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.