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.
