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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

Diabetes Obesity and Metabolism 18(12):1176–1190, 2016

Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M, Jansson-Löfmark R, Naylor J, Rossi A, Bednarek MA, Bhagroo N, Salari H, Will S, Oldham S, Hansen G, Feigh M, Klein T, Grimsby J, Maguire S, Jermutus L, Rondinone CM, Coghlan MP

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.
  • Potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell lines.
  • Stimulate hepatic glucose output (HGO) by primary hepatocytes.

The effects of MEDI0382 on body weight, energy balance (food intake and energy expenditure), and blood glucose control were assessed in:

  • Diet-induced obesity (DIO) mice, following single and repeated daily subcutaneous administration for up to 2 months.
  • Healthy cynomolgus monkeys, using the same dosing regimen.

Results:

  • Receptor Activation: MEDI0382 potently activated rodent, cynomolgus, and human GLP-1 and glucagon receptors, showing a fivefold bias for GLP-1 receptor activation over the glucagon receptor.
  • Weight Loss and Glucose Control: MEDI0382 induced superior weight loss and comparable glucose-lowering effects to the GLP-1 analogue liraglutide when administered at comparable daily doses in DIO mice.
  • Mechanisms of Action:
    • Glucagon receptor activation contributed to increased energy expenditure, driving additional fat mass reduction.
    • GLP-1 receptor activation suppressed food intake.
  • Cynomolgus Monkey Results: The significant weight loss observed in DIO mice was replicated in cynomolgus monkeys, confirming the translational potential of the findings.

Conclusions: Repeated administration of MEDI0382:

  • Elicits profound weight loss in both DIO mice and non-human primates.
  • Produces robust glucose control.
  • Reduces hepatic fat content, fasting insulin, and glucose levels.

The combined GLP-1 and glucagon receptor activities of MEDI0382 are optimally balanced, making it a promising therapeutic candidate for achieving weight reduction and glucose control in overweight or obese Type 2 diabetic patients.

Subjects
DIO mouseTherapeutic AreaTargetCompoundNon-human primateMethod/EndpointSpeciesDiabetesObesityEnergy expenditure monitoringGLP-1 receptorGlucagon receptorIntraperitoneal glucose tolerance test (IPGTT)LiraglutideMEDI0382Oxyntomodulin

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