Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia

ABSTRACT

Introduction: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that arises as a complication of exposure to dopamine receptor blocking agents. Vesicular monoamine transporter type 2 (VMAT2) inhibitors reduce dyskinesia by decreasing transport of monoamines, including dopamine, into presynaptic vesicles, leaving unpackaged dopamine to be metabolized by monoamine oxidase. Deutetrabenazine was adapted from an earlier VMAT2 inhibitor, tetrabenazine, by substituting three deuterium isotopes in place of three hydrogen isotopes at the site of metabolic degradation to improve upon the pharmacokinetics of the parent compound.

Areas covered: The authors reviewed the pivotal trials examining the safety and efficacy of deutetrabenazine, as well as long-term data from an open-label extension. Also reviewed were posters and oral presentations, as well as information from the product label and the United States Food and Drug Administration.

Expert opinion: Deutetrabenazine is effective at decreasing dyskinesia in TD, but drug selection and cost-effectiveness between existing VMAT2 inhibitors are evolving areas of study. Other areas of investigation include novel anti-dyskinetic agents and use of deep brain stimulation.

KEYWORDS:

• Abnormal involuntary movements
• abnormal involuntary movement scale
• deutetrabenazine
• dopamine receptor blocking agent
• SD-809
• tardive dyskinesia
• tardive syndromes
• vesicular monoamine transporter type 2
• VMAT2 inhibitor

Article highlights

• Tardive dyskinesia (TD) is a common, frequently permanent, and potentially disabling adverse event (AE) resulting from exposure to dopamine receptor blocking agents.

• Vesicular monoamine type 2 inhibitors are thought to decrease TD symptoms by preventing transport of monoamines, including dopamine, into vesicles in presynaptic neurons. Unpackaged dopamine remaining in the cytosol is broken down by monoamine oxidase, effectively depleting the presynaptic neuron of dopamine.

• Tetrabenazine has been used as treatment for TD, but its short half-life and high peak plasma concentration (Cmax) limit its ease of use and tolerability. Newer VMAT2 inhibitors include deutetrabenazine and valbenazine.

• Replacing protium isotopes with deuterium at sites of enzymatic action in a drug’s structure may decrease the rate of metabolism due to the increased stability of deuterium-carbon bonds. This may lead to both prolonged half-life and more stable Cmax. Deutetrabenazine was the first deuterated compound to be approved by the United States Food and Drug Administration, and was designated as a New Chemical Entity.

• Deutetrabenazine is a deuterated version of tetrabenazine, and has been shown to significantly reduce AIMS score compared to placebo while allowing patients with TD to maintain their baseline neuroleptic medications. The suggested starting dose is 12mg/day divided into two doses, which is titrated weekly by increments of 6mg until TD symptoms remit or the maximum dose of 48mg/day is reached.

• Results from an open-label extension show continued, and possibly increasing, benefit over 158 weeks of therapy, without risk for new emergence of side effects.

• Clinical trials have shown good safety and tolerability for deutetrabenazine. Most common AEs include somnolence, headache, nausea, upper respiratory infections/nasopharyngitis, fatigue, insomnia, diarrhea, akathisia, anxiety, depression, dizziness, and dry mouth. Care should be taken when using in patients with prolonged QTc interval and poor CYP2D6 metabolizer status.

• Data from real-world long-term patient exposure to drugs used to treat TD including patient reported outcomes will be informative to assess differential responses to these treatments, and identify whether the relative dosing flexibility offered by deutetrabenazine yields a favorable efficacy, tolerability, or therapy maintenance profile.

Declaration of interest

J Jimenez-Shahed has received consulting fees from Teva, Nuvelution, and Bracket for work related to the clinical development of deutetrabenazine, and research support from Teva. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.