Selective Thyroid Receptor-β Agonist
Overview & Profile
We are developing a unique series of selective thyroid hormone receptor beta (TRβ) agonists for metabolic disorders. Our lead candidate, VK2809, is a novel, orally available small molecule thyroid hormone receptor agonist that possesses selectivity for liver tissue, as well as the beta receptor subtype, suggesting promise for the treatment of metabolic disorders, including non-alcoholic steatohepatitis (NASH). The liver-targeting properties of our TRβ agonists are designed to reduce or eliminate the deleterious effects of extra-hepatic thyroid receptor activation. In particular, high tissue and TRβ selectivity may lead to reduced activity at the TRα receptor, which can be associated with increased respiration and cardiac tissue hypertrophy.
Thyroid hormones are known to reduce body mass, affect growth, modulate lipid metabolism and impact the functions of multiple organs in humans. Their physiologic activity is derived from binding to hormonal receptors located in the nuclei of cells (nuclear hormone receptors). Characteristics of thyroid hormone activity that are of importance to drug development include the ability to reduce atherogenic lipids associated with cardiovascular disease and induce an increase in metabolism, resulting in weight loss. Patients with abnormally high or low thyroid hormone levels demonstrate clinical profiles consistent with these characteristics. Numerous animal models have provided further support of these physiologic effects.
Graphic: Harrison’s Principles of Internal Medicine, 17th Edition, Chapter 335, Fig 335-4, copyright McGraw-Hill, 2008.
Thyroid Receptor Subtypes
- Predominantly in the liver and brain
- Modulates cholesterol and triglyceride levels
- Predominantly in cardiac tissue
- Modulates heart rate, contraction
Therapeutic goal for lipid-targeting:
- β-receptor selectivity
In a Phase 2 trial for the treatment of non-alcoholic fatty liver disease (NAFLD) and elevated LDL-C, patients who received VK2809 demonstrated statistically significant reductions in LDL-C and liver fat content compared with patients who received placebo. VK2809 was shown to be safe and well-tolerated in this study.
In a Phase 1 multiple-ascending dose study in patients with mild hypercholesterolemia, patients who received VK2809 demonstrated significant reductions in LDL-C, triglycerides and atherogenic proteins. VK2809 was shown to be safe and well-tolerated in this study.
In a rodent model of diet-induced NASH, VK2809 has demonstrated potent reductions in plasma and liver lipids, as well as improvements in liver fibrosis. VK2809-treated rodents also demonstrated improvement in genes associated with lipid metabolism and suppression of genes associated with fibrogenic signaling.
in animal models of hypercholesterolmeia, or high levels of cholesterol in the blood, VK28091,2 demonstrated promising reductions in plasma cholesterol with minimal effects on the thyroid hormone axis at doses effective for cholesterol reduction.
Fatty Liver Disease and Hypercholesterolemia
In the U.S., the number of patients with hypercholesterolemia is estimated to be greater than 100 million.3 and approximately 31.7% of American adults, or 73.5 million people, have high LDL cholesterol.3 In the U.S., NAFLD affects up to 25% of the population.4 NAFLD can lead to NASH, a severe form which involves inflammation and cell damage. NASH is a growing epidemic in the U.S. and is quickly becoming a leading cause of cirrhosis and liver failure. It is estimated that NASH affects 2% to 5% of Americans.5
- Fujitaki JM, Cable EE, Ito BR, Zhang BH, Hou J, Yang C, Bullough DA, Ferrero J, van Poelje PD, Linemeyer DL, Erion MD. 2008. Preclinical Pharmacokinetics of a HepDirect Prodrug of a Novel Phosphonate-Containing Thyroid Hormone Receptor Agonist. DMD 36:2393-2403.
- Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, Zhang BH, Hou J, Boyer SH, van Poelje PD, Linemeyer DL. 2007. Targeting Thyroid Hormone Receptor-β Agonists to the Liver Reduces Cholesterol and Triglycerides and Improve the Therapeutic Index. PNAS 104 (39): 15490-15495.
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- American Liver Foundation: NAFLD: nonalcoholic fatty liver disease
- National Digestive Diseases Information Clearinghouse (NDDIC): Nonalcoholic steatohepatitis
- VK2809 data presented at the American Heart Association 2016 Scientific Sessions
- VK2809 data presented at the 2016 Meeting of the American College of Cardiology