Introduction: Preclinical data suggest myostatin and activin A are important negative regulators of muscle mass. Trevogrumab (a monoclonal antibody [mAb]) binds and blocks myostatin signalling, while garetosmab (a mAb) binds and blocks activin A, AB and AC signalling. Here, the effects of administering trevogrumab and garetosmab, alone or in combination, on body composition in healthy participants was assessed. Methods: This Phase 1, double-blind, placebo-controlled study randomized healthy males and postmenopausal females to single-dose or multiple-dose parts of the study. For single-dose, females received: trevogrumab 6 mg/kg (n=6); garetosmab 10 mg/kg (n=6); combination trevogrumab 6 mg/kg and garetosmab (1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=12); or placebo (PBO; n=12). For multiple‑dose, females received: garetosmab 10 mg/kg every 4 weeks (Q4W; n=6) or PBO (n=2); combination trevogrumab 6 mg/kg and garetosmab 10 mg/kg every 2 weeks (n=6) or PBO (n=4). In the multiple dose part, males received garetosmab 10 mg/kg Q4W (n=8) or PBO (n=8). Results: Thigh muscle volume (TMV) increased from baseline 7.7% with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (nominal P&amp;lt;0.001 vs PBO) and 4.6% with trevogrumab 6 mg/kg (nominal P&amp;lt;0.05 vs PBO) 8 weeks after single-dose. Total fat mass and android fat mass (AFM) decreased from baseline with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (-4.6% and -6.7%; both nominal P&amp;lt;0.05 vs PBO). After multiple-dose, TMV initially increased after 3 doses of trevogrumab 6 mg/kg + garetosmab 10 mg/kg but decreased to similar levels as PBO at Week 28; AFM and visceral fat mass decreased from baseline by 14.3% and 20.1%, respectively (both nominal P&amp;lt;0.05 vs PBO). No safety concerns were identified in any active treatment groups. Conclusion: Combined administration of trevogrumab and garetosmab led to dose-dependent, greater‑than‑additive increases in TMV and lean mass, while decreasing fat mass in healthy participants. Disclosure D. Gonzalez Trotter: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. S. Donahue: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. C. Wynne: Employee; NZCR. Stock/Shareholder; NZCR. S. Ali: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. P. Parasoglou: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. A. Boyapati: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. K. Mohammadi: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. B.J. Musser: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Merck Sharp &amp; Dohme Corp. P. Meier: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Mastaitis: Employee; Regeneron Pharmaceuticals Inc. E. Gasparino: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Trejos: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.D. Davis: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. G.A. Herman: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R. Pordy: Employee; Regeneron Pharmaceuticals Inc. Funding Regeneron Pharmaceuticals, Inc.

34-OR: The Effect of Combined Activin A and Myostatin Blockade on Body Composition—A Phase 1 Trial