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Therapeutic pipeline in nonalcoholic steatohepatitis

Abstract

Our understanding of nonalcoholic fatty liver disease pathophysiology continues to advance rapidly. Accordingly, the field has moved from describing the clinical phenotype through the presence of nonalcoholic steatohepatitis (NASH) and degree of fibrosis to deep phenotyping with a description of associated comorbidities, genetic polymorphisms and environmental influences that could be associated with disease progression. These insights have fuelled a robust therapeutic pipeline across a variety of new targets to resolve steatohepatitis or reverse fibrosis, or both. Additionally, some of these therapies have beneficial effects that extend beyond the liver, such as effects on glycaemic control, lipid profile and weight loss. In addition, emerging therapies for NASH cirrhosis would have to demonstrate either reversal of fibrosis with associated reduction in portal hypertension or at least delay the progression with eventual decrease in liver-related outcomes. For non-cirrhotic NASH, it is the expectation that reversal of fibrosis by one stage or resolution of NASH with no worsening in fibrosis will need to be accompanied by overall survival benefits. In this Review, we summarize NASH therapies that have progressed to phase II and beyond. We also discuss some of the potential clinical challenges with the use of these new therapies when approved.

Key points

  • There are several novel treatments currently under development for treatment of non-cirrhotic and cirrhotic nonalcoholic steatohepatitis.

  • Resolution of steatohepatitis and reversal of fibrosis are two important histological end points in the ongoing clinical trials.

  • Emerging therapies are beginning to differentiate through extra-hepatic benefits such as improvement in glycaemic control, lipid profile and weight loss.

  • Safety and tolerability of the emerging therapies will determine compliance that would result in sustained benefits and, ultimately, improvement in long-term survival.

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Fig. 1: Mechanism of action of NASH drugs currently in phase II and phase III development.
Fig. 2: The design of phase III RCTs currently testing medications to treat NASH.
Fig. 3: Major causes of morbidity and mortality in various NAFLD subphenotypes.

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Acknowledgements

We acknowledge N. Chalasani for his thoughtful review and suggestions. We thank Y. Rahimi for sharing the detailed list of drug candidates currently under development for NASH and their timelines as listed on ClinicalTrials.gov.

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The authors contributed equally to substantial discussion of content, writing and reviewing/editing the manuscript before submission. R.V., M.N. and N.A. researched data for the article.

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Correspondence to Arun J. Sanyal.

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R.V. has received consulting fees for serving on the Data Safety Monitoring Boards for Covance, Enyio and Enanta; R.V. also received research grant support from Gilead Sciences, Zydus Discovery, Cara Therapeutics, Novo Nordisk, Eli Lilly, Astra Zeneca, Terns Pharmaceuticals and Intercept where his institution receives the funding; M.N. has been on the advisory board or a speaker for Allergan, Gilead, Intercept, Pfizer, Novartis, Blade, EchoSens North America, OWL, Simply Speaking and Abbott; M.N. has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Novartis, Shire and Zydus; M.N. is a minor shareholder or has stocks in Anaetos and Viking. N.A. has received research funding from Albireo, Akero, Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Galmed, Genfit, Gilead, Intercept, Madrigal, MedImmune, Novartis, Novo Nordisk, Pfizer, Poxel and Zydus, and has acted as a speaker for AbbVie, Alexion, Allergan, Eisai, Exelixis, Gilead, Intercept and Salix and as a consultant for Allergan, Gilead and Intercept. A.J.S. is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect, Exalenz and Hemoshear; A.J.S. has served as a consultant to AstraZeneca, Nitto Denko, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Fibrogen, Jannsen, Gilead, Lilly, Poxel, Artham, Cymabay, Boehringer Ingelheim, Novo Nordisk, Bird Rock Bio, Novartis, Pfizer, Jannsen and Genfit; A.J.S. has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Afimmune, ChemomAb, Nordic Bioscience and Bristol Myers Squibb; his institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, AstraZeneca, Mallinckrodt, Cumberland and Novartis; A.J.S. receives royalties from Elsevier and UptoDate.

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Nature Reviews Gastroenterology & Hepatology thanks H. Cortez-Pinto, V. Ratziu and V.S. Wong for their contribution to the peer review of this work.

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Related links

ClinicalTrials.gov: https://clinicaltrials.gov/

Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): https://litmus-project.eu/

Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE): https://fnih.org/what-we-do/biomarkers-consortium/programs/nimble

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Vuppalanchi, R., Noureddin, M., Alkhouri, N. et al. Therapeutic pipeline in nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 18, 373–392 (2021). https://doi.org/10.1038/s41575-020-00408-y

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