2546-P: Preclinical Efficacy and Safety of HDM1014, a Novel GalNAc-siRNA Targeting INHBE, for Weight Management with Muscle Preservation

Introduction and Objective: Body weight management with GLP-1R agonist often causes muscle wasting or gastrointestinal adverse events, reducing adherence. Inhibin-β E (INHBE), a liver-expressed TGF-β member, suppresses lipolysis via PPARγ. Human genetics link INHBE loss-of-function mutations to a lower waist-hip ratio, decreased T2D risk, and improved cardiovascular outcomes. We developed HDM1014, a GalNAc-siRNA, to enable fat-specific weight loss while preserving muscle. Methods: The hepatic INHBE mRNA knock-down efficacy was evaluated in Cynomolgus monkeys after s.c. 5 mg/kg on Day 0 and Day 29. Weight-loss efficacy was evaluated in DIO-hINHBE mice treated with HDM1014 alone or combined with HDM1005 (a GLP-1R/GIPR agonist developed by the company). The preliminary repeated dose toxicity studies were performed in SD rats and Cynomolgus monkeys, respectively. The animals were administrated with HDM1014 via subcutaneous injection once weekly for 3 dose, and complete toxicity assessment was conducted. Results: In monkeys, HDM1014 achieved a superior and more durable hepatic INHBE mRNA knockdown than competitor (Max KD: 79% vs. 60%, >70% suppression lasting 112 days vs. 50%~60% suppression lasting 84 days). In DIO mice, HDM1004 (10 mg/kg) significantly reduced body weight (-9.4%) via fat loss (-18.5%). Notably, this was achieved with a concurrent preservation in lean mass (+5.2%). Combination with HDM1005 further amplified weight loss and blunted post-treatment rebound by 41.7%. All findings in toxicity studies, including hepatocellular vacuolation, kidney tubular vacuolation, lymph nodes macrophage vacuolation, were similar to that of commercial GalNAc-siRNA products as anticipated. The NOAEL was 100 m/kg and 300 mg/kg for rats and monkeys, respectively. Conclusion: HDM1014 exhibits a potential best-in-class profile with robust and durable INHBE inhibition with significant fat-selective weight loss and full preservation of lean mass. Favorable safety margin was conformed based on available toxicity studies. Disclosure H. Pan: Employee; Ended; Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd. Employee; Current; Nanjing GenScript Biotechnology Co., Ltd. L. Teng: None. C. He: None. X. Yang: None. Q. Tian: None. Z. Su: None. X. Xu: Employee; Current; Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd. Employee; Ended; Green Leaf Life Sciences Group Co., Ltd. D. Liu: None.