The approval, awarded to Madrigal Pharmaceuticals, was based on phase 3 data demonstrating that resmetirom achieved broad treatment effects in patients with MASH with liver fibrosis.
The FDA has granted accelerated approval to resmetirom (Rezdiffra) from Madrigal Pharmaceuticals for the treatment of metabolic dysfunction-associated steatohepatitis (MASH) in adult patients with moderate to advanced liver fibrosis, the federal agency announced in a release.1 The decision makes resmetirom the first approved treatment for MASH, an advanced form of nonalcoholic fatty liver disease (NAFLD) formerly known as non-alcoholic steatohepatitis (NASH).
FDA headquarters at White Oak Campus in Silver Spring, Maryland / JHVE Photo - stock.adobe.com
The approval was based on data from a comprehensive clinical development program consisting of 18 clinical studies: 12 phase 1 studies, 2 phase 2 studies, and 4 phase 3 studies. The hallmark of the program was the pivotal MAESTRO-NASH (NCT03900429) trial, which showed that resmetirom demonstrated broad treatment effects in patients with MASH with liver fibrosis, as well as reduced levels of low-density lipoprotein (LDL) cholesterol and other lipids associated with heart disease.
Trial Name: A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis
ClinicalTrials.gov Identifier: NCT03900429
Sponsor: Madrigal Pharmaceuticals
Summary: A double-blind placebo controlled randomized Phase 3 study to determine if 80 or 100 mg of MGL-3196 as compared with placebo resolves NASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease.
“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” Nikolay Nikolov, MD, acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research, said in a release.1 “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”
Resmetirom is a liver-directed thyroid hormone receptor (THR)-β agonist oral therapy. It is taken once daily and targets key underlying causes of MASH in the liver. Thyroid hormone receptor (THR)-β activation is crucial to liver function and research has shown the liver has low (THR)-β activity in patients with MASH, which can exacerbate mitochondrial dysfunction, lipotoxicity, and fibrosis.2
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MAESTRO-NASH is an ongoing, double-blind, placebo controlled, randomized, phase 3 clinical trial assessing resmetirom versus placebo for NASH resolution and improvement in fibrosis.3 The study included 966 adult patients with biopsy-confirmed MASH and a fibrosis stage of F1B, F2, or F3. Of those, 322 received 80 mg of resmetirom, 323 received 100 mg, and 321 received placebo. The 2 primary end points at week 52 were MASH resolution with no worsening of fibrosis and a reduction in fibrosis by at least 1 stage.
The study found that 25.9% of patients in the 80 mg group and 29.9% of patients in the 100 mg group achieved MASH resolution with no worsening of fibrosis, compared to 9.7% of patients in the placebo group. Fibrosis improvement by at least 1 stage was achieved in 24.2% of patients in the 80 mg group and 25.9% of patients in the 100 mg group, compared to 14.2% in the placebo group.
LDL cholesterol level changes from baseline to week 24 were −13.6% in the 80 mg group and −16.3% in the 100 mg group, compared to 0.1% in the placebo group. Additionally, diarrhea and nausea were more common in the resmetirom group, and incidence of serious adverse events was comparable across the 3 groups.
Madrigal said in a release that “continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.”4 The company expects resmetirom to be available in the US in April and will distribute it through a limited specialty pharmacy network.
“This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy," Wayne Eskridge, co-founder and CEO of the Fatty Liver Foundation, said in a release.4 "I believe this approval milestone will bring new energy and momentum to the NASH community, accelerating our efforts to improve disease education, build care pathways, and expand investment in NASH research.”
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