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Groundbreaking results from a phase III trial have set the stage for resmetirom to become the first drug approved for patients with nonalcoholic steatohepatitis (NASH) and liver fibrosis.

In the so-called MAESTRO-NASH study, NASH resolution with no worsening of fibrosis was achieved in 25.9% of patients who received the investigational drug at the 80-mg dose and 29.9% of those receiving the 100-mg dose, as 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 (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 80-mg group and 25.9% of the 100-mg 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.

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 in order 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 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 stabilize or improve fibrosis are really, really important and meaningful."

In an editorial accompanying the NEJM paper, Kenneth Cusi, MD, of the University of Florida in Gainesville, 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 also speculated that if resmetirom is approved to treat moderate to advanced fibrosis it will likely 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, and noted 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 4 to 5 million potential candidates for treatment in the U.S. alone.

"The large number of persons 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 said.

From March 2019 to July 2021, the phase III 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 diarrhea 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 needs to be assessed in subsequent analyses.

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