Hyperkinetic Movement Disorders

Hyperkinetic movement disorders reflect abnormal dopaminergic signaling in the basal ganglia with an hyper-dopaminergic state and include abnormal involuntary movements such as chorea, dystonia, myoclonus, athetosis, ballism. Moderate to severe movements can be painful and physically/mentally disabling and affect people’s quality of life.¹ Involuntary excessive movements such as tardive dyskinesia (TD) and Huntington’s disease’s chorea (HD) have limited therapeutic options; TD had no FDA approved treatments prior to 2017. Blocking vesicular monoamine transporter type 2 (VMAT2) to deplete presynaptic dopamine has been shown safer compared with dopamine receptor-blocking agents with lower risk for TD.² Tetrabenazine (TBZ) is a Food and Drug Administration (FDA)-approved VMAT2 inhibitor used to treat chorea associated with HD since 2008.² Newer VMAT2 inhibitors such as deutetrabenazine and valbenazine have pharmacokinetic advantages over TBZ and they have been studied in the treatment of hyperkinetic movement disorders including chorea and TD.

Valbenazine

Valbenazine (VBZ) is a novel highly-selective reversible vesicular monoamine transporter type 2 (VMAT2) inhibitor that is the first Food and Drug Administration (FDA)-approved treatment for tardive dyskinesia (TD) in the US.³ Approval was based on a pivotal trial in which 234 participants with TD were randomly assigned to receive VBZ 40 mg daily, VBZ 80 mg daily, or placebo for 6 weeks. The primary endpoint was change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score at 6 weeks. Individuals treated with 80 mg daily had a 3.2 point reduction in AIMS score, those treated with 40 mg daily had a 1.9 point reduction, and those treated with placebo had a 0.1 point reduction. The results were statistically significant. Overall, VBZ was well tolerated. The most common adverse events were somnolence, which occurred in 5.3% of both groups treated with VBZ compared with only 3.9% of those who received placebo.⁴

In an open-label extension trial, the long-term safety and efficacy of VBZ was evaluated.⁵ Individuals who had received placebo during the double-blind phase of the trial were randomly assigned to receive either 40 mg/day or 80 mg/day. People who received placebo were rerandomized to receive either VBZ 40 mg or 80 mg. All participants and examiners remained blinded to dose throughout the extension study, which continued for 42 additional weeks followed by a 4-week washout period. The only adverse event leading to discontinuation in more than 2 participants was somnolence, reported in 3 participants who were treated with 80 mg/day of VBZ. Treatment benefits were maintained or increased through the end of the total 48-week extension period, although TD symptoms returned to baseline levels after the 4-week washout.⁵

Deutetrabenazine

Deutetrabenazine (DBZ) is a VMAT2 inhibitor containing 6 deuterium atoms in place of 6 hydrogen atoms in the tetrabenazine (TBZ) molecule. The replacement of hydrogen with deuterium leads to increased metabolite halflife of 9 to10 hours compared to TBZ. Approved for chorea associated with Huntington’s disease (HD) in 2017,⁶ DBZ improved chorea with an overall favorable safety profile compared with placebo over a 12-week period in clinical trials.⁷ Possibly because of the reduced plasma fluctuation and lower peak concentrations, DBZ has also been well tolerated.⁶ More recently, DBZ has been used in the treatment of TD after studies showed significant reduction in abnormal movements with a good tolerability profile.^8,9 Before DBZ, TBZ was the first drug approved by the FDA for treatment of HD-associated chorea; however, fluctuations in plasma levels and high peak plasma concentrations were thought to contribute to neuropsychiatric side effects.^2,10

Doses of 6 mg, 9 mg, and 12 mg as tablets are available for DBZ, and individuals can safely be switched from TBZ 3 times daily to DBZ twice daily,⁶ with TBZ 12.5 mg being equivalent to a 6-mg dose of DBZ.¹¹ Contraindicated in patients who are suicidal or who have inadequately treated or untreated depression, DBZ should also be avoided by people with hepatic impairment. Reserpine, monoamine oxidase inhibitors (MAOIs), and TBZ should not be used in combination with DBZ, and DBZ should not be started until 14 days after discontinuing an MAOI.⁶ The most common adverse reactions observed (> 8% and greater than placebo) in people with Huntington’s chorea were somnolence, diarrhea, dry mouth, and fatigue.⁷ For individuals with TD, the most common side effects were somnolence, insomnia, akathisia, nasopharyngitis, and diarrhea.^8,9 As observed with TBZ, it is postulated that DBZ may cause an increase in QTc of about 8 msec; this may be clinically relevant in people with CYP2D6, who are poor metabolizers or when coadministered with a strong CYP2D6 inhibitor, which notably includes some selective serotonin reuptake inhibitors (SSRIs).⁶

The dose of DBZ given for HD or TD did not exceed 48 mg/day. In people with the cytochrome isoform CYP2D6, who are poor metabolizers, the daily dose should not exceed 36 mg (maximum single dose of 18 mg).⁶ Although tapering is unnecessary for DBZ discontinuation, if there is more than a 7-day break in treatment, DBZ should be retitrated when restarted. If the interruption in treatment was less than 7 days, the drug can be restarted at the previous maintenance dose without titration.¹¹

Future and Conclusions

The growth over the past few years in movement disorders provides clinicians and patients with new options. Novel indications provide robust data for conditions that previously lacked appropriate treatment. Similarly, new formulations and novel delivery mechanisms provide clinical benefit with better efficacy, tolerability, and reduction of disability for Huntington’s disease’s chorea. We remain optimistic for the “holy grail” of movement disorders medications that provide true disease modification and halt or slow down the progression of neurodegeneration.