An update on drug development for the treatment of nonalcoholic fatty liver disease – from ongoing clinical trials to future therapy

ABSTRACT

Introduction

Nonalcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence of 25% in the general population. Given the epidemic increase, regulatory agencies have defined an unmet medical need and implemented initiatives to expedite the development of drugs for NASH treatment.

Areas covered

Literature search in Medline and worldwide web was accessed latest in 23.01.2021. In recent years new drugs acting on various pathophysiological processes in NASH have entered clinical development. These drugs combine beneficial metabolic effects with anti-inflammatory and anti-fibrotic effects to treat NASH. Current drug classes being investigated for NASH treatment are agonists of nuclear receptors such as FXR agonists (including FGF19), PPAR agonists, chemokine receptor inhibitors, thyroid hormone receptor-ß agonists and analogues of enterohepatic hormones including GLP-1 and FGF21 or SGLT2 inhibitors.

Expert opinion

Obeticholic acid is the only drug with significant benefit in the phase 3 interim results and remains the candidate for first conditional approval as a NASH therapeutic. However, monotherapy with these drugs leads to a histological resolution of NASH in less than one-third of patients in recent trials. Therefore, the future of NASH therapy will putatively be a combination therapy of two different drug classes with complementary effects.

KEYWORDS:

• NAFLD
• NASH
• fatty liver
• noninvasive testing
• clinical studies
• therapeutics

Article highlights

• Patients at risk for progression are candidates for therapeutic intervention and should be identified by non-invasive screening algorithms.

• Current drug classes being investigated for NASH treatment combine beneficial metabolic effects with anti-inflammatory and anti-fibrotic effects: agonists of nuclear receptors FXR and PPAR, thyroid hormone receptor-ß agonists, analogues of enterohepatic hormones GLP-1 and FGF21, SGLT2 inhibitors.

• Negative interim results from ongoing phase 3 trials document the complexity of the pathophysiological scenario underlying NASH fibrosis.

• Obeticholic acid is currently the only drug with significant histological benefit in phase 3 interim analysis.

• Obeticholic acid remains the candidate for first conditional approval as a NASH therapeutic.

• Since monotherapy leads to a histological resolution of NASH and/or fibrosis in less than one-third of patients in recent trials, the future will putatively be a combination therapy of two different drug classes with complementary effects.

Declaration of interest

A. Geier has declared receiving grants from Intercept, Novartis, Exalenz, Falk and Kibion and has received personal fees from Intercept, Novartis, Gilead, Pfizer, Falk, MSD, BMS, Ipsen, Sanofi-Aventis, Bayer, Eisai, CSL Behring, Sequana, Merz, Abbvie, and Alexion. 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 in this manuscript have no relevant financial or other relationships to disclose.