Detailed data from the phase 3 VALIANT study, presented at the 2024 American Society of Nephrology (ASN) Kidney Week, highlight the potential of systemic pegcetacoplan treatment for patients with C3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN). These rare, debilitating kidney diseases currently lack treatments that target the underlying cause.
The VALIANT study 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. Study participants were randomized to receive pegcetacoplan or placebo twice weekly for 26 weeks.
Key Findings from the VALIANT Study
Pegcetacoplan demonstrated a statistically significant and clinically meaningful 68.1% reduction in proteinuria (log-transformed ratio of urine protein-to-creatinine ratio) compared to placebo at Week 26 (p<0.0001). This reduction was observed as early as Week 4 and sustained throughout the six-month treatment period. The effect was consistent across various patient subgroups, including adolescent and adult patients, C3G and primary IC-MPGN patients, and those with native and post-transplant kidneys.
"Pegcetacoplan is the only treatment to achieve substantial and clinically meaningful effects across all key markers of disease: proteinuria, eGFR stabilisation, and C3c staining," said Carla Nester, M.D. MSA, FASN, lead principal investigator for the VALIANT study. "C3G and primary IC-MPGN often affect patients as early as adolescence, often leading to either a kidney transplant or lifelong dialysis, so there is an urgent need for an approved treatment that can prolong kidney function."
Stabilization of eGFR and Reduction in C3c Staining
Treatment with pegcetacoplan resulted in stabilization of estimated glomerular filtration rate (eGFR), a critical measure of kidney function, with a difference of +6.3 mL/min/1.73 m2 compared to placebo over six months (95% CI 0.5, 12.1; nominal p value =0.03).
Furthermore, a significant proportion of patients treated with pegcetacoplan showed a reduction in C3c staining intensity, a key marker of disease activity that can lead to kidney inflammation, damage, and failure:
- 74.3% of patients in the pegcetacoplan group achieved a reduction in C3c staining intensity by two or more orders of magnitude from baseline, compared to 11.8% in the placebo group (nominal p value <0.0001).
- 71.4% of pegcetacoplan-treated patients achieved zero C3c staining intensity, indicating clearance of C3c deposits.
Secondary Endpoints and Safety Profile
All secondary endpoints favored treatment with pegcetacoplan, including the composite renal endpoint (combining proteinuria reduction and eGFR stabilization) and proteinuria reduction of at least 50% compared to baseline. The study also noted a numerical improvement in the C3G histologic index activity score.
Pegcetacoplan demonstrated a favorable safety and tolerability profile during the 26-week randomized, controlled treatment period, with a high compliance rate. Rates of treatment-emergent adverse events (AEs), serious AEs, severe AEs, and AEs leading to study discontinuation were similar between the pegcetacoplan and placebo groups. Notably, there were no cases of meningococcal meningitis or serious infections attributed to encapsulated bacteria.
Regulatory Submissions and Future Plans
Sobi plans to submit a marketing application with the European Medicines Agency (EMA) in 2025. Apellis plans to submit a supplemental new drug application to the U.S. Food and Drug Administration (FDA) in early 2025.
Patients who completed the VALIANT study were eligible to enroll in the VALE long-term extension study.
About C3G and IC-MPGN
C3G and primary IC-MPGN are rare kidney diseases that can lead to kidney failure. Approximately 50% of individuals with these conditions experience kidney failure within 5 to 10 years of diagnosis, often requiring kidney transplant or lifelong dialysis. The diseases are estimated to affect 5,000 people in the United States and up to 8,000 in Europe.
