1993-LB: BGM1812, a Novel Amylin Analog, Enhances Receptor Agonism and Induces Superior Weight Loss in Preclinical Models

Introduction and Objective: Amylin receptor agonists (e.g. petrelintide and cagrilintide) have shown promise for weight management. BGM1812 is a novel amylin analog designed using AI/ML-driven optimization to enhance agonist activities and formulation properties. This study evaluates BGM1812’s pharmacological properties, weight loss efficacy, and potential synergy with a GLP-1/GIP dual agonist (BGM0504) in diet-induced obese (DIO) rats. Methods: Receptor activation: cAMP assays measured EC50 for amylin and calcitonin receptor activation. Pharmacokinetics: PK studies were conducted in rats to assess exposure and clearance profiles after subcutaneous administration. Weight loss efficacy: DIO rats received subcutaneous BGM1812 (0.012-0.12 mg/kg, Q3D) for 28 days, with weight monitored. Combination therapy: BGM1812 (0.4 mg/kg) and BGM0504 (0.15 mg/kg) were tested alone and in combination, with weight loss effects compared to monotherapies in DIO rats. Formulation study: Solubility and stability of BGM1812 formulations were evaluated at physiological pH (6.5-7.5). Results: Stronger receptor activation: BGM1812 showed 1.8x and 2.2x increased agonist activity (EC50) at the amylin and calcitonin receptors, respectively, versus petrelintide. Enhanced weight loss: BGM1812 demonstrated dose-dependent weight loss in 0.012 - 0.12 mg/kg dose range. At 0.04 mg/kg, BGM1812 induced greater weight reduction than petrelintide. Combination therapy: BGM1812 + BGM0504 led to deeper and more sustained weight loss (-28%) compared to BGM0504 (-15%) or BGM1812 (-13%) alone, suggesting a synergistic effect. PK properties: BGM1812 displayed similar PK profile to petrelintide. Formulation properties: BGM1812 exhibits high solubility and maintains stability without fibril formation. Conclusion: BGM1812 demonstrates superior receptor activation, robust weight loss effects, and synergistic potential with GLP-1/GIP dual agonism, supporting its development as a next-generation amylin analog for obesity treatment. Disclosure J. Yuan: Employee; BrightGene Bio-Medical Technology Co., Ltd. Y. Huang: Employee; BrightGene Bio-Medical Technology Co., Ltd. H. Ding: Employee; BrightGene Bio-Medical Technology Co., Ltd. X. Jiang: Consultant; BrightGene Bio-Medical Technology Co., Ltd.