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  • Review Article
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Challenges and opportunities in NASH drug development

Nature Medicine volume 29, pages 562–573 (2023)Cite this article

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Abstract

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.

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Fig. 1: Common reasons for screen failure in NASH clinical trials.
Fig. 2: Fibrosis, steatosis, inflammation and ballooning in NASH.
Fig. 3: Targeted pathways for the treatment of NASH.

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Authors and Affiliations

  1. Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Stephen A. Harrison

  2. Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN, USA

    Alina M. Allen

  3. Summit Clinical Research, San Antonio, TX, USA

    Julie Dubourg

  4. Houston Methodist Hospital, Houston, TX, USA

    Mazen Noureddin

  5. Department of Hepatology, Arizona Liver Health, Chandler, AZ, USA

    Naim Alkhouri

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Correspondence to Stephen A. Harrison.

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Competing interests

S.A.H.: grant support for research (Akero Therapeutics, Altimmune, Axcella Health, Cirius Therapeutics, CiVi Biopharma, CymaBay Therapeutics, Enyo Pharma, Galectin Therapeutics, Galmed Research and Development, Genfit, Gilead Sciences, Hepion Pharmaceuticals, HighTide Therapeutics, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Metacrine, NGM Biopharmaceuticals, NorthSea Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, Poxel, Sagimet Biosciences, Terns Pharmaceuticals, Viking Therapeutics, 89Bio), advisory board and/or consultant (Akero Therapeutics, Alentis Therapeutics, Alimentiv, Altimmune, Arrowhead, Axcella Health, Boston Pharmaceuticals, B Riley FBR, ChronWell, Corcept Therapeutics, Echosens North America, ENYO Pharma, Foresite Labs, Galectin Therapeutics, Genfit, Gilead Sciences, GNS, GSK, Hepion Pharmaceuticals, HighTide Therapeutics, HistoIndex, Intercept Pharmaceuticals, Ionis, Kowa Research Institute, Madrigal Pharmaceuticals, Medpace, Merck, Metacrine, NeuroBo, NGM Biopharmaceuticals, NorthSea Therapeutics, Novo Nordisk, Nutrasource, Perspectum Diagnostics, Piper Sandler, Poxel, Sagimet Biosciences, Sonic Incytes Medical, Terns, Viking Therapeutics), stock and/or options (self-managed) (Akero Therapeutics, ChronWell, Cirius Therapeutics, Galectin Therapeutics, Genfit, Hepion Pharmaceuticals, HistoIndex, Metacrine, NGM Biopharmaceuticals, NorthSea Therapeutics). J.D.: shareholder in Poxel. A.M.A.: research support to her institution from Novo Nordisk, Pfizer and Target Pharma and is a consultant for Novo Nordisk and Pfizer. M.N.: advisory board and/or consultant for 89Bio, Altimmune, BI, Gilead, CohBar, CytoDyn, Pfizer, GSK, Novo Nordisk, Echosens, Madrigal, NorthSea, Perspectum, Terns, Takeda, Sami-Sabinsa Group, Siemens and Roche Diagnostics; M.N. has received research support from Allergan, Akero, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; M.N. is a shareholder or has stocks in Anaetos, ChronWell, CytoDyn, Ciema, Rivus Pharma and Viking. N.A.: research funding (89Bio, Akero, AbbVie–Allergan, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking and Zydus), speaker bureau (AbbVie–Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix and Theratechnologies), consultant (AbbVie–Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer and Zydus).

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Harrison, S.A., Allen, A.M., Dubourg, J. et al. Challenges and opportunities in NASH drug development. Nat Med 29, 562–573 (2023). https://doi.org/10.1038/s41591-023-02242-6

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