Combination Therapy of Icovamenib and Semaglutide Enhances Body Weight Loss and Glycemic Control While Increasing Lean Mass in a Type 2 Diabetes Animal Model

Introduction and Objective: Icovamenib (BMF-219) is an oral, covalent menin inhibitor in clinical development for the treatment of T1D and T2D. Menin is a key negative regulator of beta cell mass and GLP-1 receptor expression. Icovamenib induced durable glycemic control and controlled beta cell proliferation in animal and human islet models. Icovamenib enhanced responsiveness of human islets to GLP-1 receptor agonists while increasing GLP-1 receptor expression and insulin content. Here we assessed the effects of icovamenib in combination with semaglutide in diabetic rats. Methods: Zucker diabetic fatty (ZDF) rats were treated with icovamenib (200mg/kg, QD) or vehicle for 14 days followed by 14 days with low dose semaglutide (0.02mg/kg, QD). The effects of combination therapy vs. single agent semaglutide on glycemic parameters, body weight and body composition were measured. Results: Combination treated ZDF rats displayed significant reductions in fasting and fed blood glucose (BG) levels as early as one week, with 60% reduction in fasting BG at two weeks vs. semaglutide alone. Combination therapy for two weeks substantially improved OGTT (50% AUC reduction ) and HbA1c (1.4% reduction) vs. semaglutide. Insulin resistance (HOMA-IR) declined 75% in the combination therapy arm vs. semaglutide. HOMA-B and c-peptide index were notably improved after one week of combination therapy, indicating enhanced beta cell function. Importantly, combination therapy reduced body weight, exclusively by fat loss. The lean mass fraction was significantly increased (>10%) in the combination arm. Conclusion: Icovamenib enhanced the effects of semaglutide in ZDF rats, demonstrating improved glycemic control, weight loss and lean mass. Assessment of this novel combination in persons with T2D and obesity is warranted, as it may provide greater glycemic and weight loss efficacy while potentially improving the overall side effect profile. Disclosure: P. Somanath: Employee; Biomea Fusion. T. Butler: Employee; Biomea Fusion. 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. M. Balakrishnan: None.