Introduction and Objective: Amylin is a hormone co-secreted from pancreatic beta cells with insulin. It activates amylin receptors to elicit food intake reduction via a satiety signal in the brain. Amylin agonists have shown promise for weight management and cause additive body weight with glucagon-like peptide 1 receptor (GLP-1R) agonists. Here this study evaluates IBI3040’s formulation characterization, pharmacological properties, weight loss efficacy, and potential synergy with a GLP-1 agonist (semaglutide) in diet-induced obese (DIO) rats. Methods: Cell lines expressing human or rat amylin or calcitonin (CTR) receptors were used to determine the potency of IBI3040 through measuring cAMP accumulation. High-fat diet fed rats (DIO) were used to evaluate body-weight-lowering effects of IBI3040.IBI3040 (2 nmol/kg) and semaglutide (2 nmol/kg) were tested alone and in combination, with weight loss effects compared to monotherapies in DIO rats. PK studies were conducted in rats to assess exposure and clearance profiles after subcutaneous administration. Solubility and stability of IBI3040 formulations were evaluated at physiological pH(7-8). Results: IBI3040 is a highly potent agonist of the amylin and calcitonin (CTR) receptors. IBI3040 at 2 and 10 nmol/kg Q3D over a 2-week study in DIO rats resulted in dose-dependent reductions in body weight gain compared to vehicle treated rats of 8.82%and 11.11 %, respectively. In a further study, IBI3040 and semaglutide led to deeper and more sustained weight loss (-14.7%) compared to IBI3040 (-10.12%) or semaglutide (-3.01%) alone, suggesting an additional effect.IBI3040 displayed favorable PK profile to cagrilintide.IBI3040 exhibits high solubility and maintains stability without fibril formation at physiological pH(7-8). Conclusion: IBI3040 demonstrates superior receptor activation, robust weight loss effects, and synergistic potential with semaglutide, supporting its development as a next-generation amylin analog for obesity treatment. Disclosure W. Wu: Employee; Current; Innovent Biologics, Inc. Z. Kuang: Employee; Current; Innovent Biologics, Inc. Y. Wang: Employee; Current; Innovent Biologics, Inc. Y. Feng: None. D. Ren: None. Y. Niu: Employee; Current; Innovent Biologics, Inc.
WU et al. (Fri,) studied this question.