Introduction and Objective: Myostatin (GDF8), a member of the transforming growth factor-β (TGF-β) superfamily, is a key negative regulator of skeletal muscle mass. Preservation of lean body mass (LBM) during pharmacologically induced weight loss remains an unmet need. BGM2618 is a potent and selective macrocyclic peptide inhibitor of myostatin. This study characterized its pharmacological profile and evaluated its ability to preserve LBM in diet-induced obese (DIO) mice undergoing GLP-1/GIP dual agonist-induced weight loss. Methods: Inhibitory potency against mature GDF8 was assessed using a cell-based reporter gene assay. In vivo efficacy was evaluated in DIO mice treated for 4 weeks with BGM0504 (0.15 mg/kg), a GLP-1/GIP dial agonist alone or in combination with BGM2618 (1 mg/kg), with comparison to the reference myostatin inhibitor 99m. Body weight and body composition were monitored, and changes from baseline in total body weight and lean mass were analyzed at end of study. Pharmacokinetics were assessed in rats following a single subcutaneous dose of BGM2618 (1 mg/kg). Results: BGM2618 potently inhibited mature GDF8 in vitro (IC50 0.87 nM), comparable to 99m (IC50 0.63 nM), and demonstrated selectivity over GDF11 with no binding to activin. In DIO mice, combination treatment with BGM2618 and BGM0504 produced body-weight reduction comparable to BGM0504 monotherapy. Importantly, BGM2618 significantly preserved lean body mass during weight loss and showed greater efficacy than 99m. In rats, BGM2618 exhibited favorable pharmacokinetics, with an extended terminal half-life (23.9 h) compared with 99m (11.7 h) and comparable exposure. Conclusion: BGM2618 is a potent and selective myostatin inhibitor that preserves lean body mass during GLP-1/GIP agonist-induced weight loss in obese mice, supporting its potential as an adjunct strategy to improve body composition during pharmacological weight management. Disclosure J. Yuan: Employee; Current; BrightGene BioMedical. Y. Huang: Employee; Current; BrightGene BioMedical. H. Ding: Employee; Current; BrightGene BioMedical. X. Jiang: Consultant; Current; BrightGene BioMedical.
Yuan et al. (Fri,) studied this question.