Significant metabolic benefits seen with dual receptor agonist MEDI0382
medwireNews: MEDI0382, a novel glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist, induces clinically meaningful improvements in glycemic control and bodyweight in patients with type 2 diabetes, show data published in The Lancet.
The data indicate “that for the first time, a pharmacological therapy might be able to meet treatment goals in type 2 diabetes of both durable glycaemic control and weight loss of a magnitude that will have a considerable impact on clinical outcomes,” say Philip Ambery (MedImmune, Cambridge, UK) and co-authors.
The phase IIa study, which was also presented at the ADA’s 78th Scientific Sessions in Orlando, Florida, USA, included 51 overweight and obese (BMI 27–40 kg/m2) patients aged 18–65 years and older with controlled type 2 diabetes (glycated haemoglobin [HbA1c] 6.5–8.5%).
Individuals randomly assigned to receive a maximum 200 μg subcutaneous MEDI0382 once daily for up to 41 days (n=25) experienced an average 32.8% reduction in the area under the postprandial plasma glucose concentration curve up to 4 hours after a mixed meal. This was significantly greater than the 10.2% reduction observed among those assigned to receive placebo (n=26).
There was also a significantly greater mean reduction in fasting plasma glucose from baseline to the last day of treatment with MEDI0382 than with placebo, at 2.8 versus 1.1 mmol/L.
Patients in the MEDI0382 group lost an average 2.1 kg more body weight than those in the placebo group (3.8 vs 1.7 kg), which the researchers described as “greater than that seen for any pharmacological interventions in obesity so far, over the same time period.”
Magnetic resonance imaging revealed that MEDI0382 treatment was associated with a significantly greater reduction in liver fat than placebo (6.0 vs 3.2%).
“This result is striking given the short duration of dosing of just 41 days,” Ambery et al remark, adding that it was of “greater magnitude than would be expected from weight loss alone.”
There was also a significantly greater reduction in HbA1c (0.9 vs 0.6%) and significant increases in fasting insulin concentrations (2.2 vs –3.94 mU/L) and C peptide concentrations (0.3 vs –0.03 nmol/L) with MEDI0382 than with placebo.
The treatment-emergent adverse event (TEAE) rate was 88% in both treatment groups, but gastrointestinal disorders (72 vs 50%) and decreased appetite (20% vs none) occurred more frequently with MEDI0382 than with placebo.
“The treatment effects on glycaemic control, bodyweight, and liver fat suggest that with longerterm therapy, MEDI0382 has potential to be a diseasemodifying therapy for type 2 diabetes,” Ambery and team concludes.
In an accompanying comment, Christopher Rayner and Michael Horowitz, both from the University of Adelaide in South Australia, say: “Although the outcomes are impressive, the study has limitations, as acknowledged by the authors.”
“In particular, there was no active comparator, so by definition, it is impossible to know how much, if anything, was gained by glucagon receptor agonism over stimulation of GLP-1 receptors alone,” they write.
In spite of this, Rayner and Horowitz believe the data “support the ongoing development of MEDI0382, but a comprehensive understanding of mechanisms will be pivotal to successful therapeutic developments based on the gut–pancreas hormone axis.”
They conclude: “In this area, whether two (or more) [receptor agonists] will prove to be better than one remains to be determined.”
By Laura Cowen
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