Iptacopan Receives Third FDA Approval for Adult Patients With C3 Glomerulopathy

Iptacopan (Fabhalta; Novartis) has received its third FDA approval for the treatment of adults with C3 glomerulopathy (C3G) to reduce proteinuria. Data from a phase 3 trial showed the agent yielded sustained proteinuria reduction at 1 year with a favorable safety profile. The decision eaffirms iptacopan as the first and only treatment for C3G.

Blood test for C3, C4 protein detection | Image Credit: © MdBabul - stock.adobe.com

C3G is a form of membranoproliferative glomerulonephritis that affects approximately 1 to 2 million individuals around the world. It is characterized by the abnormal activation of the complement system, which is a collection of proteins in the blood that help the immune system fight bacteria and viruses. However, when abnormally activated normal complement proteins such as C3 are broken down, become lodged in the kidneys, and injure the glomeruli, leading to a number of complications. When damaged, the glomeruli cannot properly filter blood, and urine production is reduced. If left untreated, these toxins build up in the blood and kidney tissues, eventually resulting in impaired kidney functioning.^1,2

Treatment for C3G has historically involved supportive care and symptom management rather than slowing the process of kidney damage. This is typically done through the use of steroids or immunosuppressive agents for calming the immune system, blood pressure medications to reduce protein loss, as well as lifestyle modifications such as diet changes. However, the development and approval of iptacopan may drastically change outcomes for patients who otherwise had no therapeutic options designed to slow disease progression and kidney damage.²

“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 [iptacopan] APPEAR-C3G study co-investigator, said in a news release. “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.”¹

Iptacopan is an oral inhibitor that targets the alternative complement pathway, which investigators believe is the underlying cause of the disease. In the phase 3 APPEAR-C3G study (NCT04817618), iptacopan demonstrated clinically meaningful capabilities in proteinuria reduction. The multicenter, randomized, double-blind, parallel group, placebo-controlled study was designed to evaluate the safety and efficacy of twice-daily iptacopan at a dose of 200 mg or placebo in patients with native kidney C3G. The study was comprised of a 6-month double-blind period followed by a 6-month open-label period.^1,3

Patients were randomized 1:1:1 to receive either iptacopan or placebo plus supportive care. The primary end point of the double-blind period was proteinuria reduction from baseline at 6 months for iptacopan compared to placebo as measured by 24-hour urine protein-creatinine ratio (UPCR).¹

Treatment with iptacopan yielded significant reductions in proteinuria as soon as 14 days into treatment, which was sustained for 12 months. This reduction was also observed in the open-label period.¹

Additionally, the safety profile was favorable, and the investigators reported no new safety signals. Nasopharyngitis and viral infections were the most common adverse events in greater than or equal to 10% of patients receiving iptacopan. However, iptacopan may lead to severe infections caused by encapsulated bacteria. Given this risk, iptacopan is only available through a Risk Evaluation and Mitigation Strategy (REMS) that requires specific vaccinations.¹

REFERENCES

1. Novartis receives third FDA approval for oral Fabhalta® (iptacopan) – the first and only treatment approved in C3 glomerulopathy (C3G). Novartis. March 21, 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. Complement 3 glomerulopathy (C3G). National Kidney Foundation. Accessed March 21, 2025. https://www.kidney.org/kidney-topics/complement-3-glomerulopathy-c3g

3. Study of efficacy and safety of iptacopan in patients with C3 glomerulopathy. (APPEAR-C3G). Updated March 4, 2025. Accessed March 21, 2025. https://clinicaltrials.gov/study/NCT04817618