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Aims  To characterize the pharmacology of  MEDI0382 , a peptide dual agonist of glucagon‐like peptide‐1 ( GLP ‐1) and glucagon receptors.    Materials and methods   MEDI0382  was evaluated  in vitro  for its ability to stimulate  cAMP  accumulation in cell lines expressing transfected recombinant or endogenous  GLP ‐1 or glucagon receptors, to potentiate glucose‐stimulated insulin secretion ( GSIS ) in pancreatic β‐cell lines and stimulate hepatic glucose output ( HGO ) by primary hepatocytes. The ability of  MEDI0382  to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.    Results   MEDI0382  potently activated rodent, cynomolgus and human  GLP ‐1 and glucagon receptors and exhibited a fivefold bias for activation of  GLP ‐1 receptor versus the glucagon receptor.  MEDI0382  produced superior weight loss and comparable glucose lowering to the  GLP ‐1 peptide analogue liraglutide when administered daily at comparable doses in  DIO  mice. The additional fat mass reduction elicited by  MEDI0382  probably results from a glucagon receptor‐mediated increase in energy expenditure, whereas food intake suppression results from activation of the  GLP ‐1 receptor. Notably, the significant weight loss elicited by  MEDI0382  in  DIO  mice was recapitulated in cynomolgus monkeys.    Conclusions  Repeated administration of  MEDI0382  elicits profound weight loss in  DIO  mice and non‐human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the  GLP ‐1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese  T ype 2 diabetic patients.

Robust anti‐obesity and metabolic effects of a dual GLP ‐1/glucagon receptor peptide agonist in rodents and non‐human primates