ABSTRACT
Nonalcoholic steatohepatitis (NASH) is a chronic, progressive inflammatory condition, potentially leading to advanced liver disease and its complications, but no drug treatment has been so far approved. Intrahepatic inflammation is a key driver of oxidative stress and enhanced fibrogenesis, as well as the result of multiple derangements in the cell pathways across metabolic dysfunctions. Insulin resistance, lipid and energy metabolism are relevant pathophysiologic factors affecting NASH and fibrosis. Resolution of liver inflammation is the major endpoint for current clinical trials exploring investigational products. Multiple strategies have been so far explored, with relevant understanding of key disease drivers. This chapter discusses the most relevant approaches in the NASH drug treatment landscape: the selective modulation of peroxisome proliferator-activated receptors and farnesoid X receptor; the improvement of glucose metabolism through incretins of fibroblast growth factors; the role of thyroid hormone metabolism. In addition, an overview of the phase 2 and phase 3 trial failures will help understand the complexity of the NASH treatment approach and suggest strategies to improve the design and conduct of future studies.
