Phase 3 VALIANT Results for Pegcetacoplan In C3G, IC-MPGN, With Andrew Bomback, MD

Positive phase 3 VALIANT results showed pegcetacoplan reduced proteinuria by 68% and stabilized kidney function in adult and adolescent patients with C3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).1

The findings also reported evidence of C3 deposit clearance, including in patients with post-transplant recurrent C3G, highlighting pegcetacoplan’s potential to directly target pathogenic complement activity.1

Pegcetacoplan is a PEGylated cyclic peptide designed to bind C3 and C3b, inhibiting C3 activation and downstream complement cascade signaling, including the alternative pathway amplification loop. This C3-targeted therapy is intended to regulate excessive complement activation. In July 2025, the US Food and Drug Administration (FDA) approved pegcetacoplan for use in patients with C3G and IC-MPGN based on 26-week results from the VALIANT trial. 1,2

The randomized, double-blind, placebo-controlled, multicenter phase 3 VALIANT trial evaluated the efficacy and safety of pegcetacoplan over 26 weeks. The primary endpoint was proteinuria reduction, measured by the urine protein-to-creatinine ratio (uPCR). Secondary endpoints included C3c staining, assessed via immunofluorescence microscopy on kidney biopsy samples, and kidney function, measured by estimated glomerular filtration rate (eGFR).3

Study investigators evaluated 124 patients ≥ 12 years of age with native and post-transplant kidneys, marking it as the first and largest trial conducted in this patient population.1,3

In patients treated with pegcetacoplan (n = 63), investigators reported a 68.3% uPCR reduction (95% Confidence Interval [CI], –76.3 to –57.7; P<.0001) compared to placebo (n = 61). They also observed significant reductions in C3c staining (P <.0001), including 71% of patients achieving zero C3 staining intensity, and clinically significant eGFR stabilization, with a difference of +6.3 mL/min/1.73 m2 compared to placebo (nominal P = .03).1

In VALIANT’s 26-week open-label extension, many patients achieved remission (≤0.5 g/g) or normalization (≤0.2 g/g) in uPCR, underscoring sustained proteinuria reductions and stable eGFR in the pegcetacoplan-treated patient population.2

For additional insight into pegcetacoplan’s potential in C3G and primary IC-MPGN and the VALIANT data, the editorial team of HCPLive Nephrology spoke with study investigator Andrew Bomback, MD, MPH, the director of clinical research in the nephrology division at Columbia University, in the following Q&A:

HCPLive: What is the therapeutic rationale for targeting C3 with pegcetacoplan in C3G and IC MPGN, and how does this approach differ from other complement-directed strategies?

Bomback: These diseases are driven by hyperactivity and loss-of-control of the alternative complement pathway, and C3 is a major protein involved in activating this pathway; targeting C3 with pegcetacoplan is intended to restore control of the alternative pathway and thus halt any ongoing kidney injury from complement.

HCPLive: Can you walk us through the key elements of the VALIANT trial design?

Bomback: This trial enrolled C3G and primary IC-MPGN patients, both those with disease in their native kidneys and those with recurrent disease in transplanted kidneys. Enrollment was primarily C3G patients with native kidney disease. Participants were randomized to pegcetacoplan versus placebo for 6 months, with a biopsy done at 6 months as part of the trial's endpoints, and then there was an open label extension of an additional 6 months.

HCPLive: What are some of the key findings, and what do they mean for the current treatment landscape for C3G and primary IC-MPGN?

Bomback: With C3G and primary IC-MPGN trials, the key outcomes to focus on are proteinuria reductions, GFR changes, and histologic markers of complement activation. This trial met all of its endpoints, with a highly significant reduction in proteinuria (about 65%), improved GFR trajectory compared to placebo, and almost 75% of patients on active drug clearing all the C3 from their biopsies at 6 months. This means the drug is an effective treatment at halting disease progression in patients with these diseases and is doing so by targeting the pathogenesis of injury.

HCPLive: Could you elaborate on the clinical significance of achieving complete clearance of C3 deposits in 71% of treated patients?

Bomback: We don't have reliable non-invasive biomarkers that can tell us a drug has restored control of the complement pathway, so we currently need a biopsy showing this degree of C3 clearance to show that complement activity has been checked and control restored.

HCPLive: Were there any unexpected adverse events or tolerability issues that warrant attention or might affect patient selection?

Bomback: No, other than some skin reactions to the subcutaneous injections and some cases of pneumococcal pneumonia, which highlights the importance of vaccinations against encapsulated organisms for any patients taking the drug.

HCPLive: How do you envision pegcetacoplan fitting into the broader landscape of complement inhibitors now emerging for glomerular diseases?

Bomback: Right now, its use is solely in the realm of C3G and primary IC-MPGN, and I think it will be (along with iptacopan, the other drug recently approved) used for a large majority of C3G and primary IC-MPGN patients, since these are usually progressive diseases.

HCPLive: Where do you see the field headed in terms of complement-focused drug development for glomerular diseases over the next few years?

Bomback: We already have a complement inhibitor for atypical hemolytic uremic syndrome (aHUS), 1 for IgA nephropathy (IgAN), and 2 for C3G, so I think this is a growing field that will continue to show efficacy in other glomerular injuries.

HCPLive: What are the larger implications for C3G patients?

Bomback: This is a major achievement for C3G patients who have put a lot of effort into getting trials done appropriately, and I am happy for this community that they now have drugs to change what was previously considered to be a grim natural history. I think we'll see major changes in outcomes for these disease groups.

Editor’s Note: Bomback reports relevant disclosures with Amgen, Genentech, Novartis, and others.

References

1. The New England Journal of Medicine Publishes Positive Phase 3 VALIANT Results of EMPAVELI® (pegcetacoplan) for C3G and Primary IC-MPGN | Apellis Pharmaceuticals, Inc. Apellis Pharmaceuticals, Inc. Published 2025. Accessed December 15, 2025. https://investors.apellis.com/news-releases/news-release-details/new-england-journal-medicine-publishes-positive-phase-3-valiant

2. Nester CM. VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN. HCPLive. Published November 17, 2025. Accessed December 15, 2025. https://www.hcplive.com/view/valiant-pegcetacoplan-shows-sustained-efficacy-in-c3g-and-ic-mpgn-with-carla-nester-md

3. October 2024 - Volume 35 - Issue 10S : Journal of the American Society of Nephrology. Lww.com. Published 2024. https://journals.lww.com/jasn/fulltext/2024/10001/valiant__a_randomized