Erin Johanek, PharmD

This article was originally published on 

According to the National Institutes of Health (NIH), nonalcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD). The NIH defines NAFLD as a condition in which a buildup of fat-not caused by heavy alcohol consumption-occurs in the liver. Patients with NASH also have inflammation of the liver, known has hepatitis, and resultant liver cell damage.

 NASH currently affects between 6.5 million to 16.3 million Americans.

Current Management and NASH Pipeline Drugs 

According to the American Association for the Study of Liver Diseases, the management of NASH consists of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and type 2 diabetes.

There are currently no FDA-approved medications for the treatment of NASH, but the guidelines recommend lifestyle modifications like weight loss, pioglitazone (biopsy-proven NASH), and vitamin E as treatment options.

Empagliflozin ( Jardiance) is showing promise for patients with type 2 diabetes and NAFLD based on positive results from the E-LIFT trial and study demonstrating the medication reduces liver fat.

 Intercept has submitted the new drug application for obeticholic acid (Ocaliva) for the treatment of liver fibrosis due to NASH and was granted priority review by the FDA, with a target approval date of March 26, 2020.

Obeticholic acid has a unique mechanism of action as an oral farnesoid X receptor (FXR) agonist. It’s the only therapy the FDA has designated as a Breakthrough Therapy for NASH with fibrosis, according to results from the phase 3 REGENERATE study.

"If approved, obeticholic acid would be the first FDA-approved product for NASH, and it would likely have a year or more marketing head start over the rest of the pipeline," said David Calabrese, RPh, MHP, senior vice president and chief pharmacy officer, OptumRx.

GENFIT is studying elafibranor, an oral medication currently in a phase 3 trial RESOLVE-IT for the treatment of NASH. After a favorable safety review, the study is continuing and expected to be completed in 2021.

 Elafibranor is a dual agonist of PPAR-alpha and PPAR- delta receptors, which both play an important role in numerous processes involved in the development of NASH and its comorbidities. The FDA has granted elafibranor fast track designation for the treatment of NASH.

"Allergan's cenicriviroc and Madrigal Pharmaceutical's resmetirom are in phase 3 trials and are anticipated to be approved in 2021-2022,” said Nicole Kjesbo, PharmD, BCPS, principal clinical program pharmacist, Prime Therapeutics.

The phase 3 study AURORA is currently recruiting an estimated 2000 participants to evaluate cenicriviroc for the treatment of NASH, with topline results expected in the fourth quarter of 2020.

 Resmetirom would be a first- in-class oral thyroid hormone receptor-beta selective agonist, and the phase 3 study MAESTRO-NASH began March 2019.

 The endpoint is resolution of NASH after 1 year of treatment. In addition to the drugs mentioned, Kjesbo revealed there are at least 10 other drugs for the treatment of NASH that are in Phase 2/3 trials and are anticipated to be approved in 2021 and beyond.

"Many of the pipeline drugs are being developed by different manufacturers and some manufacturers are developing multiple drugs for NASH," said Calabrese. "Therefore, there may be potential for combination therapy down the road which would further increase the future cost of treatment."

"This is going to be an emerging category in the coming years," said Kjesbo. "Currently, pharmacotherapy is reserved for NASH patients with fibrosis; it will be interesting to see if lifestyle changes will continue to be the first-line treatment over medications." According to Kjesbo, analysts have forecasted the market for NASH drugs could reach $20 billion by 2025.

1. National Institute of Diabetes and Digestive and Kidney Diseases. Definition & Facts of NAFLD & NASH. National Institute of Health. 

https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts

2. American Liver Foundation. The Silent Liver Diseases You Need to Know About: NAFLD and NASH [infographic]. American Liver Foundation’s website. 

https://liverfoundation.org/wp-content/uploads/2018/04/ALF-NAFLD-NASH-Infographic.pdf

3. Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial (E-LIFT trial). Diabetes Care. 2018. Doi: 

4. Sattar N, Fitchett D, Hantel S, et al. Empagliflozin is associated with improvements in liver enzymes potentially consistent with reductions in liver fat: results from randomized trials including the EMPA-REG OUTCOME® trial. 

https://doi.org/10.1007/s00125-018-4702-3

5. FDA Accepts Intercept’s NDA for OCA for the Treatment of Liver Fibrosis due to NASH and Grants Priority Review [news release]. Intercept’s website. 

http://ir.interceptpharma.com/news-releases/news-release-details/fda-accepts-intercepts-nda-oca-treatment-liver-fibrosis-due-nash

6. GENFIT: Positive 42-month DSMB recommendation for continuation of phase 3 RESOLVE-IT study of elafibranor in NASH. GENFIT’s website. 

https://ir.genfit.com/news-releases/news-release-details/genfit-positive-42-month-dsmb-recommendation-continuation-phase

7. Tobira Therapeutics. AURORA: Phase 3 Study for the Efficacy and Safety of CVC for the Treatment of Liver Fibrosis in Adults With NASH. ClinicalTrials.gov. 

https://clinicaltrials.gov/ct2/show/NCT03028740

8. Madrigal Pharmaceuticals Announces First Patient Dosed in MAESTRO-NAFLD-1, a Second Phase 3 Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of Resmetirom (MGL-3196) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Presumed NASH (NASH/NAFLD (non-alcoholic fatty liver disease)) [news release]. Madrigal’s website. 

https://www.madrigalpharma.com/wp-content/uploads/2019/12/Madrigal-Pharmaceuticals-Announces-Second-Phase-3_NAFLD-1-12-18-2019.FINAL_.pdf

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Analysts have forecasted the market for NASH drugs could reach $20 billion by 2025.