2871-LB: Menin Inhibitor Icovamenib Activates Mechanisms That Support Metabolic Health

Introduction and Objective: Icovamenib is an investigational, menin-targeted, oral drug candidate in clinical development for the treatment of diabetes. In T2D patients failing standard of care, a 12-week course of icovamenib resulted in durable HbA1c reduction and C-peptide increase through 52 weeks. As a scaffolding protein that can modulate transcription, menin negatively regulates beta cell mass, GLP-1R expression and myogenesis. In ZDF rats, icovamenib enhanced the efficacy of semaglutide, with improved weight reduction driven by fat loss and preservation of lean mass. Here we report studies in vitro to probe the MOA. Methods: GLP-1 and menin expression were assessed in the human colonic NCI-H716 cells following icovamenib treatment. Effects on lipolysis and fat browning were assessed in human preadipocyte-derived adipocytes by measuring glycerol release, cell morphology and gene expression. Effects of icovamenib on ex vivo human myoblast cultures were assessed by imaging. Results: Icovamenib increased GLP-1 expression and reduced menin levels in the enterocyte cells. In skeletal myoblasts, icovamenib induced dose-dependent increase in myotube width and length, upregulated myosin heavy chain, increased cell fusion and reduced activin-induced atrophy. Icovamenib promoted adipocyte browning and lipolysis evidenced by reduction in lipid droplet size, increased glycerol release and upregulation of AGTL, UCP1 and PGC1, key molecular regulators in triglyceride hydrolysis and energy metabolism. Conclusion: Icovamenib-induced GLP-1 expression, myogenesis and protection from atrophy, align with menin’s negative regulation of these events. Results additionally reveal icovamenib’s potential to promote adipose tissue metabolism. Overall findings help provide mechanistic insights on the icovamenib-induced enhancements in glycemic control, fat reduction and lean mass preservation during combination treatment with low dose semaglutide in ZDF rats, and support icovamenib’s potential for treating obesity in addition to diabetes.