In NASH with liver fibrosis, resmetirom improved NASH resolution and reduced fibrosis at 1 y
This was an interim analysis of an industry trial, and final results are needed to determine whether patients with nonalcoholic (or metabolic dysfunction-associated) steatohepatitis (NASH) show clinically meaningful benefits, an ACP Journal Club commentary said.
An interim analysis of an industry-funded, randomized trial found that oral resmetirom, at 80 mg or 100 mg per day, improved resolution of nonalcoholic steatohepatitis (NASH), also referred to as metabolic dysfunction-associated steatohepatitis, and reduced fibrosis stage compared with placebo at one year. NASH resolved with no worsening of fibrosis in 25.9% of the 80-mg group and 29.9% of those in the 100-mg group versus 9.7% of those in the placebo group. Fibrosis improved by at least one stage with no worsening of the nonalcoholic fatty liver disease activity score in 24.2%, 25.9%, and 14.2%, respectively.
The study was published Feb. 7, 2024, by the New England Journal of Medicine. The following commentary by Maria Mironova, MD, ACP Resident/Fellow Member, and Averell H. Sherker, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on June 4.
Harrison and colleagues report an interim analysis of the ongoing MAESTRO-NASH phase 3, multicenter, clinical trial of resmetirom in patients with NASH (also referred to as metabolic dysfunction–associated steatohepatitis, or MASH) sponsored by Madrigal Pharmaceuticals. Resmetirom is an oral, liver-directed, thyroid hormone receptor (THR)-β–selective agonist. THR-β activation is associated with systemic lipid reduction, increased bile acid synthesis, and β-oxidation of fatty acids—all favorable effects in NASH.
Adults with precirrhotic NASH with fibrosis received once daily resmetirom, 80 or 100 mg, or placebo for 54 months. This analysis reports blinded liver biopsy readings for 966 patients at 1 year. Both doses of resmetirom increased U.S. Food and Drug Administration (FDA) histologic end points of improvement of fibrosis or resolution of NASH compared with placebo. The resmetirom groups were not compared with each other. Importantly, histologic improvement occurred without meaningful weight loss. Resmetirom groups had reduced atherogenic lipids. At baseline, about 15% of patients across all groups were receiving stable doses of glucagon-like peptide-1 receptor agonists and about 50% were receiving statins.
The trial was performed during the COVID-19 pandemic, and adverse events were common in all treatment groups. Diarrhea and nausea were more frequent in the resmetirom groups, and discontinuation of the trial due to adverse events was more frequent in the group receiving resmetirom, 100 mg/d.
Final results of the 54-month trial will be important to determine if meaningful clinical outcomes are achieved. Additionally, it will be important to evaluate if endocrinopathy or bone disease are increased as a result of the slightly altered thyroid status observed with resmetirom at 1 year.
On 14 March 2024, through the accelerated pathway, the FDA approved resmetirom for use with diet and exercise for treating adults with noncirrhotic NASH with moderate to advanced fibrosis. It remains to be seen whether this approval will affect the liver disease and extrahepatic manifestation of NASH.