Viking Therapeutics announced positive top-line results from a 25-week proof-of-concept study of VK0214 in an in vivo model of X-linked adrenoleukodystrophy (X-ALD). The results of this study showed that VK0214 led to statistically significant reductions in plasma levels of multiple very long chain fatty acids (VLCFAs) in treated animals compared with vehicle controls. Additionally, VK0214-treated animals demonstrated statistically significant reductions in VLCFA levels within key tissues, including liver, brain and spinal cord. As the accumulation of VLCFAs is believed to contribute to the underlying pathology of X-ALD, these data provide additional support for the continued evaluation of VK0214 in this indication.
The results showed that 25 weeks of treatment with VK0214 led to robust effects on multiple VLCFAs, including statistically significant reductions in plasma levels of saturated C26, C24, C22, and C20 fatty acids ranging from 45% to 82% relative to controls. Importantly, these reductions were generally maintained or increased in magnitude over the course of the 25-week study, suggesting a potentially progressive and durable effect. These data compare favorably to results from a prior six-week study, with improvements observed on all key VLCFA measures relative to the prior study. These results further support the thesis that activation of the thyroid beta receptor can lead to an improved metabolic profile in this setting.
The study also evaluated the effect of VK0214 on VLCFA levels in various tissues. After 25 weeks of treatment, VK0214 was shown to reduce levels of VLCFAs in liver, brain and spinal cord. This suggests an added potential therapeutic benefit, as elevated tissue VLCFA levels may contribute to the underlying cerebral and myelotoxicities observed in X-ALD. Detailed results will be presented at the upcoming 87th Annual Meeting of the American Thyroid Association, October 18-22 in Victoria, British Columbia.
"This is the second study in which we have generated encouraging evidence of the therapeutic potential of VK0214 in this debilitating disease. The impressive effects on plasma VLCFAs strengthen our belief that activation of the thyroid beta receptor can lead to improved lipid processing. The reduction in tissue VLCFAs is particularly exciting, as it suggests a potential direct benefit on tissue-related toxicities," said Brian Lian, Ph.D., chief executive officer of Viking. "Importantly, these longer-term results demonstrate improved pharmacologic effects relative to the prior six-week study, with no evidence of safety or tolerability issues. We look forward to continuing our evaluation of VK0214 in this setting."
The 25-week proof-of-concept study, conducted at the Kennedy Krieger Institute under a sponsored research agreement with Viking, was designed to evaluate changes in VLCFA levels in the ABCD1 knockout mouse model. This model is intended to mirror the loss of ABCD1 transporter activity that is considered the hallmark of X-ALD. Mice received VK0214 or vehicle daily for 25 weeks. Plasma VLCFA levels were determined by measuring unsaturated lysophosphatidylcholine fatty acid esters, which are biomarkers for VLCFAs in X-ALD. Additional work is underway to better understand VK0214's therapeutic effect in models of this disease, including an elucidation of anti-inflammatory properties that have been observed in preliminary studies in human macrophages.
VK0214 has been granted orphan drug status by the U.S. Food and Drug Administration for the treatment of X-linked adrenoleukodystrophy. The molecule is a novel, orally available thyroid receptor beta (TRβ) agonist that selectively modulates lipoprotein and triglyceride levels in liver tissue. This mechanism has been demonstrated to affect the expression of the genes that are relevant to the manifestation of X-ALD. In X-ALD, mutations in the ABCD1 gene lead to the accumulation of very long-chain fatty acids (VLCFAs) which is believed to be a fundamental cause of the disease. Research has shown that increasing the expression of the ABCD2 gene can counteract this process and lead to normalization of VLCFA levels. In preclinical studies, VK0214 has been shown to induce expression of ABCD2 by increasing TRβ activity, leading to the belief that it may provide therapeutic benefit to X-ALD patients.