MON-715 Silencing Hepatokine Activin E Production in Mice Recapitulates Human Genetic Data and Demonstrates Improved Healthy Weight Loss Profile

Abstract Disclosure: W. Liu: None. H. Yang: None. K. Bowman: None. S. Briem: None. M. Byrne: None. C. Caracta: None. J. Desai: None. A. Ghosh: None. N. Iwamoto: None. P. Kandasamy: None. T. Kawamoto: None. A. Lamattina: None. K. Longo: None. K. Luu: None. S. Marappan: None. P. Narayanan: None. L. Owen: None. P. Prakasha: None. J. Rheinhardt: None. D. Schwahn: None. H. Shah: None. K. Singh: None. S. Standley: None. K. Taborn: None. C. Vargeese: None. E. Ingelsson: None. INHBE (Inhibin βE) encodes Activin E, a hepatokine that regulates adipocyte lipolysis. Heterozygous INHBE loss-of-function (LoF) carriers have reduced abdominal fat, and reduced risk for type 2 diabetes and coronary artery disease, suggesting that lowering INHBE expression by greater than 50% may restore a healthy metabolic profile in obesity. We investigated the impact of reducing Inhbe expression, via N-acetylgalactosamine-conjugated small interfering RNA (GalNAc-siRNA) targeting Inhbe mRNA (INHBE-00003), on body weight and composition in a diet induced obesity (DIO) mouse model, alone or in addition to semaglutide, a GLP-1 receptor agonist (GLP-1RA). C57BL/6 mice were fed a 60% high-fat diet to model DIO phenotypes and were treated with PBS or INHBE-00003 in PBS, alone or added to daily semaglutide injections. Body weight, fat pad weight, skeletal muscle weight, and adipose inflammation were assessed. 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 demonstrated 43% less diet-induced adipocyte enlargement than PBS-treated mice. Infiltration of activated macrophages in visceral adipose tissue was also decreased by up to 68% compared with controls. Quadricep muscle mass was preserved. Overall, 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. Activin E appears to regulate body weight through a peripheral mechanism distinct from GLP-1RAs; therefore, we next investigated whether INHBE-00003 could enhance weight loss if added to treatment with the GLP-1 agonist semaglutide. After 28 days of semaglutide, DIO mice weighed 9% less than PBS-treated mice. Adding INHBE-00003 to semaglutide treatment increased weight loss to 18% by day 28, compared with PBS controls. Mice treated with semaglutide for 28 days regained all weight that was lost by day 56, whereas mice also treated with INHBE-00003 on days 21 and 28 maintained weight loss relative to PBS controls. These preclinical data support reducing hepatokine Activin E levels through 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 dosing in the INLIGHT clinical trial for WVE-007, an investigational INHBE GalNAc-siRNA, for the treatment of people living with obesity, in Q1 2025. Presentation: Monday, July 14, 2025