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The first FDA-approved product for NASH on the horizon.
According to the National Institutes of Health (NIH), nonalcoholic steatohepatitis (NASH) is a form of nonalcoholic 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.
According to the American Liver Foundation (ALF), NASH currently affects between 6.5 million to 16.3 million Americans, and up to 25% of adults with NASH may also have liver cirrhosis. By 2030, ALF reports NASH is expected to be the most frequent reason for liver transplants in the United States.
Current management and NASH pipeline drugs
According to the American Association for the Study of Liver Diseases the management of patients with NASH consists of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus.
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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 Diabetologia 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," says 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,” says Nicole Kjesbo, PharmD, BCPS, principal clinical program pharmacist, Prime Therapeutics.
The phase 3 study AURORA is currently recruiting an estimated 2,000 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 one 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 II/III 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," says 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," says 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.
Erin Johanek, PharmD, RPh is a staff pharmacist at Southwest General Health Center, Middleburg Heights, Ohio.