Pharma Focus America

Madrigal Pharmaceuticals Commences Rolling Submission of New Drug Application to U.S. FDA for Accelerated Approval of Resmetirom in NASH Treatment with Liver Fibrosis

Saturday, July 01, 2023

Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL) is a clinical-stage biopharmaceutical company specializing in the development of therapeutics for nonalcoholic steatohepatitis (NASH), a liver disease characterized by liver fibrosis and inflammation. The company has initiated a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for their drug candidate, resmetirom, with the goal of seeking accelerated approval for the treatment of NASH with liver fibrosis.

The rolling submission process allows Madrigal Pharmaceuticals to submit sections of the NDA as they are completed, rather than waiting for the entire application to be finished. The majority of the NDA has already been submitted, and the remaining components are planned to be submitted in July 2023. Madrigal Pharmaceuticals intends to request a priority review for the NDA, which would expedite the FDA's review process.

Resmetirom, the drug being evaluated by Madrigal Pharmaceuticals, was granted Breakthrough Therapy designation by the FDA in April 2023 for the treatment of NASH with liver fibrosis. This designation is given to therapies that show promising potential in treating serious or life-threatening conditions and provides certain benefits, including enhanced FDA guidance and expedited review.

Dr. Becky Taub, Chief Medical Officer and President of Research & Development at Madrigal Pharmaceuticals, expressed confidence in the positive results obtained from the MAESTRO-NASH biopsy trial. Resmetirom demonstrated improvement in liver histological endpoints that are considered reasonably likely to predict clinical benefit, as proposed by the FDA. The drug also exhibited a well-tolerated safety profile. Dr. Taub believes that these findings support the potential of resmetirom to become a foundational therapy for NASH with liver fibrosis. The MAESTRO development program aims to provide a comprehensive data package to support the FDA's review of the resmetirom NDA.

Dr. Paul Friedman, Chief Executive Officer of Madrigal Pharmaceuticals, emphasized the company's commitment to addressing the unmet needs of patients who currently lack approved treatments for NASH with liver fibrosis. He considers the NDA submission for resmetirom to be an important milestone and looks forward to close collaboration with the FDA throughout the review process.

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

MAESTRO-NASH: Initiated in March 2019, this is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study. It involves over 1,000 patients with liver biopsy-confirmed NASH. The patients are randomized 1:1:1 to receive once-daily doses of resmetirom 80 mg, resmetirom 100 mg, or placebo. After 52 weeks of treatment, a second liver biopsy is performed to evaluate the primary surrogate endpoints, which include NASH resolution with a ≥2-point reduction in NAFLD Activity Score (NAS) and no worsening of fibrosis, or a 1-point decrease in fibrosis with no worsening of NAS. The study also assesses secondary endpoints such as LDL-C reduction.

MAESTRO-NAFLD-1: This Phase 3 study, initiated in December 2019, is a 52-week multicenter, randomized, placebo-controlled trial involving over 1,200 patients with nonalcoholic fatty liver disease (NAFLD), presumed to be NASH. Patients are randomized 1:1:1:1 to receive once-daily doses of resmetirom 80 mg, resmetirom 100 mg, placebo in double-blind arms, or resmetirom 100 mg in an open-label arm. The study aims to evaluate the safety and tolerability of resmetirom, as well as assess key secondary efficacy endpoints including LDL-C, apolipoprotein B, and triglyceride levels, and reduction of liver fat as determined by MRI-PDFF. Unlike MAESTRO-NASH, this study does not involve liver biopsies.

MAESTRO-NAFLD-OLE: This is an open-label extension study of MAESTRO-NAFLD-1, allowing patients to continue treatment with resmetirom beyond the initial 52-week period.

MAESTRO-NASH-OUTCOMES: Initiated in August 2022, this randomized double-blind, placebo-controlled study involves approximately 700 patients with early NASH cirrhosis. The study aims to monitor the progression to liver decompensation events using noninvasive methods. Positive outcomes from this study may support the full approval of resmetirom for noncirrhotic NASH and potentially add an additional indication for well-compensated NASH cirrhosis.

NASH is a more advanced form of NAFLD and poses a significant burden on healthcare systems. Currently, there are no FDA-approved treatments for NASH. Madrigal Pharmaceuticals aims to gather data from these Phase 3 trials, along with data from earlier phases, to support the submission of a New Drug Application (NDA) to the FDA for accelerated approval of resmetirom for the treatment of NASH with liver fibrosis.

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