Madrigal Pharmaceuticals, Inc. (Nasdaq: 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. The company has advanced its lead candidate, resmetirom, also known as MGL-3196, a first-in-class, orally administered, small-molecule, liver-directed, thyroid hormone receptor (THR) β-selective agonist, through Phase 2 clinical trials in non-alcoholic steatohepatitis (NASH). Primary and key secondary endpoints were achieved, including reduction of liver fat on a sensitive non-invasive imaging test, lowering of multiple atherogenic lipids including LDL-cholesterol and triglycerides, and resolution of NASH on liver biopsy.
Based on evidence of broad activity and a favorable safety profile, Madrigal has initiated a Phase 3 clinical study in NASH patients with advanced liver fibrosis, MAESTRO-NASH, in which the primary endpoint after one year of dosing is resolution of NASH and key secondary endpoints include LDL-cholesterol lowering and reduction in liver fibrosis. Clinical benefit in reducing progression to more advanced liver disease, including cirrhosis, is a long-term goal of this trial.
A second Phase 3 clinical study, MAESTRO-NAFLD-1 (NAFLD: non-alcoholic fatty liver disease), has also been initiated. This 52-week, non-invasive study in a broader segment of NASH patients will provide additional safety information to support the NASH indication and will include key efficacy endpoints: LDL-cholesterol lowering, triglyceride lowering, reduction of liver fat as determined by magnetic resonance imaging proton density fat fraction (MRI-PDFF), as well as reduction of elevated liver enzymes and reduction in fibrosis biomarkers. This is a non-biopsy study in people with NASH, as documented using non-invasive techniques or historical liver biopsy.
“Resmetirom, with its pleotropic actions, has the potential to effectively treat NASH with advanced fibrosis, by addressing its root causes. Additionally, and importantly, by decreasing atherogenic lipids in the blood as well as fat in the liver, resmetirom has the potential to reduce the heightened cardiovascular risk present in the NASH population including people with both early NASH and people with advanced NASH and liver fibrosis. We expect resmetirom to demonstrate multiple benefits across a broad spectrum of NASH and NAFLD patients in our Phase 3 trials.”