Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis

ABSTRACT

Introduction

Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important.

Areas covered

This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis.

Expert opinion

Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.

KEYWORDS:

• Non-alcoholic fatty liver disease
• non-alcoholic steatohepatitis
• obeticholic acid
• fibroblast growth factor
• peroxisome proliferator-activated receptors

Article highlights

• Since liver fibrosis has been shown to be an important factor contributing to carcinogenesis and prognosis, the development of drugs targeting liver fibrosis will continue to be the focus.

• Drugs targeting various pathways may be a potential treatment for fibrosis in NASH.

• Among current NASH agents, thiazolidinediones, SGLT2 inhibitors, and PPAR agonists have been reported to be effective against fibrosis, but further evidence is needed.

• In the development stage therapeutics for NASH, the effects of Pan-PPAR agonist, FXR agonist, and FGF21 analogs on liver fibrosis are particularly interesting.

• In addition, we are focusing on combination therapies that act on multiple metabolic and inflammatory pathways.

Abbreviations

ACC, acetyl-CoA-carboxylase; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; ASK-1, apoptosis signal-regulating kinase-1; CCR2/5, C-C chemokine receptors 2 and 5; DGAT2, diacylglycerol acyltransferase 2; ER, endoplasmic reticulum; FAS, fatty acid synthase; FFA, free fatty acid; FGF19, fibroblast growth factor 19; FGF-21, fibroblast growth factor 21; FXR, farnesoid X receptor; GLP1, glucagon‑like peptide 1; HSC, hepatic stellate cell; HSP47, heat shock protein 47; LOLX2, lysyl oxidase-like; PPAR, peroxisome proliferator‑activated receptor; ROS, reactive oxygen species; SCD1, stearoyl‑CoA desaturase 1; SGLT2, sodium-glucose co-transporter 2; SREBP1, sterol regulatory element binding protein 1; SSAO/VAP1, semicarbazide-sensitive amine oxidase/vascular adhesion protein-1; CA cycle, citric acid cycle; TLR4, toll-like receptor 4; THR‑β, thyroid hormone receptor β

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.

Acknowledgments

The administrative assistance of Nahoko Kobayashi, Ayako Ujiie, Yoshiko Yamazaki, Kyoko Kato, and Hiroyuki Abe is gratefully acknowledged.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.