MEDI0382, a GLP/Glucagon Receptor Dual Agonist, Significantly Reduces Hepatic Fat Content in Subjects with Type 2 Diabetes Mellitus

Abstract

MEDI0382 is a balanced GLP-1/glucagon receptor dual agonist in development for type 2 diabetes mellitus (T2DM). We investigated the effects of MEDI0382 on hepatic fat content in overweight/obese subjects with T2DM and a BMI of 27-40 kg/m2. In a phase 2a study (NCT02548585), 51 subjects were randomized to receive MEDI0382 200 μg or placebo daily during a 41-day treatment period. Quantification of liver proton density fat fraction, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) was performed as an exploratory analysis in a subset of patients (MEDI0382 n = 17, placebo n = 21) who had MRI scans taken at baseline and day 41. Mean (SD) liver fat content at baseline was 15.7% (8.97) and 18.1% (8.38) in the MEDI0382 and placebo groups, respectively. Patients treated with MEDI0382 showed a highly significant relative reduction from baseline in hepatic fat content vs. placebo (Table). This was positively correlated with reductions in both body weight (r = 0.49, P = 0.002) and alanine aminotransferase (r = 0.42, P = 0.009). Treatment with MEDI0382 was also associated with reductions in both SAT and VAT vs. placebo. These data demonstrate the efficacy of MEDI0382 in reducing liver fat and its potential for the treatment of nonalcoholic fatty liver disease, including steatohepatitis.MeasurementChange from Baseline, LS Mean (90% CI)P MEDI0382 (n - 17)Placebo (n = 21)Hepatic fat content, absolute change (%)-5.98 (-7.67, -4.29)-3.17 (-4.68, -1.65)0.017Hepatic fat content, relative change (%)-39.12 (49.11, -29.14)-19.51 (-28.49, -10.53)0.006SAT (L)-0.39 (-0.48, -0.30)-0.21 (-0.30, -0.13)0.008VAT (L)-0.36 (-0.52, -0.19)-0.14 (-0.29, 0.01)0.057 Disclosure M. Jain: Employee; Self; MedImmune. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. P. Hockings: Other Relationship; Self; MedImmune, AstraZeneca. L. Johansson: Stock/Shareholder; Self; Antaros Medical. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.