Cogent Biosciences Submits NDA for Bezuclastinib in Non-Advanced Systemic Mastocytosis

Cogent Biosciences announced that the US FDA has accepted its New Drug Application for bezuclastinib in patients with non-advanced systemic mastocytosis (NonAdvSM), marking the first regulatory filing for this selective KIT D816V tyrosine kinase inhibitor in this indication. The bezuclastinib FDA submission, if successful, would make it only the second disease-modifying therapy available for patients with NonAdvSM, a chronic condition driven by unchecked mast cell proliferation. The agency assigned a Prescription Drug User Fee Act target action date of December 30, 2026, and indicated it does not plan to convene an advisory committee, nor has it identified potential review issues at this stage.

The NDA seeks approval for bezuclastinib as a systemic mastocytosis treatment in the non-advanced patient population, which encompasses both indolent and smoldering forms of the disease. Cogent Biosciences bezuclastinib development also extends to gastrointestinal stromal tumors (GIST) and advanced systemic mastocytosis, with separate NDA submissions expected in Q2 2026. The GIST filing is proceeding under Real-Time Oncology Review, and bezuclastinib holds Breakthrough Therapy Designation in that indication.

The bezuclastinib NDA acceptance is supported by clinical data from the SUMMIT pivotal trial, which enrolled patients with NonAdvanced systemic mastocytosis. The company reported that the SUMMIT pivotal trial met its primary endpoint and all key secondary endpoints, demonstrating statistically significant symptomatic improvements across multiple domains. Data through 48 weeks showed continued deepening of benefit over time, along with effects on bone mineral density and evidence the company characterized as consistent with disease modification. Across the trial, bezuclastinib demonstrated a tolerability profile that Cogent described as supporting chronic use, the company said. Detailed efficacy figures and study design parameters from SUMMIT have not been disclosed in the filing announcement.

The filing enters a treatment landscape that, until 2023, offered NonAdvSM patients only symptomatic management through antihistamines, mast cell stabilizers, and leukotriene inhibitors — none of which address the underlying KIT D816V mutation present in approximately 95% of cases. Blueprint Medicines' avapritinib (AYVAKIT), approved in May 2023 based on the PIONEER trial, became the first disease-modifying therapy for indolent systemic mastocytosis. However, avapritinib carries labeling warnings for cognitive effects including memory impairment and confusional state, attributed to its ability to cross the blood-brain barrier. Bezuclastinib was designed with minimal CNS penetration, a pharmacological property that Cogent has positioned as a differentiating feature for a disease requiring lifelong treatment. Blueprint Medicines is also advancing BLU-263, a next-generation KIT inhibitor, in the Phase II/III HARBOR study for the same patient population, adding further competition. The bezuclastinib FDA filing thus joins a field where selectivity, tolerability, and depth of mast cell burden reduction are emerging as the axes along which therapies will be evaluated.

Cogent Biosciences, headquartered in Waltham, Massachusetts, is also building a broader pipeline of targeted therapies against mutations in ErbB2, PI3Kα, KRAS, and JAK2.

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