1101-OR: A Novel Anti-Myostatin GLP-1RA Fusion Molecule to Preserve Muscle and Improve Body Composition during GLP-1 Therapy

Introduction and Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the treatment of obesity by driving substantial weight loss. However, 26 - 45% of the weight lost is attributable to lean mass, which may undermine long-term health benefits and hinder maintenance of a healthy body weight. Therefore, next generation weight-loss therapies that preserve lean mass are needed. Myostatin isa growth factor that acts as a negative regulator of muscle mass. Selective targeting of latent myostatin has the potential to address this unmet need. We have developed a unimolecular approach combining a novel GLP-1 RA peptide fused to a highly selective myostatin antibody. These molecules are engineered to deliver sustained GLP-1 peptide activity in vivo while maintaining selective myostatin inhibition to preserve lean mass during GLP-1RA therapy. Methods: A GLP-1R reporter cell line and a myostatin ELISA were used to screen fusion molecules. In vivo stability was assessed in a single dose PK/PD study in healthy mice. Diet-induced obesity (DIO) mice were treated with semaglutide, a combination of semaglutide and anti-myostatin, or fusion molecules for three weeks. Body weight and composition were assessed. Results: Fusion molecules activated GLP-1R (EC50; semaglutide 0.08nM, fusion 41L 0.06nM, fusion 41H 0.1nM) and inhibited myostatin activation (IC50; MSTN 0.10nM, fusion 41L 0.05nM, fusion 41H 3.08nM) in vitro. In a single dose study PK/PD in healthy mice, fusion molecules showed sustained GLP-1 peptide activity for up to 7 days compared to 1 day with semaglutide. In DIO mice, fusion molecules reduced body weight (12-13%) comparably to the semaglutide + anti-myostatin combination (15% reduction), and importantly, preserved lean mass (-0.6 to +1.5%) compared to treatment with semaglutide (-7%). Conclusion: These data demonstrate that genetic fusion of anti-myostatin antibody with a GLP-1RA represents a differentiated unimolecular strategy to achieve weight loss while preserving lean mass. Disclosure M. Alsuraih: None. J. Jackson: None. N. Phan: None. C. Chapron: None. M. Martin: None. N. Magrassi: None. F.C. Streich Jr: Employee; Current; Scholar Rock. Consultant; Current; Upstream Bio. L. Cortes: Employee; Current; Scholar Rock. Stock/Shareholder; Current; Scholar Rock. M. Qatanani: Employee; Current; Scholar Rock.