Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/glucagon receptor activity under development for type 2 diabetes mellitus (T2DM). GLP-1 has been shown to promote glucose-dependent insulin release, delay gastric emptying, and suppress appetite. Glucagon has similar effects on appetite and gastric emptying and enhances energy expenditure by upregulating energy-expensive processes such as gluconeogenesis and fatty acid oxidation.
Methods: This exploratory component of a phase 2a study measured fasting amino acid, β-hydroxybutyrate, and free fatty acid levels in overweight or obese T2DM patients randomized to once-daily SC MEDI0382 (n = 26) or placebo (n = 13) for 49 days. Doses were up-titrated weekly from 50 to 300 µg; measurements were taken at baseline and after 49 days of dosing.
Results: A significant decrease from baseline to day 49 with MEDI0382 vs. placebo in alanine was observed (-0.5 vs. 0.4 mg/dL; P = 0.017). Numerical reductions in other amino acid levels, including glutamate, cystine, valine, lysine, and tyrosine, were also seen. There were no clinically or statistically significant changes from baseline to day 49 between treatment groups in β-hydroxybutyrate or free fatty acid levels.
Conclusion: Despite the known effects of glucagon on fatty acid oxidation, MEDI0382 had no effect on ketogenesis or free fatty acids. Although the reason for this is unclear, enhanced insulin secretion may have counter-regulated this effect. MEDI0382 did promote reductions in key glucogenic amino acids, and this reduction could be related to increased gluconeogenesis and therefore glucagon receptor engagement. Similar patterns of amino acid reduction have been observed after bariatric surgery and have been attributed to excess circulating glucagon. We postulate that upregulation of an energy-consuming process such as gluconeogenesis could contribute to significant weight loss in subjects dosed with MEDI0382.
V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. T. Wang: Employee; Self; MedImmune. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.G. Posch: None. L. Plum-Moerschel: None. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. H. Schlichthaar: None. B.M. Klaus: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca.