FDA accelerated approval for Fabhalta (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy – Novartis

Novartis announced that the FDA has granted accelerated approval for Fabhalta (iptacopan), a first-in-class complement inhibitor for the reduction of proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression. This is generally defined as a urine protein-to-creatinine ratio (UPCR) greater than 1.5 g/g. Fabhalta specifically targets the alternative complement pathway of the immune system. When overly activated in the kidneys, the complement system is thought to contribute to the pathogenesis of IgAN1-4.

This indication is granted under accelerated approval based on the pre-specified interim analysis of the Phase III APPLAUSE-IgAN study measuring reduction in proteinuria at 9 months compared to placebo. It has not been established whether Fabhalta slows kidney function decline in patients with IgAN. The continued approval of Fabhalta may be contingent upon verification and description of clinical benefit from the ongoing Phase III APPLAUSE-IgAN study, 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.

“The heterogeneous and progressive nature of IgA nephropathy has made it challenging to effectively treat this disease. Thankfully, the treatment landscape is rapidly evolving,” said Professor Dana Rizk, Investigator and APPLAUSE-IgAN Steering Committee Member and professor in the University of Alabama at Birmingham Division of Nephrology. “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.”

IgAN is a progressive, rare disease in which the immune system attacks the kidneys, often causing glomerular inflammation and proteinuria1. Approximately 25 people per million worldwide are newly diagnosed with IgAN each year. Each person’s disease journey is unique as IgAN progresses differently and treatment responses vary as well. Despite current standard of care, up to 50% of IgAN patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis. These patients often require maintenance dialysis and/or kidney transplantation. Effective, targeted therapies with different mechanisms of action can help physicians select the most appropriate treatment for patients.

Data supporting approval : The ongoing Phase III APPLAUSE-IgAN study is evaluating the efficacy and safety of twice-daily oral Fabhalta (200 mg) versus placebo in adult IgAN patients on a stable dose of maximally-tolerated renin-angiotensin system (RAS) inhibitor therapy with or without a stable dose of SGLT2i. The primary endpoint for the interim analysis was the percent reduction of proteinuria, a marker of kidney damage, measured by comparing UPCR at 9 months to baseline.

Fabhalta achieved a 44% reduction in proteinuria at 9 months relative to baseline, compared with a 9% reduction in the placebo arm, demonstrating a clinically meaningful and statistically significant 38% reduction vs. placebo (p<0.0001). The treatment effect on UPCR at 9 months was consistent across all subgroups, including age, sex, race and baseline disease characteristics (such as baseline eGFR and proteinuria levels), and the use of SGLT2i1. Fabhalta demonstrated a favorable safety profile, consistent with previously reported data.