C3 Glomerulopathy in 2025: Year in Review

Before 2025, the C3 glomerulopathy (C3G) landscape was limited to immunosuppressive strategies and supportive care, such as blood pressure management and RAAS inhibition, leaving many patients to experience ongoing disease progression or recurrence after kidney transplantation. The scarcity of targeted therapies makes 2025 a landmark year for this rare kidney disease.

In March 2025, the US Food and Drug Administration (FDA) approved oral iptacopan (Fabhalta) for adults with C3G, demonstrating significant proteinuria reduction and kidney function stabilization in the phase 3 APPEAR-C3G trial. Later in July, the FDA approved pegcetacoplan (Empaveli) for adolescents and adults with C3G, including those with post-transplant recurrence. Phase 3 VALIANT trial data showed durable complement inhibition, proteinuria reduction, stabilization of estimated glomerular filtration rate (eGFR), and evidence of C3 deposit clearance.

These approvals signal the first disease-modifying therapies for C3G, moving management beyond nonspecific immunosuppression and supportive care and offering the potential to meaningfully alter disease trajectory in both native and post-transplant kidneys.

Keep reading to uncover HCPLive’s 2025 editorial coverage of the emerging treatment landscape for C3G and understand its implications for kidney care.

FDA Approvals

FDA Approves Oral Iptacopan (Fabhalta) as First C3 Glomerulopathy Therapy

Novartis announced FDA approval of oral iptacopan (Fabhalta) on March 20, 2025, for adults with C3G to reduce proteinuria. This first-ever approval for the ultra-rare disease was based on phase 3 APPEAR-C3G trial data, representing a milestone in targeted complement therapy and offering a new oral alternative for disease management.

FDA Approves Pegcetacoplan (Empaveli) for C3 Glomerulopathy, IC-MPGN

Apellis Pharmaceuticals’ pegcetacoplan (Empaveli) was approved for patients ≥12 years of age with C3G or primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), including post-transplant disease recurrence.

Announced on July 28, 2025, the approval was supported by positive 26-week results from the phase 3 VALIANT trial, the largest single study in these rare diseases. The FDA clearance provides clinicians with a targeted therapy stabilizing kidney function while addressing complement-mediated pathology across age groups and transplant settings.

Trial Updates and New Guidelines

Phase 3 VALIANT Results for Pegcetacoplan In C3G, IC-MPGN, With Andrew Bomback, MD

VALIANT demonstrated a 68% reduction in proteinuria and stabilization of kidney function in adult and adolescent patients with C3G and IC-MPGN. Evidence of C3 deposit clearance, including in post-transplant recurrence, highlights pegcetacoplan’s ability to directly target pathogenic complement activity. These results signal a meaningful shift toward precision, mechanism-based therapy in a condition that previously relied on nonspecific immunosuppression.

APPEAR-C3G: Iptacopan Shows Proteinuria Reduction, eGFR Benefits in C3G

Phase 3 APPEAR-C3G data showed iptacopan produced rapid and sustained proteinuria reduction, stabilized eGFR, and decreased C3 deposits over 12 months in patients with biopsy-confirmed C3G.

Iptacopan met the primary endpoint of reducing 24-hour urine protein-to-creatinine ratio (UPCR) by 35.1% (95% Confidence Interval [CI], 13.80 to 51.10; P = .0014), with sustained reductions at 12 months. The oral alternative complement pathway inhibitor’s efficacy reinforces the emergence of complement-targeted therapies as a new standard for ultra-rare glomerular diseases, potentially improving long-term renal outcomes.

C3G During Pregnancy Linked to Adverse Renal, Obstetric Outcomes

A retrospective analysis from the University of Iowa’s C3G Natural History Study found higher risks of preeclampsia, prematurity, and renal decline in pregnant patients with C3G compared with healthy controls.

“These data provide a preliminary maternal-risk profile for C3G patients who are considering pregnancy and allow for certain risk scenarios to be considered and managed prospectively,” Lauren Fergus, of the Molecular Otolaryngology and Renal Research Laboratories at the University of Iowa, wrote. “Ultimately, the elevated chances of adverse events support the need for multidisciplinary pre- and peri-pregnancy care involving obstetrics, nephrology, and pediatrics as a mechanism for improving outcomes of both mother and baby.”

The findings underscore the importance of coordinated, personalized care in C3G to mitigate both maternal and fetal risks.

C3G, IC-MPGN Report A Disruptive Burden Regardless of Slowed Disease Progression

A multinational, cross-sectional survey found patients and caregivers experience substantial clinical, economic, and quality-of-life impacts, even when disease progression is slow or stable. These results emphasize that, despite emerging therapies, ongoing support and management strategies remain critical to address the broader burden of ultra-rare glomerular diseases.

Feature Content/Podcasts

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

For a condition previously lacking approved therapies and relying on nonspecific immunosuppressants, the arrival of two targeted options in under a year marks a dramatic shift for patients and clinicians.

“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,” said Sayna Norouzi, MD, 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.

The new approvals signal a turning point in C3G care, moving toward mechanism-based interventions with potential to improve long-term kidney outcomes and patient quality of life.

Related: VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN, With Carla Nester, MD

Expert Perspectives: Iptacopan FDA Approval for C3 Glomerulopathy

For additional insight into the significance of the approval of iptacopan and its impact on C3G care, the editorial team of HCPLive Nephrology spoke with Gerald Appel, MD, a professor of clinical medicine, director of clinical nephrology, and director of the Glomerular Disease Center at Columbia University; Andrew Bomback, MD, an assistant professor of medicine at Columbia University Medical Center; and Jared Hassler, MD, a pathologist at the Temple University Hospital.