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The results of a phase 3 trial demonstrated significant benefit over placebo.
Tardive dyskinesia (TD) is associated with long-term exposure to dopamine receptor antagonists, including both first- and second-generation antipsychotics. This persistent and often disabling movement disorder develops in an estimated 20% to 30% of patients with long-term antipsychotic exposure.1 Currently, no medications are approved by the US FDA for the treatment of TD.
Inhibitors of vesicular monoamine transporter 2 (VMAT2)-which modulates pre-synaptic dopamine release-have shown promise in the treatment of movement disorders. Valbenazine is a novel selective VMAT2 inhibitor under development for the treatment of TD that demonstrated promise in a phase 2 randomized, double-blind, placebo-controlled trial.2Hauser and colleagues3 performed a phase 3 trial to further evaluate the efficacy, safety, and tolerability of fixed-dose valbenazine in adults with TD.
The authors performed a 6-week randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study of once-daily valbenazine (40 mg or 80 mg) or placebo. Participants then entered a 42-week extension period of valbenazine (40 mg or 80 mg). The study was performed at 63 centers in North America between 2014 and 2015.
Abnormal Involuntary Movement Scale (AIMS)
Inclusion criteria for the study were age, 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder for more than 3 months before screening; DSM diagnosis of moderate to severe TD for more than 3 months prior to screening; and a stable treatment regimen for more than 30 days before baseline. Exclusion criteria were unstable psychiatric status (based on rating scale scores) and/or high risk of suicidal or violent behavior; clinically significant unstable medical condition; a comorbid involuntary movement disorder more prominent than TD; and a score higher than 3 on 2 or more Simpson-Angus Scale items.
Subjects were randomly assigned in a 1:1:1 ratio to placebo, valbenazine 40 mg/d, or valbenazine 80 mg/d. The dosage could be reduced for tolerability, but participants who could not tolerate the “reduced” dosage were discontinued from the study. The primary efficacy endpoint was change from baseline to week 6 in the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score. The key secondary endpoint was the Clinical Global Impression of Change–Tardive Dyskinesia (CGI-TD) score. Data in the intent-to-treat population were analyzed using a mixed-effects model for repeated measures.
Two hundred thirty-four participants were randomized; 205 (88%) completed the study. The mean age of the study sample was 56 years, and 54% were male. Sixty-six percent of participants had a diagnosis of schizophrenia or schizoaffective disorder.
This is the first phase 3 trial of the VMAT2 inhibitor valbenazine for the treatment of TD.
At week 6, valbenazine 80 mg/d resulted in significant reduction in the AIMS dyskinesia score versus placebo (-3.2 vs -0.1), corresponding to a large effect size of 0.90. At week 6, valbenazine 40 mg/d was also associated with a reduction in the AIMS dyskinesia score versus placebo (-1.9 vs -0.1), corresponding to a moderate effect size of 0.52. Twenty-four percent of participants in the 40 mg/d group and 40% of those in the 80 mg/d group were AIMS responders (more than 50% reduction from baseline), compared with 9% in the placebo group. No significant between-group differences were found for the CGI-TD score.
The most common adverse effects in the valbenazine groups were somnolence and dry mouth. There were no clinically significant changes from baseline in laboratory or physical findings, vital signs, or ECGs.
This is the first phase 3 trial of the VMAT2 inhibitor valbenazine for the treatment of TD. Valbenazine 80 mg/d showed a significant reduction in the AIMS dyskinesia score at week 6 versus placebo, translating to a number needed to treat of 4. In subjects with detectable blood levels of valbenazine, both doses of valbenazine demonstrated significant benefit over placebo. Overall, valbenazine was well tolerated, and the only treatment-emergent adverse effects reported in more than 5% of subjects were somnolence and dry mouth.
The authors note that the short trial duration may limit the ability to evaluate the impact of valbenazine on the durability of TD response. However, findings from the 42-week extension period are pending. Another 52-week study of valbenazine is ongoing. The authors conclude that valbenazine may be an effective treatment option for patients with TD.
Dr. Miller is Associate Professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, GA, and Schizophrenia Section Editor for Psychiatric Times. He reports no conflicts of interest concerning the subject matter of this article.
1. Caroffs N, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin. 2011;29:127-148.
2. O’Brien CF, Jimenez R, Hauser RA, et al. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, double-blind, placebo-controlled study. Mov Disord. 2015;30:1681-1687.
3. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017. doi: 10.1176/appi.ajp.2017.16091037.