Pharmacological Breakthrough for Tardive Dyskinesia

Sahil A. Desai, Mercer University College of Pharmacy

Tardive dyskinesia (TD) is a neurological disorder causing repetitive, involuntary movements around the face and body that can include uncontrolled lip smacking, abnormal tongue movements, and side-to-side jaw displacement. Long-term treatment with first-generation antipsychotic drugs and other neuroleptic medications has been reported to cause TD as an adverse event. [1] With the exact pathophysiology claimed to be unknown, the upregulation and sensitization of dopamine-2 receptors following a consistent blockade by pharmacological agents is one theory behind this condition. [2] Ingrezza(valbenazine) was the first approved treatment of TD in April 2017 by the U.S. Food and Drug Administration (FDA). Brought to the market via fast-track development, this approval may decrease off-label prescribing for the alleviation of TD symptoms. [3,4]

Deutetrabenazine is a vesicular monoamine transporter-2 (VMAT-2) inhibitor approved by the FDA for Huntington’s disease . It acts to prevent monoamine transmitters like dopamine to be released into the neurological synapse thus attempting to improve cognition and motor function and may help with TD [5]

Randomized controlled trial of deutetrabenazine for tardive dyskinesia (The ARM-TD study) [6]
Design Phase II/III, randomized, double-blinded, parallel group; N= 117
Objective To study the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD)
Study Groups Deutetrabenazine (n= 58); placebo (n= 59)
Methods Participants were included in the study if they had TD diagnosis ≥ 3 months, Abnormal Involuntary Movement Scale (AIMS) score ≥ 6, and history of dopamine receptor antagonist treatment ≥ 3 months (patients with  ≥ 1 month of treatment and were 60 years and older were acceptable). Patients with a history of or active suicidal behavior within 6 months of screening or who were treated with dopamine agonists, levodopa, and/or stimulants within 30 days of screening were excluded.

Deutetrabenazine dosing was started at 6 mg twice a day and titrated weekly by 6 mg/day if necessary for up to 6 weeks until dyskinesia control was achieved, a significant adverse event occurred, or the maximum dose 48 mg/day was reached.

An AIMS test was administered by a clinician to measure abnormal movements. A total of seven questions were considered with each being rated on a scale of 0-4 (0: no signs; 4: severe symptoms). Least squares mean reduction from baseline to week 12 was used to show how effectively deutetrabenazine reduced AIMS scores and improved TD symptoms.

Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) are 7-point scales to measure improvement of symptoms (0: very much worse; 7: very much improved)

Duration 12 weeks
Primary Outcome Measure Change in AIMS score from baseline to week 12
Secondary Outcome Measure Proportion of patients who experienced treatment success at week 12 based on CGIC and PGIC
Baseline Characteristics  

Deutetrabenazine Placebo
Mean age, years   (SD) 55.9 (9.8) 53.3 (10.6)
Female, n (%) 29 (50.0) 32 (54.2)
White, n (%) 37 (63.8) 44 (74.6)
Patient Clinical Characteristics
  Mean weight, kg (SD) 86.9 (24.1) 85.0 (21.0)
  Mean duration of tardive dyskinesia, months 72.6 (81.7) 76.8 (82.1)
  Dopamine agonist use at baseline, n (%) 45 (77.6) 49 (83.1)
Most common antipsychotics used at baseline, n (%)
  Quetiapine 14 (24.1) 18 (30.5)
  Risperidone 9 (15.5) 7 (11.9)
  Olanzapine 8 (13.8) 5 (8.5)
Most common antidepressants used at baseline, n (%)
  Trazodone 9 (15.5) 10 (16.9)
  Bupropion 5 (8.6) 6 (10.2)
  Sertraline 6 (10.3) 4 (6.8)
  Citalopram 5 (8.6) 5 (8.5)
Most common anxiolytics used at baseline, n (%)
  Hydroxyzine 5 (8.6) 6 (10.2)
  Alprazolam 4 (6.9) 4 (6.8)
  Buspirone 1 (1.7) 2 (3.4)
  Diazepam 1 (1.7) 2 (3.4)
Psychiatric disorder, n (%)
  Schizophrenia 29 (50.0) 29 (49.2)
  Schizoaffective disorder 11 (19.0) 11 (18.6)
  Bipolar disorder 12 (20.7) 15 (25.4)
  Depression 17 (29.3) 13 (22.0)
Mean AIMS score (SD) 9.6 (4.1) 9.6 (3.8)
AIMS score ≥6, n (%) 48 (82.8) 49 (83.1)
Results
  Deutetrabenazine Placebo p value
Mean change in AIMS score
 Baseline to week 4 -2.6 -0.4 0.007
 Baseline to week 12 (SD) -3.0 (0.45) -1.6 (0.46) 0.019
 Least squares mean reduction from baseline to week 12, (standard error) -11.1 (2.14) -8.3 (2.31) >0.05
CGIC success % 48.2 40.4 >0.05
PGIC success % 42.9 29.8 >0.05

 

Adverse Events Common Adverse Events: somnolence (13.8%), fatigue (6.9%), insomnia (6.9%), headache (5.2%), diarrhea (5.2%), akathisia (5.2%), community-acquired pneumonia (1.7%)
Serious Adverse Events: substance-induced manic episode (1.7%), exacerbation of schizophrenia (1.7%)
Percentage that Discontinued due to Adverse Events: 5.2% (undisclosed reasons)
Study Author Conclusions Deutetrabenazine is well tolerated and effective for treating the symptoms of tardive dyskinesia.

 

The lack of reported depressive symptoms and suicidal ideation, along with low rates of discontinuation, is relevant to note considering this population’s risk of psychotic episodes. The CGIC and PGIC scores are subjective and percentage of success varied widely between the two scales. Therefore, it is difficult to determine whether results were actually clinically significant although no statistical significance was established. Projected costs for a 30 day supply of Ingrezza is $5,275 ($63,300 annually) [7]; the expected approval of generic deutetrabenazine for TD later this year has potential to drive the cost of treatment downwards.

References

[1] Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for an increasingly common disorder. Neurotherapeutics. 2014;11(1):166-76.

[2] Meyer JM. Forgotten but not gone: new developments in the understanding and treatment of tardive dyskinesia. CNS Spectr. 2016;21(S1):13-24.

[3] D, Virk I, Mohammad W, Kahn DA. Clozapine Treatment of Olanzapine-induced Tardive Dyskinesia: A Case Report. J Psychiatr Pract. 2017;23(1):53-59.

[4] Voelker R. Tardive Dyskinesia Drug Approved. JAMA. 2017;317(19):1942.

[5] Tritsch NX, Sabatini BL. Dopaminergic modulation of synaptic transmission in cortex and striatum. Neuron. 2012;76(1):33-50.

[6] Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017;88(21):2003-2010.

[7] Neurocrine goes high—$60K-plus high—with price for new movement drug Ingrezza. Fierce Pharma.http://www.fiercepharma.com/marketing/neurocrine-goes-high-60k-plus-high-price-for-new-movement-drug-ingrezza. Accessed May 26, 2017.

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