2582-P: A Novel Class of Unimolecular Tetra-Receptor Agonists Decreases Food Intake and Improves Glucose Tolerance in Dietary Obese Mice

Introduction and Objective: Drugs targeting the glucagon-like peptide-1 receptor (GLP-1R), particularly dual or triple agonist chimeras that co-activate the glucose-dependent insulinotropic polypeptide receptor (GIPR) and/or the glucagon receptor (GcgR), are currently the most effective treatments for obesity and Type 2 Diabetes. However, common adverse side effects of such compounds, including nausea, often results in early treatment dropout. Peptide YY (PYY) can further reduce food intake and weight loss via Y2 receptor (Y2R) agonism, and co-treatment with GIP can mitigate PYY-induced nausea. Thus, unimolecular tetra-receptor agonists (TRA) chimeras that co-induce Y2R with GLP1-R/GIPR/GcgR agonism may have superior therapeutic efficacy with better tolerability to treat obesity and diabetes. Methods: We investigated the acute impact of three novel differentially balanced TRAs on glucose metabolism and food intake. Following a single subcutaneous injection of each TRA (1-30 nmol/kg), we measured glucose tolerance and food intake in chow and high fat diet (HFD)-fed young (6-months) and old (24-29-months) female and male C57BL/6 mice. Results: Each TRA dose dependently improved glucose tolerance in young and old female and male mice versus vehicle controls, with comparable efficacies as tirzepatide (established GLP-1R/GIPR dual agonist, 30 nmol/kg) as a positive control. TRAs decreased 24-hour food intake in young HFD-fed female and male mice by up to 50% versus vehicle controls to levels similar to tirzepatide. Of note, in both sexes of young chow-fed mice, the TRAs decreased food intake to a slightly greater extent than observed after injection of tirzepatide. Conclusion: These data indicate that TRAs have beneficial acute metabolic effects that are comparable to those induced by tirzepatide and rely on co-activation of four (vs. two) different receptors. Future studies will reveal whether TRAs have superior long-term efficacy with reduced adverse effects than existing drugs for treating obesity and diabetes. Disclosure T.C. Dinsmore: None. K. Wellenstein: None. M. Beinborn: None. K. Kumar: None. J. Lee: None.