Liver and Bile
N Engl J Med. 2024;390(6):497–509
A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis
Background: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor β-selective agonist in development for the treatment of NASH with liver fibrosis.
Methods: The authors are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The 2 primary end points at week 52 were NASH resolution (including a reduction in the non-alcoholic fatty liver disease [NAFLD] activity score [NAS] by ≥ 2 points; scores range from 0–8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least 1 stage with no worsening of the NAS.
Results: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (p < 0.001 for both comparisons with placebo). Fibrosis improvement by at least 1 stage with no worsening of the NAS was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (p < 0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (p < 0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.
Conclusions: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to resolution of non-alcoholic steatohepatitis and improvement in liver fibrosis by at least 1 stage.