760-P: TERN-501 Enhances Weight Loss Efficacy of a GLP-1R Agonist in Obese Mice via Increased Fat Mass Loss without Additional Loss of Lean Mass

Introduction & Objective: GLP-1R agonists suppress food intake resulting in weight loss but efficacy is limited by metabolic adaptation, a compensatory process that lowers energy expenditure (EE). Thyroid hormone receptor beta (THRβ) regulates EE providing a potential mechanism to mitigate metabolic adaptation. TERN-501, a highly selective THRβ agonist, has shown excellent safety and significant liver fat reduction in a Ph2a study in patients with metabolic dysfunction-associated steatohepatitis. The combined effects of TERN-501 and GLP-1R agonism may offer benefits over either agent alone in reducing body weight.

Methods: Male C57BL/6JRj mice were fed high fat diet (60% HFD) for 24 weeks prior to study start. Mice (~55 g BW) were treated once daily with vehicle, TERN-501 (6 mg/kg PO), semaglutide (sema, 30 nmol/kg SQ), or 501+sema for up to 6-weeks at thermal neutrality. Body weight and food intake were measured daily. Body composition was assessed by EchoMRI and EE was measured in metabolic chambers.

Results: TERN-501 significantly enhanced the weight loss efficacy of sema (-26% vs -33%, p <0.05) with increased fat mass loss (-11.8 g vs -15.2 g, p <0.05) without additional loss of lean mass. In contrast, the effect of TERN-501 alone on body weight was similar to vehicle (-1.6% vs 1.5%, p >0.05). In mice with higher initial body weight, 501+sema resulted in an additional 17% body weight loss vs sema alone. In combination with sema, TERN-501 prevented lowering of EE typically induced by weight loss and was associated with increased levels of UCP-1 expression in subcutaneous adipose tissue.

Conclusion: In obese mice, TERN-501 significantly improved the efficacy of a GLP-1R agonist by normalizing EE, resulting in greater weight loss, increased fat mass loss, and relative preservation of lean mass. These results suggest that TERN-501, a potent and highly selective THRβ agonist, may be an ideal combination partner for GLP-1 therapies.