RX Review: Updates and Unmet Needs in C3G—The Role of Pegcetacoplan - Episode 2
Navigating Targeted Therapies for C3 Glomerulopathy
In part 2 of this 5-part HCPLive RX Review, experts discuss how to utilize the newly FDA-approved therapies for treating C3G and what questions remain.
The July 2025 FDA approval of pegcetacoplan (Empaveli) marked a pivotal moment in the treatment of C3 glomerulopathy (C3G), offering patients and clinicians multiple targeted therapies for this ultra-rare and often aggressive kidney disease. Just months earlier, the approval of iptacopan (Fabhalta) added to this therapeutic breakthrough, giving nephrologists a choice between 2 complement inhibitors with distinct mechanisms of action.
In episode 2 of this 5-part HCPLive RX Review, Shikha Wadhwani, MD, MS, Anuja Java, MD, and Corey Cavanaugh, DO, discuss how these new therapies may be used in clinical practice and raise key questions that remain unanswered. With no established standard of care and historically limited treatment options, they say the ability to personalize therapy with these novel agents is a welcomed but complex challenge.
The group questions how clinicians decide when and whom to treat, especially in the absence of reliable biomarkers or clear predictors of disease recurrence post-transplant. While some may favor preemptive therapy to avoid recurrence, others may be more cautious, weighing the long-term risks of broad complement inhibition.
The panel compares the mechanisms of action of the 2 approved agents: pegcetacoplan, a C3 inhibitor that acts centrally across all complement pathways, and iptacopan, which selectively targets factor B within the alternative pathway.
As for future directions, the group expresses cautious optimism about switching therapies in non-responders, but raises concerns about combining agents due to safety risks, particularly infection. Despite these uncertainties, they agree: having 2 FDA-approved therapies marks unprecedented progress—and sets the stage for the field to refine how best to use them through real-world experience and collaborative research.
Our Panelists:
- Shikha Wadhwani, MD, MS, is an associate professor of Medicine and the vice chair of Clinical Research at the University of Texas Medical Branch. Wadhwani, who is the co-host of HCPLive’s Kidney Compass podcast and member of our advisory board, serves as the moderator for this conversation.
- Anuja Java, MD, is an associate professor and transplant nephrologist at Washington University School of Medicine in St. Louis and director of Kidney Transplantation at John Cochran VA Medical Center in St. Louis.
- Corey Cavanaugh, DO, is a staff nephrologist at the Cleveland Clinic.
Relevant disclosures for Wadhwani include Otsuka Pharmaceuticals, GSK, Calliditas, and Travere Therapeutics. Relevant disclosures for Java include Alexion, AstraZeneca, Novartis, Dianthus Therapeutics, Aurinia Pharmaceuticals Inc., Apellis and UptoDate. Relevant disclosures for Cavanaugh include Vera Therapeutics and Travere Therapeutics.
References:
Apellis Pharmaceuticals. FDA Approves Apellis’ EMPAVELI® (pegcetacoplan) as the First C3G and Primary IC-MPGN Treatment for Patients 12 and Older | Apellis Pharmaceuticals, Inc. Apellis Pharmaceuticals, Inc. Published July 28, 2025. Accessed August 4, 2025. https://investors.apellis.com/news-releases/news-release-details/fda-approves-apellis-empavelir-pegcetacoplan-first-c3g-and
Nester CM, Bomback AS, Ariceta G, 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). Journal of the American Society of Nephrology. 2024;35(10S). doi: 10.1681/asn.2024qdwvz5bg
US Food and Drug Administration. Fabhalta approved for complement 3 glomerulopathy. U.S. Food and Drug Administration. Published March 20, 2025. Accessed August 4, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-adults-complement-3-glomerulopathy-rare-kidney-disease-reduce
