Multi-drug approaches to NASH: what’s in the development pipeline?

ABSTRACT

Introduction: The pandemic of obesity over the last two decades has triggered a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is associated with liver-related and cardiovascular complications. Despite this, the first licensed drug for NAFLD is yet to be approved. Given the scale of the problem and unmet needs, there is a myriad of agents in the development pipeline.

Areas covered: We discuss promising agents in early phase clinical trials and categorize these agents based on their action on steatosis, steatohepatitis, and fibrosis. Furthermore, given the multisystemic nature of NAFLD, we consider the effects of these agents on the liver, their cardiometabolic effects, and the potential future strategies of combination therapies.

Expert opinion: The paradigm for the ideal drug is the targeting of both steatohepatitis and fibrosis and the amelioration of cardiometabolic risk factors. New drugs that confer benefit in nonalcoholic steatohepatitis (NASH) must also be tested for their effects on type 2 diabetes mellitus and cardiovascular disease. The treatment of NASH will become analogous to the treatment of hypertension; it is very likely that multiple classes of drugs targeting different mechanistic pathways will be necessary because no single agent is likely to control all aspects of this complex liver disease.

KEYWORDS:

• NAFLD
• NASH
• obesity
• diabetes
• nonalcoholic fatty liver disease
• nonalcoholic steatohepatitis

Article highlights

• Nonalcoholic steatohepatitis (NASH) is a multisystemic disease associated with both liver-related mortality and cardiovascular complications.

• There is an array of promising pharmacological agents for NASH in early phase clinical trials which mediate an antifibrotic effect in the liver through mechanisms such as antagonism of the CC chemokine receptor (types 2 and 5), inhibition of apoptosis signal-regulating kinase 1, and targeting of the bile acid pathway.

• Although some of the pharmacological agents in development for NASH appear to ameliorate fibrosis, the effects of these agents relevant to type 2 diabetes mellitus and cardiovascular disease are mixed. Some agents in development for NASH appear to improve the lipid profile. However, some agents appear to adversely cause a significant increase in low-density lipoprotein cholesterol and triglycerides.

• The multi-mechanistic strategy of combination therapy has the potential to target liver-related changes which include steatosis, steatohepatitis, and fibrosis. Combination therapy also has the potential to treat cardiometabolic risk factors. The challenges associated with combination therapy may be the increased risk of side effects.

• It is important to highlight that pioglitazone is an already available, cost-effective agent which confers both benefits on the cardiometabolic profile and improvement in liver histology.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

CD Byrne is supported in part by the Southampton NIHR Biomedical Research Centre, UK.