Abstract 11958: Pharmacokinetics, Safety and Cholesterol Lowering in Healthy Volunteers Treated with Single and Multiple Doses of Madrigal's 3196 Liver-directed Thyroid Hormone Receptor- Agonist
Madrigal’s novel drug 3196 is an oral, liver-directed partial agonist for the thyroid hormone receptor-ß (THR-ß) that is being developed for the treatment of hypercholesterolemia/dyslipidemia. Liver THR-ß is responsible for mediating the beneficial metabolic effects of thyroid hormone while most of the systemic effects are mediated by THR-α. In preclinical animal studies, 3196 showed robust lowering of non-HDL cholesterol, triglycerides and liver triglycerides, differentiating 3196 from statins and other lipid-lowering agents. The safety profile and tolerability of THR-ß agonist 3196 was assessed in a single ascending dose (SAD) study of 9 cohorts with 8 subjects each who received escalating oral doses of 3196 or placebo (NCT01367873). 3196 was well-tolerated at all doses tested up to 200 mg with few, non-dose-related adverse events (AEs); no maximal tolerated dose was found. Drug exposure was dose-dependent and minimally affected by food. A two week multiple ascending dose (MAD) study was conducted at doses of 5, 20 and 50 mg in healthy subjects with mildly elevated LDL cholesterol (>110 mg/dL)(NCT01519531). 3196 was well-tolerated at all doses with no dose-related AEs or liver enzyme changes that have been observed with other TH analogues. There were no effects on 24h Holter heart rate or blood pressure. Drug exposure was dose-dependent. At 50 mg, total (baseline (BL) 218 mg/dL), LDL (BL 148 mg/dL), non-HDL cholesterol (155 mg/dL) and apolipoprotein B (ApoB) (BL 116 mg/dL) were reduced by 23, 22, 15, 20 mg/dL, respectively, and reduced relative to 5 mg and placebo (p=.03, .04, .08, .03). Lipid reductions were apparent after 5 days of dosing and sustained throughout the study. The ApoB/ApoA ratio decreased at 20 (p=.03) and 50 (p=.03) mg relative to 5 mg and placebo, and more 20 and 50 mg subjects showed triglyceride decreases (NS). No treatment related effect on TSH or thyroid hormones was observed in the SAD study. In the MAD study, individual changes in levels of the prohormone T4, if any, were transient, small and not clearly dose-dependent. No reduction in TSH, or the active hormone, T3, was observed at any dose. In summary, in a two-week MAD study in healthy volunteers 3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters.
- © 2012 by American Heart Association, Inc.