The US FDA has accepted for review the New Drug Application submitted by Washington-based Immunome, Inc. (Nasdaq: IMNM) for varegacestat (formerly AL102), an investigational oral gamma secretase inhibitor, for the treatment of adults with desmoid tumors. The filing represents the first NDA submission for varegacestat and, if approved, would introduce a second oral gamma secretase inhibitor to a disease that lacked any approved therapy until 2023. The FDA assigned a PDUFA target action date of April 28, 2027.
The NDA seeks approval of varegacestat as an oral, once-daily treatment for adults with progressing desmoid tumors. The company said the filing is based on results from the global Phase III RINGSIDE trial, and Immunome plans to submit a Marketing Authorization Application to the European Medicines Agency by the end of 2026.
Like SpringWorks' Ogsiveo (nirogacestat), varegacestat is an oral gamma secretase inhibitor targeting Notch signaling in desmoid tumors. If approved, it would become the second drug in the class available for the disease. Ogsiveo received FDA approval in November 2023 based on the Phase III DeFi trial reporting an objective response rate of approximately 41%. Varegacestat's RINGSIDE data suggest a substantially deeper response profile — a 56% ORR and an 84% reduction in progression risk — though cross-trial comparisons carry inherent limitations given differences in patient populations and trial design. The competitive significance is nonetheless material: if approved, varegacestat would enter a market currently occupied by a single approved agent, with a clinical dataset that may support differentiation within the gamma secretase inhibitor class.
The global Phase III RINGSIDE trial enrolled 156 patients with progressing desmoid tumors, the largest randomized study conducted in the disease. Patients received varegacestat 1.2 mg daily or placebo until disease progression or death. RINGSIDE met its primary endpoint, reducing the risk of progression or death by 84% versus placebo (HR 0.16; p<0.0001). Objective response rate reached 56% versus 9% with placebo, while patients also experienced significant improvements in pain. Safety was consistent with the known gamma secretase inhibitor class, with mostly grade 1 or 2 adverse events.