3073-LB: HM500197, a De Novo–Designed Long-Acting Peptide Myostatin Inhibitor, Improves Skeletal Muscle Mass and Body Composition in Diet-Induced Obese Mice

Introduction and Objective: Incretin therapies effectively reduce body weight and improve metabolic parameters but are frequently accompanied by lean mass loss, underscoring inhibition of the myostatin (MSTN)/activin pathway—exemplified by bimagrumab (Bima)—as a rational therapeutic strategy. However, the antibody-based modality and multi-ligand inhibitory profile of existing agents may limit suitability for combination with incretin therapies. Here, we report a development of HM500197, a long-acting MSTN selective peptide generated through de novo design, and evaluate its ability to preserve skeletal muscle during incretin-induced weight loss in DIO mice. Methods: In vitro inhibitory activity against MSTN, activins, and BMPs was evaluated in A204 cells. DIO mice were treated for 4 weeks to compare the efficacy of HM500197 with Bima and assess its effects in combination with incretin therapies. Body weight and composition were measured, and skeletal muscle mass was quantitatively assessed. Results: HM500197 demonstrated MSTN inhibitory activity comparable to Bima (105.3%) while showing markedly reduced activity against Activin A (0.01%), Activin B (0.01%), and BMP9 (0.02%). In DIO mice, HM500197 dose-dependently increased lean mass by up to 6.7% from baseline (vs. 11.0% with Bima) and reduced fat mass by up to 17.0% (vs. 21.0% with Bima). Although the lean mass gain was lower than that achieved with Bima, HM500197 increased skeletal muscle mass comparable to Bima without increases in liver or heart weight, supporting its skeletal muscle-selective activity. Furthermore, in combination with incretin therapies, HM500197 effectively preserved muscle mass over a 4-week treatment period. Conclusion: HM500197 significantly increased skeletal muscle mass relative to Bima and prevented muscle loss during caloric restriction-induced weight reduction, supporting its potential to improve weight loss quality and serve as an optimal combination partner for incretin therapies. Disclosure J. Choi: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: None. J. Kim: None. W. Jang: None. J. Lee: None. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. S. Bae: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. I. Choi: None.