Abstract 14497: Reduction of Atherogenic Lipoprotein (a) and Apolipoprotein B in Humans With the Selective Thyroid Receptor Beta Agonist Vk2809

Introduction: Thyroid hormones are important modulators of many aspects of lipid homeostasis and metabolism. In humans, activation of the beta isoform of the thyroid hormone receptor (TRβ) has been shown to increase low-density lipoprotein (LDL) receptor expression and stimulate cholesterol metabolism, resulting in reduced circulating LDL cholesterol (LDL-C). VK2809 is a liver-targeted small molecule prodrug of a potent, selective TRβ agonist, VK2809A. VK2809 derives its liver-targeting properties via selective activation by the cytochrome P450 isozyme 3A4 (CYP3A4), an enzyme found predominantly in liver tissue. This generates elevated hepatic exposure to VK2809A, with reduced systemic exposure to other tissues, such as heart and skeletal muscle. In animals, VK2809 has demonstrated potent reductions of plasma cholesterol, triglycerides, and liver fat content. Hypothesis: In a previous 14-day Phase 1b trial in subjects with elevated LDL-C (≥100 mg/dL), treatment with VK2809 at doses of 5 mg to 40 mg daily resulted in placebo-adjusted reductions in LDL-C (LSM) of 15% to 41%. In view of this robust reduction in LDL-C, we set out to determine if the atherogenic particles lipoprotein(a) [Lp(a)] and Apolipoprotein B-100 (Apo B) were similarly reduced by treatment with VK2809. Methods: Archival blood samples from subjects who had completed the 14 day Phase 1b study were retrieved and analyzed for Lp(a) and Apo B. Results: Following 14 days of treatment, placebo-adjusted, least square mean reductions in Lp(a) ranged from 9% to 55% across the doses studied. Similarly, ApoB levels declined by 5% to 40%. These differences were highly statistically significant at doses ≥5 mg ApoB and ≥10 mg for Lp(a). Conclusions: Statistically significant reductions of the atherogenic proteins Lp(a) and Apo B were observed after 14 days of daily treatment with the selective TRβ agonist VK2809. Thus, treatment with a TRβ receptor agonist may represent a promising potential therapy for the treatment of patients with elevated plasma lipids who are at risk for cardiovascular disease. A proof of concept study is underway to evaluate the effects of VK2809 on atherogenic lipids and liver fat content in patients with hypercholesterolemia and fatty liver disease.