Encouraging results from a phase 3 trial have set the stage for resmetirom to become the first drug approved for patients with non-alcoholic steatohepatitis (NASH) and liver fibrosis, according to the US researchers.
In the MAESTRO-NASH study, NASH resolution with no worsening of fibrosis was achieved in 25.9% of patients who received the investigational drug at the 80mg dose and 29.9% of those receiving the 100mg dose, compared with 9.7% of those in a placebo group (P<0.001 for both comparisons with placebo), reported Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio, and colleagues in the New England Journal of Medicine (NEJM).
Resmetirom also improved liver fibrosis in patients with biopsy-confirmed NASH and a fibrosis stage of F1B, F2 or F3.
Fibrosis improvement – by at least one stage with no worsening of non-alcoholic fatty liver disease (NAFLD) activity score – was achieved in 24.2% of the patients in the 80mg group and 25.9% of the 100mg group versus 14.2% of placebo recipients (P<0.001 for both comparisons with placebo).
“This is the first treatment to achieve meaningful effects on both primary liver endpoints and (to be) reasonably likely to produce clinical benefit with these NASH patients,” Harrison said last year at the European Association for the Study of the Liver (EASL) congress, where the results were first presented.
Medpage Today reports that resmetirom is an oral, liver-directed, thyroid hormone receptor-β selective agonist designed to target key underlying causes of NASH (also referred to as metabolic dysfunction-associated steatohepatitis, or MASH) in the liver.
MAESTRO-NASH is planned to continue for 54 months to evaluate liver-related outcomes, including progression to cirrhosis, and is one of several studies evaluating the safety and efficacy of the drug for NASH.
Developer Madrigal Pharmaceuticals is seeking accelerated approval of resmetirom for the treatment of NASH with liver fibrosis, and the FDA is expected to make a decision by mid-March.
“When this drug is approved, it will honestly be a game changer,” said Aleksander Krag, MD, PhD, of the University of Southern Denmark in Odense, during an EASL Congress press briefing. “Both the change in NASH and the ability to stabilise or improve fibrosis are really important and meaningful."
In an editorial accompanying the NEJM paper, Kenneth Cusi, MD, of the University of Florida, called the results “encouraging to the field”.
If FDA grants a conditional approval, “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),” he wrote.
Cusi suggested that if resmetirom is approved to treat moderate to advanced fibrosis, it would probably be expensive and lead to issues regarding access.
“How would resmetirom be used among less expensive medications that are effective for NASH and recommended in current guidelines?” he asked, noting that since the estimated prevalence of stage F2 or F3 fibrosis is 12% to 15% among patients with type 2 diabetes – a population with the highest risk of cirrhosis – there could be as many as 4m to 5m potential candidates for treatment in the US alone.
“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, so as to avoid futile long-term therapy," Cusi said.
Between March 2019 and July 2021, the phase 3 MAESTRO-NASH trial randomly assigned patients 1:1:1 to resmetirom (at 80-mg or 100-mg doses) or to placebo. The 966 patients who had a fibrosis stage of F1B, F2, or F3 at baseline represented the primary population for evaluating safety and efficacy.
Regarding its safety, 92% of patients who received resmetirom and 93% of those who received placebo reported an adverse event, most of which were mild to moderate in severity.
The most common of these were gastrointestinal, with nausea, vomiting and diarrhoea occurring more frequently with resmetirom than with placebo.
The incidence of serious adverse events was similar across the three groups – 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.
Harrison and colleagues noted that the safety of long-term use of resmetirom still needed to be assessed in subsequent analyses.
Study details
A Phase 3, Randomised, Controlled Trial of Resmetirom in NASH with Liver Fibrosis
Stephen Harrison, , Cynthia Guy, Manal Abdelmalek, et al.
Published in NEJM on 8 February 2024
Abstract
Background
Non-alcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis.
Methods
We 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 two primary end points at week 52 were NASH resolution (including a reduction in the non-alcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.
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 one stage with no worsening of the NAFLD activity score 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). Diarrhoea 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 NASH resolution and improvement in liver fibrosis by at least one stage.
NEJM – Selective Agonists of Thyroid Hormone Receptor Beta for the Treatment of NASH (Open access)
Medpage Today article – Resmetirom Poised to Become First NASH Treatment (Open access)
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