Novartis 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 data, presented at the American Society of Nephrology (ASN) Kidney Week 2024, highlight Fabhalta's potential as the first oral treatment targeting the underlying cause of this ultra-rare kidney disease.
Sustained Proteinuria Reduction and Improved Kidney Function
The APPEAR-C3G trial demonstrated that Fabhalta, when added to supportive care, resulted in a clinically meaningful reduction in proteinuria that was observed as early as 14 days and sustained over 12 months. Furthermore, an exploratory analysis showed an improvement in the estimated glomerular filtration rate (eGFR) slope upon Fabhalta initiation, compared to the historical rapid decline in these patients. This improvement in eGFR suggests a potential benefit in preserving kidney function over time.
Safety Profile and Investigator Commentary
The study also reported a favorable safety profile for Fabhalta, with no new safety signals identified during the 12-month study period. Most treatment-emergent adverse events were mild to moderate in severity, and there were no deaths or discontinuations due to adverse events.
Dr. Carla Nester, Professor of Pediatrics-Nephrology at the University of Iowa and APPEAR-C3G Co-Investigator, emphasized the challenges in treating C3G and the vital need for dedicated treatments. She stated, "I am encouraged to see these data, which reinforce the clinically meaningful impact on kidney health measures we saw at 6 months...Fabhalta could provide new hope for people living with this condition."
Dr. Andrew Bomback, Associate Professor of Medicine at Columbia University Irving Medical Center and APPEAR-C3G Co-Investigator, 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 is a Phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of twice-daily oral Fabhalta (200 mg) in adult C3G patients. The trial included a 6-month double-blind period comparing Fabhalta to placebo, followed by a 6-month open-label period where all participants received Fabhalta. The primary endpoint was proteinuria reduction from baseline at 6 months, as measured by the 24-hour urine protein to creatinine ratio (UPCR). The study enrolled adult patients, with ongoing enrollment in an adolescent cohort.
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 the 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, necessitating dialysis or kidney transplantation.
Regulatory Outlook and Novartis' Commitment
Regulatory submissions for Fabhalta in C3G are completed in the EU, China, and Japan, with submissions expected in the US by the end of the year. Fabhalta has already received FDA approval for paroxysmal nocturnal hemoglobinuria (PNH) and accelerated approval for IgA nephropathy (IgAN). Novartis is also advancing two additional IgAN therapies, atrasentan and zigakibart, further demonstrating their commitment to transforming patient care in kidney disease.
