2053-LB: Taldefgrobep Alfa Improves Body Composition as Monotherapy and in Combination with Semaglutide in a DIO Mouse Model

Introduction & Objective: Incretin-based obesity treatments (GLP-1R) demonstrate significant weight reduction and metabolic benefits; however, along with tolerability issues, patients exhibit a significant loss of lean muscle. Inhibition of myostatin and activin A signaling induces significant fat loss and increase in lean mass, an ideal combination with GLP-1R therapy. Taldefgrobep alfa is a novel myostatin inhibitor that has demonstrated clinical improvements in lean mass and loss of fat. This high-fat diet (HFD) induced obese mouse study is designed to evaluate the ability of taldefgrobep to impact body composition as monotherapy and in combination with semaglutide.

Methods: Six-week-old C57BL/6J male mice received a HFD for 13 weeks prior to their subcutaneous treatment assignment: vehicle BIW, taldefgrobep 100 mg/kg BIW, semaglutide 20 µg/kg QD, semaglutide 40 µg/kg QD, taldefgrobep 100 mg/kg BIW with semaglutide 20 µg/kg QD or 40 µg/kg QD for 8 weeks. All animals were followed for 4 weeks post-dosing. Body composition (EchoMRI) and metabolic markers were assessed at baseline, posttreatment and study end. Histopathology of adipose, muscle, and liver was also performed.

Results: Within 4 weeks of treatment, all taldefgrobep treatment groups, including monotherapy and combination with semaglutide, demonstrated significant reductions in fat mass and increased lean mass, relative to vehicle or semaglutide alone. The following body composition changes (% fat mass, % lean mass) were observed at 4 weeks: taldefgrobep (-25.8%, +14.9%), vehicle (+6.9%, +6.7%), semaglutide 40 (-11.5%, +0.2%), taldefgrobep/semaglutide 40 (-31.8%, +12.3%). In addition, taldefgrobep-treated mice achieved a significant reduction in TBW relative to vehicle (-6.7%).

Conclusion: This study supports the development of taldefgrobep as a monotherapy or combination with GLP-1R agonists to reduce fat and maintain lean mass in individuals living with overweight and obesity.