Resmetirom delivers improved outcomes for NASH patients with fibrosis
The THR-β selective agonist resmetirom helps resolve nonalcoholic steatohepatitis (NASH) and reduce fibrosis, with the drug being safe and well-tolerated, according to data from the large phase III pivotal MAESTRO-NASH trial presented at EASL 2023.
Compared with placebo, resmetirom at either 80 or 100 mg met the coprimary endpoints of (1) NASH resolution (ballooning 0, inflammation 0, 1 with at least a 2-point reduction in NAFLD activity score [NAS]) with no worsening of fibrosis (26 percent and 30 percent vs 10 percent; p<0.0001 for both) and (2) ≥1-stage reduction in fibrosis with no worsening of NAS (24 percent and 26 percent vs 14 percent; p=0.0002 and p<0.0001) at week 52. [EASL 2023, abstract GS-001]
The same was true for the secondary endpoint, with low-density cholesterol levels decreasing by 14 percent with resmetirom 80 mg and by 16 percent with the 100 mg as opposed to remaining unchanged with placebo (p<0.001 for both).
“Resmetirom is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints that are reasonably likely to predict clinical benefit,” reported lead investigator Dr Stephen Harrison of Pinnacle Research, Anniston, Alabama, US.
Harrison added that the results were independent of diabetes status or baseline fibrosis stage.
Multiple liver biopsy endpoints including reduction in alanine transaminase, aspartate aminotransferase, and gamma-glutamyl transferase, enhanced liver fibrosis, magnetic resonance imaging proton-density-fat-fraction, controlled attenuation parameter, and FibroScan vibration controlled transient elastography were met.
“[These] multiple supportive analyses and additional data using noninvasive measures increase the confidence in the liver biopsy data,” Harrison said.
Meanwhile, the safety profile of resmetirom in MAESTRO-NASH was found to be consistent with previous phase II/III trials in which the most common treatment-emergent adverse events (TEAEs) were diarrhoea and nausea only at the beginning of therapy. The number of serious TEAEs was similar across the treatment arms: 11.8 percent with resmetirom 80 mg, 12.7 percent with resmetirom 100 mg, and 12.1 percent with placebo.
While the study discontinuation rate in the 100-mg arm was increased relative to placebo during the first 12 weeks, the rates were similar in all treatment arms for the remaining period of the first 52 weeks, Harrison noted. After 52 weeks, the proportion of patients who discontinued therapy was higher in the placebo than in the active treatment arms. TEAE-related discontinuations in the 100-mg arm involved gastrointestinal events.
“Resmetirom is an oral, liver-targeted THR-β selective agonist in development for NASH. In patients with NASH, selectivity for THR-β may provide metabolic benefits of thyroid hormone that are mediated by the liver (reduction of excess hepatic fat & atherogenic lipids/lipoproteins), while avoiding negative systemic effects of excess thyroid hormone in heart and bone,” Harrison explained. [J Med Chem 2014;57:3912-3923]
Overall, “these data from the MAESTRO-NASH trial support the potential for resmetirom to provide benefit to patients with NASH,” he added.
MAESTRO-NASH is an ongoing 54-month, phase 3, registrational double-blind, placebo-controlled trial. The analysis included 966 patients who were enrolled at 200 global sites. Of these patients, 322 received resmetirom 80 mg, 323 received 100 mg, and 321 received placebo. The mean age of the population was 57 years, and 56 percent were women, 90 percent were White, 67 percent had diabetes, 78 percent had hypertension, and 71 percent had dyslipidemia. The mean body mass index was 36 kg/m2.