1 to pegcetacoplan or placebo. The primary endpoint was the log-transformed ratio of urinary protein-to-creatinine ratio (UPCR) at week 26 compared with baseline. Key secondary endpoints were tested hierarchically and included a composite renal endpoint (stabilization of estimated glomerular filtration rate [eGFR] with ≥50% reduction in UPCR), and the proportion achieving ≥50% reduction in UPCR. A subset of patients had evaluable kidney-biopsy samples for assessment using the C3 glomerulopathy histologic index activity score.
Key Findings
Primary endpoint: Pegcetacoplan produced a large, statistically significant reduction in proteinuria at 26 weeks compared with placebo. The geometric mean change in UPCR from baseline was −67.2% (95% CI, −74.9 to −57.2) in the pegcetacoplan group versus +2.9% (95% CI, −8.6 to 15.9) with placebo. The relative reduction versus placebo was 68.1% (95% CI, 57.3 to 76.2).
Secondary endpoints: In hierarchical testing of key secondaries, pegcetacoplan outperformed placebo for clinically relevant composite and categorical endpoints. The percentage meeting the composite renal endpoint (eGFR stabilization plus ≥50% reduction in UPCR) was 49% in the pegcetacoplan arm versus 3% in the placebo arm. The proportion achieving at least a 50% reduction in UPCR was 60% with pegcetacoplan versus 5% with placebo. These are substantial absolute and relative differences that suggest a clinically meaningful antiproteinuric effect within 26 weeks of therapy.
Histology and kidney biomarkers: Among 69 patients with evaluable kidney-biopsy samples, the change in the activity score of the C3 glomerulopathy histologic index did not differ significantly between groups at week 26. Subsequent end points (including decrease in C3 immunofluorescence staining and change in eGFR) were not formally tested in the hierarchical sequence. The disconnect between rapid proteinuria improvement and lack of early histologic change raises questions about timing: histologic recovery may lag behind improvements in proteinuria, or the index may be insensitive to early immunologic changes driven by upstream complement blockade.
Safety: Pegcetacoplan was not associated with a higher overall adverse-event rate than placebo during the 26-week blinded period. Importantly, no serious infections due to encapsulated bacteria (a theoretical risk with complement inhibition) were reported in the study interval. One patient receiving pegcetacoplan died of COVID-19 pneumonia. There were no reports of allograft rejection or graft loss among transplant recipients during the study period. These safety findings are reassuring but must be interpreted cautiously given the trial size and relatively short duration.
Expert Commentary and Interpretation
The VALIANT trial provides the most robust randomized evidence to date that upstream complement inhibition at the level of C3 can substantially reduce proteinuria in patients with C3G and IC‑MPGN. The magnitude of proteinuria reduction (geometric mean ≈67% and 60% of patients achieving ≥50% reduction) is impressive and clinically meaningful: sustained reductions of this magnitude would be expected to translate into lower risk of progression for proteinuric kidney diseases, though confirmation with long-term endpoints is required.
Why might C3 inhibition succeed where C5 inhibition has had variable results? Blocking C3 prevents formation of C3b and C3-derived opsonins that deposit in the glomerulus and drive inflammation, while C5 blockade only prevents terminal pathway effects. Therefore, C3 blockade may address the underlying driver of deposition in C3-dominant disease. The rapid antiproteinuric effect supports a direct pathogenic role for continued complement activation in driving glomerular permeability.
However, absence of a significant change in the histologic activity score at 26 weeks tempers enthusiasm; histologic repair may require more time, or the histologic index may not capture early anti-inflammatory changes. Additionally, eGFR outcomes were not formally tested within the hierarchical sequence, and the impact on long-term kidney survival, ESKD, or transplant loss is unknown.
Limitations and Generalizability
Key limitations include the relatively short primary endpoint timing (26 weeks) for a progressive structural kidney disease, a modest sample size (n=124) for rarer outcomes and safety events, and a biopsy-evaluable subgroup that was smaller (n=69). The trial enrolled a heterogeneous population (native and post-transplant disease; C3G and IC‑MPGN), which improves generalizability but may mask subgroup-specific effects. The short duration also limits safety conclusions regarding uncommon but important risks such as serious infections with encapsulated organisms and long-term immunologic consequences of sustained C3 blockade.
Clinical Implications and Practical Considerations
If these results are confirmed with longer follow-up and real-world use, pegcetacoplan could become the first broadly effective disease-modifying therapy to reduce proteinuria in C3G and IC‑MPGN. Practical considerations for clinicians include rigorous vaccination and prophylaxis strategies against encapsulated bacteria before initiating complement inhibition, careful infection surveillance, and shared decision‑making about risks and benefits given the uncertainty about long-term outcomes.
Complement genetic testing and measurement of complement biomarkers may help identify patients most likely to benefit, though VALIANT did not report differential responses by molecular subtype in the main results. Cost, access, and the need for parenteral administration will also influence uptake.
Research and Policy Directions
Important next steps include longer-term follow-up studies to assess durability of proteinuria reduction, impact on eGFR decline, time to doubling of serum creatinine, progression to ESKD, and effects on kidney histology. Larger datasets are needed to characterize rare or delayed safety events (particularly infections), effects in the transplant population, and efficacy across molecularly defined patient subsets (e.g., genetic complement defects, autoantibodies such as C3 nephritic factor).
Comparative effectiveness studies versus other complement-targeted strategies, and investigations of combination regimens or sequencing (for example, complement modulation plus antiproteinuric RAS blockade) would be informative. Health policy considerations should address the cost-effectiveness of pegcetacoplan in preventing progression to dialysis and transplantation, balancing short-term drug costs against long-term savings from preserved kidney function.
Conclusion
The VALIANT phase 3 trial demonstrates that pegcetacoplan, a C3/C3b inhibitor, produces a large and clinically meaningful reduction in proteinuria at 26 weeks among patients with C3 glomerulopathy or primary immune-complex MPGN, with comparable short-term safety to placebo in this trial. These results represent an important advance for rare glomerular diseases driven by alternative-pathway complement dysregulation and support further evaluation of pegcetacoplan for longer-term renal outcomes and in molecularly stratified patient subgroups. Until longer-term data are available, clinicians should weigh promising antiproteinuric efficacy against remaining uncertainties about histologic improvement, kidney survival, and long-term safety.
Funding and Trial Registration
The VALIANT trial was funded by Apellis Pharmaceuticals and Sobi (Swedish Orphan Biovitrum). ClinicalTrials.gov number: NCT05067127.
Reference
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 Dec 4;393(22):2210-2220. doi: 10.1056/NEJMoa2501510. PMID: 41337715.
