ICA6150349, a Highly Selective Glucagon Agonist, in Combination with Exenatide Significantly Reduces Weight and Glucose in Obese and Diabetic Rats

ICA6150349, a 38-amino acid analog of glucagon, is peptidase resistant and highly selective for the glucagon receptor. ICA6150349 continuously infused SC at 50 mcg/kg/d (ED50) in DIO LE rats reduced weight (21%), fat mass (37%), and food intake (17%) and normalized triglycerides and cholesterol to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) further reduced weight (38%), fat mass (70%), and food intake (52%) and also normalized glucose and lipids to lean control levels. ICA6150349 continuously infused at 50 mcg/kg/d in ZDF rats increased HbA1c (1.3%), reduced weight (29%), fat mass (42%), and food intake (13%) and normalized triglycerides (66%) and cholesterol (38%) to lean control levels. ICA6150349 (50 mcg/kg/d) in combination with exenatide (10 mcg/kg/d) decreased HbA1c (1.5%), off-setting the increase seen with ICA6150349 monotherapy. The ICA6150349 and exenatide combination reduced weight (19%), fat mass (25%), food intake (29%) cholesterol (27%) and triglycerides (41%). In rodent models of obesity/T2D, ICA6150349 in combination with exenatide can significantly reduce weight, fat mass, glucose and lipids, sometimes normalizing these parameters to lean control levels.