2589-P: Combination LUM-201 and Semaglutide Enhances Weight Loss and Preserves Lean Mass in Diet-Induced Obesity: Translational Rationale for a Phase 2 Study in Adults with Obesity

Introduction and Objective: GLP-1 receptor agonists produce weight and fat-mass reduction in obesity, but concurrent loss of lean mass may diminish metabolic and functional outcomes. Obesity reduces endogenous growth hormone (GH), which may limit lean-mass preservation during weight loss. LUM-201 (ibutamoren), an investigational oral GH secretagogue, increases lean mass without increasing fat mass in humans (Nass 2008). We hypothesized combining LUM-201 and semaglutide would enhance weight loss and preserve lean mass in diet-induced obesity (DIO) mouse model. Methods: Male DIO mice (>18 weeks on high-fat diet) were stratified by body composition & metabolic markers & randomized to: vehicle, LUM-201 (25mg/kg/d via osmotic pump), semaglutide (10 nmol/kg), or LUM-201 + semaglutide (n=10/group). Outcomes included body weight, lean & fat mass (echo MRI), lean:fat ratio, food intake, fasting glucose, fasting insulin, & oral glucose tolerance. Results: Combination therapy produced superior outcomes compared to semaglutide alone, resulting in greater overall weight loss, augmented fat-mass reduction, and preservation of lean mass, leading to improvements in lean:fat ratio (all p<0.015). Lean mass preservation for LUM-201 was compared to semaglutide alone vs combination therapy via EchoMRI measurement. By D14, changes were observed in lean mass (increase in combo; p=0.013), in fat mass (decrease in combo; p=0.019), and lean:fat mass ratio (increase in combo; p=0.017). Unlike semaglutide monotherapy, the combination didn't significantly reduce food intake, suggesting mechanisms beyond appetite suppression. Also, lower fasting glucose and enhanced glucose tolerance were observed in combination group. Conclusion: LUM-201 and semaglutide combination enhances weight loss, preserves lean mass, and improves metabolic function in DIO mice. These effects will be evaluated in a Phase 2 trial in obesity focusing on weight loss, muscle preservation, motor function and quality of life. Disclosure P. Pitukcheewanont: Employee; Current; Lumos Pharma LLC. A.P. Cagle: Employee; Current; Lumos Pharma. E.L. Brincks: Employee; Current; Lumos Pharma, LLC. J.C. McKew: Employee; Current; Lumos Pharma LLC. M.C. Murphy: None. M.O. Thorner: Consultant; Current; Lumos Pharma LLC. Other - Founder and Board Member; Current; Ammonett Pharma.