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Madrigal Pharmaceuticals Submits New Drug Application for Accelerated Approval of Resmetirom as a Treatment for NASH with Liver Fibrosis

Tuesday, July 18, 2023

Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL) has recently announced the completion of the rolling submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for resmetirom, a potential treatment for nonalcoholic steatohepatitis (NASH) in adults with liver fibrosis. NASH is a condition that currently has no approved therapies.

Resmetirom is an oral, once-daily medication designed to target key underlying causes of NASH in the liver by acting as a selective agonist of the thyroid hormone receptor (THR)-β. The NDA for resmetirom is supported by an extensive clinical development program, including Phase 1, Phase 2, and Phase 3 studies. The pivotal Phase 3 MAESTRO-NASH trial demonstrated positive efficacy results, meeting the FDA's proposed endpoints for liver histological improvement, including the resolution of NASH and the reduction of liver fibrosis. These endpoints are considered reasonably likely to predict clinical benefit and support accelerated approval for the treatment of NASH with liver fibrosis. Throughout the development program, resmetirom has shown a favorable safety profile and has been well-tolerated by patients.

Resmetirom has also demonstrated promising results in reducing atherogenic lipids and lipoproteins, such as LDL cholesterol and triglycerides, and improving noninvasive measures of liver health in patients with NASH. In April 2023, resmetirom was granted Breakthrough Therapy designation by the FDA for the treatment of adults with NASH and liver fibrosis.

Dr. Becky Taub, Chief Medical Officer and President of Research & Development at Madrigal, expressed confidence in resmetirom's potential to become the first approved treatment for patients with NASH and liver fibrosis. She highlighted the positive efficacy results observed in the MAESTRO-NASH trial and the extensive safety database established across the MAESTRO trials. Madrigal is committed to conducting two ongoing Phase 3 outcomes studies to further evaluate the clinical benefit of resmetirom following a potential accelerated approval, one of which is already fully enrolled.

Paul Friedman, Chief Executive Officer of Madrigal, emphasized the significance of the NDA filing as a crucial milestone in providing a treatment option for patients with NASH and liver fibrosis who currently lack approved medications. He expressed gratitude to the patients and investigators who contributed to the clinical research supporting the resmetirom NDA.

Madrigal Pharmaceuticals, Inc. is currently conducting a Phase 3 registration program to evaluate the safety and efficacy of resmetirom for the treatment of NASH (nonalcoholic steatohepatitis). The program consists of four clinical trials: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES.

MAESTRO-NASH is a randomized, double-blind, placebo-controlled Phase 3 study involving over 1,000 patients with liver biopsy-confirmed NASH and fibrosis. The study's primary endpoints were NASH resolution with a ≥2-point reduction in the NAFLD Activity Score (NAS) and no worsening of fibrosis, or a 1-point decrease in fibrosis with no worsening of NAS after 52 weeks of treatment. Resmetirom achieved both primary endpoints and demonstrated improvements in secondary endpoints such as atherogenic lipids, liver enzymes, fibrosis biomarkers, and imaging tests. The safety profile of resmetirom was favorable and well-tolerated.

Patients participating in MAESTRO-NASH continue to receive treatment beyond the initial 52-week period for up to 54 months to evaluate long-term clinical outcomes including progression to cirrhosis, hepatic decompensation events, and all-cause mortality.

MAESTRO-NAFLD-1 is a 52-week Phase 3 study involving approximately 1,200 patients with presumed NASH diagnosed through noninvasive measures rather than liver biopsy. The primary goal of the study was to assess the safety and tolerability of resmetirom. The study demonstrated that resmetirom was well-tolerated and showed significant improvements in LDL-C, apolipoprotein B, triglycerides, and liver fat as measured by MRI-PDFF.

MAESTRO-NAFLD-OLE is an open-label active treatment extension study of MAESTRO-NAFLD-1, currently ongoing and including around 700 patients.

Data obtained from the 52-week phase of MAESTRO-NASH, combined with data from MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, as well as Phase 2 and Phase 1 trials, will be used for Madrigal's submission to the FDA for accelerated approval of resmetirom as a treatment for NASH with liver fibrosis.

Madrigal has also initiated MAESTRO-NASH-OUTCOMES, a randomized, double-blind, placebo-controlled study involving approximately 700 patients with early NASH cirrhosis. This study aims to monitor the progression to liver decompensation events and potentially support the full approval of resmetirom for noncirrhotic NASH.

NASH is an advanced form of nonalcoholic fatty liver disease (NAFLD) and is a significant cause of liver-related mortality. Currently, there are no FDA-approved therapies available for NASH.

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