medwireNews: Patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis experience significantly greater histologic improvements in both conditions when given daily resmetirom rather than placebo, phase 3 study findings indicate.
The results of “the MAESTRO-NASH trial, together with data from completed resmetirom trials, support the potential for resmetirom to provide benefit to patients with NASH and liver fibrosis,” write Stephen Harrison (Pinnacle Clinical Research, San Antonio, Texas, USA) and co-authors in The New England Journal of Medicine.
Currently, there is no approved pharmacologic treatment for NASH, which is characterized by impaired thyroid hormone beta function in the liver. Instead, guidelines recommend reversing the disease by targeting obesity or type 2 diabetes.
The goal of the ongoing MAESTRO-NASH trial is to evaluate the efficacy and safety of resmetirom, an oral, liver-directed, thyroid hormone receptor beta–selective agonist, in adults with biopsy-confirmed NASH and moderate-to-severe fibrosis.
In all, 966 patients (mean age 57 years, 44% men) were randomly assigned to receive once-daily oral resmetirom 80 mg (n=322), resmetirom 100 mg (n=323), or placebo (n=321). The participants had a mean BMI of 35.7 kg/m2 and a high incidence of metabolic risk factors such as hypertension (78.1%), dyslipidemia (71.3%), and type 2 diabetes (67.0%).
Baseline biopsies showed that 83.5% of patients had a nonalcoholic fatty liver disease (NAFLD) activity score of 5 points or more on a scale of 0 to 8 points, with higher scores indicating more severe disease, while 5.1% had stage F1B fibrosis, 33.0% had stage F2 fibrosis, and 60.4% had stage F3 fibrosis.
The researchers report that, at 1 year, the proportion of patients with NASH resolution, defined as achieving a hepatocellular ballooning score of 0, a lobular inflammation score of 0–1, and a reduction in the NAFLD activity score of at least 2 points, and no worsening of fibrosis was significantly higher in the resmetirom 80 mg and 100 mg arms than in the placebo arm, at 25.9% and 29.9% versus 9.7%.
The rate of fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was also significantly higher with resmetirom 80 mg and 100 mg than with placebo, at 24.2% and 25.9% versus 14.2%.
Patients given resmetirom 80 mg experienced a 13.6% reduction in low-density lipoprotein (LDL) cholesterol levels from baseline to week 24, while those given the 100 mg dose had a 16.3% reduction. By comparison, LDL cholesterol increased by 0.1% in the placebo arm, with the difference in outcome statistically significant relative to the two resmetirom arms.
Harrison et al say that the effect on LDL cholesterol appeared to be maintained until week 52 and that levels of additional lipids, lipoproteins, liver enzymes, liver stiffness, and liver and spleen volume also seemed to decrease more from baseline in the resmetirom groups than in the placebo group during follow-up.
The investigators found that the safety profile of resmetirom was consistent with that observed in previous trials. Patients given resmetirom experienced more diarrhea (27.0% for the 80 mg dose and 33.4% for the 100 mg dose vs 15.6% with placebo) and nausea (22.0 and 18.9% vs 12.5%) than those given placebo, but the rates of any serious adverse events (AEs) were similar across the three arms (10.9 and 12.7% vs 11.5%).
Harrison and colleagues acknowledge that more information is needed regarding how the histologic data relate to clinical outcomes as well as the treatment’s long-term safety, but they note that “[t]he trial is planned to continue to 54 months in order to accrue and evaluate liver-related outcomes, including progression to cirrhosis.”
In an accompanying editorial, Kenneth Cusi, from the University of Florida in Gainesville, USA, describes the study as “a step forward that brings hope to a field in desperate need of new therapies.”
He says: “If conditional approval [of resmetirom] is given by the Food and Drug Administration, it may boost guideline recommendations to screen in primary care persons at high risk for NASH, especially to identify those with stage F2 or higher fibrosis (known as “at risk” NASH).”
However, he also points out that the placebo-adjusted rates of NASH resolution and fibrosis improvement were “modest” and indicate that “approximately 2 of 10 patients treated will have NASH resolution and approximately 1 of 10 patients treated will have fibrosis improvement.” This means that most patients will still also need to be treated with agents targeting obesity and type 2 diabetes.
“The large number of [people] needing treatment will open a debate about treatment access and about how to best monitor treatment response and when to discontinue resmetirom in patients who do not have a response in order to avoid futile long-term therapy,” Cusi remarks.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2024; 390: 497–509
N Engl J Med 2024; 390: 559–561