The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Fabhalta (iptacopan), a first-in-class complement inhibitor developed by Novartis, for the treatment of primary immunoglobulin A nephropathy (IgAN) in adults at risk of rapid disease progression. This approval marks a significant advancement in the treatment landscape for IgAN, a rare and progressive kidney disease. Fabhalta's approval is based on interim data demonstrating a substantial reduction in proteinuria, a key marker of kidney damage, offering new hope for patients facing this challenging condition.
Clinical Efficacy and Safety
The approval was based on the pre-specified interim analysis of the Phase III APPLAUSE-IgAN study, a multicenter, randomized, double-blind, placebo-controlled trial. The study evaluated the efficacy and safety of twice-daily oral Fabhalta (200 mg) versus placebo in adult IgAN patients already receiving a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy, with or without SGLT2i. The primary endpoint of the interim analysis was the percent reduction of proteinuria, measured by urine protein-to-creatinine ratio (UPCR) at 9 months compared to baseline.
Fabhalta demonstrated a 44% reduction in proteinuria at 9 months relative to baseline, compared to a 9% reduction in the placebo arm. This translated to a clinically meaningful and statistically significant 38% reduction versus placebo (p<0.0001). The treatment effect on UPCR was consistent across various subgroups, including age, sex, race, baseline eGFR, proteinuria levels, and SGLT2i use. The safety profile of Fabhalta was also favorable, aligning with previously reported data. Common adverse reactions (≥5%) included upper respiratory tract infection, lipid disorder, and abdominal pain. It is important to note that Fabhalta carries a risk of serious infections caused by encapsulated bacteria and is available only through a Risk Evaluation and Mitigation Strategy (REMS) that necessitates specific vaccinations.
Mechanism of Action and Disease Context
Fabhalta (iptacopan) inhibits the alternative complement pathway, which is implicated in the pathogenesis of IgAN. IgAN is a rare, progressive disease where the immune system attacks the kidneys, leading to glomerular inflammation and proteinuria. Approximately 25 people per million worldwide are newly diagnosed with IgAN annually. Up to 50% of IgAN patients with persistent proteinuria progress to kidney failure within 10 to 20 years, often requiring dialysis or kidney transplantation. By targeting the alternative complement pathway, Fabhalta aims to reduce kidney damage and slow disease progression.
Future Development and Regulatory Considerations
This indication is granted under accelerated approval based on the interim analysis of proteinuria reduction. Continued approval may be contingent upon verification and description of clinical benefit from the ongoing Phase III APPLAUSE-IgAN study, which is evaluating whether Fabhalta slows disease progression as measured by estimated glomerular filtration rate (eGFR) decline over 24 months. The eGFR data are expected at study completion in 2025 and are intended to support traditional FDA approval. Novartis is also advancing the late-stage development of two additional IgAN therapies: atrasentan, an investigational oral endothelin A receptor antagonist, and zigakibart, an investigational subcutaneously administered anti-APRIL monoclonal antibody, both currently in Phase III development.
Expert Commentary
Professor Dana Rizk, Investigator and APPLAUSE-IgAN Steering Committee Member, noted, "The heterogeneous and progressive nature of IgA nephropathy has made it challenging to effectively treat this disease. Thankfully, the treatment landscape is rapidly evolving. Mounting clinical evidence underscores the pivotal role of complement activation in IgA nephropathy. I am thrilled that this advancement is now available to help enable a targeted treatment approach for IgAN patients."
Victor Bultó, President US, Novartis, stated, "Today’s approval of Fabhalta as a first-in-class medicine for IgA nephropathy is an important milestone in our journey to evolve rare renal disease care by bringing new treatments to people in urgent need of options. We are deeply committed to those living with rare renal diseases and look forward to continued partnership with this community as we further advance our broad portfolio."
