Novartis today revealed encouraging top-line results from the pre-specified interim analysis of the Phase III APPLAUSE-IgAN study (NCT04578834) at 9 months. 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.
The safety profile of iptacopan (200 mg twice daily) in the research was similar with previously reported data. The study will continue in a double-blind method to assess iptacopan’s capacity to decrease IgAN progression by monitoring eGFR slope over 24 months – the primary endpoint at the study’s conclusion, with topline results expected in 2025.
Expected US Filing
Novartis is expected to file for accelerated approval of Iptacopan in H1 2024
Expert opinion on Positive Phase III Results of Iptacopan in Proteinuria Reduction:
“These positive data from the Phase III APPLAUSE study reinforce the potential of iptacopan to provide clinically meaningful benefit to patients with IgAN, a debilitating disease that affects mostly young adults,” said Shreeram Aradhye, M.D., President, Development and Chief Medical Officer, Novartis. “We are excited about this milestone in the development of our factor B inhibitor of the alternative complement pathway and remain focused on further advancing our portfolio of renal programs through pivotal trials.”
IgA nephropathy (IgAN) and Unmet Need:
Each year, it is anticipated that roughly 25 persons per million are newly diagnosed with IgAN. Within 10 years, up to 30% of persons with IgAN who have chronic higher levels of proteinuria (1 g/day) may develop renal failure.
IgAN is caused by an autoimmune response to an aberrant type of IgA, which results in the development of immune complexes that deposit in the kidney. These immunological complexes cause an inflammatory response, resulting in gradual kidney damage and kidney function loss.
Within 10 years, up to 30% of persons with IgAN who have chronic higher levels of proteinuria (1 g/day) may develop renal failure
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.
About Iptacopan:
Iptacopan is a proximal complement inhibitor that is taken orally and inhibits the alternative complement pathway by binding to factor B.
Novartis discovered and developed iptacopan, which intends to treat IgAN and other complement-mediated illnesses by blocking factor B, a protease required for the alternative complement pathway.
Iptacopan, discovered at Novartis Biomedical Research, is currently being developed for a variety of complement-mediated diseases, including PNH, IgAN, C3 glomerulopathy (C3G), immune complex membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).
Clinical Trials of Iptacopan in multiple complement-mediated diseases:
Following promising Phase III results in paroxysmal nocturnal hemoglobinuria (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04558918]), regulators are reviewing iptacopan. Iptacopan is also being studied in Phase III clinical trials for C3 glomerulopathy (APPEAR-C3G [NCT04817618]), atypical hemolytic uremic syndrome (APPELHUS [NCT04889430]), and immune complex membranoproliferative glomerulonephritis (APPARENT [NCT05755386]).
Iptacopan Designations:
Iptacopan has received FDA Breakthrough Therapy Designation in PNH, FDA Breakthrough Therapy Designation in C3G, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN based on disease prevalence, unmet needs, and data from Phase II studies.
| S.No | Indication | Region | Designation |
|---|---|---|---|
| 1 | paroxysmal nocturnal hemoglobinuria (PNH) | US | FDA Breakthrough Therapy Designation |
| 2 | C3 glomerulopathy (C3G) | US | FDA Breakthrough Therapy Designation, orphan drug designations |
| 3 | paroxysmal nocturnal hemoglobinuria (PNH) | US | orphan drug designations |
| 4 | paroxysmal nocturnal hemoglobinuria (PNH) | EU | orphan drug designations |
| 5 | C3 glomerulopathy (C3G) | EU | orphan drug designations, PRIME designation |
| 6 | IgA nephropathy (IgAN) | EU | orphan drug designations |
The recent acquisition of Chinook Therapeutics strengthens Novartis’ renal portfolio with two more late-stage IgAN therapies under development, supplementing the existing pipeline.
Novartis intends to submit for possible accelerated approval with the FDA in H1 2024.
