DAY 3 - Higher-Dose Resmetirom Is the Best Strategy for Overweight Patients with Metabolic Dysfunction-Associated Steatohepatitis

The latest analysis of data from the ongoing MAESTRO-NASH clinical trial confirmed that patients with metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis who have a high body weight (>100 kg) need a higher dose of resmetirom to achieve optimal histologic response.

A post-hoc analysis showed that people with MASH, formerly known as nonalcoholic steatohepatitis (NASH), who weighed more than 100 kg or had a body mass index (BMI) of more than 35 kg/m² had a better response with the 100 mg dose of resmetirom than with the 80 mg dose. Lead author Mazen Noureddin, MD, MHSc, a hepatologist at Houston Methodist Hospital in Houston, Texas, presented the findings at the ACG 2024 Annual Scientific Meeting in Philadelphia, Pennsylvania.

MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled phase 3 trial designed to evaluate the efficacy of resmetirom in patients with biopsy-confirmed MASH/NASH and fibrosis. A total of 966 patients were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo, administered once daily. The dual histologic endpoints, which consisted of resolution of disease with no worsening of fibrosis and at least one-stage reduction in fibrosis with no worsening of NASH activity score (NAS), were achieved with both doses at week 52. 
After the initial results showed that body weight was the major factor influencing exposure to resmetirom in patients with steatohepatitis, Noureddin and colleagues further explored the relationship between resmetirom dose, baseline body weight, and BMI.

“The only variable that determined exposure to resmetirom in the NASH population was body weight,” Noureddin explained. “More patients treated with 100 mg when compared with 80 mg achieved targets for sex hormone binding globulin (SHBG) and MRI-proton density fat fraction response (MRI-PDFF).” PDFF reduction was highly associated with NASH resolution and improvement in fibrosis in patients treated with resmetirom. The presenter noted that the dose-related differences in response were seen primarily in patients who weighed at least 100 kg. These findings reinforce the dosing recommendations for resmetirom, which are based on actual body weight.

“Slightly lower rates of fibrosis improvement and NASH resolution on biopsy were observed in patients who weighed at least 100 kg or had a BMI of 35 kg/m² or higher and were treated with 80 mg versus 100 mg,” the author added. “Responses on FibroScan in resmetirom-treated patients were durable out to 3 years of treatment and showed improvement and less worsening than placebo.” 
Noureddin also reported that discontinuation of therapy and adverse events, such as diarrhea, were more common with the 100 mg dose. However, the highest rates of discontinuation at 100 mg were documented in patients with a lower body weight (<100 kg).