Icovamenib Rescues Human Myotube Atrophy Ex Vivo and Displays Complete Lean Mass Preservation in a Type 2 Diabetes Rat Model

Introduction and Objective: GLP-1-based therapies have reported lean mass reductions of up to 40 to 60% of total weight loss in the clinic. Menin, a key regulator of beta cell mass, also modulates signaling pathways critical for muscle health. Menin-depleted mice display increased intercostal muscle mass and enhanced myogenesis. Icovamenib, an oral covalent menin inhibitor, enhanced response to GLP-1 therapies and beta cell proliferation in human islets and in a T2D rat model. The direct impact of icovamenib on myotube recovery and lean mass preservation was investigated. Methods: Ex-vivo derived 3D-engineered healthy human myotubes were cultured with icovamenib or garetosmab for 16 days, beginning one day prior to atrophy induction with Activin A or dexamethasone (dex), and myotube morphology was assessed. Additionally, Zucker diabetic fatty (ZDF) rats treated with icovamenib or vehicle for 14 days followed by 14 days with low dose semaglutide (sem) were examined for body composition parameters. Results: Icovamenib treatment resulted in a dose-dependent increase in healthy myotube length and width. Icovamenib protected against Activin A-induced myotube atrophy, displaying a pronounced increase in myotube width, outperforming the Activin A antagonist, garetosmab. Dex decreased myotube width, which was rescued by icovamenib. In the ZDF rat, icovamenib in combination with sem enhanced body weight reduction through selectively promoting fat loss vs. sem alone. Notably, combination-treated rats displayed a +12% change from baseline in the lean mass fraction (p=0.01), surpassing sem alone. Conclusion: Icovamenib enhanced healthy myotube morphology and promoted recovery from drug-induced atrophy ex vivo. In ZDF rats, combination of icovamenib and low dose sem induced greater body weight reduction with protected lean mass. Collectively, these results support combination of icovamenib with GLP-1RA based therapies as a promising strategy to enhance body weight reduction with preservation of muscle homeostasis. Disclosure: P. Somanath: Employee; Biomea Fusion. M. Balakrishnan: None. T. Kirschberg: None. J.P. Frias: Employee; Biomea Fusion. Stock/Shareholder; Biomea Fusion. Board Member; T1D Exchange. Consultant; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk, Sanofi. Research Support; Sanofi. Consultant; Sanofi. Speaker's Bureau; Sanofi. Research Support; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc, Altimmune Inc. Research Support; Altimmune Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc. Consultant; Pfizer Inc. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Speaker's Bureau; Merck & Co., Inc. Consultant; Akero Therapeutics, Inc. Research Support; Akero Therapeutics, Inc, 89bio, Inc. Consultant; 89bio, Inc. T. Butler: Employee; Biomea Fusion.