Viking Therapeutics announced the initiation of a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial of VK0214, a novel, orally available thyroid receptor beta (TRβ) agonist in development as a potential treatment for X-linked adrenoleukodystrophy (X-ALD). Enrollment in this study is underway following clearance of the company's Investigational New Drug (IND) application by the United States Food and Drug Administration (FDA).

Activation of the thyroid beta receptor has been shown to affect the expression of genes that are relevant to the manifestation of X-ALD. In X-ALD, mutations in the ABCD1 gene lead to dysfunction of the adrenoleukodystrophy protein (ALDP), an important peroxisomal transporter. In patients, this leads to an accumulation of very long chain fatty acids (VLCFAs), which is believed to contribute to the onset and progression of the disease. Research in disease models has shown that increasing the expression of a related gene called ABCD2, which encodes a compensatory transporter called the adrenoleukodystrophy related protein (ADLRP), can result in normalization of VLCFA levels.

In preclinical studies, VK0214 has been shown to potently activate the thyroid beta receptor, leading to increased expression of ABCD2. Data from in vivo studies have demonstrated that administration of VK0214 produces a significant reduction of VLCFAs in both plasma and tissue, potentially leading to a therapeutic benefit. VK0214 has been granted orphan drug designation by the FDA for the treatment of X-ALD.

The Phase 1 trial is a randomized, double-blind, placebo-controlled, SAD and MAD study in healthy subjects. The primary objectives of the study include evaluation of the safety and tolerability of single and multiple oral doses of VK0214, as well as the identification of VK0214 doses for further clinical development in the setting of X-ALD. Study investigators will also assess pharmacokinetics of single and multiple oral doses of VK0214. Upon successful completion of the SAD/MAD study, the company plans to initiate a Phase 1b study in patients with X-ALD.

"We are excited to advance VK0214 into clinical development to evaluate as a potential treatment for X-ALD, a progressive, debilitating disease for which there is no approved therapy. The safety, tolerability and pharmacokinetic data from this study will provide key insights for future trials of VK0214 in patients with X-ALD," said Brian Lian, Ph.D., chief executive officer of Viking Therapeutics. "Our prior results in this area indicate that the thyroid receptor beta is an important regulator of VLCFA metabolism, and we look forward to demonstrating the therapeutic potential of VK0214 in combatting this disease."

X-ALD is a rare and often fatal metabolic disorder characterized by a breakdown in the protective barriers surrounding brain and nerve cells; a process known as demyelination. The disease, for which there is no approved treatment, is caused by mutations in a peroxisomal transporter of VLCFAs, known as ABCD1. As a result, transporter function is impaired and patients are unable to efficiently metabolize VLCFAs. The resulting accumulation can trigger a rapid, inflammatory demyelination, which leads to cognitive impairment, motor skill deterioration, and even death. X-ALD is estimated to occur in approximately 1 in 17,000 births.

The thyroid beta 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.