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Madrigal Pharmaceuticals Announces NDA Acceptance and Priority Review of the New Drug Application for Resmetirom for the Treatment of NASH with Liver Fibrosis
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CONSHOHOCKEN, Pa., Sept. 13, 2023 (GLOBE NEWSWIRE) -- Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage biopharmaceutical company pursuing novel therapeutics for nonalcoholic steatohepatitis (NASH), today announced that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Application (NDA) for resmetirom for the treatment of adult patients with NASH with liver fibrosis. The FDA has granted Priority Review and assigned a Prescription Drug User Fee Act date for resmetirom of March 14, 2024, the target date by which the FDA intends to complete its review and take action on the NDA. The Agency noted that it is not currently planning to hold an advisory committee meeting to discuss the application.
EASL: Resmetirom Resolves NASH and Lessens Fibrosis in 52-Week Placebo Trial - (06/28/23)
The Newark investigators concluded that the prevalence of NAFLD is "alarmingly high" in people with HIV infection. Gaining a better understanding of NAFLD in HIV patients is urgent, they stressed, "to prevent the potentially severe consequences of NASH." Because their study suggested longer antiretroviral duration may favor development of NAFLD, the Newark team urged closer monitoring of liver health as soon as ART begins. Prevalence of NAFLD was 51.6% in group 1 where 68% were Black, and 42.7% in group 2 where 87% were white.
IDWeek 2019: Over Half of Mostly Black US HIV Group Has NAFLD--and Many Have NASH - Mark Mascolini (10/4/19)
IDWeek: A Comparison Study of Prevalence and Risk Factors for Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH) by Transient Elastography (TE) in HIV Infected Patients - (10/8/19)
Fatty Liver/Metabolic Changes - CROI: Risk factors for liver fibrosis progression in HIV: a multi-center longitudinal study - (03/16/23)
Resmetirom is a once daily, oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH in the liver. The clinical development program for resmetirom is comprised of 18 clinical studies supporting the NDA: twelve Phase 1 studies, two Phase 2 studies, and four Phase 3 studies. Madrigal is seeking approval of resmetirom for the treatment of patients with NASH and liver fibrosis under the FDA's accelerated approval pathway.
Bill Sibold, Chief Executive Officer of Madrigal, stated, "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. 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. The FDA's acceptance of our NDA with priority review is an important step forward as we pursue our goal of delivering the first approved treatment to patients with NASH with liver fibrosis."
The FDA grants Priority Review to applications for medicines that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. A Priority Review designation means FDA's goal is to take action on an application within 6 months (compared to 10 months under standard review).
Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, "We believe that we have delivered a compelling data package to support the FDA's benefit-risk evaluation of resmetirom for the treatment of NASH with liver fibrosis. The NDA is supported by the positive efficacy results observed in our pivotal Phase 3 trial, the large safety database we have established through the MAESTRO program, and two ongoing outcomes studies that are designed to verify clinical benefit following a potential accelerated approval. We look forward to beginning this critical next phase of the review process."
About the Resmetirom Phase 3 Registration Program for the Treatment of NASH
Resmetirom is a once daily, oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH in the liver.
Madrigal is currently conducting four Phase 3 clinical trials to demonstrate the safety and efficacy of resmetirom for the treatment of NASH: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES.
MAESTRO-NASH is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of resmetirom in patients with liver biopsy-confirmed NASH. The portion of the study designed to support a subpart H approval enrolled more than 1,000 patients with biopsy-proven NASH with fibrosis, randomized 1:1:1 to receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo. The dual primary surrogate endpoints on biopsy were NASH resolution with ≥2-point reduction in NAS (NAFLD Activity Score), and with no worsening of fibrosis OR a 1-point decrease in fibrosis with no worsening of NAS after 52 weeks of treatment. Achievement of either primary endpoint was considered a successful trial outcome.
In December 2022, Madrigal announced that both daily oral doses of resmetirom achieved both MAESTRO-NASH primary liver biopsy endpoints. Multiple secondary endpoints were also achieved, including statistically significant reductions by resmetirom as compared with placebo in atherogenic lipids and lipoproteins, liver enzymes, fibrosis biomarkers, and imaging tests.
Resmetirom was generally safe and well-tolerated at both the 80 mg and 100 mg doses. Consistent with previous Phase 2 and Phase 3 data, the most common adverse event reported with greater frequency in the resmetirom groups versus placebo was an excess of generally mild and transient diarrhea and nausea at the beginning of therapy.
Data from the 52-week first 1,000 patient portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, Phase 2 and Phase 1 data, including safety parameters, form the basis for Madrigal's subpart H submission to FDA for accelerated approval of resmetirom for treatment of NASH with liver fibrosis.
In August 2022, Madrigal initiated MAESTRO-NASH-OUTCOMES, a randomized double-blind placebo-controlled study in approximately 700 patients with early NASH cirrhosis to allow for noninvasive monitoring of progression to liver decompensation events. A positive outcome is expected to support the full approval of resmetirom for noncirrhotic NASH, potentially accelerating the timeline to full approval. In addition, this study has the potential to support an additional indication for resmetirom in patients with well-compensated NASH cirrhosis.
https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority
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