Novartis' oral Fabhalta (iptacopan) has demonstrated sustained clinically meaningful results at one year in the Phase III APPEAR-C3G trial for patients with C3 glomerulopathy (C3G). The data, presented at the American Society of Nephrology (ASN) Kidney Week 2024, highlight the potential of Fabhalta as a targeted treatment for this ultra-rare kidney disease.
The APPEAR-C3G study evaluated the efficacy and safety of twice-daily oral Fabhalta in adult patients with C3G. The study included a 6-month randomized, double-blind treatment period comparing Fabhalta to placebo, followed by a 6-month open-label treatment period where all participants received Fabhalta. The primary endpoint was proteinuria reduction at 6 months. Longer-term data now show sustained results with oral Fabhalta.
Sustained Proteinuria Reduction
The study confirmed 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. These findings suggest a consistent and durable effect of Fabhalta on reducing protein levels in the urine, a key indicator of kidney damage in C3G patients.
Improvement in Kidney Function
An exploratory analysis revealed an improvement in the estimated glomerular filtration rate (eGFR) slope upon Fabhalta initiation compared to the patients’ historical rapid decline. eGFR is a critical measure of kidney function, and this improvement suggests that Fabhalta may help slow the progression of kidney damage in C3G patients.
Safety Profile
Fabhalta demonstrated a favorable safety profile throughout the 12-month study, with no new safety signals identified. The majority of treatment-emergent adverse events were mild to moderate in severity, and there were no deaths or discontinuations due to adverse events. This safety profile is particularly important for a chronic treatment in a patient population that often includes children and young adults.
Expert Commentary
"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."
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."
C3 Glomerulopathy (C3G)
C3G is an ultra-rare, progressive kidney disease characterized by overactivation of the alternative complement pathway, leading to C3 protein deposits in the kidney glomeruli. This results in 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.
Regulatory Landscape
Fabhalta, the only 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 the end of the year. Fabhalta received FDA approval in December 2023 for paroxysmal nocturnal hemoglobinuria (PNH) and accelerated approval in August 2024 for IgA nephropathy (IgAN).
