Novartis' oral Fabhalta (iptacopan) has demonstrated sustained and clinically meaningful results at one year in patients with C3 glomerulopathy (C3G), according to data presented from the Phase III APPEAR-C3G study at the American Society of Nephrology (ASN) Kidney Week 2024. The study evaluated the efficacy and safety of Fabhalta in adult patients with C3G.
Sustained Proteinuria Reduction and Improved Kidney Function
The APPEAR-C3G trial's 12-month data confirm that treatment with Fabhalta resulted in a clinically meaningful reduction in proteinuria, observed as early as 14 days and sustained at 12 months. Participants who switched to Fabhalta during the open-label period of the study also experienced proteinuria reduction. Furthermore, an exploratory analysis revealed an improvement in the estimated glomerular filtration rate (eGFR) slope following Fabhalta initiation, compared to the patients' historical rate of decline.
Safety Profile and Expert Commentary
The safety profile of Fabhalta remained favorable throughout the study, with no new safety signals detected. 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, emphasized the need for dedicated treatments for C3G patients, stating, "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. 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. I am optimistic that these iptacopan APPEAR-C3G findings bring us a step closer to revolutionizing the treatment paradigm in this ultra-rare disease with no approved therapies."
APPEAR-C3G Study Design
The APPEAR-C3G study (NCT04817618) is a Phase III, multicenter, randomized, double-blind, placebo-controlled trial designed to assess 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 in addition to 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 is characterized by overactivation of the alternative complement pathway, leading to C3 protein deposits in kidney glomeruli, causing inflammation, glomerular damage, proteinuria, hematuria, and reduced kidney function. Approximately 50% of C3G patients progress to kidney failure within 10 years of diagnosis.
Regulatory Outlook
Fabhalta, an 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.
