FORT WASHINGTON, PA--(Marketwire - November 06, 2012) - Madrigal Pharmaceuticals, a development company focused on novel small-molecule drugs addressing major unmet needs in cardiovascular and metabolic diseases, today announced that results from single and multiple dose Phase I clinical trials of the Company's lead product candidate, MGL-3196, were presented at the American Heart Association 2012 Scientific Sessions, taking place November 3-7 in Los Angeles, California.
In the single dose study, MGL-3196 appeared safe and was well-tolerated at all doses tested. The Phase I multiple dose, proof of concept study enrolled 48 healthy volunteers with mildly elevated LDL cholesterol to evaluate the safety, pharmacokinetics and pharmacodynamics of MGL-3196 after two weeks of daily dosing. Results showed that MGL-3196 was well tolerated and appeared safe at all doses tested. Few adverse events were reported and were generally mild, unrelated to study drug and not dose-related. Daily doses of 50-200 mg showed highly statistically significant reductions, relative to placebo, in LDL-cholesterol of up to 30% (p=.05- < .0001); 28% for non-HDL cholesterol (p=.027-.0001); and 24% for Apolipoprotein B (p=.008-.0004), in addition to strong trends for an up to 60% reduction in triglycerides (p=.13-.016).
MGL-3196 is a liver-directed thyroid hormone receptor-beta (THR-ß) agonist for the treatment of hypercholesterolemia, or high blood cholesterol levels, other dyslipidemias and high triglycerides. It is designed to specifically target receptors in the liver involved in triglyceride metabolism and cholesterol regulation, delivering the validated benefits of THR-ß agonism, which include a lowering of LDL cholesterol, liver triglycerides and triglycerides, while avoiding the side effects associated with receptor activation outside the liver. MGL-3196 has excellent safety in comparative studies with other THR agonists tested previously because of its high liver uptake and high ß-selectivity, with nearly complete lack of THR-a activity.
"These results suggest that MGL-3196 has a unique lipid lowering profile as compared with other agents, with the potential to significantly reduce cholesterol, triglycerides and liver triglycerides. And unlike other thyroid hormone ß-agonists, MGL-3196 is also well tolerated," said Rebecca Taub, M.D., Chief Executive Officer of Madrigal Pharmaceuticals. "Elevated cholesterol, triglycerides and fatty liver are an underlying cause of many metabolic and cardiovascular diseases, which, themselves, are associated with increased mortality. Our next step is to move into disease directed studies where control of these lipid levels in the blood and liver, particularly triglycerides, is clinically important and measurable -- areas such as diabetes with associated fatty liver disease or patients whose very high triglyceride levels put them at elevated risk for pancreatitis and heart disease. We are considering clinical development paths in which large cardiovascular outcome studies may not be required for drug approval."
MGL-3196 is an orally administered, small-molecule ß-selective THR agonist designed to specifically target receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with thyroid hormone receptor activation outside the liver, including those mediated by THR-a receptors. Based on preclinical studies, MGL-3196 is a potent regulator of hepatic triglyceride metabolism and cholesterol lowering. Preclinical studies demonstrated a rapid reduction of non-HDL cholesterol and the drug was shown to be synergistic with statins in animal studies. THR-ß agonists are believed to promote reverse cholesterol metabolism by causing increased uptake of cholesterol into the liver and increased cholesterol elimination from the body through excretion into the bile. The compound also reduces triglycerides in the plasma and liver by increasing fat metabolism and shows an anti-diabetic action.
About Madrigal Pharmaceuticals, Inc.
Madrigal Pharmaceuticals, Inc. is a company focused on the development of novel compounds for the treatment of cardiovascular and metabolic diseases. Madrigal's drug candidates include MGL-3196 and other compounds that address the underlying causes of metabolic and cardiovascular disease: high cholesterol, triglycerides and diabetes. For more information, visit: http://www.madrigalpharma.com.