Challenges and opportunities in NASH drug development

Stephen A. Harrison, Alina M. Allen, Julie Dubourg, Mazen Noureddin, Naim Alkhouri

Research output: Contribution to journalReview articlepeer-review

73 Scopus citations


Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials. Over the past decades, several non-invasive tests have been developed to correlate with liver histology and, eventually, outcomes to assess disease severity and longitudinal changes non-invasively. However, further data are needed to ensure their endorsement by regulatory authorities as alternatives to histological endpoints in phase 3 trials. This Review describes the challenges of drug development in NAFLD–NASH trials and potential mitigating strategies to move the field forward.

Original languageEnglish (US)
Pages (from-to)562-573
Number of pages12
JournalNature Medicine
Issue number3
StatePublished - Mar 2023


  • Humans
  • Non-alcoholic Fatty Liver Disease/drug therapy
  • Liver/pathology
  • Liver Cirrhosis/pathology
  • Drug Development
  • Severity of Illness Index

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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