The therapeutic landscape of non-alcoholic steatohepatitis.

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and hepatocellular ballooning, and may be associated with liver fibrosis leading to cirrhosis and its complications. A pharmacological approach is necessary to treat NASH because of failure to change dietary habits and lifestyle in most patients. Insulin resistance with an increased release of free fatty acids, oxidative stress and activation of inflammatory cytokines seem to be key features for disease progression. Thiazolidinediones, such as pioglitazone and antioxidant agents, such as vitamin E, were the first pharmacological options to be evaluated for NASH. In recent years, several new molecules that target different pathways related to NASH pathogenesis, such as liver metabolic homeostasis, inflammation, oxidative stress and fibrosis, have been developed. Obeticholic acid (INT-747) and elafibranor (GFT-505) have provided promising results in phase IIb, randomized, placebo-controlled clinical trials and they are being evaluated in ongoing phase III studies. Most of the potential treatments for NASH are under investigation in phase II studies, with some at phase I. This diversity in possible treatments calls for a better understanding of NASH in order to enrich trial populations with patients more susceptible to progress and to respond. This manuscript aims to review the pharmacological NASH treatment landscape.