Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults

ABSTRACT

Introduction: Multiple parallel factors are implicated in the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). Currently recommended therapies for NASH include vitamin E and pioglitazone, besides dietary and lifestyle changes.

Areas covered: This review focuses on the clinical development of several emerging drugs for the treatment of NASH and the impact of these drugs on current treatment standards.

Expert opinion: Four drug classes (FXR agonists, CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) have moved into phase 3 trials for their investigation as NASH treatments. Results from phase 2 trials of other therapeutic agents with other pharmacological actions are also expected. The importance of combinational therapies with synergistic benefits engaging different targets, is now understood. Furthermore, studies have determined that the Mediterranean diet is beneficial for patients with NAFLD, while the traditional Okinawan diet is also considered useful. In the future, it will be important to establish new biomarkers to assess NAFLD activity, furthermore non-invasive diagnostic methods will promote the development of new drugs for NASH.

KEYWORDS:

• Non-alcoholic fatty liver disease
• non-alcoholic steatohepatitis
• pharmacologic therapy
• clinical trial

Article highlights

• Currently recommended therapies for NASH include vitamin E and pioglitazone, which are not Federal Drug Administration (FDA)- or European Medicines Agency (EMA)-approved therapies, in addition to dietary and other lifestyle changes.

• Currently, phase III trials of four classes of drugs (FXR agonists [obeticholic acid], CCR2/CCR5 antagonists, ASK1 inhibitors, and PPARα/δ agonists) for the treatment of NASH are under way.

• Phase II trials of FGF21, an FGF19 variant, GLP1, an inhibitor of the apical sodium-dependent bile acid transporter, a pan-caspase inhibitor, selective PPARα modulators, a second-generation FXR, and a thyroid hormone receptor β agonist for the treatment of NASH are under way.

• The Mediterranean diet is the dietary regimen recommended for NAFLD patients; in addition, the traditional Okinawan diet is also considered to be useful to improve the pathogenesis of NAFLD.

• Magnetic resonance elastography (MRE) and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) imaging are used to assess the changes in the degrees of fibrosis and steatosis with therapy. It is also important to establish a new biomarker(s) for assessing the disease activity, such as the NAS. Development of a non-invasive method for the diagnosis of NASH is expected to promote the development of new drugs.

• NAFLD is considered as a precursor of the metabolic syndrome and a multisystem disease. Since multiple parallel factors are implicated in the pathogenesis and progression of NAFLD/NASH, the combination therapies engaging different targets is important to obtain the synergistic effects.

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Declaration of interest

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

The authors were supported by a grant from the Japan Society for the Promotion of Science KAKENHI 18K07637.