1. In this randomized controlled trial, among patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis, resmetirom was superior to placebo in improving fibrosis.
2. Diarrhea and nausea were the most common adverse events associated with resmetirom.
Evidence Rating Level: 1 (Excellent)
Study Rundown: NASH is a progressive liver disease associated with metabolic dysfunction characterized by fat infiltration resulting in hepatocellular injury, inflammation, and fibrosis. Clinically significant fibrosis carries an elevated risk of adverse outcomes and mortality. Nevertheless, there is no current pharmacologic therapy for NASH. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist designed to improve mitochondrial function and fatty acid b-oxidation – key pathophysiologic mechanisms underlying NASH. This phase 3 trial assessed the safety and efficacy of resmetirom in adults with NASH and liver fibrosis stages F1B-F3 against a placebo. At 52 weeks, significantly higher proportions of participants receiving resmetirom showed histologic NASH resolution and fibrosis improvement by at least one stage compared to placebo. Resmetirom also reduced levels of low-density lipoprotein cholesterol (LDL-C) by 24 weeks compared to placebo. Diarrhea and nausea, but no serious adverse events, were associated with resmetirom. The trial was limited by the lack of clinical outcomes associated with the histologic evaluation and the short duration, although it is ongoing until 54 months. These results demonstrated that resmetirom provided histologic improvements in patients with NASH with fibrosis.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: This study was a phase three, double-blind, randomized, placebo-controlled trial to evaluate resmetirom in treating NASH with liver fibrosis. Patients 18 years of age or older with metabolic syndrome, liver fibrosis between stages F1B, F2, and F3 as demonstrated via FibroScan or biopsy, histologically diagnosed NASH, and non-alcoholic fatty liver disease (NAFLD) activity score of ≥4 were included for randomization. Exclusion criteria included weight instability over the preceding three months, dose changes in glucagon-like peptide-1 agonists in the preceding six months, significant alcohol consumption, HbA1c levels greater than 9.0%, and chronic liver diseases other than NASH. Nine hundred ninety-six patients were randomized 1:1:1 to receive once daily resmetirom at 80mg or 100mg, or placebo. The primary outcomes at 52 weeks were NASH resolution and improvement of fibrosis by at least one stage without worsening of NAFLD activity score. Overall, by week 52, 25.9% of patients who received 80mg resmetirom and 29.9% of those who received 100mg resmetirom saw NASH resolution without worsening of fibrosis, compared to 9.7% of those receiving placebo (p<0.001). Conversely, fibrosis improvement by at least one stage without worsening of NAFLD activity score was seen in 24.2% of the 80mg resmetirom recipients, 25.9% of the 100mg resmetirom recipients, versus 14.2% of the placebo recipients (P<0.001). The change from baseline in LDL-C at 24 weeks was -13.6% for patients who received 80mg resmetirom, -16.3% for those who received 100mg resmetirom, and 0.1% for those receiving placebo (p<0.001). In summary, resmetirom was demonstrated in this trial to improve NASH and liver fibrosis.
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