The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success

Abstract

Introduction: Numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of nonalcoholic steatohepatitis (NASH) are currently in clinical testing. So far, there are no regulatory approvals.

Areas covered: This paper sheds light on the molecular pathways involved in NASH and the drugs targeting these pathways. We have identified 10 compounds whose clinical development program has been halted. Moreover, we explore early phase clinical trials and dissect the reasons for termination of development.

Expert opinion: The main goal of NASH pharmacotherapy is to halt or reverse hepatic fibrosis or to achieve the resolution of steatohepatitis. There is an intense competition to develop compounds with disease-modulating properties with a focus on anti-metabolic, anti-inflammatory or anti-fibrotic properties. Numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. This underscores the urgent need to provide robust preclinical data and an extensive clinical trial program that builds on reliable data generated in earlier stages of clinical development before moving into late stage development.

Keywords: NAFLD; NASH; discontinued drugs; drug development; fatty liver; nonalcoholic steatohepatitis; pharmacological intervention; phase 2 clinical trial; regulatory approval; regulatory trial.