The March 2024 approval of resmetirom by the U.S. Food and Drug Administration represents a turning point for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH), providing the first pharmacologic therapy shown to reduce both fat and scarring in the liver.1
Approved to treat patients with NASH with moderate to advanced scarring along with diet and exercise, resmetirom is a thyroid hormone receptor-β (THR- β)-selective agonist that triggers a loss of fat in the liver. It is appropriate for patients with portal fibrosis with few septa or portal fibrosis with numerous septa without cirrhosis, F2 or F3 on the fibrosis scale.
In announcing its decision, the FDA estimated that up to 8 million people in the U.S. could qualify for the therapy and that the number was expected to increase.
The FDA used an accelerated approval pathway for resmetirom because of the seriousness and prevalence of NASH and the lack of available therapies. The FDA previously designated resmetirom a breakthrough therapy and granted the drug fast track and priority review status for this indication.
The FDA based its decision on the ongoing phase III MAESTRO-NASH trial. All participants had biopsy-verified NASH with fibrosis stages 1 to 3, liver inflammation and liver fat of at least 8% on MRI-proton density fat fraction. The mean age was 57 years with a mean BMI of 36/kg/m; 89% of the participants were White, 2% Black and 21% Hispanic. Of the participants, 5% had F1B fibrosis, 33% had F2 and 62% had F3.2
The primary analysis of the trial at 12 months included 966 patients randomly assigned on a 1:1:1 basis to receive resmetirom at doses of 80 mg (322) or 100 mg (323) or placebo (321) orally once daily for 52 weeks. Eleven patients were not available for final biopsy analysis due to COVID-19.
Resolution of NASH with no worsening of fibrosis occurred in 25.9% of the participants in the 80 mg resmetirom group and 29.9% of those in the 100 mg resmetirom group compared to 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo).
Fibrosis improved by at least one stage with no worsening of the NAFLD activity score in 24.2% of the patients in the 80 mg resmetirom arm and 25.9% of those in the 100 mg resmetirom arm versus 14.2% of those in the placebo arm (P<0.001 for both comparisons with placebo).
“Demonstration of these changes in a proportion of patients after just one year of treatment is notable, as the disease typically progresses slowly with a majority of patients taking years or even decades to show progression,” noted the FDA in its approval announcement.
The low-density lipoprotein cholesterol levels declined 13.6% from baseline to week 24 in the 80 mg resmetirom group and 16.3% in the 100 mg resmetirom group, while it rose 0.1% in the placebo group (P<0.001 for both comparisons with placebo).
Subgroup analysis – defined by baseline fibrosis score, baseline NAFLD activity score, diabetes status, age and sex – showed similar results as the overall study.
Adverse events were reported by 91.6% to 91.9% of participants who took resmetirom and 92.8% of those taking placebo. Participants taking resmetirom experienced more diarrhea and nausea than those taking placebo, though the researchers reported no episodes of severe diarrhea and cases of diarrhea resolved within about 20 days. All three groups had similar rates of serious adverse events: 10.9% in the 80 mg resmetirom arm, 12.7% in the 100 mg resmetirom arm and 11.5% in the placebo arm.
At week 52, 6.8% of the participants in the 100 mg group, 1.9% in the 80 mg group and 2.2% of those in the placebo group discontinued the trial.
The trial is expected to continue for a total of 54 months to enable long-term safety and assess liver-related outcomes, including progression to cirrhosis.
