Evaluating the Sub-chronic Effects of MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, on Weight Loss in Male ob/ob Mice

Abstract

MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of type 2 diabetes (T2DM). MEDI0382 reduces food intake and improves glucose control in lean and obese mice. Here, we determined the effects of MEDI0382 on body weight in leptin-deficient ob/ob mice. MEDI0382 (10, 20 or 30 nmol/kg), liraglutide (30 nmol/kg; a GLP-1 analog), or G1437 (30 nmol/kg; a lipidated glucagon receptor agonist) was administered to ob/ob mice for 21 days. Body weight was reduced by MEDI0382 treatment compared to vehicle controls, with 15% weight loss observed in the highest dose group. In comparison, liraglutide reduced body weight by 8% and G1437 by 29% (both p<0.0001 vs. vehicle and high-dose MEDI0382). Glucose tolerance was improved by MEDI0382 (30 nmol/kg), similar to liraglutide, whereas G1437 worsened glucose tolerance. Additionally, 4-h fasted glucose on day 7 and 14 in high-dose MEDI0382- and liraglutide-treated groups was lower than vehicle, whereas G1437-treated mice exhibited higher glucose levels. Overnight fasting glucose was also reduced in all groups relative to vehicle except G1437. Liver fat was reduced in a dose-dependent manner (11%, 14% and 22%, respectively) by MEDI0382 compared to vehicle. Both liraglutide (12%) and G1437 (10%) also reduced liver fat (both p<0.vs. vehicle and MEDI0382 30 nmol/kg dose). Serum ALT levels were also dose-dependently reduced by MEDI0382 and liraglutide, but not G1437. Expression of thermogenic genes (Ucp1, Ppargc1a and/or Adrb3) tended to be increased in brown and white adipose tissue by MEDI0382 administration, whereas negligible effects were observed following liraglutide or G1437 administration. In summary, these data indicate that high-dose MEDI0382 produced superior body weight loss and improved liver health compared to liraglutide but the improved glucose homeostasis was similar to liraglutide. Disclosure S. Oldham: Stock/Shareholder; Self; AstraZeneca. Employee; Self; MedImmune. C.D. Church: Employee; Self; MedImmune. S. Will: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. A. Konkar: Employee; Self; Sanofi. Other Relationship; Self; MedImmune. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. G.R. Davies: Employee; Self; MedImmune.