MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Dramatically Reduces Hepatic Collagen in a Mouse Model of NASH

Abstract

Nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation and fibrosis is an unmet medical need. MEDI0382, a balanced GLP-1/glucagon dual receptor agonist, is under development for the treatment of T2DM. Here we examined the effects of MEDI0382 on NASH compared to liraglutide, a GLP-1 analog. Leptin-deficient ob/ob mice were maintained on high trans-fat, fructose and cholesterol diet for 8 weeks to induce NASH then randomized to four treatment groups: vehicle, MEDI0382 (30 nmol/kg), liraglutide (30 nmol/kg) or vehicle-treated and switched to low-fat diet (LFD). Treatment with MEDI0382 and liraglutide reduced body weight and improved glucose tolerance. Hepatic lipid was reduced by 40% with MEDI0382 treatment (p<0.0001), which was more effective than liraglutide or switch to LFD. Hepatic collagen, quantified by type 1 collagen immunohistochemistry, was increased more than 2-fold with NASH and was reduced by 40% in MEDI0382-treated mice (p=0.005). Consistently, type 1 collagen gene expression increased 2-fold with NASH and was reduced by 85% in MEDI0382-treated livers (p<0.0001). No reductions in collagen were observed with liraglutide or switch to LFD. The NASH score, integrating pathology scores for steatosis, lobular inflammation, fibrosis, hepatocyte ballooning, biliary hyperplasia, and CD68 expression was significantly reduced by MEDI0382 (p<0.0001), greater than liraglutide or switch to LFD. Consistent with histopathology improvements, MEDI0382 treatment also reduced inflammatory gene expression (Tnf, Tgfb1, Il1b, and Ccl2) to a greater extent than liraglutide or LFD switch. In conclusion, MEDI0382 exerted similar metabolic control relative to liraglutide, but exhibited superior effects on primary NASH endpoints. Disclosure M. Beaton: Employee; Self; MedImmune. Employee; Spouse/Partner; MedImmune. S. Guionaud: None. J.P. Conway: None. J. Grimsby: Employee; Self; AstraZeneca. C.J. Rhodes: Stock/Shareholder; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes

“…Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of therapeutics in type 2 diabetes (T2D) 1 – 3 and Non-Alcoholic Steato Hepatitis (NASH) 4 – 6 . This class of drugs aims to combine the effects of agonism at the GLP1R (glucose lowering, decreased appetite) with those of GCGR activation (increased energy expenditure, reduced food intake), thus potentially providing improved glycaemic control in combination with substantial weight reduction.…”

“…This class of drugs aims to combine the effects of agonism at the GLP1R (glucose lowering, decreased appetite) with those of GCGR activation (increased energy expenditure, reduced food intake), thus potentially providing improved glycaemic control in combination with substantial weight reduction. GLP1/glucagon dual agonists have furthermore been shown to ameliorate hepatic fat content 4 , 5 and fibrosis 6 as well as promoting liver regeneration 4 .…”