1668-P: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist

DA-1726 is a novel oxyntomodulin analogue preparing for phase I clinical trials for obesity. In this study, the pharmacological effect of DA-1726 compared to other competitor peptides was evaluated. DA-1726 showed superior efficacy compared to other glucagon-like peptide-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist (Cotadutide; COTA) in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. DIO control at 30 nmol/kg, p<0.05) and improving plasma glucose, insulin, and HOMA-IR (-91% for DA-1726 vs. -52% for COTA) in diet-induced obese mice. In addition, superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA were confirmed by DA-1726. These data suggested that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Meanwhile, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. Thus, DA-1726 was injected for 3 weeks and glucose tolerance test was performed at 72-h after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72-h after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist (Tirzepatide; TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p<0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control.