1105-OR: In Vitro and In Vivo Characterization of CC-18, a Novel GLP-1R/ActRIIA/ActRIIB Dual Pathway-Targeting Fusion Protein That Reduces Weight while Increasing Muscle in Preclinical Models

Introduction and Objective: GLP-1 receptor agonists (GLP-1RAs) induce substantial weight loss but also often reduce lean mass. CC-18 is a novel GLP-1/anti-ActRIIA&B fusion protein designed to preserve muscle while maintaining GLP-1-mediated benefits. This study evaluated the dual-pathway engagement (GLP-1R activation and ActRII blockade) and metabolic effect of CC-18 in preclinical models. Methods: In vitro activity profile of CC-18 was characterized using cell-based assays evaluating GLP-1R and ActRII signaling. In vivo metabolic efficacy was evaluated in diet-induced obese (DIO) mice and monkeys treated with either CC-18 or comparator agents, with assessments of body weight, body composition, food intake, glycemic control, and post-treatment durability. Results: In in-vitro reporter cell system, CC-18 exhibited potent GLP-1 receptor agonism (Emax=101% of comparator agent semaglutide). Interestingly, ActRII blockade with bimagrumab impaired GLP-1R signaling, reducing Emax to 52%, an effect not observed with CC-18. CC-18 also showed high binding (Emax>90%) and potent inhibitory activity against both ActRIIA and ActRIIB. In DIO mice, single dose of CC-18 achieved >30% greater weight loss than semaglutide, with selective fat-mass reduction and lean-mass increase. Glycemic control and OGTT response were comparable to semaglutide, while semaglutide plus bimagrumab impaired OGTT response. CC-18 additionally reduced blood lipid levels. After treatment withdrawal, CC-18 attenuated weight regain, with 58% less weight than the semaglutide-treated group. Furthermore, CC-18 induced dose-dependent decrease in body weight, fat mass, food intake and glucose levels, while preserving lean mass. Similar results were observed in DIO monkeys. Conclusion: CC-18 conferrs robust and durable metabolic benefits via coordinated GLP-1R activation and ActRII blockade, supporting its further development as a promising dual-mechanism metabolic therapy. Disclosure J. Ni: None. X. Cai: None. X. Wang: None.