Positive top-line results announced from the interim analysis of the Phase III APPLAUSE-IgAN study of iptacopan for IgA nephropathy

Iptacopan, an investigational factor B inhibitor targeting the alternative complement pathway, demonstrated superiority versus placebo in proteinuria (protein in urine) reduction and provided a clinically meaningful and highly statistically significant proteinuria reduction on top of supportive care in patients with IgA nephropathy (IgAN), a complement-mediated disease. In the study, the safety profile of iptacopan (200 mg twice daily) was consistent with previously reported data. The study continues in a double-blind fashion to evaluate iptacopan’s ability to slow IgAN progression by measuring estimated glomerular filtration rate (eGFR) slope over 24 months – the primary endpoint at the study end with topline results expected in 2025.

It is estimated that approximately 25 people per million worldwide are newly diagnosed with IgAN each year. Up to 30% of people who have IgAN with persistent higher levels of proteinuria (greater than 1 g/day) may progress to kidney failure within 10 years. There is a need for effective, targeted therapies for IgAN that slow or prevent progression to kidney failure.

Although current supportive care and treatment can help, they don’t address a key pathogenic step in the progression of IgAN: activation of the complement system. Discovered and developed by Novartis, iptacopan aims to address IgAN and other complement-mediated diseases by inhibiting factor B, a protease essential to the alternative complement pathway.

Iptacopan is under review by regulators following positive Phase III results in paroxysmal nocturnal hemoglobinuria (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04558918]). Iptacopan is also being investigated in Phase III studies for C3 glomerulopathy (APPEAR-C3G [NCT04817618]), atypical hemolytic uremic syndrome (APPELHUS [NCT04889430]) and immune complex membranoproliferative glomerulonephritis (APPARENT [NCT05755386]).

With the recent acquisition of Chinook Therapeutics, the Novartis renal portfolio expands with two additional late-stage medicines in development for IgAN, complementing the existing pipeline.

Novartis intends to submit for possible accelerated approval with the FDA in 2024.

About the study: APPLAUSE-IgAN (NCT04578834) is a Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of twice-daily oral iptacopan (200mg) in 470 adult primary IgAN patients. The two primary endpoints of the study for the interim and final analysis, respectively, are proteinuria reduction at 9 months as measured by urine protein to creatinine ratio (UPCR), and the annualized total estimated glomerular filtration rate (eGFR) slope over 24 months.

At the time of final analysis, the following secondary endpoints will also be assessed: i. proportion of participants reaching (UPCR) <1g g without receiving corticosteroids immunosuppressants or other newly approved drugs or initiating new background therapy for treatment of igan or initiating kidney replacement therapy (krt), ii. time from randomization to first occurrence of composite kidney failure endpoint event (reaching either sustained greater than 30% decline in egfr relative to baseline or sustained egfr><15 ml min 1.73m or maintenance dialysis or receipt of kidney transplant or death from kidney failure), iii.change from baseline to 9 months in the fatigue scale measured by the functional assessment of chronic illness therapy-fatigue questionnaire.