Cogent Biosciences submitted an FDA NDA for bezuclastinib in advanced systemic mastocytosis, supported by pivotal APEX trial data showing durable responses, disease modification, and favorable tolerability.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Cogent Biosciences has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration seeking approval of bezuclastinib for adults with advanced systemic mastocytosis (AdvSM). The application is supported by positive results from the pivotal Phase 2 APEX trial, which demonstrated high response rates, durable clinical benefit, and manageable safety in patients with this rare and aggressive mast cell disorder.
Advanced systemic mastocytosis is driven in most patients by activating KIT D816V mutations that promote uncontrolled mast cell proliferation and organ damage. Current treatment options can be limited by toxicity or incomplete disease control, highlighting the need for more selective targeted therapies.
Bezuclastinib is a highly selective KIT D816V inhibitor developed to suppress disease-driving signaling while minimizing off-target effects associated with less selective kinase inhibitors.
APEX trial demonstrated durable responses across AdvSM subtypes
The NDA is supported by efficacy and safety data presented at the 2026 European Hematology Association (EHA) Congress. As of the March 31, 2026 data cutoff, 81 patients received bezuclastinib 150 mg daily, including 57 patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), 11 with aggressive systemic mastocytosis (ASM), and 13 with mast cell leukemia (MCL).
Among 68 efficacy-evaluable patients, the primary endpoint of overall response rate (ORR) assessed by modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (mIWG-MRT-ECNM) criteria reached 65%, including 57% of patients achieving complete remission (CR), complete remission with partial hematologic recovery (CRh), or partial remission (PR).
The key secondary endpoint, assessed using pure pathological response (PPR) criteria in all 81 treated patients, showed an 81% ORR.
Bezuclastinib also produced substantial reductions in objective disease markers. Eighty-nine percent of patients achieved at least a 50% reduction in serum tryptase levels and bone marrow mast cell burden, while 91% experienced at least a 50% reduction in KIT D816V variant allele frequency. Approximately one-third of treated patients achieved undetectable KIT D816V levels, supporting the drug’s potential to modify the underlying disease biology.
The therapy also reversed several pathological features of AdvSM, including normalization of mast cell morphology, improvement in bone marrow cellularity and fibrosis, and rapid reductions in aberrant CD25 and CD30 expression.
Safety profile supports long-term treatment
Clinical benefit remained durable, with a 12-month progression-free survival (PFS) rate of 79% and a 12-month overall survival (OS) rate of 87%. Median PFS and OS had not yet been reached at the time of analysis.
Bezuclastinib was generally well tolerated, with relatively few treatment-related dose reductions or discontinuations. The most common treatment-related adverse events included hair color change (31%), neutropenia (31%), altered taste (28%), thrombocytopenia (25%), and elevations in alanine and aspartate aminotransferase (21%). Most liver enzyme elevations were low grade, asymptomatic, and reversible.
Regulatory review advances first potential approval
President and Chief Executive Officer Andrew Robbins said the NDA submission reflects the strength of the APEX results, noting that the selective KIT inhibitor delivered meaningful clinical benefit without the tolerability challenges associated with currently available therapies. He added that the company is working closely with the FDA on multiple regulatory submissions and expects bezuclastinib to achieve its first approvals later this year.
Cogent has also established FDA-supported Expanded Access Programs in the United States for eligible patients with systemic mastocytosis or gastrointestinal stromal tumors (GIST) who may benefit from bezuclastinib alone or in combination with sunitinib while regulatory review continues.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.