3059-LB: Combination of MS 001 with GLP-1R Agonist Semaglutide Induces Further Weight Loss while Supporting Muscle Health in Mice

Introduction and Objective: MS 001 (ulodesine hemiglutarate), a purine nucleoside phosphorylase inhibitor, in combination with semaglutide (sema) addresses challenges presented by GLP-1R agonist and exhibits promising metabolic benefits in mouse model of DIO Methods: MS 001 at 1mg/kg, 3 days a week (days 1, 2 and 3) given orally, or sema at 10 nmole/kg Q3D given SC or sema and MS 001 (combo) were evaluated in DIO mouse model Results: While sema treatment led to expected decrease in body weight (BW) gain compared to control mice, the combo had a significant further decrease in BW (Fig 1A), with no reduction in food intake compared to sema. Importantly, there was significant increase in muscle weight in the combo compared to both vehicle and sema (Fig 1B) and a trend towards increase in exhaustion time in the treadmill test (Fig 1C). Furthermore, the combo demonstrated remarkable decrease in white adipose tissue (iWAT) (Fig 1D), along with reduction in cholesterol and triglycerides. RNAseq analysis of iWAT of combo vs sema demonstrated upregulation of thermogenesis through futile calcium cycling for the combo. MS-001 at 2 mg/kg, 3 days, orally increased thermogenesis in mice (P<0.0001). MS 001 elevated plasma inosine and NAD+ levels (p< 0.001), likely contributors to the metabolic benefits. Conclusion: MS 001 with GLP-1R agonist offers a novel therapeutic approach for enhancing weight loss, preserving muscle and improving metabolic health. Disclosure S. Bantia: None. T.J. Mehrling: None. A. Chow: None. Q. Zhang: None. V. Sorrentino: None.