Introduction and Objective: The current paradigm in obesity management is shifting from maximizing weight loss to improving weight loss quality (WLQ). Clinical studies combining incretin therapies with myostatin/activin pathway inhibition, such as bimagrumab (Bima), suggest benefits for WLQ. HM17321 is a CRFR2-selective UCN2 analog developed to promote fat-selective body weight loss (BWL) with favorable metabolic effects. This study evaluated HM17321 alone or with Bima in male and female DIO mice. Methods: Male and female DIO mice were treated for 4 weeks with HM17321 alone or with Bima. Body weight and body composition were assessed, and skeletal muscle function was evaluated using wire hang and grip strength tests. Results: HM17321 (100 nmol/kg) induced significant BWL in both male and female DIO mice (-17.5%, -12.7% vs. day 0), whereas Bima (20 mg/kg) alone showed minimal or opposite effects (-1.1%, +3.1%). The combination treatment (COMBO) achieved greater BWL (-22.6%, -24.8%). HM17321 reduced fat mass with modest lean mass gains in both sexes (-41.1%/+3.2% and -34.0%/+3.5% vs. baseline), whereas Bima primarily increased lean mass with marginal fat mass reduction (-15.7%/+12.9% and -15.6%/+18.6%). COMBO showed the most pronounced improvement in body composition, with substantial fat mass reduction and lean mass gain (-67.9%/+19.2% and -69.3%/+25.0%) compared with either monotherapy. Improvements in muscle function were confirmed following HM17321 treatment; however, no functional benefit was observed in the Bima monotherapy or COMBO groups despite pronounced muscle mass accrual in both sexes. Conclusion: HM17321 induced fat-selective BWL with functional lean mass gain in both sexes, supporting its potential as a novel foundational WLQ therapy. These findings provide proof-of-concept for additional benefits of incorporating myostatin/activin pathway inhibition for body weight and body composition, warranting longer-term evaluation. Disclosure S. Lee: None. E. Kim: None. H. Kwon: Employee; Current; Hanmi Pharm. Co., Ltd. D. Lee: None. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: None. S. Bae: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. I. Choi: None.
LEE et al. (Fri,) studied this question.