Emerging synthetic drugs for the treatment of liver cirrhosis

ABSTRACT

Introduction: The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically.

Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials.

Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.

KEYWORDS:

• Liver cirrhosis
• fibrosis
• hepatic stellate cell
• extracellular matrix
• nonalcoholic steatohepatitis
• synthetic drugs
• noninvasive biomarkers

Acknowledgement

The authors would like to thank Aurora Piñas-Fernández (Edinburgh Innovations, University of Edinburgh, UK) for assistance in searching Pharma market intelligence databases.

Declaration of interest

JA Fallowfield has served as a consultant or advisory board member for Novartis, Ferring Pharmaceuticals, Macrophage Pharma, Aquilla BioMedical, Galecto Biotech, Caldan Therapeutics, Cypralis Ltd, Rallybio, Tectonic, Gilde Healthcare, Guidepoint, Techspert.io and has received research grant funding from Novartis and Intercept Pharmaceuticals. M Jimenez-Ramos is an iCASE PhD student funded by the Medical Research Council and Galecto Biotech. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.