High accuracy in predicting advanced NASH fibrosis (F2-F3) in Phase 3 MAESTRO-NASH study using clinical characteristics and simple, readily available non-invasive imaging and biomarkers
Data from ongoing MAESTRO-NAFLD-1 open label arm confirm robust liver fat reduction on MRI-PDFF and reduction in liver fibrosis measured on magnetic resonance elastography (MRE) at Week 16 of resmetirom treatmentQuality of life improvements in resmetirom-treated patients demonstrated in NASH Phase 2 studyDr. Stephen Harrison will present resmetirom data from ongoing Phase 3 MAESTRO studies at AASLD on Friday November 13, 2020CONSHOHOCKEN, Pa., Oct. 01, 2020 (GLOBE NEWSWIRE) — Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), announced today that, based on data from studies with MGL-3196 (resmetirom), three posters and an oral presentation of these data will be presented at The Liver Meeting Digital Experience™, The American Association for the Study of Liver Diseases Meeting in November 2020. Resmetirom is the first orally administered, small-molecule, liver-directed, truly β-selective thyroid hormone receptor (THR) agonist and is currently in Phase 3 development for the treatment of NASH patients both with biopsy-confirmed fibrosis stage 2-3 (ClinicalTrials.gov NCT03900429) and in presumed NASH subjects diagnosed non-invasively (ClinicalTrials.gov/NCT04197479).Madrigal, a Silver Level Sponsor of The Liver Meeting Digital Experience™, is looking forward to Dr. Stephen Harrison’s oral presentation as well as three poster presentations to registered attendees with access via The Liver Meeting Digital Experience™ website, beginning on Friday November 13, 2020, at 9:00AM ET:Friday, November 13, 2020, from 4:30-5:00 PM ET, Dr. Stephen Harrison, M.D., Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University, and Principal Investigator of the MAESTRO studies, will make a presentation in Madrigal’s product theater titled: “Resmetirom for the Treatment of NASH: Early Data from the Phase 3 MAESTRO Clinical Trials.”
Dr. Harrison commented, “In the MAESTRO-NASH study, using a series of readily available tests such as fibroscan, MRI-PDFF and PRO-C3 in patients with metabolic risk factors (diabetes, obesity, dyslipidemia and hypertension) we have demonstrated that, in recruiting a clinical trial, NASH with advanced fibrosis (F2-F3) may be confirmed on liver biopsy with an increasing level of confidence. Interestingly, the PRO-C3 biomarker, a measure of production of liver collagen that is correlated with liver fibrosis on biopsy, is also statistically significantly correlated with the level of inflammatory activity in the NASH liver.”“We remain confident in achieving the primary and key secondary endpoints in both of our studies. Open label MAESTRO-NAFLD-1 data, using non-invasive measures, predict a favorable probability of demonstrating primary and key secondary liver biopsy and lipid endpoints in the ongoing MAESTRO-NASH serial liver biopsy registration study,” stated Paul Friedman, M.D., Madrigal’s Chief Executive Officer.Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, “The data from the ongoing open label arm of MAESTRO-NAFLD-1 confirm the robust effects of a 100 mg dose of resmetirom with direct actions in the liver at 16 weeks to statistically significantly reduce, compared to baseline, both hepatic fat on serial MRI-PDFF as well as meaningfully reduce a measure of liver fibrosis assessed by serial MRE. MRI-PDFF reduction was 53% overall and up to 62% in key subgroups. Marked lowering (p<0.0001) of multiple atherogenic lipids and lipoproteins was also observed, including LDL-C and apolipoprotein B >22%, triglycerides >25% and lipoprotein (a) >30%. These data at a dose used in the ongoing serial liver biopsy study, MAESTRO-NASH, predict that a high percentage of MAESTRO-NASH patients will achieve a level of liver fat reduction that has been shown, with this mechanism of action, to be associated with improvement in NASH and liver fibrosis on liver biopsy.”POSTER PRESENTATIONSALGORITHM FOR PREDICTING ADVANCED NASH FIBROSIS ON SCREENING BIOPSY IN RESMETIROM PHASE 3 MAESTRO-NASH CLINICAL TRIAL
Dr. Stephen A Harrison1, Dr. Rebecca A. Taub2, Prof. Morten Asser Karsdal3, John Franc2, Dr. Mustafa R Bashir4, Mr. Jordan Mark Barbone2, Dr. Guy Neff5, Dr. Nadege T Gunn1 and Dr. Sam Moussa6, (1) Pinnacle Clinical Research, (2) Madrigal Pharmaceuticals, (3) Biomarkers & Research, Nordic Bioscience, (4) Department of Radiology, Duke University Medical Center, (5) Covenant Research, LLC, (6) Medical, Adobe Gastroenterology
MAESTRO-NASH is a Phase 3 double-blind placebo-controlled serial liver biopsy study to evaluate resmetirom for the treatment of NASH with F2 or F3 fibrosis and an exploratory F1 arm. Data was assessed for the power of the screening paradigm to predict eligible NASH with fibrosis on liver biopsy. These data suggest that PRO-C3 is a marker not only of fibrosis stage in NASH but also of the level of NASH activity (inflammation and ballooning) in the NASH liver. In the absence of a liver biopsy, elevated PRO-C3 in the setting of metabolic syndrome (or FIBC3 (PRO-C3 [age, BMI, platelets, T2D]), fibroscan and MRI-PDFF may predict advanced NASH.TREATMENT WITH RESMETIROM IN PHASE 3 MAESTRO-NAFLD-1 NASH STUDY OPEN LABEL ARM: EFFECTS ON BIOMARKERS AND IMAGING
Dr. Stephen A Harrison, Pinnacle Clinical Research, Dr. Naim Alkhouri, Arizona Liver Health, Dr. Rebecca A. Taub, Madrigal Pharmaceuticals, Dr. Guy Neff, Covenant Research, LLC, Dr. Seth J Baum, Excel Medical Clinical Trials and Dr. Mustafa R Bashir, Department of Radiology, Duke University Medical Center
Data from the ongoing Open Label Arm of Madrigal’s MAESTRO-NAFLD-1 trial will be presented.
In this 52 week Phase 3 open label study, NASH patients identified using non-invasive imaging and biomarkers were treated with resmetirom 100 mg and demonstrated rapid reduction in hepatic fat, biomarkers and atherogenic lipids after 12-16 weeks of treatment, potentially supporting use of non-invasive tests to monitor individual NASH patient response to resmetirom treatment.IMPROVEMENT OF HEALTH-RELATED QUALITY OF LIFE IS ASSOCIATED WITH IMPROVEMENT OF FAT FRACTION BY MRI-PDFF IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS TREATED WITH RESMETIROM
Dr. Zobair M. Younossi, MD, MPH, FAASLD1, Maria Stepanova2, Dr. Rebecca A. Taub3, Mr. Jordan Mark Barbone3, Dr. Sam Moussa4and Dr. Stephen A Harrison5, (1) Center for Liver Disease, Department of Medicine, Inova Health System, (2) Center for Outcomes Research in Liver Diseases, Washington, DC, United States, (3) Madrigal Pharmaceuticals, (4) Medical, Adobe Gastroenterology, (5) Pinnacle Clinical Research
A review of patient reported outcome data from resmetirom’s Phase 2 NASH study demonstrates that NASH patients treated with resmetirom who had liver fat reduction also improved some quality of life measures, particularly physical components such as bodily pain. Ongoing Phase 3 studies will assess long-term sustainability of quality of life improvements with resmetirom treatment.
About Resmetirom (MGL-3196)
Thyroid hormone, through activation of its β-receptor in hepatocytes, plays a central role in liver function impacting a range of health parameters from levels of serum cholesterol and triglycerides to the pathological buildup of fat in the liver. Thyroid hormone receptor (THR)-β action in the liver is key to proper function of the liver, including regulation of mitochondrial activity such as breakdown of liver fat and control of the level of normal, healthy mitochondria. Patients with NASH have reduced levels of thyroid hormone activity in the liver with resultant impaired hepatic function, in part due to the inflamed state of the liver that causes degradation of thyroid hormone.To exploit the thyroid hormone receptor (THR)-β pathway for therapeutic purposes in cardio-metabolic and liver diseases, it is important to avoid activity at the THR- receptor, the predominant systemic receptor for thyroid hormone that is responsible for activity outside the liver including in heart and bone. The lack of selectivity of older thyromimetic compounds, chemically-related toxicities and undesirable distribution in the body led to safety concerns. Madrigal recognized that greater selectivity for thyroid hormone receptor (THR)-β and liver targeting might overcome these challenges and deliver the full therapeutic potential of THR-β agonism. Resmetirom has been shown to be highly selective based on 1) THR- β receptor functional selectivity based on both in vitro and in vivo assays 2) specific uptake into the liver, its site of action, virtually avoiding any uptake into tissues outside the liver. In short and long term human and animal studies, resmetirom has been confirmed to be safe and devoid of activity at the THR- receptor and without impact on bone or cardiac parameters. Resmetirom does not impact the thyroid axis hormones, including the central thyroid axis. Madrigal believes that resmetirom is the first orally administered, small-molecule, liver-directed, truly β-selective THR agonist.About the Phase 3 Registration Program for the Treatment of NASH (Non-alcoholic steatohepatitis)
Analyses from the resmetirom Phase 2 NASH study demonstrate that the magnitude of liver fat reduction accurately predicts NASH resolution and liver fibrosis reduction and, specifically, that the resmetirom doses being used in Madrigal’s Phase 3 MAESTRO-NASH trial could achieve the level of fat reduction predictive of NASH resolution and fibrosis reduction [Madrigal COVID and ABSTRACT Press Release_20200414].Madrigal has also reported, including in presentations by NASH experts at The Digital International Liver Congress™ 2020 (EASL), secondary analyses of data from our Phase 2 NASH study which demonstrate that liver fat reduction at three months after starting treatment has clear predictive power for NASH resolution and fibrosis reduction on subsequent liver biopsy. Data from these analyses demonstrate that resmetirom robustly and statistically significantly (p<0.001) reduces markers of net collagen deposition in the liver, supporting the anti-fibrotic action of resmetirom. The related presentations by NASH experts at EASL are available here: EASL Presentations by NASH Experts August 2020.The Phase 3 MAESTRO-NASH trial is expected to enroll 900 patients with biopsy-proven NASH (fibrosis stage 2 or 3), randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. After 52 weeks of treatment a second biopsy is performed. The primary surrogate endpoint on biopsy will be NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score), and with no worsening of fibrosis. Two key secondary endpoints are liver fibrosis improvement of at least one stage, with no worsening of NASH, and lowering of LDL-cholesterol [ClinicalTrials.gov/NCT03900429].A second 52-week Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom, MAESTRO-NAFLD-1, was initiated in December 2019 targeting 700 patients with non-alcoholic fatty liver disease (NAFLD), presumed NASH, randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. MAESTRO-NAFLD-1 also includes a 100 mg resmetirom open label arm in up to 100 patients. Unlike MAESTRO-NASH, MAESTRO-NAFLD-1 is a non-biopsy study and represents a “real-life” NASH study. NASH or presumed NASH is documented using historical liver biopsy or non-invasive techniques including fibroscan and MRI-PDFF. Using non-invasive measures, MAESTRO-NAFLD-1 is designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular and liver related endpoints. These key secondary endpoints include LDL-cholesterol, apolipoprotein B and triglyceride (TG) lowering; reduction of liver fat as determined by magnetic resonance imaging, proton density fat fraction (MRI-PDFF); and reduction of PRO-C3, a NASH fibrosis biomarker. [ClinicalTrials.gov/NCT04197479] Additional secondary and exploratory endpoints will be assessed including reduction in liver enzymes, fibroscan scores and other fibrosis and inflammatory biomarkers.About Resmetirom’s Potential to Confer Cardiovascular Risk Reduction in NASH patients
Additionally, resmetirom lowers multiple atherogenic lipids, including LDL cholesterol, apolipoprotein B, triglycerides, and lipoprotein (a), as demonstrated in Phase 2, a key differentiating factor compared with other NASH therapeutics. The magnitude of reduction of these lipids support a potential indication for treatment of hyperlipidemia in NASH patients and predicts a potential for benefit on cardiovascular (CV) events in NASH patients who die most frequently of CV, not liver disease.Because of their diabetes, dyslipidemia, hypertension, obesity in concert with an inflamed, fatty liver, NASH patients, particularly those with advanced fibrosis, are at a substantially increased CV risk compared to the general population. Resmetirom’s ability to decrease liver fat, which is an independent risk factor for CV events, and resmetirom’s effect to reduce atherogenic lipids are being further evaluated in several key secondary endpoints in both MAESTRO Phase 3 clinical studies.About Madrigal Pharmaceuticals
Madrigal Pharmaceuticals, Inc. (Nasdaq Global Select: MDGL) is a clinical-stage biopharmaceutical company pursuing novel therapeutics that target a specific thyroid hormone receptor pathway in the liver, which is a key regulatory mechanism common to a spectrum of cardio-metabolic and fatty liver diseases with high unmet medical need. Madrigal’s lead candidate, resmetirom, is a first-in- class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR)-β selective agonist that is in currently in two Phase 3 clinical studies, MAESTRO-NASH and MAESTRO-NAFLD-1, designed to demonstrate multiple benefits across a broad spectrum of NASH (non-alcoholic steatohepatitis) and NAFLD (non-alcoholic fatty liver disease) patients. For more information, visit www.madrigalpharma.com.Forward-Looking Statements
This communication contains “forward-looking statements” made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, that are based on our beliefs and assumptions and on information currently available to us, but are subject to factors beyond our control. Forward-looking statements include but are not limited to statements or references concerning: our clinical trials; research and development activities; the timing and results associated with the future development of our lead product candidate, MGL-3196 (resmetirom); our primary and secondary study endpoints for resmetirom and the potential for achieving such endpoints and projections; optimal dosing levels for resmetirom; projections regarding potential future NASH resolution, safety, fibrosis treatment, cardiovascular effects, lipid treatment or biomarker effects with resmetirom; the predictive power of liver fat reduction on NASH resolution with fibrosis reduction or improvement; the predictive power of readily available non-invasive imaging and biomarkers, such as fibroscan, MRI-PDFF and PRO-C3; the achievement of enrollment objectives concerning patient number, safety database and/or timing for our studies; potential NASH or NAFLD patient risk profile benefits with resmetirom; and our possible or assumed future results of operations and expenses, business strategies and plans, capital needs and financing plans, trends, market sizing, competitive position, industry environment and potential growth opportunities, among other things. Forward-looking statements: reflect management’s current knowledge, assumptions, judgment and expectations regarding future performance or events; include all statements that are not historical facts; and can be identified by terms such as “anticipates,” “be,” “believes,” “continue,” “could,” “demonstrates,” ”design,” “estimates,” “expects,” “forecasts,” “future,” “goal,” “hopeful,” “intends,” “may,” “might,” “plans,” “potential,” “predicts,” ”predictive,” “projects,” “seeks,” “should,” “will,””will achieve,” “would” or similar expressions and the negatives of those terms. Although management presently believes that the expectations reflected in such forward-looking statements are reasonable, it can give no assurance that such expectations will prove to be correct and you should be aware that actual results could differ materially from those contained in the forward-looking statements.Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to: our clinical development of resmetirom; enrollment uncertainties, generally and in relation to COVID-19 shelter-in-place and social distancing measures and individual precautionary measures that may be implemented or continued for an uncertain period of time; outcomes or trends from competitive studies; the risks of achieving potential benefits in studies that includes substantially more patients than our prior studies; the timing and outcomes of clinical studies of resmetirom; and the uncertainties inherent in clinical testing. Undue reliance should not be placed on forward- looking statements, which speak only as of the date they are made. Madrigal undertakes no obligation to update any forward-looking statements to reflect new information, events or circumstances after the date they are made, or to reflect the occurrence of unanticipated events. Please refer to Madrigal’s filings with the U.S. Securities and Exchange Commission for more detailed information regarding these risks and uncertainties and other factors that may cause actual results to differ materially from those expressed or implied. We specifically discuss these risks and uncertainties in greater detail in the section entitled “Risk Factors” in our Annual Report on Form 10-K for the year ended December 31, 2019 and our Quarterly Report on Form 10-Q for the period ended June 30, 2020, as well as in our other filings with the SEC.Investor Contact:
Marc Schneebaum, Madrigal Pharmaceuticals, Inc. IR@madrigalpharma.comMedia Contact:
Mike Beyer, Sam Brown Inc. mikebeyer@sambrown.com 312 961 2502A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/ddef7e87-55ed-4683-9a20-04a4b83cd5ba
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