Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-β agonist

• Published in: Atherosclerosis Vol. 230; no. 2; pp. 373 - 380
• Main Authors: Taub, Rebecca, Chiang, Edward, Chabot-Blanchet, Malorie, Kelly, Martha J., Reeves, Richard A., Guertin, Marie-Claude, Tardif, Jean-Claude
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.10.2013
• Subjects: Adult; adverse effects; agonists; analogs & derivatives; apolipoprotein B; atherosclerosis; blood; Body Mass Index; Cardiovascular; chemistry; Cholesterol; Cholesterol, LDL; Cholesterol, LDL - blood; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; drug effects; drug therapy; Female; Healthy Volunteers; high density lipoprotein cholesterol; Humans; Hypercholesterolemia; Hypercholesterolemia - drug therapy; hyperlipidemia; liver; Liver - drug effects; Liver - metabolism; low density lipoprotein cholesterol; Male; metabolism; Middle Aged; Patient Safety; pharmacokinetics; Pyridazines; Pyridazines - adverse effects; Pyridazines - chemistry; Pyridazines - pharmacokinetics; Thyroid Gland; Thyroid Gland - drug effects; Thyroid Gland - metabolism; Thyroid hormone receptor agonist; Thyroid Hormone Receptors beta; Thyroid Hormone Receptors beta - agonists; thyrotropin; Thyrotropin - blood; Thyroxine; Thyroxine - blood; Time Factors; triacylglycerols; Triglycerides; triiodothyronine; Triiodothyronine - blood; Uracil; Uracil - adverse effects; Uracil - analogs & derivatives; Uracil - chemistry; Uracil - pharmacokinetics; volunteers; Thyroid hormone receptor agonist; Triglycerides; Cholesterol
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2013.07.056

MGL-3196 is an oral, liver-targeted selective agonist for the thyroid hormone receptor-β (THR-β) that is being developed for the treatment of dyslipidemia. The safety profile and tolerability of THR-β agonist MGL-3196 was assessed in first-in humans studies, including a single ascending dose study (NCT01367873) in which MGL-3196 appeared safe at all doses tested. A two-week multiple dose study was conducted at doses of 5, 20, 50, 80, 100, and 200 mg per day in healthy subjects with mildly elevated low density lipoprotein (LDL) cholesterol (>110 mg/dL) (NCT01519531). MGL-3196 was well-tolerated at all doses with no dose-related adverse events or liver enzyme, ECG or vital-sign changes. At the highest dose, there was a reversible reduction of ∼20% in the level of pro-hormone, free thyroxine (free T4) that was significantly different from placebo (p < 0.0001) that may be explained by increased hepatic metabolism of T4. There was no change in thyrotropin (TSH) or triiodothyronine (free T3) or other evidence of central thyroid axis dysfunction at any dose. Doses ranging from 50 to 200 mg demonstrated highly statistically significant reductions relative to placebo of up to: 30% for LDL cholesterol (range, p = 0.05–<0.0001); 28% for non- high density lipoprotein (HDL) cholesterol (range, p = 0.027–0.0001); 24% for Apolipoprotein B (range, p = 0.008–0.0004), and statistical trends of up to 60% reduction in triglycerides (TG) (range, p = 0.13–0.016). The near maximal lipid effects were observed at a dose of 80 mg daily. In summary, in a two-week study in healthy volunteers with mild LDL cholesterol elevation, MGL-3196 appeared safe, was well-tolerated and showed a beneficial effect on lipid parameters. •First time in-human, MGL-3196, a thyroid receptor-β agonist, was dosed for 14 days.•MGL-3196 appeared safe at all doses with no effect on liver enzymes or vital signs.•The clinical safety profile differentiates MGL-31196 from other thyroid agonists.•Daily oral doses of MGL-3196 (50–200 mg) demonstrated rapid reductions in lipids.•LDL cholesterol was reduced up to 30%, with trends to reduce triglycerides up to 60%.