The first medication for the treatment of nonalcoholic steatohepatitis (NASH) and liver fibrosis received accelerated approval. Previously, the only treatment available to patients was implementing lifestyle changes aimed at weight reduction.
The FDA has granted accelerated approval to resmetirom (Rezdiffra; Madrigal Pharmaceuticals), the first medication to treat nonalcoholic steatohepatitis (NASH) and liver fibrosis, in conjunction with diet and exercise.1 Resmetirom is a once daily, oral, thyroid hormone receptor-β selective agonist.
The company priced the drug with an annual wholesale acquisition cost of $47,400.2
The Institute for Clinical and Economic Review had assessed the health-benefit price benchmark for resmetirom to be between $39,600 and $50,100 per year.3
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” Nikolay Nikolov, MD, acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research, said in a statement.1 “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”
The approval was based on 18 clinical studies: 12 phase 1 studies, 2 phase 2 studies, and 4 phase 3 studies. When NASH with liver fibrosis is left untreated, it can increase the risk of cirrhosis, liver failure, liver cancer, and premature mortality, explained Bill Sibold, CEO of Madrigal.4
“Global Liver Institute is thrilled with the FDA's approval of the first-ever medication to treat NASH, Madrigal Pharmaceutical's resmetirom,” Jeff McIntyre, vice president, Liver Health Programs, Global Liver Institute, said in a statement to The American Journal of Managed Care®. “This approval addresses a here-and-now problem by giving current NASH patients medication to address their chronic, progressive disease today. The FDA's action brings those supporting liver patients to an important starting line.”
In 2023, another NASH treatment hopeful was unsuccessful. The FDA issued a complete response letter for obeticholic acid from Intercept Pharmaceuticals.5 A resubmission for the treatment would require the completion of a long-term phase of the REGENERATE study. As a result, Intercept announced it would discontinue investment into NASH.
The approval of resmetirom represents the first FDA-approved treatment available for people with nonalcoholic steatohepatitis with liver fibrosis.
Image credit: SewcreamStudio - stock.adobe.com
NASH is the more advanced form of nonalcoholic fatty liver disease (NAFLD). Approximately 25% of US adults are estimated to have NAFLD,6 and of those patients, 20% may have NASH.7
Currently, the only treatment option available for these patients are lifestyle and behavioral changes aimed at fat reduction, McIntyre explained. The new anti-obesity medications are being studied in NAFLD to focus on weight reduction,8 which could prevent NAFLD from developing into NASH with fibrosis.
The results of the phase 3, randomized controlled trial MAESTRO-NASH were recently published in New England Journal of Medicine.9 The trial included 966 patients in the primary analysis: 322 received 80-mg resmetirom, 323 received 100-mg resmetirom, and 321 received placebo.
Overall, 25.9% of patients on 80-mg resmetirom and 29.9% of patients on 100-mg resmetirom experienced NASH resolution with no worsening of fibrosis compared with just 9.7% on the placebo. In approximately a quarter of patients on resmetirom (24.2% on 80 mg and 25.9% on 100 mg), fibrosis improved by at least 1 stage with no worsening of NALFD activity score compared with 14.2% on placebo.
Most adverse events (AEs) were mild or moderate in severity with the most frequent being diarrhea, COVID-19, nausea, arthralgia, back pain, urinary tract infection, fatigue, pruritus, and vomiting.
“We must now take the pivotal next steps to address coding, reimbursement, and patient access,” McIntyre said. “With this important approval, we dramatically strengthen how liver patients can treat their condition and set the precedent for how other exciting medications in the pipeline can reach NASH patients and those at risk of serious liver disease."
He expects that the approval of a drug for NASH will drum up excitement for other companies with drugs in the pipeline from companies that want to compete and might address a different stage of NAFLD or NASH.
Resmetirom should be available in the US in April and will be distributed through a limited specialty pharmacy network.10
While the approval is technically for NASH, the condition was recently renamed metabolic dysfunction–associated steatohepatitis.11 Hepatologists had expressed concern that the word “alcoholic” had a stigmatizing nature. Similarly, nonalcoholic fatty liver disease was also renamed to metabolic dysfunction–associated steatotic liver disease because of the same concern around the word “fatty.”
References
1. FDA approves first treatment for patients with liver scarring due to fatty liver disease. News release. FDA. March 14, 2024. Accessed March 14, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease
2. Leo L, Sunny ME. US FDA approves first drug for fatty liver disease NASH. Reuters. March 14, 2024. Accessed March 15, 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-approves-first-drug-fatty-liver-disease-nash-2024-03-14/
3. Tice JA, Suh K, Fahim SM, et al. Resmetirom and obeticholic acid for non-alcoholic steatohepatitis (NASH): final evidence report. Institute for Clinical and Economic Review. Published online May 25, 2023. Accessed March 11, 2024. https://icer.org/assessment/nonalcoholic-steatohepatitis-2023/
4. Madrigal Pharmaceuticals announces NDA acceptance and priority review of the new drug application for resmetirom for the treatment of NASH with liver fibrosis. News release. Madrigal Pharmaceuticals. September 13, 2023. Accessed March 11, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority
5. Intercept receives complete response letter from FDA for obeticholic acid as treatment for pre-cirrhotic fibrosis due to NASH. News release. Intercept Pharmaceuticals. June 22, 2023. Accessed March 11, 2024. https://www.globenewswire.com/news-release/2023/06/22/2693358/0/en/Intercept-Receives-Complete-Response-Letter-from-FDA-for-Obeticholic-Acid-as-a-Treatment-for-Pre-Cirrhotic-Fibrosis-due-to-NASH.html
6. Nonalcoholic fatty liver disease (NAFLD). American Liver Foundation. Updated March 7, 2024. Accessed March 11, 2024. https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-fatty-liver-disease-nafld/
7. NASH definition & prevalence. American Liver Foundation. Updated January 18, 2024. Accessed March 11, 2024. https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-definition-prevalence/
8. Nevola R, Epifani R, Imbriani S, et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: current evidence and future perspectives. Int J Mol Sci. 2023;24(2):1703. doi:10.3390/ijms24021703
9. Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509. doi:10.1056/NEJMoa2309000
10. Madrigal Pharmaceuticals announces FDA approval of Rezdiffra (resmetirom) for the treatment of patients with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. News Release. Madrigal Pharmaceuticals. March 14, 2024. Accessed March 14, 2024. https://finance.yahoo.com/news/madrigal-pharmaceuticals-announces-fda-approval-201500691.html
11. Brooks A. From NAFLD to MASLD: 2023 brings new liver disease nomenclature. HCPLive® website. December 13, 2023. Accessed March 11, 2024. https://www.hcplive.com/view/from-nafld-to-masld-2023-new-liver-disease-nomenclature
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