Abstract
Obesity-related metabolic disorders, including non-alcoholic fatty liver disease and its more progressive form non-alcoholic steatohepatitis, are causing an increased health burden, especially due to the lack of approved treatment options. Using preclinical models of NASH, obesity, and type 2 diabetes, we investigated the effects of a long-acting glucagon-like peptide-1(GLP-1) and glucagon (GCG) receptor agonist OXM-104 head to head with once-daily GLP-1/GCG receptor agonist cotadutide and once-weekly GLP-1 receptor agonist semaglutide. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrosis biomarkers, were more prominent with OXM-104 and cotadutide than effects seen with semaglutide. This is demonstrated by improved NAFLD activity score (NAS) by OXM-104 and cotadutide which underlines the importance of the GCG receptor. Thus, these results underline the potential of OXM-104 as a promising therapeutic option for the resolution of NASH, but also as a therapeutic option for type 2 diabetes and obesity.
Targeting the serotonin 2C receptor for the treatment of obesity and type 2 diabetes