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The FDA to resmetirom (Rezdiffra) as the first treatment for adults with noncirrhotic non-alcoholic steatohepatitis (NASH), also now referred to as metabolic dysfunction-associated steatohepatitis (MASH).

A once-daily oral agent, resmetirom is a liver-directed thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH; the drug is specifically indicated for NASH patients with moderate to advanced liver fibrosis, consistent with stages F2 to F3 fibrosis, and should be used along with diet and exercise, according to the agency.

"Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage," said Nikolay Nikolov, MD, of FDA's Center for Drug Evaluation and Research, in a statement. "Today's approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise."

A result of non-alcoholic fatty liver disease (NAFLD) progression, NASH can lead to liver fibrosis and dysfunction, raising the risk of transplant and hepatocellular carcinoma. The condition is often associated with hypertension and diabetes.

According to some estimates, 6 million or more Americans have NASH with stages F2 to F3 fibrosis, a number only expected to increase in the coming years.

Findings from the ongoing phase III MAESTRO-NASH study supported the approval, which reported NASH resolution with no worsening of fibrosis in 25.9% of patients on an 80-mg dose of resmetirom and 29.9% of those receiving a 100-mg dose, as compared with 9.7% of those given placebo (P<0.001 for both comparisons with placebo).

Fibrosis improvement by at least one stage with no worsening of NAFLD activity score was achieved in 24.2%, 25.9%, and 14.2%, respectively (P<0.001 for both comparisons with placebo).

The trial only included patients with a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring, though the drug's does not include a biopsy requirement for diagnosis, noted drugmaker Madrigal Pharmaceuticals.

"The approval of the first medication for NASH is a true game-changer for healthcare providers, the research community and, most importantly, patients living with this serious liver condition," said MAESTRO investigator Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio, in a from Madrigal. "Based on the robust efficacy and safety data generated in two large phase III MAESTRO studies, I believe Rezdiffra will become the foundational therapy for patients with NASH with moderate to advanced liver fibrosis."

As a condition of the accelerated approval, Madrigal Pharmaceuticals will be required to conduct a postmarketing study to verify and describe the drug's clinical benefit in this patient population.

That research will "determine if the positive results observed in the MAESTRO studies will lead to reduced risk of progression to cirrhosis, liver failure, need for liver transplant, and premature mortality," said Harrison.

In trials, the most common side effects of resmetirom included diarrhea, nausea, pruritus, abdominal pain, vomiting, constipation, and dizziness. Diarrhea and nausea usually started early in treatment initiation and were mild to moderate in severity.

Resmetirom should not be used in patients with decompensated cirrhosis, said FDA, and the drug should be stopped if patients develop signs or symptoms of worsening liver function. Resmetirom also should not be taken at the same time as certain other drugs, particularly cholesterol-lower agents.

Tablets of resmetirom will come in three doses: 60 mg, 80 mg, and 100 mg, but the recommended dosage is based on a patient's body weight: 100-mg once-daily for patients weighing 100 kg (220 lbs) or more or 80-mg once-daily for those under that weight.

Madrigal said resmetirom is expected to be available in the U.S. in April and will be distributed through a limited specialty pharmacy network.

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