Resmetirom successfully treats NASH, reduces liver scarring in trial

FDA's decision on approval of fatty liver disease therapy due March 14

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by Steve Bryson, PhD |

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A pair of hands, a stethoscope and a handful of oral medications surround a graph labeled

One year of daily resmetirom, Madrigal Pharmaceuticals’ investigational oral therapy, was shown to successfully treat nonalcoholic steatohepatitis (NASH), a severe type of fatty liver disease, while easing liver scarring, or fibrosis, among patients.

That’s according to new data from an ongoing Phase 3 clinical trial, called MAESTRO-NASH (NCT03900429), specific to more than 950 people with the condition who also have moderate to severe liver fibrosis.

The U.S. Food and Drug Administration (FDA) is reviewing an application from Madrigal that’s seeking accelerated approval of resmetirom for adults with NASH with liver fibrosis. A decision is expected by March 14.

“As a liver-directed therapy that has demonstrated efficacy in both reversing fibrosis and resolving NASH in a pivotal Phase 3 clinical trial, we believe resmetirom will change the treatment paradigm for patients with NASH with significant fibrosis if it receives accelerated approval from the FDA,” Becky Taub, MD, Madrigal’s chief medical officer and president of research and development, said in a company press release.

Accelerated approval would allow the therapy’s use based on positive data on a biomarker or clinical marker rather than the type of measures typically used for traditional approval. However, subsequent confirmatory clinical data would be needed to potentially obtain full approval of the therapy.

The trial’s findings were detailed in “A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis,” which was published in the New England Journal of Medicine.

No treatments have been approved to date for NASH

“The publication of detailed efficacy and safety data … will provide clinicians with valuable information about the medication that may soon become the first approved therapy for patients with NASH,” said Stephen Harrison, MD, the trial’s lead principal investigator, a visiting professor from Oxford University, in the U.K., and the chairman of Pinnacle Clinical Research and Summit Clinical Research, in Texas.

“MAESTRO-NASH is a landmark study in a disease that has historically been very challenging for drug development,” Harrison added.

NASH, more recently classified as metabolic dysfunction-associated steatohepatitis or MASH, is a serious form of nonalcoholic fatty liver disease (NAFLD), marked by liver inflammation and fibrosis. NAFLD is now known as metabolic dysfunction-associated steatotic liver disease under the new classification.

Taub noted that this form of the fatty liver disease is linked to poor outcomes for patients.

“Patients with NASH with significant fibrosis are at increased risk of progressing to cirrhosis [permanent liver scarring], liver failure, liver cancer and premature death,” Taub said, adding that “NASH is the leading cause of liver transplant among women in the U.S. and may soon be the leading cause overall.”

“Despite its serious impact on patients and the health system, there are no approved treatments for the disease,” Taub added.

Resmetirom is an oral, liver-directed therapy designed to activate THR-beta, fully thyroid hormone receptor beta, whose activity is impaired in the liver among NASH/MASH patients. This, in turn, increases the risk of fibrosis.

MAESTRO-NASH is testing resmetirom in a total of more than 1,700 adults with biopsy-confirmed NASH and significant liver fibrosis. Among a population of 966 individuals in this primary analysis, patients were divided into three groups: 322 were randomly assigned to 80 mg of resmetirom, while 323 were given a 100 mg dose, and 321 were administered a placebo. All treatments were taken once daily.

Less disease activity seen at 1 year for those on resmetirom vs. placebo

This study portion had two main objectives at 52 weeks, or the one-year mark. The first was to assess the proportion of patients with NASH resolution, including a reduction of at least two points on the NAFLD Activity Score (NAS) — indicating less disease activity — without fibrosis worsening.

Data showed that a significantly greater proportion of resmetirom-treated patients achieved this goal relative to those on the placebo — 25.9% in the 80 mg group and 29.9% in the 100 mg group versus 9.7% in the placebo group.

The second main objective was the proportion of patients showing fibrosis lessening without NAS increase, or worsening. Again, this goal was met by significantly more patients on resmetirom, specifically 24.2% with 80 mg and 25.9% with 100 mg versus 14.2% with the placebo.

The results were similar regardless of age, sex, the patients’ initial fibrosis stage, and NAS — as well as among those with or without type 2 diabetes.

One secondary study measure was assessing the levels of liver enzymes at the trial’s start, known as baseline, versus the one-year point. Among patients, elevated liver enzymes at baseline, a sign of liver injury, were more reduced with resmetirom than the placebo.

Assessing levels of low-density lipoprotein cholesterol, known as bad cholesterol, was another secondary measure. These levels dropped significantly more with resmetirom at six months (by 13.6%-16.3% vs. 0.1% with a placebo), and these differences seemed to be sustained through one year.

Resmetirom treatment also reduced fibrosis biomarkers, liver fat content, and liver stiffness versus a placebo.

Additional Phase 3 trials now testing experimental therapy

As to side effects, temporary diarrhea and nausea were more frequently reported with resmetirom than the placebo at the beginning of the study, but not after a few weeks of treatment. The incidence of serious adverse events was similar across groups: 10.9% with 80 mg resmetirom, 12.7% with 100 mg, and 11.5% in the placebo group.

“The unprecedented efficacy and safety results from the pivotal MAESTRO-NASH Phase 3 trial provide Madrigal with a unique opportunity to establish resmetirom as the foundational therapy for NASH with significant fibrosis and transform care for patients who currently have no approved treatment options,” said Bill Sibold, Madrigal’s CEO.

MAESTRO-NASH is still ongoing, and participants will also undergo a liver biopsy after about four years. If those results confirm resmetirom’s observed benefits at one year, those findings would be expected to support the therapy’s potential full approval, according to Madrigal.

Resmetirom is the only investigational medication to achieve both fibrosis improvement and NASH resolution [goals] in Phase 3, and we intend to build on our … NASH drug development with two ongoing outcomes trials that carry the potential to confirm clinical benefit and expand the eligible patient population for resmetirom to include patients with more advanced disease.

Additional Phase 3 trials are testing resmetirom for treating NASH/MASH. These include MAESTRO-NAFLD-1 (NCT04197479) and its open-label extension (NCT04951219), which aim to collect additional safety data in NAFLD patients, including those without cirrhosis and patients with well-compensated NASH cirrhosis.

Also, the MAESTRO-NASH outcomes trial (NCT05500222) is evaluating liver decompensation events in patients with well-compensated NASH cirrhosis treated with either resmetirom or a placebo.

“Resmetirom is the only investigational medication to achieve both fibrosis improvement and NASH resolution [goals] in Phase 3, and we intend to build on our leadership position in NASH drug development with two ongoing outcomes trials that carry the potential to confirm clinical benefit and expand the eligible patient population for resmetirom to include patients with more advanced disease,” Sibold said.