Prevention of Weight Rebound and Restoration of Muscle Mass after Semaglutide Withdrawal Using Bc-006, an INHBE siRNA, in a Nonhuman Primate Obesity Model

Introduction and Objective: GLP-1 treatments for obesity are associated with muscle loss, poor adherence, and weight regain accompanied with unfavorable body composition changes upon withdrawal. These challenges highlight the unmet need for new therapies that preserve lean mass and offer sustainable weight maintenance. We report results of BC-006, a GalNAc-conjugated siRNA targeting INHBE, in weight maintenance after GLP-1 withdraw in a monkey model of established obesity. Methods: Cynomolgus monkeys fed a high fat diet for > 2yr with a mean age of ~18 yr and BMI of 50 kg/m2 were randomly assigned to vehicle (n=8) or treatment group (n=12). Animals were treated with Semaglutide 10-90 μg/kg sc BIW for 35 days and switched to vehicle (n=4) or BC-006 (n=8, 10 mg/kg sc) treatment on Day 28 and Day 99. PD, food intake, body weight and body composition were measured for up to 126 days. Results: BC-006 demonstrated ~70% knockdown of INHBE without significant impact on food intake. After Semaglutide withdraw, BC-006 prevented weight rebound (Fig. 1A) and fat mass regain (Fig. 1B) while restored lean mass (Fig. 1C). Conclusion: Data in the obese monkey model supports clinical development of BC-006 to promote more physiologic and healthy long-term weight maintenance. Disclosure: J. Yang: None. P. Pandarinathan: None. X. Ge: None.