Pegcetacoplan's Approval & Shifting C3G Landscape, with Sayna Norouzi, MD

Years of uncertainty in C3 glomerulopathy (C3G) care have given way to rapid momentum. With the recent US Food and Drug Administration approval of pegcetacoplan (Empaveli) for the treatment of adults and adolescents with C3G, the complement C3 inhibitor becomes the second FDA-approved therapy for this rare and progressive kidney disease, following the March 2025 approval of iptacopan (Fabhalta), an oral factor B inhibitor.

For a condition that, until recently, had no approved treatments and relied heavily on off-label use of nonspecific immunosuppressants, the arrival of 2 new targeted therapies in less than a year marks a dramatic and welcome shift for patients and clinicians alike.

“This is really, really groundbreaking news for our patients and for us as nephrologists because for years and years, patients with C3G came to our clinics and we didn't have any specific FDA approved medications for them,” Sayna Norouzi, MD, an assistant professor of medicine, clinical nephrologist, and founder and director of the glomerular disease and polycystic kidney disease clinics at Loma Linda University Medical Center, told HCPLive.

Historically, C3G has been an incredibly challenging disease to manage. Caused by dysregulation of the alternative complement pathway, the disease often leads to significant proteinuria, progressive loss of kidney function, and often kidney failure. Many patients are diagnosed in adolescence or early adulthood and face the prospect of dialysis or transplant in what Norouzi says should be the prime years of their lives.

“I always think of my patients sitting in the clinic asking if there is any way that they can prevent dialysis or transplant, and I see in their eyes that they're really concerned about the future,’ Norouzi described. “They're in their 20s, 30s… they are in the midst of trying to figure out life, trying to plan a family. You make a lot of decisions in your 20s and 30s, and getting diagnosed with C3G and IC-MPGN should not affect them.”

Until now, nephrologists treating C3G have had to rely on medications borrowed from other glomerular diseases or autoimmune conditions, with limited or no disease-specific evidence. Treatment decisions were often based on clinician experience, anecdotal reports, or small case series.

The approvals of iptacopan and now pegcetacoplan represent a pivotal moment, as these therapies not only offer targeted mechanisms that directly address complement dysregulation, but they are also backed by trial data showing meaningful reductions in proteinuria and markers of disease activity in the APPEAR-C3G and VALIANT trials, respectively.

Having 2 distinct options—1 oral and 1 subcutaneous—also allows for a more personalized approach. Pegcetacoplan’s recent approval includes adolescents and post-transplant patients, offering an advantage for younger patients and those with complex disease histories, while iptacopan, taken as a twice-daily capsule, offers ease of use and strong data from adult trials.

The availability of both therapies reinforces the importance of shared decision-making between clinicians and patients, taking into account not only efficacy and safety but also factors like patient age, comorbidities, treatment preferences, and route of administration.

“Patients are so different. They are going to show up in the clinic in different phenotypes, and deciding which treatment option is going to be the best option for them is going to be on us, because we have 2 great options out there and both of the clinical trials are showing us significant results. How to navigate that goes back to patient characteristics,” Norouzi explained.

While the approvals are a breakthrough, they also come with responsibility, as providers will need to stay up to date with evolving data, monitor long-term safety outcomes, and understand which patient characteristics may predict a better response to each agent. Real-world experience will be key in refining treatment strategies, especially as new therapies enter the pipeline and the possibility of combination treatment approaches emerges.

References

1. Brooks A. FDA Approves Pegcetacoplan (Empaveli) for C3 Glomerulopathy, IC-MPGN. HCPLive. July 28, 2025. Accessed July 31, 2025. https://www.hcplive.com/view/fda-approves-pegcetacoplan-empaveli-for-c3-glomerulopathy-ic-mpgn

2. Campbell P. FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy. HCPLive. March 20, 2025. Accessed July 31, 2025. https://www.hcplive.com/view/fda-approves-oral-iptacopan-fabhalta-as-first-c3-glomerulopathy-therapy