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Madrigal Pharmaceuticals Announces Publication of the Phase 3 MAESTRO-NASH Trial of Resmetirom in the New England Journal of Medicine
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• Resmetirom is the first investigational medicine for NASH to achieve fibrosis
improvement and NASH resolution primary endpoints in a Phase 3 trial
• Detailed analyses reinforce the safety profile of resmetirom
• Resmetirom has the potential to become the first and only medicine approved for NASH; PDUFA date is March 14, 2024
CONSHOHOCKEN, Pa., Feb. 08, 2024 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), today announced the publication of the pivotal Phase 3 MAESTRO-NASH trial of resmetirom in the New England Journal of Medicine.
NASH is a leading cause of liver-related mortality and an increasing burden on healthcare systems globally. Resmetirom received Breakthrough Therapy designation from the FDA and is under review to become the first medicine approved to treat patients with NASH with liver fibrosis. The FDA granted resmetirom Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) date of March 14, 2024, the target date by which FDA intends to complete its review.
Stephen Harrison, M.D., Chairman for both Pinnacle Clinical Research and Summit Clinical Research, San Antonio, Texas, Visiting Professor of Hepatology, Oxford University, and lead Principal Investigator of the MAESTRO studies, commented, "MAESTRO-NASH is a landmark study in a disease that has historically been very challenging for drug development. The publication of detailed efficacy and safety data in the New England Journal of Medicine will provide clinicians with valuable information about the medication that may soon become the first approved therapy for patients with NASH."
The MAESTRO-NASH trial evaluates resmetirom treatment vs. placebo in patients with NASH with significant fibrosis (consistent with fibrosis stages 2 and 3), a population at elevated risk of progressing to cirrhosis and other adverse liver outcomes. The study includes a 52-week biopsy assessment to support accelerated approval and an ongoing 54-month outcomes study designed to generate confirmatory data that, if positive, will help verify resmetirom's clinical benefit and support full approval.
Based on the results of the 52-week biopsy portion of the trial, MAESTRO-NASH is the only Phase 3 study in NASH to achieve both primary endpoints that FDA proposed as reasonably likely to predict clinical benefit: NASH resolution with no worsening of fibrosis and fibrosis reduction with no worsening of NAFLD activity score (NAS). Approximately 50% of patients treated with resmetirom 100 mg with biopsies at Week 52 showed either NASH resolution or fibrosis improvement. More than 80% of patients with biopsies at Week 52 had either fibrosis reversal or no progression of fibrosis.
Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, "Patients with NASH with significant fibrosis are at increased risk of progressing to cirrhosis, liver failure, liver cancer and premature death. Additionally, NASH is the leading cause of liver transplant among women in the U.S. and may soon be the leading cause overall. Despite its serious impact on patients and the health system, there are no approved treatments for the disease. As a liver-directed therapy that has demonstrated efficacy in both reversing fibrosis and resolving NASH in a pivotal Phase 3 clinical trial, we believe resmetirom will change the treatment paradigm for patients with NASH with significant fibrosis if it receives accelerated approval from the FDA."
In addition to the two primary endpoints, multiple secondary endpoints were achieved in the MAESTRO-NASH study, including statistically significant reduction from baseline in liver enzymes (ALT, AST and GGT). Reductions in atherogenic lipids and lipoproteins, fibrosis biomarkers and imaging tests (MRI-PDFF, CAP and liver stiffness measures) were observed in resmetirom treatment arms as compared with placebo. MAESTRO-NASH also included many biomarker and imaging assessments that may be used in real world clinical practice to identify appropriate patients for treatment and monitor response to resmetirom, if approved.
The incidence of serious adverse events was similar across the treatment groups, 10.9%, 12.7%, and 11.5% in 80 mg, 100 mg and placebo groups respectively. Transient diarrhea and nausea were more frequent with resmetirom at the beginning of therapy. No increase in the incidence of diarrhea and nausea was noted among resmetirom-treated patients relative to placebo-treated patients after the first few weeks of treatment. There was no incidence of drug-induced liver injury. There were no increases in bone fractures, or fracture risk score with resmetirom or increase in adverse events related to thyroid hormone effects outside the liver such as heart rate changes or sex hormone abnormalities.
Bill Sibold, Chief Executive Officer of Madrigal, stated, "The unprecedented efficacy and safety results from the pivotal MAESTRO-NASH Phase 3 trial provide Madrigal with a unique opportunity to establish resmetirom as the foundational therapy for NASH with significant fibrosis and transform care for patients who currently have no approved treatment options. Resmetirom is the only investigational medication to achieve both fibrosis improvement and NASH resolution endpoints in Phase 3, and we intend to build on our leadership position in NASH drug development with two ongoing outcomes trials that carry the potential to confirm clinical benefit and expand the eligible patient population for resmetirom to include patients with more advanced disease."
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