Thyroid hormone regulation of lipid metabolism beneficially affects a wide range of interrelated health parameters, including aiding in maintaining normal levels of cholesterol and triglycerides in the blood, preventing pathological buildup of fat in the liver and stimulating hepatic mitochondrial biogenesis. In the liver, these multiple actions are mediated through selective activation of thyroid hormone receptor beta (THR)-β.
Madrigal has advanced its lead candidate, resmetirom (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 NASH with liver fibrosis and heterozygous familial hypercholesterolemia (HeFH). In both Phase 2 trials, resmetirom lowered multiple atherogenic lipids and lipoproteins, including LDL-cholesterol (LDL) and triglycerides.
Based on evidence of broad activity and a favorable safety profile, Madrigal initiated a Phase 3 clinical program in NASH with advanced liver fibrosis, called MAESTRO-NASH (ClinicalTrials.gov NCT03900429). The Phase 3 MAESTRO-NASH trial largely replicates the Phase 2 clinical trial using doses that are most likely to be both safe and effective. Madrigal initiated MAESTRO-NASH in NASH patients with advanced liver fibrosis (stages F2 and F3) in March 2019. The primary endpoint for that trial, after one year of treatment, is resolution of NASH; key secondary endpoints include LDL-cholesterol lowering and reduction in liver fibrosis. Additionally, clinical benefit in reducing progression to more advanced liver disease, including cirrhosis, is a long-term goal of MAESTRO-NASH. (ClinicalTrials.gov NCT03900429)
Madrigal has also initiated a second Phase 3 clinical trial with resmetirom, MAESTRO-NAFLD-1 (ClinicalTrials.gov NCT04197479). MAESTRO-NAFLD-1 is a 52-week, Phase 3, double-blind, placebo-controlled clinical study in 700 patients designed to evaluate the safety and biomarkers in resmetirom compared to placebo-treated patients in a broad segment of patients with NASH and to support registration for the treatment of NASH. The primary endpoint of the study is safety. MAESTRO-NAFLD-1 is also expected to provide additional data regarding clinically relevant efficacy endpoints, including lowering of atherogenic lipids and lipoproteins. Key secondary endpoints include LDL-cholesterol; apolipoprotein B 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. Reduction of liver enzymes, fibroscan scores and other NASH and lipid biomarkers will be assessed.
Patients in both the MAESTRO-NASH and MAESTRO-NAFLD-1 studies are at high risk of cardiovascular disease because of their metabolic risk factors, hyperlipidemia, and fatty liver disease. NASH patients in both these studies will have hyperlipidemia and other evidence of elevated cardiovascular risk that is currently inadequately treated with their standard of care. Resmetirom has the potential to reduce the heightened cardiovascular risk in this patient population. Seth Baum, M.D. AASLD 2019 Presentation