2566-P: Silencing Hepatokine Activin E Promotes a Healthy Body Composition and Metabolic Profile in Mice

Introduction and Objective: INHBE encodes Activin E (Act E), a hepatokine that regulates adipocyte lipolysis. Human genetic studies suggest that lowering INHBE may provide therapeutic benefits for obesity. We evaluated the impact of INHBE-3, a GalNAc-conjugated siRNA targeting INHBE, on Act E levels, body weight, body composition and metabolic profile in a diet-induced obesity (DIO) mouse model. Methods: C57BL/6 mice were fed a 60% high-fat diet. Mice then received a single dose of INHBE-3 or PBS. In some experiments, mice were also treated with semaglutide daily for 28 days. Body weight and composition were monitored through 28 days post-last dose. Macrophage markers and fibrosis were evaluated by IHC on day 56. Gene expression was analyzed by qPCR and RNA-Seq on days 2, 28 and 70. Results: A single dose of INHBE-3 reduced Inhbe mRNA and Act E (>75%) levels at day 28 compared to PBS. Comprehensive dose- and time-dependent effects of INHBE-3 on Act E levels and impact on body weight and composition will be presented. At day 28, INHBE-3 treated mice weighed 9% less than controls, with a 40% reduction in visceral fat mass and 43% less adipocyte hypertrophy. There was no statistically significant change in quadricep muscle mass. Gene expression changes, along with reductions in total (41%) and pro-inflammatory (80%) macrophages and fibrosis (58%) were observed in visceral fat. Combining a single dose of INHBE-3 with daily semaglutide doubled the reduction in baseline-adjusted weight relative to PBS compared to either agent alone. INHBE-3 treatment also suppressed weight regain upon discontinuation of semaglutide. Conclusion: A single dose of INHBE-3 led to potent target engagement and impacted body weight, composition and adipose tissue remodeling in DIO mice. These preclinical data support INHBE-siRNA as a potential therapeutic for people living with obesity. Wave Life Sciences is evaluating WVE-007, an investigational INHBE GalNAc-siRNA, for the treatment of overweight or obesity in the Phase 1 INLIGHT clinical trial. Disclosure H. Yang: None. W. Liu: None. M. Byrne: Employee; Current; Wave Life Sciences. P. Kandasamy: None. K. Bowman: None. C. Caracta: Employee; Current; Wave Life Sciences. J. Desai: Employee; Current; Wave Life Science. A. Ghosh: None. D. Ghosh: None. J. Haegele: Employee; Current; Wave Life Sciences. N. Iwamoto: Employee; Current; Wave Life Sciences. T. Kawamoto: None. A.M. Lamattina: Employee; Current; Wave Life Sciences. S. Liu: None. K. Longo: None. K.L. Luu: None. S. Marappan: None. P. Narayanan: None. L. Owen: None. P. Shiva Prakasha: None. J.M. Rheinhardt: None. D. Schwahn: None. H. Shah: None. K. Singh: None. S. Standley: Employee; Current; Wave Life Sciences. K. Taborn: None. H. Yang: None. C. Vargeese: None. E. Ingelsson: Employee; Current; Wave Life Sciences.