Taldefgrobep Alfa Reduces Fat and Increases Muscle in an Obese Mouse Model

• Published in: Obesity (Silver Spring, Md.) Md.), 2023-11, Vol.31, p.136-136
• Main Authors: Ackerman, Peter, Aman, Ansarullah, Luo, Shouqi, Sharpe, Neal, Granit, Volkan, Lu, Jonathan, Bechtold, Cliff
• Format: Article
• Language: English
• Subjects: Body composition; Body fat; Metabolism; Obesity
• ISSN: 1930-7381; 1930-739X

Background: Obesity-related morbidity and mortality is driven by the presence of excess abnormal adipose tissue. Approved anti-obesity medications not only lead to meaningful reductions in body fat but also undesirable loss of lean muscle mass with unknown long-term consequences. Drugs that inhibit myostatin and activin-A signaling have demonstrated the ability to reduce fat while increasing lean mass and improving metabolic parameters. Taldefgrobep alfa is a novel myostatin inhibitor currently in clinical development with the potential to antagonize both myostatin and activin A signaling. This ongoing study evaluates taldefgrobep's ability to improve body composition in a high-fat diet-(HFD) induced obese mouse model. Methods: 8-week-old C57BL/6 male mice (12/arm) were assigned into four groups based on diet (standard [STD] or HFD) and timing of intervention (0 [HFD0], 4 [HFD4], or 8 [HFD8] weeks into HFD). Taldefgrobep (100 mg/kg) or vehicle was administered subcutaneously twice weekly for 8 (HFD4, HFD8) or 12 (STD, HFD0) weeks. HFD4 included taldefgrobep 25 mg/kg and 100 mg/kg. Body composition (EchoMRI) and metabolic markers were assessed at baseline and post-treatment. Histopathology of adipose, muscle, and liver was also performed. Results: After 8 weeks of treatment, all taldefgrobep dose groups demonstrated lower fat mass and greater lean mass, relative to vehicle. In HFD8, at just 4 weeks of treatment (8-wk data pending), taldefgrobep-treated mice had a change in baseline fat mass of -12% and lean mass of +18% while the placebo-treated mice increased +17% and +3%, respectively. There was no change in food intake. Conclusions: In this DIO mouse model, taldefgrobep monotherapy significantly reduced adipose tissue while increasing lean muscle, relative to placebo. These data support further development of taldefgrobep as a drug candidate with the potential for differentiated benefit in individuals living with overweight and obesity.