Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), is becoming a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC). In fact, NASH has become the leading indication for listing and receiving liver transplantation in women since 2016. Fortunately, there has been tremendous interest in the development of therapeutic agents to treat this epidemic; we anticipate the first FDA approval of a drug to treat NASH in 2020 after the release of positive efficacy results for obeticholic acid in a phase 3 clinical trial. The pipeline for NASH therapeutics is rich and is the focus of this special issue of Expert Opinion on Investigations Drugs.
The reader is introduced to several key drugs in phase II and III clinical development for NASH and is given a comprehensive review of the molecular basis of NASH development and progression. This will provide clinicians and researchers with a deep understanding of the rationale behind the targeting of specific pathways to treat NASH and NAFLD.
An eclectic collection of Drug Evaluation articles includes incisive appraisals of GS-0976 (Firsocostat) and elafibranor. Firsocostat is an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor that blocks de novo lipogenesis in hepatocytes and has yielded promising efficacy data on hepatic fat reduction. Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist that modulates lipid synthesis with potential anti–inflammatory and anti-fibrotic effects within the liver. The phase 3 trial results are expected in early 2020 and if positive, may pave the way for FDA approval.
A selection of discerning editorials examines practical aspects of NASH drug development in terms of the effects of lifestyle changes on clinical trial outcomes and the association between NASH and HCC with implications for surveillance and long-term outcomes.
Original research papers include insights on the utilization of pioglitazone. This agent has proven efficacy against NASH especially in diabetic patients in a representative sample of the United States adult population, highlighting the fact that this medication is underutilized in patients with diabetes and NASH.
Finally, the content is complemented with two interviews with a few key names in the field.
We hope that this special issue of Expert Opinion on Investigational Drugs will be of use to clinicians, researchers, and individuals in the pharmaceutical industry. The references at the end of each article will provide the readers with the background to delve deeper into chosen specific topics. The future looks bright for patients with NASH and the rich drug development pipeline provides hope for a more personalized approach and the possibility of combination therapy to increase efficacy.