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

Oral iptacopan (Fabhalta) has received approval from the US Food and Drug Administration (FDA) for the treatment of adults with C3 glomerulopathy (C3G), to reduce proteinuria.

Announced by Novartis on March 20, 2025, the approval marks the first approval for the ultra-rare kidney disease and is based on data from the phase 3 APPEAR-C3G trial.

“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,” said APPEAR-C3G study coinvestigator Carla Nester, MD, MSA, professor of Pediatrics-Nephrology at the University of Iowa.1 “This approval of Fabhalta 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.”

Launched in 2021, APPEAR-C3G was a multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of iptacopan. The trial included a 6-month double-blind period where patients were randomized 1:1 to iptacopan or placebo, followed by a 6-month open-label extension in which all participants could receive iptacopan.1,2,3

Initial 6-month data showed iptacopan met its primary endpoint of reducing 24-hour urine protein-to-creatinine ratio (UPCR) by 35.1% (95% CI, 13.8% to 51.1%; P = .0014), with sustained reductions at 12 months.2

Additional analyses revealed iptacopan use was also associated with a higher proportion of patients meeting the composite renal endpoint—defined as a ≥50% UPCR reduction and ≤15% eGFR decline—occurring in 43.5% of iptacopan-treated patients versus 25.0% of those who switched from placebo at 6 months. Additional analysis indicated a favorable effect on eGFR trajectory relative to historical trends.2,3

The March 2025 approval for C3G marks the second approval in a rare kidney disease in as many years for iptacopan. The oral alternative complement pathway inhibitor received accelerated approval from the FDA in August 2024 for reduction of proteinuria in adults with primary immunoglobulin A nephropathy at risk of rapid disease progression. The agent’s initial approval came in December 2023 for the treatment of adults with paroxysmal nocturnal hemoglobinuria.1,3

“We extend our deepest gratitude to the patients and investigators who participated in our clinical trials, without whom this first FDA approval in C3G wouldn’t have been possible,” said Victor Bultó, President US, Novartis.1 “With this additional approval for [iptacopan] – the second in kidney disease – we will leverage our established capabilities and expertise to bring this innovative treatment to patients in need as we work to help transform care for people living with kidney diseases.”

For more, check out our video interview with Nester from the American Society of Nephrology Kidney Week 2024:

Relevant disclosures for Nester include Apellis, Biocryst, Kira, Novartis, Silence Therapeutics, and Biocryst.

References:

1. Novartis. Novartis receives third FDA approval for oral Fabhalta® (iptacopan) – the first and only treatment approved in C3 glomerulopathy (C3G). GlobeNewswire. March 20, 2025. Accessed March 20, 2025. https://www.globenewswire.com/news-release/2025/03/20/3046800/0/en/Novartis-receives-third-FDA-approval-for-oral-Fabhalta-iptacopan-the-first-and-only-treatment-approved-in-C3-glomerulopathy-C3G.html.

2. Nester CM, Smith RJ, Kavanagh D, 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 Kidney Week 2024. San Diego, CA. October 23-27, 2024.

3. Novartis presents latest phase III Fabhalta® (iptacopan) data in C3 glomerulopathy (C3G) showing clinically meaningful and statistically significant 35.1% proteinuria reduction vs. placebo. Novartis. May 25, 2024. Accessed October 27, 2024. https://www.novartis.com/news/media-releases/novartis-presents-latest-phase-iii-fabhalta-iptacopan-data-c3-glomerulopathy-c3g-showing-clinically-meaningful-and-statistically-significant-351-proteinuria-reduction-vs-placebo.