Fabhalta demonstrated a 44% reduction in proteinuria during the Phase III APPLAUSE-IgAN interim analysis, compared to a 9% reduction with placebo, marking a significant 38% improvement over placebo.
Novartis announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Fabhalta (iptacopan), a first-of-its-kind complement inhibitor designed to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) who are at risk of rapid disease progression. Typically, this is indicated by a urine protein-to-creatinine ratio (UPCR) of ≥1.5 g/g. Fabhalta targets the alternative complement pathway, which, when excessively activated in the kidneys, is believed to play a key role in the development of IgAN.
The approval is based on data from a pre-specified interim analysis of the Phase III APPLAUSE-IgAN study, which assessed proteinuria reduction at 9 months compared to a placebo. While it has not yet been confirmed whether Fabhalta slows the decline in kidney function in IgAN patients, ongoing studies are being conducted to evaluate this further. The continued approval of Fabhalta will depend on the verification of clinical benefits, with the ongoing Phase III APPLAUSE-IgAN study expected to provide additional data on the treatment's impact on the estimated glomerular filtration rate (eGFR) decline over a 24-month period. This data is anticipated to be available in 2025 and will support the pursuit of traditional FDA approval.
IgA nephropathy (IgAN) is a progressive and rare condition in which the immune system mistakenly attacks the kidneys, leading to glomerular inflammation and proteinuria. Each year, approximately 25 individuals per million worldwide are diagnosed with IgAN, a disease that progresses uniquely in each patient, with varying responses to treatment. Despite existing treatments, up to half of IgAN patients with persistent proteinuria may eventually progress to kidney failure within 10 to 20 years after diagnosis. These patients often require ongoing dialysis or kidney transplantation. The development of targeted therapies with different mechanisms of action offers physicians new tools to better tailor treatment plans to individual patient needs.
Supporting Data for Fabhalta's Approval
The ongoing Phase III APPLAUSE-IgAN trial is assessing the efficacy and safety of twice-daily oral Fabhalta (200 mg) compared to a placebo in adult IgAN patients who are on a stable dose of maximally tolerated renin-angiotensin system (RAS) inhibitor therapy, with or without a stable dose of SGLT2 inhibitors. The primary endpoint of the interim analysis was the percentage reduction in proteinuria, a key indicator of kidney damage, as measured by comparing the UPCR at 9 months to baseline.
Fabhalta achieved a 44% reduction in proteinuria after 9 months, compared to a 9% reduction in the placebo group. This significant 38% improvement over placebo was consistent across all subgroups, regardless of age, sex, race, baseline disease characteristics (including eGFR and proteinuria levels), or the use of SGLT2 inhibitors. Fabhalta was well-tolerated, with a safety profile in line with previous data. The most common side effects in IgAN patients using Fabhalta were upper respiratory tract infections, lipid disorders, and abdominal pain. Due to the risk of serious infections caused by encapsulated bacteria, Fabhalta is available only through a Risk Evaluation and Mitigation Strategy (REMS) that requires specific vaccinations.
Novartis’ Renal Pipeline
In addition to Fabhalta, Novartis is advancing the late-stage development of two other potential IgAN treatments, each with a distinct mechanism of action. These include atrasentan, an oral endothelin A receptor antagonist that has recently received FDA filing acceptance, and zigakibart, an anti-APRIL monoclonal antibody currently in Phase III trials.
Details of the APPLAUSE-IgAN Study
APPLAUSE-IgAN is a Phase III, multicenter, randomized, double-blind, placebo-controlled study involving 518 adult patients with primary IgAN. The study’s two main endpoints are the reduction in proteinuria at 9 months (as measured by 24-hour UPCR) and the annualized eGFR slope over 24 months. Secondary endpoints to be assessed at the final analysis include the proportion of patients achieving a UPCR of less than 1 g/g without the need for corticosteroids, immunosuppressants, or other newly approved drugs, the time from randomization to the first occurrence of a composite kidney failure event, and changes from baseline to 9 months in fatigue levels, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire.
The primary study population consisted of 250 IgAN patients with an eGFR of ≥30 mL/min/1.73 m² and a UPCR of ≥1 g/g at baseline. Additionally, a smaller group of patients with severe renal impairment (eGFR 20-30 mL/min/1.73 m² at baseline) was included to provide supplementary information, though they will not contribute to the main efficacy analyses.