Therapeutic Potential of DA-1726, a Novel Oxyntomodulin Analogue, in a Diet-Induced NASH Mouse Model

DA-1726 is a novel balanced long-acting GLP-1/glucagon receptor dual agonist, which is under preclinical development for the treatment of obesity. DA-1726 represented a superior efficacy to semaglutide (SEMA) in weight loss in various animal studies. In this study, we evaluated the therapeutic potential of DA-1726 for the treatment of nonalcoholic steatohepatitis (NASH) . To induce NASH, male mice were given a diet containing 40% total fat, 20% fructose, and 2% cholesterol for 30-week. After then DA-1726 and SEMA were subcutaneously injected every three days for 8-week. At the end of treatment, vehicle control, DA-1726 (100 or 200 nmol/kg) and SEMA (250 nmol/kg) significantly reduced body weight compared to baseline (+10.4%, -8.9%, -17.2%, and -12.9%, respectively) . Plasma clinical chemistry parameters (ALT, AST, ALP and T-BIL) and hepatic fat accumulation were significantly decreased by DA-1726. The reduction of plasma glucose and total cholesterol induced by DA-1726 200 nmol/kg was superior to that of SEMA. In a histopathological analysis of steatosis, lobular inflammation, and ballooning in the liver, DA-1726 showed an excellent improvement in NAFLD Activity Score compared to SEMA (NAS: 6.75 for vehicle control, 3.88 and 3.63 for DA-1726, and 5.00 for SEMA) . Liver fibrosis was assessed by Masson Trichrome stain. Improvement of hepatic fibrosis by DA-1726 was also observed (fibrosis score: 1.88 for vehicle control, 1.25 and 1.13 for DA-1726, and 1.50 for SEMA) . In the liver tissue, the expression of inflammatory (Tnfa, Il-1β, and Ccl2) and fibrotic (Acta2, Timp1, Col1a1, Col3a1, and Mmp9) genes were significantly decreased by DA-1726 treatment. In particular, the DA-1726 low-dose group showed a higher efficacy despite lower weight loss compared to SEMA. This is thought to be a result of the dual actions of DA-1726 to GLP-1 and glucagon receptors. Taken together, our findings suggest that DA-1726 has a therapeutic potential for NASH in addition to obesity and type 2 diabetes. Disclosure I.Jung: None. T.Kim: None. M.Goo: None. M.Kim: None. Y.Chae: None.