2059-LB: NA-931, a Novel Triple IGF-1/GLP-1/GIP Incretin Receptor Agonist Reduces Body Weight and Improves Metabolic Profile in DIO Mice

Background: Insulin-like Growth Factor 1 (IGF-1) plays a major part in fuel metabolism and regulation of body composition. GIP and GLP-1 have been shown to be effective for weight loss in non-diabetic patients with obesity when given as adjunctive therapy to diet and exercise. IGF-1 contributes to modulate glucagon secretion in which IGF-1 inhibits the ability of low glucose concentration to stimulate glucagon expression and secretion. NA-931 and its analogs, NA-932 and NA-933 (“NA-931 Compounds”) are metabolites of IGF-1. Acting as a receptor agonists targeting IGF-1, GLP-1 and GIP, NA-931 Compounds may provide enhanced therapeutic benefits. Methods: Male diet-induced obese (DIO) mice were treated with daily subcutaneous injections of vehicle or one of novel triple IGF-1/GLP-1/GIP receptor agonists, NA-931, NA-932 and NA-933 (10 nmol/kg), for 14 days. Tirzepatide (10 nmol/ kg) as used as positive controls. Cohorts were then assessed for changes in BW, glucose, and lipids. Results: Treatment with NA-931 Compounds resulted in reductions to BW (up to 26%, p<0.0001), plasma glucose, plasma triglycerides, (up to 23% and 34%, respectively, p<0.003 for each), and liver triglycerides (up to 46%, p<0.05) compared to vehicle treatment. Weight loss effects in cohorts treated with NA-931 Compounds were comparable to those observed in tirzepatide-treated animals. In addition, liver lipid reductions were numerically greater among animals treated with the NA-931Compounds. Conclusions: NA-931 and its analogs produced significant reductions in BW in DIO mice. Effect sizes were comparable to those observed in the tirzepatide control group. The NA-931 Compounds have been shown to produce desirable changes to lipid profile, suggesting global cardiometabolic benefit, represent a promising therapeutic approach to metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic steatohepatitis. Additional research on these drug candidates is ongoing.