On May 19, 2022 Biomea Fusion, Inc. (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 the nomination of its second product candidate, BMF-500, a highly selective and potent covalent investigational third-generation FLT3 inhibitor (Press release, Biomea Fusion, MAY 19, 2022, View Source [SID1234614853]).
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Approximately 30% of AML patients present with a FLT3 mutation and remain poorly controlled with currently available therapies. First and second-generation FLT3 inhibitors frequently have a narrow therapeutic window and patients often acquire rapid resistance to treatment, limiting the clinical efficacy of these agents. As a third-generation FLT3 inhibitor, BMF-500 is designed to overcome some of the characteristics that are believed to limit the duration of response and utility of these earlier generation FLT3 inhibitors.
BMF-500 was discovered and developed in-house at Biomea using the company’s proprietary FUSION System. BMF-500, like BMF-219, was designed to be clinically effective at relatively low drug concentrations in order to deliver an optimal therapeutic profile. Specifically, BMF-500 was observed in preclinical studies to be a highly active inhibitor of FLT3 with picomolar affinity for key isoforms of FLT3 while avoiding other key kinases tested, including structurally related KIT.
Because patients often acquire rapid resistance to treatment with first and second-generation FLT3 inhibitors, BMF-500 is designed to strongly inhibit FLT3 variants that are key drivers of resistance. Additionally, BMF-500 is designed to potentially have a therapeutic profile that may allow for combination with standard of care and/or targeted agents like BMF-219. Many patients with AML are older and unfit candidates for intensive chemotherapy but could benefit from BMF-500 and BMF-219 either as monotherapy or in combination.
AML is often described as the result of two broad complementary classes of mutations: Type I – those that confer a proliferative/survival advantage to hematopoietic progenitors including activating FLT3 mutations or their downstream effectors such as RAS, and Type II – those that impair hematopoietic differentiation and drive cell cycle progression, including NPM1, MLL-r, RUNX1, and DNMT3A mutations. With BMF-500 and BMF-219, Biomea plans to interrogate multiple molecular mechanisms that drive AML in the pursuit of establishing long-term disease management or a potential cure for these patients.
"FLT3 has been a challenge for companies to effectively target with either non-covalent or covalent approaches due to the homology of various kinases and other receptors, leading to off-target toxicities at potentially clinically relevant drug concentrations. Leveraging our FUSION System, we have quickly developed BMF-500, which we believe is among the most promising investigational FLT3 inhibitors to date," said Thomas Butler, Biomea’s Chief Executive Officer and Chairman of the Board. "With picomolar activity against key isoforms of FLT3, high specificity to FLT3 observed in preclinical studies, and the potential benefits of covalent engagement, we believe that BMF-500 is poised to become a leading targeted therapy for AML patients with FLT3 mutations, if approved. We look forward to leveraging the existing clinical infrastructure and know-how that we have developed through the planning and execution of our ongoing trial with BMF-219, COVALENT-101, and plan to explore the potential synergy between BMF-500 and BMF-219."
About FLT3 (fms-like tyrosine kinase 3)
FLT3 is a tyrosine kinase receptor that plays a central role in the survival, proliferation, and differentiation of immature blood cells. Notably, 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 United States each year. While FLT3-specific and pan-tyrosine kinase inhibitors are FDA approved across various lines of therapy in AML, these agents have produced relatively low rates of durable responses and overall survival remains an unmet need.