Selective Thyroid Receptor-β Agonist
X-Linked Adrenoleukodystrophy (X-ALD)
Overview & Profile
Viking is developing VK0214, which is also a novel, orally available small molecule thyroid hormone receptor agonist that possesses selectivity for the beta receptor subtype. VK0214 has been granted orphan drug designation by the FDA for the treatment of X-ALD.
In June 2021, Viking initiated a Phase 1b clinical trial of VK0214 in patients with X-ALD. The Phase 1b trial is a placebo-controlled study in adult male patients with the adrenomyeloneuropathy, or AMN, form of X-ALD. The primary objectives of the study are to evaluate the safety and tolerability of VK0214 administered once-daily over a 28-day dosing period. Secondary and exploratory objectives include an evaluation of the pharmacokinetics, pharmacodynamics, and the efficacy of VK0214 at lowering plasma levels of very long chain fatty acids (VLCFAs) in patients with AMN, following 28 days of dosing. VK0214 was advanced into this Phase 1b study after completing a successful Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects. Results from that trial showed that VK0214 demonstrated encouraging safety and tolerability, predictable pharmacokinetics, as well as statistically significant reductions of key lipids. Data from previous 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.
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 the gene for a peroxisomal transporter of VLCFAs, known as ABCD1. These mutations lead to dysfunction of the adrenoleukodystrophy protein (ALDP), an important peroxisomal transporter, which prevents patients from efficiently metabolizing VLCFAs. The resulting accumulation of VLCFAs, which is believed to contribute to the onset and progression of the disease, can trigger demyelination of nerve cells, resulting in cognitive impairment, motor skill deterioration, and even death.
The thyroid beta receptor (TRβ) is known to regulate expression of a related gene called ABCD2, which encodes a compensatory transporter called the adrenoleukodystrophy related protein (ALDRP).1 Research in various preclinical disease models has shown that increasing ABCD2 expression can result in normalization of VLCFA levels.2 Viking believes that our thyroid receptor agonists, which have the potential to normalize metabolism of VLCFAs peripherally, and potentially centrally, may positively impact all forms of X-ALD, including the currently untreatable AMN form.
TRβ and X-Linked Adrenoleukodystrophy
In June 2021, Viking announced the results of the first-in-human Phase 1 SAD and MAD clinical trial of VK0214 in healthy volunteers. This study successfully achieved its primary and secondary objectives, with VK0214 shown to be safe and well-tolerated at all doses evaluated. No serious adverse events were reported, and no treatment or dose-related trends were observed for vital signs, cardiovascular measures, or gastrointestinal side effects such as diarrhea or nausea. Treatment with VK0214 demonstrated dose-dependent exposures, no evidence of accumulation, and a half-life consistent with anticipated once-daily oral dosing. Further, subjects who received VK0214 experienced reductions in LDL-cholesterol (up to 21% from baseline), triglycerides (up to 45% from baseline), apolipoprotein B (up to 28% from baseline) and lipoprotein (a) (up to 42% from baseline) following 14 days of treatment. Many of the observed lipid reductions achieved statistical significance, though the study was not powered to demonstrate statistical significance on lipid assessments.
In addition to general lipid assessments in the Phase 1 SAD/MAD study, an evaluation of very long chain fatty acids (VLCFAs) was also performed. Despite relatively low baseline levels and the presence of a functional ABCD1 gene in these healthy volunteers, treatment with VK0214 produced reductions in VLCFA levels at all doses above 5 mg. Numerical improvements in excess of 20% from baseline were observed for multiple VLCFAs, including the key C26:0 VLCFA marker that is often elevated in patients with X-ALD, compared with a mean increase of 2.6% in placebo subjects. The VLCFA-reducing activity of VK0214 may provide benefit in a population of XALD patients, who by nature have high levels of accumulated VLCFAs due to pathogenic mutations in the ABCD1 gene.
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.3 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 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 served to provide support for the role of selective TRb activation as a potential therapeutic approach to the disease and for advancing VK0214 into the clinic.
X-ALD and AMN
The estimated birth incidence of X-ALD is 1 in 17,000 newborns4 (male and female), which makes it the most common peroxisomal disorder.
The ABCD1 gene responsible for X-ALD resides in the X chromosome. Since women have two copies of the X chromosome, most women who carry a defective copy of ABCD1 on the X-chromosome also carry one good copy of the gene, so they often will not have any symptoms of the disease.5 As a result, X-ALD affects mainly males.
There are several forms of X-ALD based on clinical severity.5 One of the most common and the most severe, affecting approximately 30% of all patients with X-ALD, is childhood cerebral ALD (CCALD). The average time between the initial symptoms of CCALD and a vegetative state or death is approximately 2 years, although it can range anywhere from 6 months to 20 years. Another form is adrenomyeloneuropathy (AMN), which is the most common form of X-ALD and affects approximately 40% of all X-ALD patients, with the first symptoms of AMN usually occurring in the twenties. AMN progresses slowly, and within 5 to 15 years the patient will generally need the aid of a cane or wheelchair.
- Weinhofer I, Kunze M, Rampler H, Forss-Petter S, et al. Distinct Modulatory Roles for Thyroid Hormone Receptors TRa and TRb in SREBP1-activated ABCD2 Expression. Eur. J. Cell Biol. 2008;87:933-945 (link).
- Genin EC, Gondcaille C, Trompier D, Savary S. Induction of the Adrenoleukodystrophy-related Gene (ABCD2) by Thyromimetics. J Steroid Biochem Mol Biol. 2009;116:37-43 (link).
- Masamune H, Moser A, Watkins P, Fatemi A, et al. Long-Term Dosing with the Thyroid Hormone Receptor Agonist VK0214 Reduces VLCFA Levels in Plasma and Tissue in an In Vivo Model of X-Linked Adrenoleukodystrophy. Poster presented at the 87th Annual Meeting of the American Thyroid Association (2017) (link).
- Bezman L, Moser HW. Incidence of X-linked Adrenoleukodystrophy and the Relative Frequency of its Phenotypes. Am J Med Genet. 1998;76(5):415-419 (link).
- United Leukodystrophy Foundation: Adrenoleukodystrophy (link).