Current and future pharmacological therapies for NAFLD/NASH

Area of Science:

• Hepatology and Gastroenterology
• Pharmacology and Drug Development
• Metabolic Diseases

Background:

• Nonalcoholic fatty liver disease (NAFLD) is the most common liver condition globally, with no approved drug therapies.
• Nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD, has established treatments like vitamin E and pioglitazone.
• Emerging drug classes, including GLP-1 receptor agonists (GLP-1RA) and SGLT2 inhibitors, show early promise for NASH and offer cardiovascular/renal benefits.

Purpose of the Study:

• To review innovative therapeutic pathways for nonalcoholic steatohepatitis (NASH).
• To highlight key drug targets including hepatic fat accumulation, oxidative stress, inflammation, apoptosis, gut microbiome, and hepatic fibrosis.
• To identify promising drug candidates currently in advanced clinical trials.

Main Methods:

• Review of current literature on NAFLD and NASH pharmacotherapy.
• Categorization of novel therapeutic strategies based on molecular targets.
• Identification of drugs in ongoing Phase 3 clinical trials for NASH treatment.

Main Results:

• Four main therapeutic pathways are being explored: targeting hepatic fat, oxidative stress/inflammation/apoptosis, gut microbiome/endotoxemia, and hepatic fibrosis.
• Specific drug examples include peroxisome proliferator-activator receptors modulators, farnesoid X receptor agonists, de novo lipogenesis inhibitors, fibroblast growth factor-21 analogues, apoptosis signaling kinase 1 inhibitors, caspase inhibitors, and antifibrotic agents.
• Obeticholic acid (OCA), elafibranor, ASK1 inhibitor, and cenicriviroc (CVC) are in international Phase 3 trials for NASH.

Conclusions:

• Multiple innovative therapeutic strategies are under investigation for NASH.
• The development of targeted therapies targeting diverse pathways offers significant hope for managing NASH.
• The availability of new treatments in the near future could significantly impact the rising incidence of NASH-related complications.