Cogent Biosciences has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for bezuclastinib in advanced systemic mastocytosis (SM), the company recently announced. The application is based on data from the APEX trial, which showed responses in most evaluable patients and reductions in several markers of disease activity.
The application is part of a broader regulatory push for bezuclastinib. The advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm. filing was the company’s third FDA submission for the drug in six months, with other reviews already underway for bezuclastinib in nonadvanced SM and in gastrointestinal stromal tumors.
Bezuclastinib is designed to target KIT D816V, a mutation the biotechnology company describes as “responsible for driving systemic mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults..”
What is a KIT gene mutationKIT gene mutation Most SM cases are caused by the KIT D816V mutation. The KIT gene codes for a type of protein called a receptor tyrosine kinase, which signals mast cells to grow, divide and move.?
SM is usually caused by a sporadic mutation in the KIT gene, which codes for a protein called CD117 transmembrane tyrosine kinase. The protein is involved in the growth, survival and migration of mast cells. The most common KIT mutation associated with SM is the D816V mutation, which results in the amino acid aspartic acid being replaced by the amino acid valine in the protein chain.
The APEX trial results were most recently presented at the 2026 European Hematology Association (EHA) Congress. Cogent reported that 65% of evaluable patients with advanced SM had an objective response to bezuclastinib, meaning they had remission, partial remission or clinical improvement.
Among assessed patients, 89% had reductions of at least 50% in serum tryptaseTryptase A protein enzyme that is primarily produced by mast cells and stored in small pockets within the cells, known as granules. High levels of tryptase are a key indicator of SM., a blood marker linked to mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. activity. The same proportion had reductions in bone marrow mast cell burden or clearance of mast cell aggregates, while 91% of those assessed for KIT D816V variant allele frequency (a measure of how often the KIT D816V mutation was detected) had a reduction of at least 50%.
Read more about APEX trial results in advanced systemic mastocytosis
The most common treatment-related side effects were hair color changes and neutropenia (low levels of a type of white blood cell), each reported in 31% of patients. Other common side effects included altered taste in 28%, thrombocytopenia (low platelet levels) in 25% and changes in blood tests related to liver function in 21%. Most of these liver-related blood test changes were mild, did not cause symptoms and improved.
The APEX trial did not directly compare bezuclastinib with currently approved treatments for advanced SM. That means the results do not show whether bezuclastinib works better or is safer than existing options.
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The company also stated it has active expanded access programs for eligible patients in the U.S. with SM or gastrointestinal stromal tumors. The programs may include bezuclastinib alone or, for some patients, bezuclastinib with sunitinib, depending on disease-specific criteria. Expanded access programs can allow some patients with serious diseases to receive an investigational treatment before it is approved, if they meet specific criteria.
If approved, bezuclastinib would add to the current FDA-approved treatment options for adults with advanced SM, which include avapritinib and midostaurin. Cogent has not announced a target FDA decision date for the application.
