FDA Accepts Resmetirom NDA, Grants Priority Review, and Sets PDUFA Date

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The FDA has accepted the new drug application (NDA) for Madrigal Pharmaceuticals’ resmetirom for treatment of adults with nonalcoholic steatohepatitis (NASH) with liver fibrosis. The agency also has granted the investigational drug priority review and set a Prescription Drug User Fee Act date of March 14, 2024, according to a company news release.

NASH, a leading cause of liver-related mortality, is an advanced form of nonalcoholic fatty liver disease (NAFLD), which is estimated to affect approximately 30% of US adults. Among individuals with NAFLD, approximately 20% may have NASH. Adults with NASH, particularly those with comorbid metabolic risk factors such as hypertension and type 2 diabetes, are at significantly increased risk for adverse cardiovascular events.

Resmetirom is a once daily, oral, thyroid hormone receptor (THR)-β selective agonist that targets a key underlying cause of NASH in the liver—impaired THR activity. The reduced THR action causes reduced mitochondrial function and beta-oxidation of fatty acids, the latter of which potentiates inflammation and fibrotic changes, according to the release.

“NASH with liver fibrosis represents a significant unmet need in healthcare today: the disease has a serious impact on patients and, without treatment, it can lead to increased risk of cirrhosis, liver failure, liver cancer, and premature mortality,” Bill Sibold, CEO of Madrigal, said in the announcement. "Resmetirom is a liver-directed therapy that has demonstrated the potential to treat the liver fibrosis that is associated with these negative outcomes, while resolving the underlying steatohepatitis that drives the disease.”

NASH progression to significant liver fibrosis (stages F2 and F3) dramatically increases the risk of adverse hepatic outcomes; in fact the disease has become the primary cause of liver transplantation in the US. Although there have been numerous agents advanced to phase 2 and 3 clinical trials, currently there are no FDA-approved therapies available for the treatment of NASH, said Madrigal.

The Madrigal NDA is based on the pivotal phase 3 MAESTRO-NASH clinical trial, where resmetirom met both primary endpoints reflecting histologic improvement: resolution of NASH and reduction of liver fibrosis. These endpoints had been proposed by FDA to support accelerated approval for the treatment of NASH with liver fibrosis. In both MAESTRO-NASH and the phase 3 safety study MAESTRO-NAFLD-1, resmetirom was associated with reduced levels of LDL cholesterol and triglycerides as well as potentially meaningful improvements in noninvasive measures of liver health, the company said.

Approximately 1750 patients were enrolled in the MAESTRO-NASH study, which is continuing to assess patients after the initial 52-week treatment period for up to 54 months. This portion of the study is designed to generate confirmatory data that and will measure hepatic clinical outcomes including progression to biopsy-confirmed cirrhosis and hepatic decompensation events, as well as all-cause mortality.

A separate 52-week phase 3 clinical trial, an open-label active treatment extension study of MAESTRO-NAFLD-1 (MAESTRO-NAFLD-OLE) in 700 patients is also ongoing.

Source: Madrigal Pharmaceuticals announced NDA accpetance and priority review of the new drug application for resmetirom for the treatment of NASH with liver fibrosis. News release. Madrigal Pharmaceuticals. September 13, 2023. Accessed September 15, 2023. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority