3079-LB: CMS-D008 Specifically Silences INHBE mRNA, Delivering Fat-Selective Weight Loss in Preclinical Study

Introduction and Objective: Even though current approved anti-obesity medications have been proven to be effective for the treatment of overweight and obesity, limitations such as muscle mass loss and poor tolerability have subsequently emerged, promoting the development of next-generation therapies. Human genetics provides strong evidence supporting INHBE as a compelling target for sustainable weight management. Inhibiting INHBE could represent a novel and promising approach for long-term weight maintenance with favorable metabolic profiles. Methods: CMS-D008 is a novel siRNA drug targeting INHBE administered via subcutaneous injection. The pharmacological effects of CMS-D008 were evaluated in humanized INHBE DIO mice and obese cynomolgus macaque models. Body weight, body composition, INHBE mRNA levels, and the target protein Activin E were assessed over the course of the studies. Results: In humanized INHBE DIO mouse models, weekly administration of CMS-D008 (1, 3, and 9 mpk) significantly reduced hepatic INHBE mRNA expression and serum Activin E protein levels, leading to marked decreases in body weight, total body fat, and regional fat mass while preserving lean mass. In obese cynomolgus macaque models, CMS-D008 (1.5, 4.5, 10 mpk) administered on Days 1 and 29 significantly lowered plasma Activin E expression and effectively suppressed weight gain induced by a sustained high-fat diet. Conclusion: CMS-D008 effectively reduced INHBE mRNA expression and lowered its gene product Activin E protein levels in both humanized INHBE DIO mice and obese cynomolgus macaque models. This target engagement promoted healthy weight loss by reducing fat mass while retaining lean mass. Disclosure J. Jia: Employee; Ended; Shenzhen Kangzhe Biotechnology Co., Ltd. J. Sun: None. Y. Wei: None. J. Zhang: None. Z. Zhu: None. T. Zhao: None. Q. Xu: None. L. He: None. D. Yang: None. R. Lu: Employee; Current; Shenzhen Kangzhe Biotechnology Co., Ltd.