Assessment of Resmetirom Efficacy (80 mg vs. 100 mg) Stratified by Baseline Body Mass Index and Weight in Patients From the MAESTRO-NASH Trial

Noureddin and colleagues presented a second analysis of the MAESTRO-NASH trial, which focused on the efficacy of resmetirom according to baseline BMI and weight.¹ The recommended dosage of resmetirom is based on actual body weight; for patients weighing under 100 kg, the recommended dosage is 80 mg orally once daily, whereas for patients who weigh 100 kg or more, the recommended dosage is 100 mg orally once daily.²

The only variable found to determine exposure to resmetirom among patients with MASH was body weight. Pharmacokinetic modeling indicated that patients with a higher exposure to resmetirom showed a higher rate of sex hormone-binding globulin (SHBG) response (>120% increase in SHBG) and also a higher rate of MRI-PDFF response (>30% reduction in MRI-PDFF). More patients treated with resmetirom 100 mg vs resmetirom 80 mg achieved these targets for SHBG and PDFF, with differences between doses occurring primarily in patients with a body weight of 100 kg or more.

These data provide reassurance that dosing resmetirom based on the prescribing information provided by the FDA (80 mg daily for those with weight <100 kg and 100 mg daily for those with weight >100 kg) is appropriate and will not be associated with lower response rates with the lower dose. Providers should strive to keep patients who weigh over 100 kg, or who have a BMI of 35 or more, on the higher dose.

— Naim Alkhouri, MD

Further exposure modeling showed that higher exposure to resmetirom was also associated with higher rates of both MASH and fibrosis responses on biopsy (Figure 4). Among patients weighing less than 100 kg, the rate of MASH resolution was 32% and 36% among patients treated with resmetirom 80 mg and resmetirom 100 mg, respectively. In patients weighing 100 kg or more, the rate of MASH resolution was 27% and 36% in the resmetirom 80 mg and resmetirom 100 mg treatment groups, respectively. For the outcome of fibrosis improvement, among patients weighing less than 100 kg, 35% and 34% achieved fibrosis improvement with resmetirom 80 mg and resmetirom 100 mg, respectively. In patients weighing 100 kg or more, the rate of fibrosis improvement was 23% and 33% in the resmetirom 80 mg and resmetirom 100 mg treatment groups, respectively.

Figure 4.

Liver biopsy responses to resmetirom doses of 80 mg and 100 mg in patients with MASH from the MAESTRO-NASH trial stratified by weight. Paired biopsy population (both baseline and week 52 not placebo corrected). MASH, metabolic dysfunction-associated steatohepatitis. Adapted from Noureddin M, et al. AASLD abstract 1644. Hepatology. 2024;80(suppl 1).¹

Among patients who had both a baseline and week 52 liver biopsy, equivalent biopsy responses for both MASH resolution (22% with resmetirom 80 mg and 21% with resmetirom 100 mg) and fibrosis improvement (13% with resmetirom 80 mg and 12% with resmetirom 100 mg) were achieved in patients with a BMI less than 35. However, among patients with a higher BMI (>35), the rates of MASH resolution (10% with resmetirom 80 mg and 20% with resmetirom 100 mg) and fibrosis improvement (7% with resmetirom 80 mg and 11% with resmetirom 100 mg) were both higher with resmetirom 100 mg.

Other biomarkers, such as ALT, FibroScan, and controlled attenuation parameter, showed similar improvements relative to placebo at both resmetirom doses.

The frequency of diarrhea was higher with the resmetirom 100 mg dose compared with the resmetirom 80 mg dose (33.4% vs 27.0%) and was higher with both than with placebo (15.6%). The rate of discontinuation owing to an AE was higher with resmetirom 100 mg (6.8%) but was relatively similar between resmetirom 80 mg (1.9%) and placebo (2.2%). Further, the rate of overall discontinuations of the resmetirom 100 mg dose was highest in the lower body weight group (19% in the <100 kg group compared with 17% in the >100 kg group), but the opposite was true for the resmetirom 80 mg dose (10% in the <100 kg group compared with 15% in the >100 kg group).