84-OR: Sirna-Inhbe Silencing in Mice Recapitulates Human Genetic Data and Demonstrates Improved Healthy Weight Loss Profile

Introduction and Objective: Heterozygous INHBE loss-of-function carriers have reduced abdominal fat, reduced risk for T2D and coronary artery disease, suggesting that lowering INHBE expression by 50% may restore a healthy metabolic profile in obesity. We investigated the impact of reducing Inhbe expression, via GalNAc-siRNA (INHBE-00003), on body weight and composition in a DIO mouse model, alone or added onto semaglutide. Methods: C57BL/6 mice were fed a high-fat diet and were treated with PBS or INHBE-00003 in PBS, alone or added onto daily semaglutide treatment. Body weight, fat pad weight, skeletal muscle weight, and adipose inflammation were assessed. Results: By 28 days after a single dose of INHBE-00003, DIO mice weighed 9% less, had 40% less diet-induced visceral adipose mass accumulation, and had 43% less diet-induced adipocyte enlargement than PBS-treated mice. Infiltration of activated macrophages in visceral adipose was also decreased by up to 68% compared with controls. Quadricep muscle mass was also preserved. After 28 days of semaglutide, DIO mice weighed 9% less than PBS-treated mice. INHBE-00003 added onto semaglutide increased weight loss to 18% by day 28, compared with PBS controls. In a separate study, mice treated with semaglutide for 28 days regained all weight that was lost by day 56. Mice also treated with INHBE-00003 on days 21 and 28 maintained weight loss relative to PBS controls. Conclusion: DIO mice treated with INHBE-00003 recapitulate human genetic findings for INHBE LoF, supporting the reduction of INHBE expression as means to support healthy weight loss. These preclinical data support INHBE-siRNA treatment as a potential next-generation anti-obesity agent for patients living with obesity and other metabolic co-morbidities. Wave Life Sciences expects to initiate a clinical trial for WVE-007, an investigational INHBE GalNAc-siRNA, for the treatment of people living with obesity, in 1Q 2025. H. Yang: Employee; Wave Life Sciences. E. Ingelsson: None. K. Singh: Employee; Wave Life Sciences. J. Rheinhardt: None. A. Ghosh: None. K. Longo: None. L. Owen: None. P. Kandasamy: None. C.N. Vargeese: None. N. Iwamoto: None. M. Byrne: Employee; Wave Life Sciences.