Novartis has announced positive 12-month data from the Phase III APPEAR-C3G study, revealing that Fabhalta (iptacopan) sustained clinically meaningful results in patients with C3 glomerulopathy (C3G). The findings, presented at the American Society of Nephrology (ASN) Kidney Week 2024, highlight the potential of Fabhalta as an oral treatment option for this ultra-rare kidney disease.
Sustained Proteinuria Reduction and Improved Kidney Function
The APPEAR-C3G study demonstrated that treatment with Fabhalta resulted in clinically meaningful proteinuria reduction, observed as early as 14 days and sustained at 12 months. An open-label extension of the study showed similar proteinuria reduction in participants who switched to Fabhalta. Furthermore, an exploratory analysis revealed an improvement in estimated glomerular filtration rate (eGFR) slope upon Fabhalta initiation compared to the historic rapid decline in these patients. The safety profile of Fabhalta remained favorable throughout the study, with no new safety signals identified.
Expert Perspectives
"As a clinician treating young people living with C3G, I see firsthand the challenges with therapies used to treat this condition today, underscoring the vital need for dedicated treatment for these patients," said Carla Nester, M.D., M.S.A., F.A.S.N., Professor of Pediatrics-Nephrology at the University of Iowa and APPEAR-C3G Co-Investigator. "I am encouraged to see these data, which reinforce the clinically meaningful impact on kidney health measures we saw at 6 months..."
Andrew Bomback, M.D., M.P.H., Associate Professor of Medicine at Columbia University Irving Medical Center and APPEAR-C3G Co-Investigator and Steering Committee Member, added, "These results mark an important milestone for the management of C3G, as the first study to shed light on longer-term treatment targeting the underlying mechanism of this disease via the alternative complement pathway..."
APPEAR-C3G Trial Design
The APPEAR-C3G trial (NCT04817618) is a Phase III multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of twice-daily oral Fabhalta (200 mg) in C3G patients. The study included a 6-month double-blind period, where adult patients were randomized 1:1 to receive Fabhalta or placebo on top of supportive care, followed by a 6-month open-label period where all patients received Fabhalta. The primary endpoint was proteinuria reduction from baseline at 6 months for Fabhalta compared to placebo, measured by 24-hour urine protein to creatinine ratio (UPCR).
C3 Glomerulopathy: An Unmet Need
C3G is an ultra-rare, progressive kidney disease affecting approximately 1-2 people per million worldwide annually. It often presents in children and young adults. In C3G, overactivation of the alternative complement pathway leads to C3 protein deposits in kidney glomeruli, causing inflammation and damage. This results in proteinuria, hematuria, and reduced kidney function. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis, requiring lifelong dialysis or kidney transplantation.
Regulatory Outlook and Future Development
Fabhalta, the only oral Factor B inhibitor of the alternative complement pathway, has the potential to become the first FDA-approved treatment for C3G. Regulatory submissions for Fabhalta in C3G have been completed in the EU, China, and Japan, with a US submission expected by the end of the year. Novartis is also developing two additional IgAN therapies: atrasentan and zigakibart.
