FDA Approves Oral Iptacopan for C3 Glomerulopathy

The FDA approved oral iptacopan (Fabhalta; Novartis) to reduce proteinuria in adults with C3 glomerulopathy (C3G), according to a press release from Novartis.¹ Iptacopan is now the first and only FDA-approved treatment for C3G, an ultrarare, progressive kidney disease.

Iptacopan is an oral inhibitor of the alternative complement pathway and selectively targets what is thought to be the underlying cause of C3G. Its approval was based on data from the pivotal phase 3 APPEAR-C3G study (NCT04817618), which assessed the safety and efficacy of twice-daily oral iptacopan. The multicenter, randomized, double-blind, placebo-controlled study included 74 adult patients with C3G and entailed a 6-month randomized, double-blinded treatment period with iptacopan vs placebo (n = 38, n = 26, respectively), followed by a 6-month open-label period with all patients receiving iptacopan.²

Iptacopan is the first and only FDA-approved treatment for C3G, an ultrarare, progressive kidney disease. | Image credit: Olivier Le Moal - stock.adobe.com

The study met its primary end point, showing a statistically significant reduction in proteinuria from baseline to 6 months with iptacopan vs placebo. Patients in the iptacopan cohort showed a 35.1% reduction in 24-hour urine protein-creatinine ratio (UPCR) compared with the placebo group (1-sided P = .0014; 95% CI, 13.8%-51.1%).

There was also sustained improvement with iptacopan as measured by a composite renal end point of at least a 50% reduction in UPCR and a maximum 15% reduction in estimated glomerular filtration rate (eGFR) at 12 months. The trajectory of eGFR also improved with iptacopan compared with patients' historical decline.

The safety profile was favorable, and the most common adverse reactions occurring in 10% or more of patients were nasopharyngitis and viral infections.¹ Iptacopan may cause serious infections due to encapsulated bacteria and is only available through a Risk Evaluation and Mitigation Strategy requiring certain vaccinations.

“C3G is a debilitating disease often affecting young people, impacting many aspects of their physical and emotional health, and our previous treatment options came with significant challenges,” Carla Nester, MD, MSA, FASN, professor of pediatrics-nephrology at the University of Iowa and APPEAR-C3G study coinvestigator, said in a statement.¹ “This approval of [iptacopan] is historic for the entire C3G community as now, for the first time, we have a therapy that is believed to treat the underlying cause of the disease, providing the potential for a new standard of care for patients.”

This is the third FDA approval for iptacopan, which is also indicated for the treatment of adults with paroxysmal nocturnal hemoglobinuria and was granted accelerated approval for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression, generally a
UPCR of 1.5 g/g or higher.³

A cohort of adolescent patients with C3G is currently being enrolled in the APPEAR-C3G trial, and iptacopan is also being studied in a range of other kidney conditions, such as atypical hemolytic uremic syndrome, immune complex membranoproliferative glomerulonephritis, and lupus nephritis.¹

References

1. Novartis receives third FDA approval for oral Fabhalta (iptacopan) – the first and only treatment approved in C3 glomerulopathy (C3G). News release. Novartis. March 20, 2025. Accessed March 21, 2025. https://www.novartis.com/news/media-releases/novartis-receives-third-fda-approval-oral-fabhalta-iptacopan-first-and-only-treatment-approved-c3-glomerulopathy-c3g

2. Smith RJ, Kavanagh D, Vivarelli M, et al. Efficacy and safety of iptacopan in patients with C3 glomerulopathy: 12-month results from the phase 3 APPEAR-C3G study. Presented at: American Society of Nephrology (ASN) Kidney Week 2024; October 23-27, 2024; San Diego, CA. Abstract SA-OR66.

3. Fabhalta. Prescribing information. Novartis; 2025. Accessed March 21, 2025. https://www.novartis.com/us-en/sites/novartis_us/files/fabhalta.pdf