2058-LB: DA-1726, a GLP1R/GCGR Dual Agonist, a Promising Approach in Obesity Treatment and Lipid Management

DA-1726 is being prepared for obesity Phase 1 clinical trials following IND approval. Our study focuses on the pharmacological effects of this novel oxyntomodulin analogue, which has been effective at improving lipid profiles and reducing weight in rodent models. In a prior study, DA-1726 showed a difference in improving lipid levels, despite similar weight loss to tirzepatide. Therefore, the direct lipid-regulating effect of DA-1726 was assessed in a hypercholesterolemia rat model compared with tirzepatide. As a result, DA-1726 was more effective than tirzepatide in suppressing the elevation of T-CHO ( -33.5%, -25.5% vs. control; P<0.05) and LDL-C (-53.2%, -41.5% vs. control; P<0.05). This differentiated impact is thought to arise from DA-1726's glucagon action, alongside its GLP-1 effect. We evaluated whether these differential effects could also be distinguished from drugs of the same class. In an obese mouse model, DA-1726 significantly lowered T-CHO (-67.7%, -49.6%; P<0.05 vs. control) and TG (-49.5%, -41.2%; P<0.05 vs. control) levels under conditions that resulted in similar weight loss effects (-31.9%, -25.4%; P<0.05 vs. control) as survodutide. Besides, DA-1726 exhibited superior glucose lowering compared to survodutide (-54.7%, -30.4% vs. control; P<0.05). Interestingly, despite the same mechanism of action, DA-1726-treated mice maintained similar levels of weight loss while consuming more food due to less dietary restriction in terms of appetite suppression. This effect might stem from DA-1726's GLP-1 and glucagon receptor activity ratio. DA-1726's glucagon action could further enhance energy expenditure (EE), and it is believed to have significantly increased the expression of EE-related genes in brown adipose tissue. In summary, it was confirmed that DA-1726 has differentiating characteristics in the competition of obesity treatment drugs with similar or identical mechanisms in its effect on improving cholesterol metabolism through glucagon action.