Novartis' oral Fabhalta (iptacopan) has demonstrated sustained, clinically meaningful results at one year in a Phase III trial for C3 glomerulopathy (C3G). The APPEAR-C3G study, presented at the American Society of Nephrology (ASN) Kidney Week 2024, showed that patients treated with Fabhalta in addition to supportive care experienced a significant reduction in proteinuria that was sustained over 12 months. This provides hope for individuals with this ultra-rare kidney disease, which currently has no approved treatments.
The APPEAR-C3G trial 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).
Sustained Proteinuria Reduction and Improved Kidney Function
The data confirm that treatment with Fabhalta resulted in clinically meaningful proteinuria reduction, observed as early as 14 days and sustained at 12 months. Participants who switched to Fabhalta during the open-label period also experienced proteinuria reduction. An exploratory analysis showed an improvement in estimated glomerular filtration rate (eGFR) slope upon Fabhalta initiation compared to the patients' historical rapid decline.
"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. As the only oral complement inhibitor intended to treat C3G, Fabhalta could provide new hope for people living with this condition."
Addressing an Unmet Need in C3G Treatment
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 causes deposits of C3 protein to accumulate in kidney glomeruli, leading to inflammation, glomerular damage, 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.
Fabhalta's Mechanism and Regulatory Status
Fabhalta, an oral Factor B inhibitor of the alternative complement pathway, has the potential to be the first FDA-approved treatment for C3G. Regulatory submissions for Fabhalta in C3G are completed in the EU, China, and Japan, with a US submission expected by year-end. Fabhalta received FDA approval in December 2023 for paroxysmal nocturnal hemoglobinuria (PNH) and accelerated approval in August 2024 for proteinuria reduction in primary IgA nephropathy (IgAN).
Novartis' Commitment to Kidney Disease
"We are thrilled to share these data, which demonstrate the potential of Fabhalta in C3G, and look forward to working with regulatory authorities with the goal of bringing this innovative medicine to this patient community," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis. Novartis is also advancing the late-stage development of two additional IgAN therapies: atrasentan and zigakibart.
