Thyroid Receptor beta Agonists for Lipid Disorders
Overview and Profile
We are developing a unique series of selective thyroid hormone receptor beta (TRβ) agonists for lipid disorders. Our lead candidates, VK2809 and VK0214, are novel, orally available, selective TRβ agonists. 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. We believe these characteristics may provide potential benefits to patients suffering from metabolic diseases such as, hypercholesterolemia, fatty liver disease, and X-linked adrenoleukodystrophy (X-ALD).
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 animal models of hypercholesterolemia, or high levels of cholesterol in the blood, both VK28091,2 and VK0214 demonstrated promising reductions in plasma cholesterol with minimal effects on the thyroid hormone axis at doses effective for cholesterol reduction. Preclinical data also suggest that both compounds may affect the expression of genes potentially relevant to X-ALD, a rare neurological disorder characterized by a breakdown in the protective barriers surrounding brain and nerve cells.
Effects of VK2809 on plasma cholesterol
In a 14-day Phase 1b trial in 56 subjects with mild hypercholesterolemia, VK2809 was shown to be safe and well-tolerated at all doses studied. The results also showed dose-related reductions in fasting LDL-C and fasting triglyceride, or TG, levels at day 14.
Highlights from Phase 1b Data
- Enrollment criterion: LDL ≥ 100 mg/dL
- Clinically, statistically significant reductions in LDL
- Up to 79% reduction in triglycerides
- Major component of liver fat
- Major component of liver fat
- Shown to be safe and well-tolerated, no SAEs
Hypercholesterolemia and Fatty Liver Disease
We are advancing VK2809 for lipid disorders, such as hypercholesterolemia and non-alcoholic fatty liver disease (NAFLD). In the U.S., the number of patients with hypercholesterolemia is estimated to be greater than 100 million.3 Approximately 31.7% of American adults, or 73.5 million people, have high LDL cholesterol.3 NAFLD affects up to 25% of people in the U.S.4 NAFLD can lead to non-alcoholic steatohepatitis (NASH), a severe form of NAFLD which causes the liver to swell and become damaged. 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
We are developing VK0214 for the potential treatment of X-linked adrenoleukodystrophy, or X-ALD. X-ALD is a rare X-linked, inherited neurological disorder characterized by a breakdown in the protective barriers surrounding brain and nerve cells. It is the most frequent inherited peroxisomal disorder, affecting approximately 1 in 17,000 newborns.6 The disease is caused by mutations in a peroxisomal transporter of very long chain fatty acids, or VLCFA, known as the adenosine triphosphate binding cassette transporter D1, or ABCD1. As a result of mutations, transporter function is impaired and patients are unable to efficiently metabolize VLCFA. The TRß receptor is known to regulate expression of an alternative VLCFA transporter, known as ABCD2. Various preclinical models have demonstrated that increased expression of ABCD2 can lead to normalization of VLCFA metabolism. Preliminary in vitro data suggest that VK0214 stimulates ABCD2 expression. We are conducting studies of VK0214 in an in vivo model of disease
- 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.
- Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Després J-P, FullertonHJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey, RH, Matchar DB, McGuire DK, Mohler ER, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart Disease and Stroke Statistics—2015 Update: A Report from the American Heart Association. Circulation. 2015; 131(4):e29-e322.
- American Liver Foundation: NAFLD: nonalcoholic fatty liver disease
- National Digestive Diseases Information Clearinghouse (NDDIC): Nonalcoholic steatohepatitis
- Adrenoleukodystrophy Database