Introduction and Objective: Apelin, an exerkine peptide hormone, acts via Apelin receptor (APJ) to impact muscle metabolism, energy expenditure, and systemic benefits. We previously showed that PSTC1201, a non-biased APJ agonist, synergizes with GLP-1R agonists to enhance weight loss and improve body composition, validating APJ as a promising anti-obesity target. Here, we report the profile of PSTC1411, a novel APJ agonist characterized by biased signaling toward the cAMP/G-protein pathway, with in vivo efficacy as monotherapy and in combination with GLP-1RAs Methods: In vitro cAMP and β-arrestin assays were used to evaluate the activity towards different APJ downstream signaling. In vivo efficacy was performed using high fat diet-induced obesity (DIO) mice. Results: In vitro characterization identified that PSTC1411 was biased for G-protein signaling but with less potency for β-arrestin signaling. In DIO mice, repeated oral dosing of single agent PSTC1411 elicited a significant dose-dependent weight loss, with highest 22% reduction. Co-administration of PSTC1411 with semaglutide led to greater weight loss (-33%) versus semaglutide alone (-19%). Further weight loss was also observed when PSTC1411 was used as an add-on treatment with plateaued orforglipron (add-on group -29% vs. orforglipron -18%). PSTC1411 achieved weight loss with higher muscle preservation than GLP-1RAs, increased the muscle fiber area, and improved the muscle function. Furthermore, PSTC1411 resulted in significant negative energy balance including reduced food intake, increased activity and energy expenditure. Finally, PSTC1411 showed favorable pharmacokinetic properties and a wide safety margin through non-GLP toxicity study. Conclusion: We have identified that a G-protein-biased APJ agonist that promotes muscle-sparing weight loss via a non-incretin mechanism by reducing appetite and altering metabolic processes, supporting further clinical development of PSTC1411 as a novel treatment for obesity. Disclosure Z. Wang: None. W. Li: None. T. Yu: None. L. Hu: None. Z. Zhu: None. Y. Liu: None. Z. Wang: None. D. Ni: None. J. Li: None. C. Chan: None. S. Chen: None.
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