Data from the VALIANT trial indicates that pegcetacoplan (Empaveli), a complement C3 inhibitor, offers clinically meaningful benefits for proteinuria, C3c staining, and eGFR stabilization in patients with C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN). The findings, presented at the American Society of Nephrology’s Kidney Week 2024, highlight the potential of pegcetacoplan as a targeted therapy for these rare kidney diseases.
The VALIANT trial is a phase 3, multicenter, randomized, placebo-controlled, double-blind study. It enrolled 124 patients with C3G or primary IC-MPGN, including adolescent, adult, and post-transplant patients. Participants were randomized 1:1 to receive either 1080 mg of pegcetacoplan or placebo twice weekly for 26 weeks.
Primary Endpoint Achieved
The primary outcome was the change in urine protein-to-creatinine ratio (UPCR) at week 26 compared to baseline. Pegcetacoplan demonstrated a mean UPCR reduction of 67.3% (95% CI, -74.9% to -57.5%) compared to a 3.2% increase with placebo (95% CI, -8.3% to 16.2%), resulting in a relative reduction of 68.3% (95% CI, -76.3% to -57.7%; P <.0001).
Secondary Endpoint Analysis
Secondary analysis revealed that 74.3% of patients treated with pegcetacoplan experienced a reduction of 2 or more orders of magnitude in C3c renal biopsy staining, compared to 11.8% in the placebo group (Odds Ratio, 27.4; 95% CI, 6.5 to 115.9; nominal P <.0001). 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 Profile
The safety profile of pegcetacoplan was generally consistent with previous studies. The frequency and severity of treatment-emergent adverse events were similar between the pegcetacoplan and placebo arms. Four serious infections occurred during the trial, three in the pegcetacoplan group, but none were attributed to encapsulated bacteria. One death occurred in the pegcetacoplan arm due to COVID-19 pneumonia, which was considered unrelated to the treatment.
Expert Commentary
"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," said 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.
Regulatory Plans
Based on these results, Sobi and Apellis plan to submit a supplemental New Drug Application to the FDA in early 2025, seeking approval of pegcetacoplan for C3G and primary IC-MPGN.
