On May 1, 2023 Biomea Fusion, Inc. ("Biomea" or "the company") (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application to begin a Phase I trial (COVALENT-103) of BMF-500, an investigational covalent FLT3 inhibitor, in adult patients with relapsed or refractory acute leukemia (Press release, Biomea Fusion, MAY 1, 2023, View Source [SID1234630753]).

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FLT3 is a receptor tyrosine kinase (RTK) that plays a central role in the survival, proliferation, and differentiation of immature blood cells. FLT3 gene mutations are common in patients with AML and are associated with a poor prognosis. Nearly 30% of AML patients have a FLT3 mutation, representing more than 6,000 incident patients in the U.S. each year. In addition, academic literature suggests that >50% of AML patients with an NMP1 mutation also harbor a FLT3 mutation. While FLT3-specific and pan-tyrosine kinase inhibitors are approved by the FDA across various lines of therapy in AML, these agents have produced relatively low rates of durable responses and overall survival remains an unmet need.

BMF-500, an investigational, novel, orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3, was discovered and developed in-house at Biomea using the company’s proprietary FUSION System and has demonstrated best-of-class potential based on extensive preclinical studies. The kinase profile of BMF-500 showed high target selectivity, suggesting the potential for minimal off-target liabilities. BMF-500 was designed to have a therapeutic profile to allow for combinations with standard of care and/or novel targeted agents like BMF-219, Biomea’s investigational covalent menin inhibitor currently in clinical development across solid and liquid tumor types.

"BMF-500 is an exceptionally potent molecule and the second covalent inhibitor we have developed in-house and advanced to the clinic showing high target selectivity and inhibition. We are planning single agent studies of BMF-500 as well as combination studies with BMF-219 to explore the potential of this powerful dual-mechanistic approach to amplify and sustain patient treatment responses," said Thomas Butler, Biomea’s CEO and Chairman of the Board. "I would like to thank the FDA, our contract research organizations partners, our consultants, our investors, and of course TEAM FUSION for the commitment, guidance, support, and tireless effort in getting BMF-500 from bench to the clinic. It has been a true community effort, and we are humbled by the opportunity to potentially help patients fight and win against these aggressive cancers."

Previous data presented at the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting showed BMF-500’s picomolar affinity to activating FLT3 mutations, including FLT3-ITD and various tyrosine kinase domain (TKD) mutations. BMF-500 demonstrated multi-fold higher potency and increased cytotoxicity than commercially available non-covalent FLT3 inhibitor gilteritinib. These data also showed complete tumor regression in mouse models of FLT3-ITD AML and maintenance of effect without continued exposure.

Data presented at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting exhibited the potential utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of BMF-500 and BMF-219. Additionally, Biomea has shown the potential of combinatorial approaches of BMF-500 and BMF-219 with MEK and BCL2 blockade in other preclinical studies. These data provide preclinical evidence for combining pathway-specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia.