VALIANT: Pegcetacoplan Significantly Reduces Proteinuria in C3 Glomerulopathy, IC-MPGN

Carla Nester, MD

Credit: University of Iowa

Apellis Pharmaceuticals and Sobi have announced positive topline results from the phase 3 VALIANT study investigating systemic pegcetacoplan in patients with C3 glomerulopathy or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN).¹

According to an August 8, 2024, press release, the study met the primary endpoint, demonstrating a statistically significant and clinically meaningful 68% (P <.0001) proteinuria reduction in patients with C3 glomerulopathy and IC-MPGN treated with pegcetacoplan compared to placebo, both in addition to background therapy, at week 26. Of note, results were consistent across all subgroups, including C3 glomerulopathy and IC-MPGN, adolescent and adult patients, and native and post-transplant kidneys. Based on these results, Apellis plans to submit a supplemental New Drug Application to the US Food and Drug Administration in early 2025, and Sobi plans to submit a marketing application with the European Medicines Agency in 2025.¹

“As a clinician, I’m thrilled by these groundbreaking results, which show that pegcetacoplan has the potential to significantly improve the lives of patients with C3G and IC-MPGN, regardless of disease type, age, and transplant status,” said Carla Nester, MD, lead principal investigator for the VALIANT study and Jean Robillard, MD, professor of pediatric nephrology at the University of Iowa Stead Family Children's Hospital.¹ “Currently, many patients living with these rare diseases will eventually require a kidney transplant or lifelong dialysis, so there is an urgent need for a treatment that targets the underlying cause of these diseases. These positive data are a major advance for the rare kidney disease community.”

A targeted C3 therapy designed to regulate excessive activation of the complement cascade, pegcetacoplan is under investigation for rare diseases across hematology and nephrology. Currently, it is approved for the treatment of paroxysmal nocturnal hemoglobinuria in the US, European Union, and other countries globally.^1,3

One-year results of the phase 2 NOBLE trial, the first randomized controlled trial of pegcetacoplan compared to standard of care in kidney transplant recipients with recurrent C3G or IC-MPGN, were presented at the 61st European Renal Association Congress and built on previous 12-week data from the trial to further demonstrate the benefits of pegcetacoplan in this patient population. Primary results of the 12-week, double-blind portion of the trial were previously presented at the American Society of Nephrology Kidney Week 2023 and showed 80% of patients treated with pegcetacoplan showed a reduction in C3c staining by 1 or more orders of magnitude of intensity from baseline and 40% of patients showed 0 staining intensity.²

A randomized, placebo-controlled, double-blinded, multi-center study, VALIANT was designed to evaluate the efficacy and safety of pegcetacoplan in 124 patients ≥ 12 years of age with C3 glomerulopathy or primary IC-MPGN. It is the largest single trial conducted in these populations and the only study to include adolescent and adult patients, with native and post-transplant kidneys. In the study, participants were randomly assigned to receive 1080 mg of pegcetacoplan or placebo twice weekly for 26 weeks, after which patients were able to proceed to a 26-week open-label phase where all patients receive pegcetacoplan.¹

In addition to meeting the primary endpoint for proteinuria reduction, pegcetacoplan also demonstrated statistical significance on key secondary endpoints for a composite renal endpoint, a combination of proteinuria reduction and estimated glomerular filtration rate (eGFR) stabilization, and proteinuria reduction of ≥ 50% compared to baseline, as well as nominal significance on the histological endpoint of reduction in C3c staining on kidney biopsy and stabilization of kidney function as measured by eGFR compared to placebo.¹

According to the release, the safety and tolerability of pegcetacoplan observed in VALIANT were consistent with its established profile. Rates of adverse events (AEs), serious AEs, and AEs leading to study drug discontinuation were similar between the pegcetacoplan and placebo groups, and there were no cases of meningitis or serious infections attributed to encapsulated bacteria.¹

“These results exceeded our already high expectations. Pegcetacoplan is the first investigational therapy to show such a strong reduction in proteinuria in C3G and IC-MPGN with supportive data across multiple measures of disease activity,” said Jeffrey Eisele, PhD, chief development officer, Apellis.¹ “Building on pegcetacoplan’s approval in PNH, we look forward to sharing these data with the FDA and working quickly to bring this treatment to patients with these debilitating kidney diseases.”

References

1. ^{Sobi. Apellis and Sobi Announce Positive Topline Results from Phase 3 VALIANT Study of Pegcetacoplan in C3G and Primary IC-MPGN. Press Releases. August 8, 2024. Accessed August 8, 2024. https://www.sobi.com/en/press-releases/sobi-and-apellis-announce-positive-topline-results-phase-3-valiant-study-pegcetacoplan-c3g-and-primary-ic-mpgn-2255513}
2. ^{Campbell, P. Pegcetacoplan Offers Potential Benefit in Post-Transplant C3G, IC-MPGN. May 26, 2024. Accessed August 8, 2024. https://www.hcplive.com/view/pegcetacoplan-offers-potential-benefit-in-post-transplant-c3g-ic-mpgn}
3. ^{Walter, K. FDA Approves First Ever Targeted C3 Therapy for PNH. May 18, 2021. Accessed August 8, 2024. https://www.hcplive.com/view/fda-targeted-c3-therapy-pnh}