Novel Combination of a Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) and Once-Weekly Basal Insulin (HM12460a) Offers Improved Glucose Lowering and Weight Loss in a Diabetic Animal Model

Obesity is an established risk factor for prediabetes, diabetes and the aggravation of preexisting diabetes by negatively affecting lipid metabolism, insulin response, and β-cell function. Thus, effective body weight loss not only prevents or delays the onset of T2DM, but also enhances the response to diabetes drugs including basal insulin in T2DM patients. Recently, we have developed a novel long-acting GLP-1/GIP/Glucagon triple agonist, HM15211, which showed potent weight loss in obese animal models. When combined with basal insulin, HM15211 might maximize the insulin response and provide additional weight loss. Here, we investigated the PK/PD properties of HM15211 and HM12460A (once weekly basal insulin developing in clinical stage) combination in animal models to evaluate the therapeutic benefits of this novel combination in diabetes. Firstly, drug-to-drug interaction (DDI) was evaluated to assess the changes in intrinsic activity and PK of the individual components. In vitro human insulin receptor phosphorylation by HM12460A was not affected by concomitant HM15211 treatment. Similarly, cAMP accumulation by HM15211 was unaffected. Analysis of PK demonstrated that the administration of HM15211 and HM12460A, either alone or in combination, did not change their extended half-lives in SD rats. Secondly, the glucose lowering and body weight loss by HM15211 in combination with HM12460A was evaluated in db/db mice. After 4 weeks treatment, a combination of HM15211 and HM12460A reduced the HbA1c more than the mono-treatment. Moreover, potent weight loss by HM15211 was well maintained even when combined with HM12460A. Based on these observation, we propose that HM15211 might be an additional combination partner for long-acting basal insulin such as HM12460A providing improved glycemic control and more favorable weight loss. Disclosure J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Jung: None. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. S. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical.