1688-P: Novel Oral Apelin Receptor Agonist PSTC1201 for Selective Weight Loss with Muscle Preservation When Combined with Semaglutide in DIO Mice Model

Introduction and Objective: GLP-1R agonists are approved for treating obesity and diabetes, offering benefits like weight loss and blood glucose control. However, they can also cause muscle reduction, impairing physical function, especially in older patients. Preserving lean mass during GLP-1R agonist therapy is an unmet need. Apelin, an endogenous peptide binding to the APJ receptor, regulates energy and muscle metabolism. A Ph1b trial with an oral APJ agonist, azelaprag, showed muscle preservation in elderly subjects. We describe a novel APJ agonist, PSTC1201, which improves body composition and muscle function in obese mice combined with GLP-1R agonist therapy. Methods: High fat diet-induced obesity (DIO) mice were treated for 21 days with semaglutide (10 nmol/kg, Q3D); semaglutide at the same dose with PSTC1201(1.1 g/L in drinking water) or azelapray (1.1 g/L in drinking water for both agents). Body weight, body composition (via EchoMRI), and muscle function test (wire hang), plasma glucose and lipid profile were measured. Results: Mouse body weight was reduced by 11%, 31% and 37% in the groups treated with semaglutide, semaglutide plus azelaprag and semaglutide plus PSTC1201 respectively. Corresponding changes in lean body mass were 47%, 57% and 57%, showing improved body composition. In the wire hang test, PSTC1201 treatment almost restored muscle function to that of lean controls: lean control (latency, 191 sec); DIO+semaglutide, 27 sec; DIO/semaglutide+PSTC1201, 141 sec; DIO/semaglutide+azelaprag, 81 sec. Fasting blood glucose and plasma lipid profiles were also improved. Conclusion: Oral APJ agonists in combination with GLP-1R agonist further reduce weight loss while improve body mass composition and muscle function vs GLP-1R agonist monotherapy. PSTC1201 shows a favorable profile for further development for combination therapy in obesity and diabetes. Disclosure Z. Wang: None. W. Li: None. L. Hu: None. Z. Zhu: None. N. Liu: None. S. Yao: None. H. Qi: None. C. Chan: None. Y. Li: None. S. Chen: None.