What is the (right) target for non-alcoholic fatty liver disease (NAFLD)?

Non-alcoholic fatty liver disease (NAFLD) is of increasing prevalence globally. While lifestyle modifications are recommended, many patients do not succeed to achieve significant and maintained weight loss from lifestyle and as such there is a high unmet need for pharmacotherapy in this group. Comparable to other metabolic diseases including diabetes and dyslipidaemia, a high proportion of patients will likely benefit from permanent pharmacological therapy. Currently there are many compounds with different mechanisms of action in clinical development including metabolic, anti-inflammatory and antifibrotic drugs. A number of phase 3 clinical trials are currently ongoing including Elafibranor, a dual PPAR alpha/delta agonist, Cenicriviroc, a CCR2/CCR5 chemokine antagonist, the nuclear bile acid receptor FXR agonist obeticholic acid, Aramchol, a fatty acid bile acid conjugate that modulates SCD-1, and Resmetrion, a liver-specific THR-beta agonist. Further studies with promising pathophysiological mechanisms of action, e.g. the ASK-1 inhibitor Selonsertib or the caspase inhibitor Emricasan have shown negative results. However, some are being further evaluated in combination therapies. The complex pathophysiology of the disease, which combines inflammation, metabolism and fibrosis, has led to the fact that even combinations of several substances are investigated with different modes of action. This review summarizes pivotal clinical trials for patients with NASH in the absence of cirrhosis which are recruiting in the fall of 2019.