Nonalcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease (NAFLD). Like its name states, NASH occurs without excessive alcohol consumption. It causes inflammation of the liver that may damage or cause scarring, known as liver fibrosis.1
NASH falls in the spectrum of NAFLD along with fatty liver and Cirrhosis (scar tissue replaces liver cells). While symptoms of NASH include loss of appetite, swelling in the legs, jaundice and nausea, many patients are often asymptomatic and are unaware that something is wrong. Without symptoms to identify and treat, NASH can proceed to end-stage liver disease or the need for a liver transplant. In fact, 20% of patients with NASH may develop cirrhosis2 and they have a reported 12x increased risk of liver cancer.
Currently, NAFLD is estimated to be present in 25% of the world’s population.3 This includes 1.5% to 6.5%3 of U.S. adults. In the U.S., the estimated annual healthcare cost associated with NAFLD was approximately $103 billion and a ten-year economic burden of $908 billion.4
Even with its high prevalence of disease, there are currently no FDA-approved medications for NASH. However, two pipeline drugs, obeticholic acid and resmetirom, have been submitted for approval. These drugs–most likely classified as specialty–could have significant impact to plan sponsors, providers and patients due to cost, safety and appropriateness.
There are multiple pathways to NASH and the buildup of fat in the liver, which makes it a difficult condition to develop a pharmacological treatment.5,6
Here are the ways NASH may develop.
Free fatty acids (FFA) are released from body fat due to insulin resistance and dietary sugar induced lipid synthesis.7 The insulin resistance contributes to the development of NAFLD and may promote progression of the disease.5
FFA are stored as triglycerides or metabolized into lipotoxic lipids (such as cholesterol or diacylglycerol) and create oxidative stress, which can cause damage to organs and tissues including the liver.
Reduced activity of antioxidants such as:
Coenzyme Q10 used for growth and maintenance
Superoxide dismutase enzyme that may prevent tissue damage.
Reduced levels of glutathione that helps with tissue building and repair.
The endoplasmic reticulum (ER), which produces proteins for the cell to function, may be stressed due to increased FFA. This can cause cell injury and inflammation.6
A leaky gut causes microbiota imbalance and contributes to inflammation in the liver.
With no FDA-approved treatments for NASH, current treatments focus on preventing further fibrosis and other liver-related and cardiovascular complications.
These include:
Weight loss: May improve liver histology, liver biochemical test, insulin levels and the patient’s quality of life. A weight loss goal of 7% to 10% is recommended in most overweight (BMI >25 kg/m2) or obese (BMI >30 kg/m2) patients. Bariatric surgery may be considered for select patients who have not achieved their weight loss goal after six months.
Limited Pharmacologic Treatment Options such as Vitamin E, Pioglitazone or GLP-1 agonist.
Successful drug development and FDA approval is dependent on the use of accurate efficacy endpoints. While the goal of NASH treatment is to slow or reverse disease progression and improve clinical outcomes including liver-related mortality, these markers are not practical as clinical endpoints.12
Drug development for NASH is also limited by the need for multiple biopsies to monitor disease progression and the lack of non-invasive biomarkers that could improve study design and feasibility.13 The chronic nature of the disease may require a study duration exceeding 10 years or more to show improvement in clinical outcomes.13
As a result of these challenges, the FDA has recommended liver histological improvements as appropriate surrogate endpoints that could support a clinical benefit and lead to an accelerated approval.
The recommended endpoints are based on the NAFLD Activity Score (NAS), which is a numerical score that measures steatosis, inflammation, and improvement of liver fibrosis stage.12
Two products that could receive FDA accelerated approval by 2024 are obeticholic acid and resmetirom.
| Drug | Manufacturer | Route | Mechanism | Estimated Approval |
| Obeticholic Acid | Intercept Pharma | Oral | Farnesoid X receptor agonist | 06/22/2023 |
| MGL-3196 Resmetirom | Madrigal Pharmaceuticals | Oral | Thyroid hormone receptor agonist | Q4 2023 |
NASH has a high prevalence of disease, so a new medication approval could have significant patient and provider interest. However, when it comes to these approvals, patients may not see the benefits of a NASH drug for many years, as some of the biggest disease concerns are progression to liver fibrosis, cirrhosis, or cancer. If a new drug has significant safety concerns, the provider will need to weigh the risk versus the benefit before prescribing.
Due to the various possible mechanisms of disease development and the variation in patients, development of one drug that resolves NASH and halts fibrosis in all patients is unlikely. It is most likely that a NASH treatment may not be a one-size-fits-all answer.
The impact of NASH medication approvals will be in commercial and Medicare plans due to the age range of the diagnosed patients. Many NASH medications, if approved, may also find their way on the prescription benefit, and be self-administered.
Elixir will continue to monitor the pipeline and approval process. Once any of the NASH medications are FDA approved, a drug or biologic undergoes clinical review by the Elixir P&T Committee.
REFERENCES:
1. Definition & Facts of NAFLD & Nash - NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health and Human Services, Apr. 2021, https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts#:~:text=NASH%20is%20the%20form%20of,is%20scarred%20and%20permanently%20damaged
2. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-1419. doi:10.1016/S0016-5085(99)70506-8
3. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10. 1002/hep.28431
4. Younossi, Z. M., Blissett, D., Blissett, R., Henry, L., Stepanova, M., Younossi, Y., Racila, A., Hunt, S., & Beckerman, R. (2016). The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology (Baltimore, Md.), 64(5), 1577–1586. https://doi-org.neomed.idm.oclc.org/10.1002/hep.28785
5. Peng, C., Stewart, A. G., Woodman, O. L., Ritchie, R. H., & Qin, C. X. (2020). Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments. Frontiers in pharmacology, 11, 603926. https://doi.org/10.3389/fphar.2020.603926
6. Rinella, Mary E.1; Neuschwander-Tetri, Brent A.2; Siddiqui, Mohammad Shadab3; Abdelmalek, Manal F.4; Caldwell, Stephen5; Barb, Diana6; Kleiner, David E.7; Loomba, Rohit8. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology ():10.1097/HEP.0000000000000323, March 17, 2023. | DOI: 10.1097/HEP.0000000000000323
7. Noureddin, M., & Sanyal, A. J. (2018). Pathogenesis of NASH: The Impact of Multiple Pathways. Current hepatology reports, 17(4), 350–360. https://doi.org/10.1007/s11901-018-0425-7
12. US Food and Drug Administration. Noncirrhotic Nonalcoholic Steatohepatitis with Liver Fibrosis: Developing Drugs for Treatment. Guidance for Industry. Draft Guidance. December 2018. https://www.fda.gov/media/119044/download. Accessed 3/31/23.
13. Ocker M. (2020). Challenges and opportunities in drug development for nonalcoholic steatohepatitis. European journal of pharmacology, 870, 172913. https://doi.org/10.1016/j.ejphar.2020.172913
14. IPD analytics. www.IPDanalytics.com. Accessed 3/31/2023.