The March 2024 approval of resmetirom by the U.S. Food and Drug Administration marked a turning point for adults with metabolic-associated steatohepatitis (MASH) and significant liver scarring. As the first pharmacologic treatment proven to reduce both liver fat and fibrosis in MASH patients, resmetirom offers an essential new option for those with advanced scarring (F2 or F3 on the fibrosis scale) and serves as a critical supplement to diet and exercise.[1]
The FDA estimates that up to 8 million people in the U.S. could qualify for the therapy—a number expected to grow as the prevalence of MASH rises.
The approval of resmetirom, which works by selectively activating thyroid hormone receptor-beta (THR-β) to reduce liver fat, was granted through an accelerated approval pathway due to the disease’s severity and the urgent need for effective treatments. It is indicated for patients with portal fibrosis with few septa or portal fibrosis with numerous septa without cirrhosis, F2 or F3 on the fibrosis scale.
Pivotal MAESTRO-NASH trial validates resmetirom’s impact
The FDA based its decision on the ongoing phase III MAESTRO-NASH trial, which enrolled adults with biopsy-verified MASH with fibrosis stages F1 to F3, liver inflammation and liver fat of at least 8% on MRI-proton density fat fraction. With an average age of 57 and mean BMI of 36, the diverse study population was 89% White, 2% Black and 21% Hispanic. The majority of participants had advanced fibrosis with 62% at F3.[2]
The primary analysis 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.
The results were compelling: 25.9% of the 80 mg group and 29.9% of the 100 mg group achieved MASH resolution with no worsening of fibrosis compared to 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). In addition, fibrosis improved by at least one stage with no worsening of MASLD activity score in 24.2% of the 80 mg resmetirom arm and 25.9% of the 100 mg resmetirom arm versus 14.2% of those receiving placebo (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.
Study showed additional benefits and with few adverse events
Beyond improving liver health, resmetirom significantly reduced low-density lipoprotein (LDL) cholesterol. LDL 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 analyses based on degree of fibrosis, disease activity, diabetes, age and sex showed similar results as the overall study.
Adverse events differed little between the resmetirom groups and placebo arms. Nearly 92% of those who took resmetirom and almost 93% of those taking placebo reported some adverse event, primarily mild gastrointestinal symptoms. The researchers reported no episodes of severe diarrhea and noted that most cases resolved within about 20 days. Participants taking resmetirom experienced more diarrhea and nausea than those taking placebo. Serious adverse events occurred at comparable levels across all three groups: 10.9% in the 80 mg resmetirom group, 12.7% in the 100 mg resmetirom group and 11.5% in the placebo group. Few participants discontinued due to adverse events, 6.8% in the 100 mg group, 1.9% in the 80 mg group and 2.2% in the placebo group had stopped treatment at 52 weeks.
With the potential to slow or reverse liver damage, resmetirom offers a novel therapeutic option for patients with MASH and liver fibrosis. The MAESTRO-NASH trial will continue for 54 months to assess long-term safety and efficacy, including progression to cirrhosis and other liver-related outcomes.
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