Resmetirom (REZDIFFRA) for Nonalcoholic Steatohepatitis (Fatty Liver Disease): Do Not Use

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver for reasons unrelated to excessive alcohol use, as discussed in the December 2023 issue of Worst Pills, Best Pills News. In March 2024, the Food and Drug Administration (FDA) granted accelerated approval for resmetirom (REZDIFFRA) as a treatment for adults with a severe form of the disease known as nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (scarring). Although resmetirom is the first drug to be approved for this condition, its clinical benefits have not been directly established. Moreover, resmetirom can cause gastrointestinal adverse effects, and its long-term safety and effectiveness are unknown. For these reasons, Public Citizen’s Health Research Group has designated resmetirom as Do Not Use. Resmetirom is also expensive: The cost of one year of treatment approaches $50,000.

About fatty liver disease

The terms used to describe fatty liver disease are confusing. NAFLD has recently been renamed metabolic dysfunction-associated steatotic liver disease, a disease that can progress to NASH, which is also now known as metabolic dysfunction-associated steatohepatitis. The prevalence of NAFLD in the United States is approximately 20%, and the prevalence of NASH is approximately 3%-5%.[1],[2] NASH is characterized by inflammation of the liver, which can lead to scarring of the liver (fibrosis and cirrhosis), liver failure and liver cancer.[3] Because the prescribing information for resmetirom uses the term NASH, this article will use that term.

The causes of NAFLD and NASH are not well understood, and effective pharmacologic treatments are lacking.[4] People with NAFLD or NASH frequently also have cardiovascular and metabolic diseases, including diabetes and obesity. Although the recommended treatment for NAFLD and NASH is weight loss through diet and exercise, this approach may be insufficient for people with more severe disease. Other recommendations are to eliminate alcohol consumption, be up to date on hepatitis vaccinations and avoid or lower the dose of drugs that can be toxic to the liver. For NASH, many potential treatments are being investigated.[5] These approaches span metabolic, anti-inflammatory and anti-scarring mechanisms of action. The agents under study include glucagon-like peptide-1 agonists (diabetes and obesity medications), cannabinoid receptors and various growth factors.

Noninvasive tests, including magnetic resonance imaging scans, are increasingly being used as diagnostic and monitoring tools for fatty liver diseases. Diagnosing NASH and providing people with an accurate prognosis are difficult, however. A 2024 commentary in Nature Reviews Endocrinology noted that even a gold standard liver biopsy test for NASH corresponds with a wide range of average improvement (7% to 20%) in fibrosis over time in groups of patients treated with a placebo.[6]

FDA approval of resmetirom

Resmetirom is formulated as a tablet and is taken once daily. The recommended dosage is adjusted based on body weight. According to the prescribing information, the drug should be avoided in patients with decompensated cirrhosis, a form of very severe liver disease.

Resmetirom is a thyroid hormone receptor-beta agonist that is believed to treat NASH, in part, by addressing subcellular (specific parts of cells, such as mitochondria) dysfunction that leads to errant oxidation (loss of negatively charged particles [electrons] through biochemical reactions) and liver fibrosis.[7] Because the accelerated approval of resmetirom was based on surrogate-marker (indirect) evidence of effectiveness, the FDA stipulated that the manufacturer continue its randomized, double-blind trial, scheduled to last 54 months, to determine whether the drug has any meaningful clinical benefit. The results of this trial are unlikely to be available until 2029.[8]

The FDA fast-tracked resmetirom to market approval based on its effects on surrogate endpoints of NASH resolution without worsening of fibrosis and of improvement of liver fibrosis without worsening of NASH. The approval was not based on clinical outcomes, such as reduced rates of liver cirrhosis, liver cancer, liver transplants or death.[9],[10]

The pivotal randomized clinical trial had three arms: 298 adults received 80 milligrams (mg) of resmetirom per day, 296 received 100 mg per day, and 294 received placebo. After one year, 24% to 36% of subjects (depending upon drug dose and the histological reading of two pathologists) who received the drug had resolution of NASH with no worsening of fibrosis, compared with 9% to 13% of subjects in the placebo group. The related endpoint of improvement in liver fibrosis similarly favored resmetirom in approximately 25% of those treated with the drug, compared with 14% treated with placebo. The most common adverse effects were gastrointestinal, such as diarrhea, nausea and vomiting. When resmetirom’s approval was announced, the FDA press release noted concerns about drug-induced liver and gallbladder toxicity and interactions with various drugs, such as statins that are taken to lower cholesterol.

A February 2024 report of the trial in the New England Journal of Medicine added 78 patients to the analysis with similar results. At the beginning of the trial, the mean age of the subjects was 57 years, 89% were White, 67% had type 2 diabetes, 78% had hypertension, 95% had stage 2 or 3 liver fibrosis (where 0 indicates no fibrosis and 4 indicates cirrhosis) and 84% had NAFLD that was histologically confirmed as the more advanced form, NASH. Although diarrhea and nausea were substantially more common with resmetirom than placebo (30% versus 16% and 20% versus 13%, respectively), severe adverse events were slightly less common in the placebo group.

What You Can Do

If you have been diagnosed with fatty liver disease or suspect that you may have NAFLD, NASH or a related condition, discuss with your clinician the best treatment approach. The cornerstone of therapy is diet and exercise to support sustained and healthy weight loss. The disease stabilizes or improves in about 75% of cases, and even advanced forms of the disease may take many years to progress.[11] For patients who require treatment to prevent more severe liver diseases, safe and effective FDA-approved treatments are urgently needed. However, because the long-term safety and effectiveness of resmetirom are not known, Public Citizen’s Health Research Group has designated it a Do Not Use drug.
 

References

[1] Antunes C, Azadfard M, Hoilat GJ, et al. Fatty liver. StatPearls. 2024 Treasure Island (FL): StatPearls Publishing.

[2] Sheth SG, Chopra S. Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults. November 7, 2022. UpToDate.

[3] Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509.

[4] Nonalcoholic fatty liver disease: a disease that is difficult to treat. Worst Pills, Best Pills News. December 2023. https://www.worstpills.org/newsletters/view/1572. Accessed July 9, 2024.

[5] Tincopa MA, Anstee QM, Loomba R. New and emerging treatments for metabolic dysfunction-associated steatohepatitis. Cell Metab. 2024;36(5):912-926.¬¬¬¬

[6] Dufour JF. A pivotal year for NAFLD and NASH therapeutics. Nat Rev Endocrinol. 2024;20(2):75-76.

[7] Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509.

[8] Food and Drug Administration. Accelerated approval letter of resmetirom (REZDIFFRA). March 14, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2024/217785Orig1s000ltr.pdf. Accessed July 9, 2024.

[9] Food and Drug Administration. FDA approves first treatment for patients with liver scarring due to fatty liver disease. March 14, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease. Accessed July 9, 2024.

[10] Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509.

[11] Singh S, Allen AM, Wang Z, et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13(4):643-654.e1-e9.