The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans

Abstract

Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115; (3-[[3,5-dibromo-4-[4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis.

Fig. 1.

Pharmacokinetic properties of KB2115 after single doses (A) or multiple doses (B).

Fig. 2.

Effects of KB2115 (KBT) on the cardiovascular system after once-daily dosing for 2 weeks. (A and B) Effects on heart rate as measured by sequential measures during the treatment period (A) or by comparing heart rate before treatment versus after the last dose (B). (C) Effects on the QTc.

Fig. 3.

Effects of KB2115 on the hypothalamic-pituitary axis and thyroid hormone homeostasis after once-daily dosing for 2 weeks. Effects on (from top to bottom) TSH, free T₃, total T₃, free T₄, and total T₄ are shown. Significant difference in AUC (0–24 h) before and after 14 days of treatment with KB2115 was found for free T₄ and total T₄ (P = 0.002 and 0.001, respectively), and all active groups differed from placebo.

Fig. 4.

Effects of KB2115 on lipids and lipoproteins after once-daily dosing for 2 weeks. Effect on total cholesterol (A; P = 0.005, 100-μg group differs from placebo), LDL cholesterol (B; P = 0,01, 100-μg group differs from placebo), HDL cholesterol (C; P = 0.68), and apoB/apoA-I ratio (D; P = 0.04, 100-μg group differs from placebo).

Fig. 5.

Effects of KB2115 on biomarkers for cholesterol synthesis and degradation after once-daily dosing for 2 weeks displayed as percent change from baseline for ratios between C4 and cholesterol (A; P = 0.01, 200-μg group differs from placebo) and ratios between lathosterol and cholesterol (B).