VALIANT: Pegcetacoplan Offers Benefit for UPCR, eGFR, C3 Staining in C3G, IC-MPGN

Carla Nester, MD
Credit: University of Iowa

Data from the VALIANT trial provide evidence positioning pegcetacoplan (Empaveli), a complement inhibitor targeting C3/C3b, as the first therapy to offer clinically meaningful benefits for proteinuria, C3c staining, and eGFR stabilization in patients with C3 glomerulopathy (C3G) or primary immune complex membranoproliferative glomerulonephritis (IC-MPGN).

Presented at the American Society of Nephrology’s Kidney Week 2024, which occurred less than 3 months after Sobi and Apellis Pharmaceuticals announced topline results, the full presentation of VALIANT sheds additional light on the safety and efficacy of pegcetacoplan for a pair of rare kidney disease without approved treatments. Based on the results of the study, Sobi and Apellis intend to file a supplemental New Drug Application to the US Food and Drug Administration in early 2025.

“So, the VALIANT study is actually quite good for a number of reasons, but the most important would be it includes a number of other populations that we hadn't seen yet before—the pediatric population and the transplant population… I would say that these types of drugs that target the alternative pathway particularly target the convertases—the C3 and C5 convertases—would be predicted to be the exact mechanistic approach to this set of diseases,” explained Carla Nester, MD, the Jean E. Robillard Chair in Pediatric Nephrology and the director of the Pediatric Glomerular Disease Clinic at the University of Iowa, in an interview with HCPLive at Kidney Week 2024.

A phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial, VALIANT was launched to explore the safety and efficacy of systemic pegcetacoplan among patients with C3G and 12 had primary IC-MPGN. Billed by Sobi and Apellis Pharmaceuticals as the largest single trial conducted in these populations and the only study to include adolescent and adult patients, with native and post-transplant kidneys, the trial randomized 124 patients in a 1:1 ratio to receive 1080 mg of pegcetacoplan or placebo twice weekly for 26 weeks.

In total, 63 patients were randomized to pegcetacoplan and 61 were randomized to placebo therapy. Among the pegcetacoplan group, 51 patients had C3G and 12 had primary IC-MPGN. The group included 28 adolescents, 35 adults, and 5 posttransplant patient. Among the placebo group, 45 patients had C3g and 16 had primary IC-MPGN. The group included 27 adolescents, 34 adults, and 4 posttransplant patients.

The primary outcome of interest for the trial was the log transformed ratio of urine protein-to-creatinine ratio (UPCR) at week 26 compared to baseline with pegcetacoplan relative to placebo therapy.

For the primary endpoint, the mean change in UPCR at week 26 was -67.3% (95% CI, -74.9% to -57.5%) with pegcetacoplan and 3.2% with placebo (95% CI, -8.3% to 16.2%), which corresponds to a relative reduction of 68.3% (95% CI, -76.3% to -57.7%; P <.0001). Secondary analysis suggested reduced C3c renal biopsy staining of 2 or more orders of magnitude was observed in 74.3% of the pegcetacoplan group relative to 11.8% in the placebo (Odds Ratio, 27.4; 95% CI, 6.5 to 115.9; nominal P <.0001).

Further analysis of secondary endpoints, indicated the adjusted mean change in eGFR was -1.6 (95% CI, -6.0 to 2.8) mL/min/1.73m² in the pegcetacoplan group and -7.9 (95% CI, -11.7 to -4.2) mL/min/1.73m² in the placebo group (mean difference, 6.3; 95% CI, 0.5 to 12.1; nominal P = .0322).

Safety analyses demonstrated the frequency and severity of treatment-emergent adverse events were similar between both study arms. A total of 4 serious infections occurred in the trial, with 3 occurring in the pegcetacoplan group, but none were attributed to encapsulated bacteria. Investigators pointed out a single death occurred in the pegcetacoplan arm as the result of COVID-19 pneumonia and was considered unrelated to pegcetacoplan.

In a press release from the American Society of Nephrology, Nester highlighted the consistency of these findings across several subgroups, including disease type, age, and transplant status.

“The results were consistent across patients with different characteristics. In addition, pegcetacoplan demonstrated favorable safety across native and post-transplant populations,” Nester said.

References:

1. Nester CM, Bomback AS, Ariceta Iraola M, et al. VALIANT: A Randomized, Multicenter, Double-Blind, Placebo (PBO)-Controlled, Phase 3 Trial of Pegcetacoplan for Patients with Native or Post-transplant Recurrent Glomerulopathy (C3G) or Primary Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN). Presented at American Society of Nephrology Kidney Week 2024. San Diego, CA. October 23-27, 2024.
2. Apellis Pharmaceuticals, Inc. Apellis and Sobi announce positive topline results from phase 3 valiant study of Pegcetacoplan in C3G and primary IC-MPGN. Apellis Pharmaceuticals, Inc. August 8, 2024. Accessed October 26, 2024. https://investors.apellis.com/news-releases/news-release-details/apellis-and-sobi-announce-positive-topline-results-phase-3.
3. American Society of Nephrology. High-Impact Clinical Trials Generate Promising Results for Improving Kidney Health: Part 2. Newswise. October 26, 2024. Accessed October 26, 2024. https://www.newswise.com/articles/high-impact-clinical-trials-generate-promising-results-for-improving-kidney-health-part-2.