Liver-directed THR-ß Agonist, MGL-3196
MGL-3196 is an orally administered, small-molecule liver-directed 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-α receptors. MGL-3196 has currently completed Phase I single and multiple dose trials in healthy volunteers. MGL-3196 is being developed for dyslipidemia/hypercholesterolemia to lower LDL cholesterol, triglyceride levels and Lp(a), and was inlicensed from Roche Pharmaceuticals. MGL-3196 has excellent safety in comparative studies with other THR agonists tested previously because of MGL-3196’s high liver uptake and high ß-selectivity and nearly complete lack of THR-α activity.
MGL-3196 has completed a single ascending dose study in healthy volunteers in which the compound appeared safe at all doses tested. The multiple ascending dose study in healthy volunteers with mildly elevated LDL cholesterol was completed in October 2012 and provided additional safety and pharmacodynamic information. 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. Daily doses of 50-200 mg showed highly statistically significant reductions relative to placebo of up to 30% LDL-cholesterol (p=.05-<.0001; 28%, non-HDL cholesterol (p=.027-.0001); 24% Apolipoprotein B (p=.008-.0004); and strong trends and up to 60% reduction of triglycerides (range, p=.13-.016).
The 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. Unlike other thyroid hormone ß-agonists, MGL-3196 is well tolerated. Elevated cholesterol, triglycerides and fatty liver are an underlying cause of many metabolic and cardiovascular diseases, which, themselves, are associated with increased mortality. The 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 with very high triglycerides at risk for associated side-effects – diseases in which large cardiovascular outcome studies may not be required for drug approval.
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.
MGL-3196 is designed to specifically activate receptors in the liver involved in metabolism and cholesterol regulation, and avoid side effects associated with THR activation outside the liver. Its mechanisms of action are distinct from and complementary to statins.