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Madrigal Pharmaceuticals Announces Publication in The Lancet of Positive Phase 2 Results for Resmetirom (MGL-3196) for the Treatment of Non-alcoholic Steatohepatitis (NASH)

Data from this 36-week, multicenter, randomized, double-blind, placebo-controlled Phase 2 clinical trial in patients with NASH:
demonstrated that resmetirom treatment resulted in statistically significant reduction in hepatic fat measured non-invasively (magnetic resonance imaging-proton density fat fraction (MRI-PDFF) at week 12, the primary endpoint of the study, and sustained fat reduction at Week 36
achieved secondary endpoints include statistically significant reduction and resolution of NASH on liver biopsy and statistically significant improvement in multiple noninvasive parameters of NASH and liver fibrosis including fibrosis biomarkers and liver enzymes
achieved secondary endpoints include statistically significant reduction in multiple atherogenic lipids and lipoproteins including LDL cholesterol, triglycerides, apolipoprotein B, apolipoprotein CIII and lipoprotein (a)First study to demonstrate a strong association between liver fat reduction by a pharmaceutical agent and improvement and resolution of NASH on liver biopsyCONSHOHOCKEN, Pa., Nov. 11, 2019 (GLOBE NEWSWIRE) — Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) announced today the online publication in The Lancet of the resmetirom (MGL-3196) Phase 2 multi-center, randomized, double-blind, placebo-controlled clinical trial in patients with non-alcoholic steatohepatitis (NASH).  See The Lancet publication – Madrigal Phase 2 NASH StudyThe 36-week Phase 2 NASH study in 125 patients, and a 36-week extension study in 31 of those patients (described below), are highly supportive of MAESTRO-NASH, an ongoing international Phase 3 registrational clinical trial of resmetirom in patients with NASH and liver fibrosis, that is powered at >90% to achieve the primary endpoint of NASH resolution and key secondary endpoints of LDL cholesterol lowering and reduction in liver fibrosis. Additional information about Madrigal’s Phase 3 study in patients with NASH can be obtained at Madrigal Pharmaceuticals Initiates Phase 3 MAESTRO-NASH Study and  www.clinicaltrials.gov [NCT03900429]Stephen Harrison, M.D., Principal Investigator of the resmetirom Phase 2 study, and Medical Director for Pinnacle Clinical Research, San Antonio, Texas, and Visiting Professor of Hepatology, Oxford University, and primary author of The Lancet paper stated, “In this trial, resmetirom as compared with placebo demonstrated statistically significant and meaningful reduction of hepatic fat at 12 weeks, the primary endpoint of the study, and this reduction was sustained over 36 weeks. Statistically significant reduction and resolution of NASH on liver biopsy, lowering and normalizing elevated liver enzymes, and reductions of markers of fibrosis were also observed. A strong association was observed between reduction in hepatic fat by resmetirom and improvement in the inflammatory components of NASH, ballooning and inflammation.”“MRI-PDFF is a noninvasive imaging biomarker that provides an accurate and reproducible assessment of hepatic fat content. It has been shown to correlate with the liver biopsy steatosis score and can be used to assess the change in hepatic fat content over time. This study shows the potential value of MRI-PDFF for assessing early treatment response in patients with NASH,” stated Mustafa R. Bashir M.D., Associate Professor of Radiology and Associate Professor in the Department of Medicine Duke University, Gastroenterology, Director MRI, Director, Center for Advanced Magnetic Resonance Imaging, Bashir Lab for Liver Imaging Research, and a coauthor of The Lancet paper.“Liver biopsy is an invasive technique with associated morbidity. A goal of the NASH field is to find noninvasive tests that predict outcome of NASH treatments to avoid use of serial liver biopsies. In addition to improving the understanding of the pharmacology and safety of resmetirom in patients with NASH, this study provides results of serial non-invasive imaging of liver fat content, serial biomarkers of liver injury and fibrosis, and serial liver biopsies at baseline and after 36 weeks of treatment, providing the potential to demonstrate associations between changes in non-invasive measures and liver histology,” stated Rebecca Taub, M.D., Chief Medical Officer and President of Research & Development at Madrigal.Based in part on the results of this study, a multi-center, double-blind, randomized, placebo-controlled Phase 3 registration study, MAESTRO-NASH, is currently enrolling 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.Summary of key results featured in The Lancet and the 36-week extension study presented today by Dr. Stephen Harrison as an oral presentation at AASLD
The Phase 2 clinical trial was designed to determine the effect of resmetirom compared to placebo on hepatic fat at week 12 (the primary endpoint) and week 36 in patients with liver biopsy confirmed NASH and stage 1-3 fibrosis. Steatosis was assessed by MRI-PDFF, a sensitive measure of hepatic fat. Secondary objectives were to assess safety and tolerability and to assess the impact of resmetirom on liver histology, serum lipids, liver enzymes and biomarkers of  fibrosis after 36 weeks of treatment. 348 patients were screened and 84 were randomized to resmetirom and 41 to placebo at 18 sites in the US. Resmetirom-treated patients (n=78) demonstrated a relative reduction (%) of hepatic fat compared with placebo (n=38) at week 12 (–32.9% resmetirom vs –10.4% placebo; least squares mean difference –22.5%, 95% CI –32.9 to –12.2; p<0·0001) and week 36 (–37.3% resmetirom [n=74] vs –8.5 placebo [n=34]; –28.8%, –42.0 to –15.7; p<0·0001). NASH resolution without worsening of fibrosis occurred in 24.7% of resmetirom treated as compared with 6.5% of placebo treated patients (p=0.024) and in resmetirom treated patients who had at least 30% reduction in liver fat at week 12, NASH resolution at 36 weeks occurred in 37% (p=0.0026).
A 36-week extension study was conducted in patients completing the 36-week main Phase 2 study who had at least some remaining elevation of liver enzymes. The treatment code was unknown at the time of entry of 31 patients into the 36-week non-invasive extension study in which all patients received active treatment with 80 or 100 mg of resmetirom. Twenty-nine patients completed all 36 weeks. Endpoints of the extension study were non-invasive. Statistically significant reductions were observed in hepatic fat (64% at the 100 mg dose), atherogenic lipids, fibrosis markers, serial fibroscan liver stiffness, and liver enzymes, suggesting that non-invasive biomarkers and imaging indicative of improvement in NASH with fibrosis could ultimately be used to monitor response to treatment.Safety in the Phase 2 NASH clinical trial and overall resmetirom development program
Resmetirom was well tolerated and appeared safe in more than 400 treated patients and healthy volunteers. There was a low incidence of severe and serious adverse events in the NASH Phase 2 clinical trial, none related to resmetirom. There was no imbalance in severe or moderate AEs with resmetirom treatment compared to placebo. There was an increase in the incidence of mild transient gastrointestinal side effects including loose stools and mild nausea, typically a single instance at the initiation of dosing; these were not observed in the NASH Phase 2 extension study. More than 50 healthy volunteers have received 1-2 weeks of 100 mg doses of resmetirom without increase in incidence of diarrhea or nausea (<2%).
Safety data in more than 150 patients treated at the top dose being used in Phase 3, 100 mg, for up to 1.5 years demonstrate that there is no effect of resmetirom on thyroid axis hormones, and no symptoms, clinical signs or incidence of either hyperthyroidism or hypothyroidism.About NASH
Non-alcoholic Steatohepatitis (NASH) is a common liver disease in the United States and worldwide, unrelated to alcohol use, that is characterized by a build-up of fat in the liver, inflammation, damage (ballooning) of hepatocytes and increasing fibrosis. Although people with NASH may feel well and often do not know they have the disease, NASH can lead to permanent damage, including cirrhosis and impaired liver function in a high percentage of patients.
Investor Contact: 
Marc Schneebaum, Madrigal Pharmaceuticals, Inc. IR@madrigalpharma.com 

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