Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

Abstract

Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

MicroRNA-122 Inhibits Lipid Droplet Formation and Hepatic Triglyceride Accumulation via Yin Yang 1

“…The synthetic FXR agonist GW4064 was able to prevent liver steatosis in obese mice, such as the ob/ob and db/db models [34]. Based on this finding, obeticholic acid (OCA) was proposed for the treatment of NASH as a synthetic FXR agonist [35]. A phase 2 trial showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.…”

NAFLD therapy and monitoring disease progression

“…While available data of its benefit in NASH is limited, a double blind placebo controlled trial of saoglitazor in NASH is currently underway in India (Clinical Trials Registry-India CTRI/2015/10/006236). 85 …”

Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

“…Two strategies directly aiming at preventing and reducing fibrosis in NASH are in clinical development with the caspase inhibitor emricasan in phase IIa and galectin 3 inhibitors in phase I [228,229,[232][233][234]. Although there is also some limited evidence that PPARγ activation itself might have anti-fibrotic activity [235], combination of anti-fibrotic approaches with PPAR agonists holds therapeutic promise.…”

“…Several anti-inflammatory targets have already proven efficacy against this aspect of NASH in animal models or even clinical trials. Except for the anti-oxidative activity of vitamin E, two anti-inflammatory strategies evolve as experimental approaches in NASH treatment [12,228,229]. The chemokine receptor antagonist cenicriviroc blocking the chemokine receptors (CCR)2 and CCR5 is currently the most advanced anti-inflammatory agent in the NASH pipeline.…”