Selective Thyroid Receptor-β Agonist


X-Linked Adrenoleukodystrophy

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.1 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.

VK0214 is a novel, orally available small molecule thyroid hormone receptor agonist that possesses selectivity for the beta receptor subtype. Data from an in vivo proof-of-concept study of VK0214 in X-ALD were presented at the 87th Annual Meeting of the American Thyroid Association, in Victoria, British Columbia. The results of this study demonstrated that long-term (25-week) treatment with VK0214 produced statistically significant reductions in plasma and tissue levels of very long chain fatty acids (VLCFAs) compared to vehicle-treated controls. VLCFA levels in central nervous system (CNS) tissues were also significantly reduced, suggesting a potential direct benefit in both brain and spinal cord. Treatment with VK0214 was also shown to stimulate significant increases in ABCD2 transporter expression in CNS tissue, providing further evidence of its effect beyond plasma exposures. These study results were consistent with the proposed mechanism of thyroid receptor beta (TRb)-mediated reductions in VLCFA levels, as ABCD2 is regulated by TRb and known to play a role in VLCFA metabolism. The successful outcome of this work serves to provide support for the role of selective TRb activation as a potential therapeutic approach to the disease. The company plans to file an IND for VK0214 in X-ALD by mid-year 2020.


  • Adrenoleukodystrophy Database