657-P: Potential Effect of a Novel Combination of GLP-1RA (efpeglenatide) and Long-Acting Glucagon Analog (HM15136) in Animal Models of Metabolic Disorders

Abstract

In addition to glycemic control, GLP-1RA efficacy is established in obesity. However, more efforts are still required to close efficacy gap with bariatric surgery. Recent studies demonstrate the favorable effect of glucagon (GCG) receptor activation on energy expenditure and hepatic lipid metabolism. So, combination of GCG with GLP-1RA not only enhances body weight loss (BWL) barely achieved by current therapy, but also expands its therapeutic utility to various metabolic disorders. Previously, we confirmed the long-acting GCG properties of HM15136 from animal to human. In addition, GLP-1 class effect of efpeglenatide (Efpe), once-weekly GLP-1RA, was confirmed in clinical studies. Thus, to develop a novel combination therapy, we investigated potential effects of Efpe and HM15136 combination in animal models of metabolic disorders. In DIO mice, 4 weeks treatment of Efpe and HM15136 combination (COMBO) showed more BWL than Efpe mono treatment. Of note, greater BWL was also confirmed for COMBO treatment compared to acylated GLP-1/GIP co-agonist (-18.5, -55.9, -44.9% vs. vehicle for Efpe, COMBO, GLP-1/GIP). Similar results were observed when measuring fat mass (-19.5%, -83.8%, -77.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) and blood lipid profiles (total cholesterol: -41.8%, -82.0%, -63.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) in DIO mice. To further demonstrate benefits of this novel COMBO, additional study was performed in DIO/STZ rats, and COMBO treatment consistently showed more BWL than Efpe (-5.1, -12.1% vs. vehicle for Efpe, COMBO) along with numerically more HbA1c reduction (-1.0, -1.5% vs. vehicle for Efpe, COMBO). Therefore, HM15136 might be a novel COMBO partner for Efpe, providing enhanced BWL and favorable metabolic profiles. These results warrants further evaluation for therapeutic potential of this novel COMBO in various metabolic disorders including dyslipidemia and NASH. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical.