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

Jul 6, 2016Diabetes, obesity & metabolism

Strong weight loss and metabolism improvements from a drug targeting two hormone receptors in rodents and monkeys

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GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

MEDI0382 produced significant weight loss in and cynomolgus monkeys.

MEDI0382 activated and glucagon receptors with a fivefold preference for the GLP-1 receptor.
Weight loss achieved with MEDI0382 was superior to that of liraglutide in DIO mice at similar doses.
The reduction in fat mass from MEDI0382 may be linked to increased energy expenditure mediated by glucagon receptors.
Food intake suppression associated with MEDI0382 likely results from GLP-1 receptor activation.
Administration of MEDI0382 led to improved glucose control and reduced fasting insulin and glucose levels.

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AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-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 . 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 Type 2 diabetic patients.

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30%

Weight Loss in

Weight loss after 4 weeks of MEDI0382 treatment.

13%

Weight Loss in Cynomolgus Monkeys

Mean body weight loss after 8 weeks of MEDI0382 treatment.

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

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