Madrigal Pharmaceuticals has announced the initiation of a rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for resmetirom, a therapeutic candidate for nonalcoholic steatohepatitis (NASH) with liver fibrosis. This action marks a significant step toward potentially providing the first approved treatment for a disease with substantial unmet medical need. The company expects to complete the full submission in July 2023 and has requested a priority review.
Breakthrough Therapy Designation Facilitates Accelerated Submission
Resmetirom received Breakthrough Therapy designation in April 2023, which allows Madrigal to submit individual sections of its NDA as they are completed. This expedited process can potentially accelerate the drug's availability to patients if approved. According to Dr. Becky Taub, Chief Medical Officer and President of Research & Development of Madrigal, the MAESTRO-NASH biopsy trial demonstrated that resmetirom achieved both liver histological improvement endpoints proposed by the FDA as reasonably likely to predict clinical benefit and exhibited a well-tolerated safety profile.
MAESTRO-NASH Trial Highlights Efficacy and Safety
The NDA is supported by data from the MAESTRO-NASH trial, a multicenter, randomized, double-blind, placebo-controlled Phase 3 study. The trial enrolled over 1,000 patients with biopsy-proven NASH, randomized to receive once-daily resmetirom (80 mg or 100 mg) or placebo. The 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. A key secondary endpoint was the lowering of LDL-C.
Ongoing Phase 3 Trials to Support Full Approval
Madrigal is conducting four Phase 3 clinical trials (MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES) to assess the safety and efficacy of resmetirom. Patients in the MAESTRO-NASH study continue on therapy for up to 54 months to measure hepatic clinical outcome events, including progression to cirrhosis and hepatic decompensation events, as well as all-cause mortality. This long-term data is intended to support full approval of resmetirom.
NASH: An Unmet Medical Need
NASH, a more advanced form of nonalcoholic fatty liver disease (NAFLD), affects an estimated 25% of the U.S. population, with approximately 25% of those progressing from NAFLD to NASH. NASH is a leading cause of liver-related mortality, and there are currently no FDA-approved therapies available for its treatment. The initiation of the NDA submission for resmetirom represents a crucial step toward addressing this significant unmet need.
Semaglutide Shows Promise in ESSENCE Trial
Recent data from the ESSENCE trial of once-weekly subcutaneous semaglutide 2.4 mg in adults with MASH and moderate to advanced fibrosis showed statistically significant and superior improvement in liver fibrosis with no worsening of steatohepatitis as well as resolution of steatohepatitis with no worsening of liver fibrosis. Novo Nordisk expects to file for regulatory approvals in the US and EU in the first half of 2025.
Future Directions in MASH Treatment
Experts emphasize the need for additional drugs targeting other disease pathways and the potential of combining different drugs for added efficacy. The development of more noninvasive tests (NITs) to eliminate the need for liver biopsy is also a key goal. Promising data from The Liver Meeting 2024 highlighted the potential of GLP-1s, THR-β agonists, FGF21s, and diacylglycerol acyltransferase (DGAT) inhibitors.
