Is there value in VMAT-2 inhibitors for tardive...

Is there value in VMAT-2 inhibitors for

tardive dyskinesia?

Samantha Vogel, PharmD

PGY2 Psychiatric Pharmacy Resident

Seton Healthcare Family

The University of Texas College of Pharmacy

September 22nd, 2017

9/16/2017

1

IS THERE VALUE IN VMAT-2 INHIBITORS FOR TARDIVE DYSKINESIA?

Samantha Vogel, PharmD PGY2 Psychiatric Pharmacy Resident Seton Healthcare Family The University of Texas College of Pharmacy


Objectives

• Describe tardive dyskinesia (TD)

• Identify at risk patients for TD

• Outline current management strategies

• Assess use of vesicular monoamine transporter-2 (VMAT-2) inhibitors in treating TD

• Recommend treatment plan for a patients with TD

2

Patient Case:

• HPI: SV is a 34 year old Hispanic female who presents to your mental health clinic for medication management. She states she began experiencing slight involuntary movements of the tongue and jaw 7 months ago which have progressed into marked movements of the tongue and jaw, grimacing, and moderate choreic movements of the upper limbs.

• PMH: Schizoaffective disorder (diagnosed 2007), type II diabetes (diagnosed 2009), acute dystonia (2010), R-wrist fracture (2010), C-section (2012)

Appendix B

3

Patient Case (part I):

• She has been stable on her current medication regimen for the past 6 years, however 12 months ago her risperidone was increased from 4 mg to 6 mg:

• Previous psychiatric medication trials:

Risperidone 6 mg PO daily Sertraline 100 mg PO daily

Metformin ER 1000 mg PO daily Acetaminophen 325 mg PO PRN

Medication Reason for discontinuation

Haloperidol 15 mg PO daily Acute dystonic reaction

Olanzapine 20 mg PO daily Weight gain; breakthrough psychosis

Quetiapine 600 mg PO qHS Weight gain, sedation

Aripiprazole 10 mg PO daily Akathisia

Duloxetine 60 mg PO daily Insomnia 4

BACKGROUND

5

Drug-Induced Movement Disorders

Extrapyramidal Symptoms

(EPS)

Acute

Akathisia Dystonia Parkinsonism

Chronic

Tardive Dyskinesia (TD)

Waln O, et al. Tremor Other Hyperkinet Mov 2013;3:[online]

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Tardive Dyskinesia (TD)

• Iatrogenic – Dopamine receptor blocking agents (DRBA)

– >3 months of drug exposure

• Choreoathetoid movement disorder – Heterogeneous, involuntary movements

– Non-rhythmic, repetitive, and purposeless

• Insidious onset – Varying severity

– Chronic course may wax and wane

• Potentially irreversible


7

Tardive Spectrum

• Classic TD (oro-bucco-lingual sterotypy)

– Lip smacking or pursing

– Facial grimacing

– Tongue movements

– Can progress to trunk and limbs

• Atypical TD

– Tremor, akathisia, or dystonia

– May present as combination


8

Presentation

Tardive Dyskinesia Compilation

https://www.youtube.com/watch?v=t_NKRS8lLWA

9

Abnormal Involuntary Movement Scale (AIMS)

• Used to detect TD and follow severity over time

• 12 item clinician administered and scored test

• Items 1-10 are rated from 0-4

– Items 1-4 assess orofacial movements

– Items 5-7 assess extremity and truncal movements

– Items 8-10 assess global severity and patient awareness

• Items 11-12 assess teeth and denture status

Appendix C National Institute of Mental Health

10

Diagnosis

DSM-5

• Involuntary athetoid or choreiform movements

• Lasting at least a few weeks

• Developed in association with the use of a neuroleptic (DRBA) for at least a few months

• May also appear after discontinuation, change, or reduction in dosage of neuroleptic medications

Schooler-Kane

• Three cumulative months DRBA exposure

• AIMS of > 3 on one item, or AIMS of > 2 on multiple items

• Exclusion of other diagnoses

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®), American Psychiatric Publishing, 2013. Witter D. et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972.

11

Agents that Cause TD Drug Class Known Offenders

Typical Antipsychotics (First generation)

Chlorpromazine, haloperidol

Atypical Antipsychotics (Second generation)

Aripiprazole, olanzapine, quetiapine, risperidone

Anticholinergics/antihistamines Benztropine

Antiepileptic agents Carbamazepine, phenobarbital, phenytoin

Antiparkinson agents Levodopa, bromocriptine

Gastrointestinal agents Metoclopramide, droperidol, prochlorperazine

Mood stabilizers Lithium

SSRI/SNRI Citalopram, duloxetine

Tricyclic Antidepressants Amitriptyline, amoxapine, doxepin

Caroff S, Psychiatr Clin N Am 2016;39:391–411. Waln O, et al. Tremor Other Hyperkinet Mov 2013;3: [online]

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https://youtu.be/t_NKRS8lLWA?t=1m52s

9/16/2017

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Epidemiology

• Cumulative annual incidence with antipsychotic exposure = 5%

– Typical antipsychotics: 8.5%

– Atypical antipsychotics: 3.1%

• May persist for years or decades

• Spontaneous remission ranges from 6-22%

Carbon M, et al. J Clin Psychiatry 2017;78(3):e264–e278 Witter D, et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Bhidayasiri, et al. Neurology 2013;81:463-469. Woods S, et al. J Clin Psychiatry. 2010 Apr; 71(4): 463–474.

13

Risk Factors

Female sex

Older age

Organic brain damage

Diabetes mellitus

Early development of

EPS

D2 receptor occupancy

Concomitant TD-causative agents

Genetics

Concomitant affective disorder

Negative symptoms of schizophrenia

Tardive Dyskinesia

Witter D, et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Caroff S, Psychiatr Clin N Am 2016;39:391–411. Gualtieri CT: Neuropsychiatry and Behavioral Pharmacology. New York, Springer Verlag, 1991. Lanning R, et al. Pharmacogenomics 2016;17(12):1339–1351.

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Patient Case (part II):

• Based on SV’s history and current medication list, what are her risk factors for TD?

Female sex

Diabetes mellitus

Concomitant affective disorder

D2 receptor occupancy Early

development of EPS

• Which assessment tool would be most useful to determine if SV has TD?

A. Mini-Mental Status Examination (MMSE)

B. Abnormal involuntary movement scale (AIMS)

C. Barnes Akathisia Rating Scale (BARS)

15

Pathophysiology of TD

Nigrostriatal pathway

Witter D, et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972.

Mesocortical pathway

Tuberoinfundibular pathway

Mesolimbic pathway

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Pathophysiology cont.

Upregulation and increased sensitivity at postsynaptic dopamine receptors

Dysfunctional GABAergic and glutamatergic neurons

Dopamine receptor

Maladaptive synaptic plasticity

Direct oxidative damage from increased dopamine metabolism

Dopamine receptor blockade

Tardive Dyskinesia

DRBA

Witter D. et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Meyer J. CNS Spectrums 2016;21:16–23.

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Consequences of TD

• Increased social stigmatization

• Negative impact on daily functioning

• Poor treatment adherence

• Lower rates of symptom remission in patients with schizophrenia

• Higher rates of relapse

• Longer hospitalizations

• Cognitive impairments

• Increased mortality

Witter D. et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Meyer J. CNS Spectrums 2016;21:16–23. Lanning R, et al. Pharmacogenomics 2016;17(12):1339–1351.

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TREAMENT OPTIONS

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Goals of Treatment

Prevent worsening of

TD

Resolve symptoms of

TD

Prevent recurrence of

TD

Maintain clinical stability

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Approach to Treatment Option Pros Cons

Continue current

therapya, b

• Reduced risk of psychotic relapse

• Up to 30% will have spontaneous reduction in TD

• Reduced likelihood of TD reversibility

Discontinue agent or

reduce dosec, d

• Discontinuation or dose reduction may provide improvement in TD in 37% of patients

• Complete resolution uncommon

• Increased risk of relapse

Switch agenta • Switching from first generation

AP to second generation AP may reduce TD

• TD likely to persist or fluctuate

• Increased risk of relapse

Initiate adjunctive

agente

• Multiple agents may benefit TD symptoms

• Can be used with AP treatment

• Small studies with varied results

a Caroff SN, et al. J Clin Psychiatry 2011;72(3): 295–303. d Glazer WM, et al. Br J Psy-chiatry 1990;157:585–92. b Egan MF, et al. Schizophr Bull 1997;23(4):583–609 e Bhidayasiri, et al. Neurology 2013;81:463-469. c Soares KV, et al. Schizophr Res 1999;39(1):1–16 [discussion: 17–8].

21

Drug Targets

Upregulation and increased sensitivity at postsynaptic dopamine receptors

Dysfunctional GABAergic and glutamatergic neurons

Maladaptive synaptic plasticity

Direct oxidative damage from increased dopamine metabolism

Dopamine receptor blockade

Development of TD

DRBA

Tetrabenazine

Reserpine

Vitamin E

Ginkgo biloba

Amantadine

Clonazepam

Amantadine

Witter D, et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Meyer J. CNS Spectrums 2016;21:16–23.

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Improve TD

Adjunctive Agents

Agent Evidence

Amantadine • 100 -400 mg daily for 2-7 weeks • Reduced AIMS by 15-22% in two studies

Clonazepam • 2-3.5 mg daily • Improved TD by 37% after 12 weeks but waned with long-term use

Ginkgo biloba

• 240 mg daily for 12 weeks • Reduced AIMS by 2.13 points • 51% of patients had >30% reduction of AIMS score • Positive effect continued after medication was withdrawn

Vitamin E • 1,200-1,600 IU daily • Several studies reporting mixed results in improving TD

Reserpine • 0.75-1.5 mg daily • Positive effect but peripheral side effects limit use

Tetrabenazine • 25-200 mg daily in various studies • Reduced TD by >50% in two studies • Reports of akathisia, parkinsonism, and depression with suicidal ideation

Bhidayasiri, et al. Neurology 2013;81:463-469. Witter D, et al. Expert Opinionon Pharmacotherapy 2017;18(10):965-972. Cloud LJ, et al. Neurotherapeutics. 2014;11(1):166-76.

23

Guideline Consensus

2010 APA • Switch to an atypical antipsychotic or reduce the dose

• Vitamin E may reduce the risk of development of tardive dyskinesia

2012 WFSBP • Switch to clozapine

• Consider application of vitamin E therapy

• ECT, deep brain stimulation, or pallidotomy for severe cases

2013 AAN • Amantadine, ginkgo biloba, and tetrabenazine should be considered for TD

• Insufficient evidence to support withdrawal or switch of current antipsychotic

Bhidayasiri, et al. Neurology 2013;81:463-469.

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VESICULAR MONOAMINE TRANSPORTER-2 (VMAT-2)

INHIBITORS

25

VMAT-2 Pharmacology

• Reversible inhibitor of VMAT-2

• Selective to central nervous system

• Inhibits release of monoamines from cytoplasmic vesicles into the synaptic cleft

• Increases monoamine metabolism

• Minimal/no affinity for VMAT1, dopaminergic, serotonergic, adrenergic, histaminergic or muscarinic receptors

Meyer J. CNS Spectrums 2016;21:16–23.

26

VMAT-2 Pharmacology cont.

Ciccarelli O, et al. Nat Rev Neurol. 2016;12(2):70-2.

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LITERATURE REVIEW

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What is the role of VMAT-2 inhibitors in TD treatment?

Definitions

• LS Mean AIMS change – least squares average change in AIMS score from baseline

• % Responders – Patients who experienced a reduction of 50% or more in AIMS score

• CGIC/CGIC-TD – Clinical Global Impression of Change; Clinician based assessment of improvement before and after treatment on a 7-point Likert scale

• PGIC – Patient Global Impression of Change; Patient based assessment of improvement before and after treatment on a 7-point Likert scale

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VALBENAZINE (Ingrezza™)

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KINECT 2

O‘Brien CF, 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(12):1681-7.

Objective • Assess efficacy, tolerability, and safety of VBZ

Design • Phase II, RDBPC, multi-center, dose-titration study • Duration: 6 weeks + 2 weeks follow-up

Inclusion • Male & female adults with moderate or severe TD by AIMS • Diagnosis of schizophrenia, schizoaffective disorder, mood

disorder with neuroleptic-induced TD (defined by DSM-IV), or GI disorder with metoclopramide-induced TD

• Stable on concomitant meds for before & during study

Interventions • VBZ 25 mg daily; escalated by 25 mg every 2 weeks to maximum of 75 mg daily

• Placebo; identical escalation strategy as active group RDBRPC: randomized, double-blind, placebo controlled; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; VBZ: Valbenazine

31

KINECT 2 Demographics

TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; VBZ: Valbenazine

Outcome VBZ Pbo

Demographics (N=89) (N=44) (N=45)

Age (y) Age at TD diagnosis (y) Male gender (%) Disease category (%)

Schizophrenia/Schizoaffective disorder Mood disorder Gastrointestinal disorder

Baseline AIMS score (mean)

56 48 62

58 42 0 8

55 50 57

62 36 2 8

Concomitant Medications (N=89)

Antipsychotics, antidepressants, and anxiolytics (%) >40 >40

Study Drug Exposure (N=n/a)

Reached 75 mg maximum (%) 76 80 Pbo: Placebo; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale

O‘Brien CF, et al. Mov Disord. 2015;30(12):1681-7.

32

KINECT 2 Results

Outcome VBZ Pbo P-value (95% CI)

Primary (N=89) (N-44) (N=45)

AIMS change at 6 weeks (LS mean) Responders (%)

-2.6 49

-0.2 18

0.0005 (-3.7, -1.1) <0.002 (n/a)

Secondary (N=89)

CGI-TD score at 6 weeks (LS mean) PGIC score at 6 weeks (LS mean)

2.2 2.6

3.1 3.3

<0.0001 (-1.2, -0.5) 0.0011 (-1.1, -0.3)

Safety (N=100) (N=51) (N=49)

Overall incidence of side effects (%) 49 33 n/a

LS: Least-squares; Pbo: Placebo; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; CGI-TD: Clinical Global Impression of Change-TD

Responders defined a those with >50% reduction in AIMS from baseline


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KINECT 2 Results cont.

Outcome VBZ Pbo Total Difference

Post-hoc Analysis (N=89) † (N=44) (N=45)

AIMS change at 6 weeks (mean) Atypical antipsychotic Typical antipsychotic No antipsychotic Schizophrenia† Mood disorder†

-2.6 -2.4 -5.9 -3.0 -4.5

-1.5 -0.4

0 -1.0 -1.4

1.1 2.0 5.9 2.0 3.1

Pbo: Placebo; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale † p-value <0.05


34

KINECT 3

Hauser RA, et al. KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia. Am J Psychiatry. 2017;174(5):476-84.

Objective • Evaluate the efficacy, safety, and tolerability of valbenazine

Design • Phase III, RDBPC, multi-center, fixed-dose study • Duration: 6 weeks

Inclusion • Male & female adults with moderate or severe TD by AIMS • Diagnosis of schizophrenia, schizoaffective disorder, or mood

disorder with neuroleptic-induced TD (defined by DSM-IV) • Stable on concomitant meds for before & during study

Interventions • VBZ 40 mg daily • VBZ 80 mg daily • Placebo

RDBRPC: randomized, double-blind, placebo controlled; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; VBZ: Valbenazine

35

KINECT 3 Demographics

TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; VBZ: Valbenazine; Pbo: Placebo; BPRS: Brief Psychiatric Rating Scale

Outcome VBZ

40 mg VBZ

80 mg Pbo

Demographics (N=227) (N=72) (N=79) (N=76)

Age (y) Male gender (%) Disease category (%)

Schizophrenia/Schizoaffective disorder Mood disorder

Baseline BPRS score Baseline AIMS score (mean)

55 58

67 33 31 10

56 49

66 34 29 10

57 57

66 34 29 10

Concomitant Medications

Antipsychotics (%) Antidepressants (%) Anticholinergics (%)

92 67 42

82 65 41

83 68 29


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KINECT 3 Results

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

Me

an A

IMS

chan

ge f

rom

bas

elin

e

Time of Assessment

Primary Outcome: LS Mean Change From Baseline in AIMS Among Participants Receiving VBZ or Placebo

VBZ 40 mg

VBZ 80 mg

Pbo

Baseline Week 2 Week 4 Week 6

-0.1

-1.9, P=0.002

-3.2, P<0.001

Hauser RA, et al. Am J Psychiatry. 2017;174(5):476-84.

37

KINECT 3 Results cont.

Outcome VBZ

40 mg P-

value VBZ

80 mg P-

value Pbo

Primary (N=225) (N=70) (N=79) (N=76)


-1.9 24

0.002 0.02

-3. 40

<0.001 <0.001

-0.1 9

Secondary (N=225)

CGI-TD score at 6 weeks (LS mean) PGIC score at 6 weeks (LS mean)

2.9 n/a

0.074 2.9 n/a

0.056 3.2

Safety (N=227) (N=72) (N=79) (N=76)

Akathisia (%) Dry mouth (%) Somnolence (%) Suicidal ideation (%)

6 7 6 4

n/a

5 0 5 1

n/a

4 1 4 5

LS: Least-squares; Pbo: Placebo; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; CGI-TD: Clinical Global Impression of Change-TD; PGIC: Patient Global Impression of Change Responders defined a those with >50% reduction in AIMS from baseline

Hauser RA, et al. Am J Psychiatry. 2017;174(5):476-84.

38

KINECT 3-Extension

Factor SA, et al. Efficacy of Valbenazine (NBI-98854) in Subjects with Tardive Dyskinesia: Results of a Long-Term Study (KINECT 3 Extension). Neurology. 2017;88(16):S56.005.

Objective • To assess long term efficacy of valbenazine

Design • Phase III, DBPC, multi-center, fixed-dose, extension study • Duration: 42 weeks of extended treatment + 4 weeks

treatment-free follow-up

Inclusion • Patients who completed first 6 weeks of KINECT 3 study • Placebo patients were randomized to treatment groups

Interventions • VBZ 40 mg daily • VBZ 80 mg daily

DBPC: Double blind, placebo controlled; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale

39

KINECT 3-Extension Results

-6

-5

-4

-3

-2

-1

0

Me

an A

IMS

chan

ge f

rom

bas

elin

e

Time of Assessment

Primary Outcome: LS Mean Change From Baseline From Baseline in AIMS Among Participants Receiving Valbenazine

VBZ 40 mg

VBZ 80 mg

Baseline Week 2 Week 4 Week 6 Week 48 Week 52

Factor SA, et al. Neurology. 2017;88(16):S56.005.

40

-1.9

-3.2

-4.8

-3.0

+3.6

+1.6

KINECT 3-Extension Results

Outcome VBZ 40 mg VBZ 80 mg Pbo

Primary (N=225)

AIMS change at 48 weeks (LS mean) AIMS change at 52 weeks (LS mean) Responders at 48 weeks (%)

-3.0 +1.6 28

-4.8 +3.6 52

- - -

Secondary (N=198)

Schizophrenia/Schizoaffective CGI-TD score at 6 weeks (LS mean) CGI-TD score at 48 weeks (LS mean) CGI-TD score at 52 weeks (LS mean)

Mood disorder CGI-TD score at 6 weeks (LS mean) CGI-TD score at 48 weeks (LS mean) CGI-TD score at 52 weeks (LS mean)

2.9 2.4 3.3

2.9 2.2 2.8

3.0 2.2 3.4

2.7 2.0 3.6

3.2

- -

3.2 - -

LS: Least-squares; Pbo: Placebo; VBZ: Valbenazine; TD: Tardive dyskinesia; CGI-TD: Clinical Global Impression of Change-TD *Results from KINECT 3

Factor SA, et al. Neurology. 2017;88(16):S56.005. Correll CU, et al. Psychopharmacol Bull. 2017;47(3): 53–60.

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KINECT 4

Safety and Tolerability Study of NBI-98854 for the Treatment of Tardive Dyskinesia. NCT02405091.

Objective • To evaluate safety and tolerability of VBZ

Design • Phase III, open-label, multi-center, fixed-dose study • Duration: 48 weeks of treatment

Inclusion • Male & female adults with moderate or severe TD by AIMS • Diagnosis of schizophrenia, schizoaffective disorder, or

mood disorder with neuroleptic-induced TD (defined by DSM-IV)

• Stable on concomitant meds for before & during study

Interventions • VBZ 40 mg daily • VBZ 80 mg daily

Results • Completed March 2017 (publication pending)

RDBPC: Randomized, double blind, placebo controlled; VBZ: Valbenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale

https://clinicaltrials.gov/ct2/show/NCT02405091

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Pooled Analyses

Remington G, et al. Safety and Neurology. 2017;88(16):P2.017. Lessig S, et al. [abstract]. Mov Disord. 2017; 32 (suppl 2).

Objective • Assess long-term safety and tolerability of valbenazine • Assess emergence of EPS symptoms with valbenazine treatment

Design • Retrospective, long-term exposure pooled-cohort

Inclusion • Patients in KINECT 2, KINECT 3, KINETC 3-Extension, and KINECT 4

Interventions • VBZ 40 mg or VBZ 80 mg daily

Results • Common side effects: somnolence (9.1%), urinary tract infection (10.7%), and headache (12.4%)

• Serious adverse events occurred in 12.6% • 6.1% required dose reduction • 13.6% discontinued VBZ • No significant differences in vital signs, ECG, or psychiatric status • Akathisia occurred in < 4%, tremor < 2.0%, parkinsonism < 0.5%,

cogwheel < 0.4%, muscle rigidity < 0.4%

Remington G, et al. Safety and Neurology. 2017;88(16):P2.017. Lessig S, et al. [abstract]. Mov Disord. 2017; 32 (suppl 2). Josiassen RC, et al. Psychopharmacol Bull. 2017 Aug 1; 47(3): 61–68.

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KINECT Series: Conclusion

Conclusion

• Once-daily VBZ significantly reduced AIMS across diagnoses, antipsychotic use, and TD severity for up to 48 weeks

• Minimally improved CGI-TD scores • No serious adverse events related to VBZ, including EPS • TD reappeared after medication was withdrawn

Strengths Limitations

• Blinded central reviewers • Analyzed effect based on diagnosis and

concomitant medications • Rapid titration schedule to effective

dose • Extended treatment with washout

period • Robust criteria for % responders

• High percentage of patients on anticholinergic medications

• No information on VBZ effect in different AIMS domains

• No data on functional improvement • PGIC not included in later studies • Some patients received shorter

treatment duration

O‘Brien CF, et al. Mov Disord. 2015;30(12):1681-7. Hauser RA, et al. Am J Psychiatry. 2017;174(5):476-84. Factor SA, et al. Neurology. 2017;88(16):S56.005.

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DEUTETRABENAZINE (Austedo™)

45

ARM-TD

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.

Objective • Determine efficacy and safety of deutetrabenazine for TD

Design • RDBPC, multi-center, dose-titration study • Duration: 6 weeks titration + 6 weeks maintenance treatment + 1

week washout • Stratified by DRBA use at baseline

Inclusion • Male & female adults with TD and DRBA treatment for > 3 months (> 1 month if patient was 60 or older)

• AIMS > 6 at screening and baseline (confirmed post-hoc) • Stable on antipsychotic for > 30 days (> 45 days for

antidepressants)

Interventions • DBZ 6 mg BID; titrated weekly by 6 mg weekly until TD was controlled, adverse event occurred, or max dose (48 mg/day) was reached

• Placebo; identical escalation strategy as active group RDBPC: Randomized, double blind, placebo controlled; DBZ: Deutetrabenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale 46

ARM-TD Results

Outcome DBZ Pbo

Demographics (N=117) (N=58) (N=59)

Age (y) Male gender (%) Duration of TD (y) Disease category (%)

Schizophrenia Schizoaffective disorder Bipolar disorder Depression

AIMS score (mean) AIMS score > 6 (%)

56 50 6

50 19 21 30 10 83

53 46 6

49 19 25 22 10 83

Concomitant Medications (N=117)

Dopamine receptor blocking agent (%) >80 >80

DBZ: Deutetrabenazine; Pbo: Placebo; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale

Fernandez HH, et al. Neurology. 2017;88(21):2003-2010.

47

ARM-TD Results cont.

DBZ: Deutetrabenazine; Pbo: Placebo; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; CGIC: Clinical Global Impression of Change; PGIC = Patient Global Impression of Change; NSD: No significant difference

Responders defined a those with >50% reduction in AIMS from baseline

Outcome DBZ Pbo P-value (95% CI)

Primary (N=113) (N=56) (N=57)


-3.0 49

-1.6 18

0.019 (-2.6, -0.2) <0.002 (n/a)

Secondary (N=113)

Treatment success based on CGIC (%) Treatment success based on PGIC (%)

48 43

40 30

NSD NSD

Safety (N=117) (N=58) (N=59)

Overall incidence of side effects (%) 48 36 n/a

Fernandez HH, et al. Neurology. 2017;88(21):2003-2010.

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AIM-TD

Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Psychiatry. 2017;4(8):595-604.

Objective • Assess efficacy, safety, and tolerability of fixed doses of deutetrabenazine for TD

Design • Phase III, RDBPC, multi-center, fixed-dose study • Duration: 4 weeks titration + 8 weeks maintenance treatment + 1

week washout • Stratified by DRBA use at baseline

Inclusion • Male & female adults with TD and DRBA treatment for > 3 months (> 1 month if patient was 60 or older)

• AIMS > 6 at screening and baseline • Stable on antipsychotic for > 30 days (> 45 days for

antidepressants)

Interventions • DBZ 12 mg, 24 mg, or 36 mg daily • Placebo; identical escalation strategy as active group

RDBPC: Randomized, double blind, placebo controlled; Deu.: Deutetrabenazine; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale 49

AIM-TD Results

DBZ: Deutetrabenazine; Pbo: Placebo; TD: Tardive dyskinesia; AIMS: Abnormal Involuntary Movement Scale; CGIC: Clinical Global Impression of Change Responders defined a those with >50% reduction in AIMS from baseline * Reported as LS mean

Outcome DBZ 12 mg

P-value DBZ

24 mg P-value

DBZ 36 mg

P-value Pbo

Primary (N=222) (N=60) (N=49) (N=55) (N=58)

AIMS change at 12 weeks* -2.1 0.217 -3.2 0.003 -3.3 0.001 -1.4

Secondary (N=222)

Treatment success based on: CGIC at 12 weeks (%)

PGIC at 12 weeks (%) Responders (%)

28 23 13

0.734 0.372 n/a

49 45 35

0.014 0.134 0.005

44 40 33

0.059 0.296 0.007

26 31 12

Safety (N=293) (N=74) (N=73) (N=74) (N=72)

Anxiety (%) Diarrhea (%) Headache (%) Somnolence (%) Suicidal ideation (%)

4 1 7 0 0

n/a

3 4 3 1 3

n/a

4 7 7 4 1

n/a

3 3 6 4 0

Anderson KE, et al. Lancet Psychiatry. 2017;4(8):595-604.

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ARM-TD and AIM-TD Conclusions

Conclusion

• Deutetrabenazine 24 mg and 36 mg daily of provided a significant reduction in TD

• Deutetrabenazine was safe and well tolerated • Long-term efficacy and safety is not established

Strengths Limitations

• Specified specific AIMS score at screening and baseline

• Stringent requirement for concomitant medication use (i.e., no strong anticholinergic medications)

• Placebo effect seen with AIMS score in both studies

• No long-term follow-up after study medication was stopped

• No comment on functional improvement

• Patients with AIMS <6 included

Fernandez HH, et al. Neurology. 2017;88(21):2003-2010. Anderson KE, et al. Lancet Psychiatry. 2017;4(8):595-604.

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VMAT-2 Inhibitor Studies Summary

Study N Duration Interventions AIMS CGIC PGIC

KINECT 2 89 6 wks Valbenazine 25 mg – 75 mg

KINECT 3 225 6 wks Valbenazine 40 mg Valbenazine 80 mg

n/a n/a

KINECT 3-ext. 225 48 wks Valbenazine 40 mg Valbenazine 80 mg

n/a n/a

ARM-TD 113 12 wks Deutetrabenazine

AIM-TD 222 12 wks

Deutetrabenazine 12 mg Deutetrabenazine 24 mg Deutetrabenazine 36 mg

Statistically significant, p<0.05

No significant differece

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Comparison of VMAT-2 Inhibitors

Valbenazine (Ingrezza™) Deutetrabenazine (Austedo™)

Dosing 40-80 mg daily

(with or without food) 6-48 mg daily†

(with food)

Formulation Capsule Tablet

Half-life 15-22 hours 9-10 hours

Metabolism • Carbonyl reductase • CYP3A4, CYP2D6

• Carbonyl reductase • CYP2D6

Dose adjustments

• CrCl <30 mL/min • Hepatic impairment • CYP3A4 and CYP2D6 inhibitors

• Hepatic impairment • CYP2D6 inhibitors

Warnings and Contra-indications

• Somnolence • QTc prolongation

• Depression/suicidal thoughts in patients with Huntington’s disease • Binding to melanin-containing tissues • Hepatic impairment • QTc prolongation • NMS

†Daily doses >12 mg should be divided BID

INGREZZA [package insert]. San Diego, California: Neurocrine Biosciences, Inc.; 2017. AUSTEDO [package insert]. North Wales, Pennsylvania: Teva Pharmaceuticals, Inc.; 2017.

53

Cost of VMAT-2 Inhibitors

Valbenazine Deutetrabenazine

AWP Monthly Cost

$12,660 (#60 of 40 mg)

$5,918 (#60 of 12 mg)

Estimated annual cost

$151,920 $71,016

Manufacturer Neurocrine Teva

Acquisition Specialty pharmacies only Specialty pharmacies only

Patient/Provider Support?

Yes – INBRACE™ Support Program Yes – Shared Solutions™

INGREZZA [package insert]. San Diego, California: Neurocrine Biosciences, Inc.; 2017. AUSTEDO [package insert]. North Wales, Pennsylvania: Teva Pharmaceuticals, Inc.; 2017. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed August 31, 2017.

54

Amantadine (#100 of 100 mg)

$201.90

Ginkgo Biloba (#100 of 120 mg)

$16.99

9/16/2017

10

Treating TD in Patients with Stable Psychiatric Diagnoses

55

Discontinue DRBA + follow-up AIMS in 3 months

Continue current treatment and assess severity and functional impairment of TD

Baseline EKG + Consider VMAT-2 inhibitor + Follow-up AIMS in 1 month

Absent or minimal impairment in function

Moderate or severe impairment in function

Consider dose reduction + follow-up AIMS in 1

month


months

Continue TD management and follow-up AIMS in 3

months

Improvement of TD?

Improvement of TD?

Add ginkgo biloba 120 mg BID OR, Amantadine 100 mg daily + follow-up AIMS in 1 month

Is chronic DRBA use necessary?

Yes

Yes

Yes

No

No

No

Patient Case (part III):

• You perform an AIMS on SV and her score is 15 indicating that she has moderate to severe TD. SV is worried about medication changes and tearfully states “this is the most stable I’ve ever been!”. However, her progression of TD is now interfering with her ability to perform house chores and work.

• What would be an appropriate first step in managing SV’s TD? A. Consider a dose reduction of risperidone with close monitoring

B. Consider switching risperidone to a typical antipsychotic such as chlorpromazine

C. Stop risperidone right away and add benztropine 1 mg BID for TD

D. Continue her current regimen, add clonazepam 1 mg BID, and recommend an over the counter vitamin E supplement

56

Patient Case (part III):

• After reducing her dose of risperidone back to 4 mg, SV returns to your clinic in 6 weeks. On a repeat AIMS she scores a 14 (indicating a 1 point improvement). SV states she is becoming increasingly upset regarding her TD and has had to recently quit her job.

• Would you consider a VMAT-2 inhibitor?

• What must you consider before prescribing a VMAT-2 inhibitor?

A. Medication cost to the patient

B. VMAT-2 inhibitors are not a cure for TD

C. The average reduction in AIMS was 3-4 points

D. Long-term effects beyond 12 months are unknown

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Conclusion

• VMAT-2 inhibitors demonstrate significant improvement in AIMS in patients with moderate to severe TD

• VMAT-2 inhibitors can be considered for patients impaired by TD in whom dose reductions or adjunctive agents do not provide relief

• All patients should be counseled on risk of TD before AP initiation and with ongoing AP use

• At minimum, all patients should be assessed yearly for TD

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Future Questions

• How do changes in AIMS score correlate to functional improvement?

• What does TD progression look like with medication noncompliance or after treatment is stopped?

• What is the feasibility for long-term use given the current cost of VMAT-2 inhibitors?

• Will we ever see head-to-head trials with previously studied agents such as ginkgo biloba or amantadine?

59

Acknowledgements

Tawny Smith, PharmD, BCPP Clinical Pharmacy Specialist – Psychiatry

Seton Shoal Creek Hospital

Lisa Mican, PharmD, BCPP Clinical Pharmacy Specialist – Psychiatry

Austin State Hospital

Evaluator: Cynthia A. Gutierrez, PharmD, MS, BCPP

Clinical Pharmacy Specialist – Mental Health South Texas Veterans Health Care System

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9/16/2017

11

IS THERE VALUE IN VMAT-2 INHIBITORS FOR TARDIVE DYSKINESIA?

Samantha Vogel, PharmD PGY2 Psychiatric Pharmacy Resident Seton Healthcare Family The University of Texas College of Pharmacy


Appendices

A. Abbreviations

B. Patient Case – SV

C. Abnormal Involuntary Movement Scale (AIMS)

D. Treating TD in Patients with Stable Psychiatric Diagnoses Algorithm

A. Abbreviations

AAN American Academy of Neurology

AIMS Abnormal Involuntary Movement Scale

AP Antipsychotic

APA American Psychiatric Association

CGIC Clinical Global Impression of Change

CGI-TD Clinical Global Impression of Change – Tardive Dyskinesia

DBZ Deutetrabenazine

DRBA Dopamine Receptor Blocking Agent

DSM-5 Diagnostic and Statistical Manual of Mental Disorders

ECT Electroconvulsive Therapy

EPS Extrapyramidal Symptoms

PBO Placebo

PGIC Patient Global Impression of Change

RDBPC Randomized, Double Blind, Placebo Controlled

SNRI Serotonin-Norepinephrine Reuptake Inhibitor

SSRI Selective Serotonin Reuptake inhibitor

TD Tardive Dyskinesia

VBZ Valbenazine

VMAT Vesicular Monoamine Transporter

WFSBP World Federation of Societies of Biological Psychiatry

B. Patient Case – SV

HPI: SV is a 34 year old Hispanic female who presents to your mental health clinic for

medication management. She states she began experiencing slight involuntary movements of

the tongue and jaw 7 months ago which have progressed into marked movements of the tongue

and jaw, grimacing, and moderate choreic movements of the upper limbs.

PMH: Schizoaffective disorder (diagnosed 2007), type II diabetes (diagnosed 2009), acute

dystonia (2010), R-wrist fracture (2010) C-section (2012)

Medications: She has been stable on her current medication regimen for the past 6 years,

however 12 months ago her risperidone was increased from 4 mg to 6 mg:

Risperidone 6 mg PO daily

Metformin ER 1000 mg PO daily

Sertraline 100 mg PO daily

Acetaminophen 325 mg PO PRN

Previous psychiatric medication trials:

Medication Reason for discontinuation

Haloperidol 15 mg PO daily Acute dystonic reaction

Olanzapine 20 mg PO daily Weight gain; breakthrough psychosis

Quetiapine 600 mg PO qHS Weight gain, sedation

Aripiprazole 10 mg PO daily Akathisia

Duloxetine 60 mg PO daily Insomnia

C. Abnormal Involuntary Movement Scale (AIMS)

MOVEMENT RATINGS: Rate highest severity observed. Rate RATER RATER RATER RATER

movements that occur upon activation one less than those observed

spontaneously. Circle movement as well as code number that applies. Date Date Date Date

Facial and 1. Muscles of Facial Expression 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Oral e.g. movements of forehead, eyebrows, periorbital area,

Movements cheeks, including frowning, blinking, smiling, grimacing

2. Lips and Perioral Area 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

e.g., puckering, pouting, smacking

3. Jaw e.g. biting, clenching, chewing, mouth opening, 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

lateral movement

4. Tongue Rate only increases in movement both in and out

of mouth. NOT inability to sustain movement. Darting in and out of mouth.

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 O 1 2 3 4

5. Upper (arms, wrists,, hands, fingers)

Include choreic movements (i.e., rapid, objectively purposeless, irregular, spontaneous) athetoid movements (i.e., slow, irregular, complex, serpentine). DO NOT INCLUDE TREMOR (i.e., repetitive, regular, rhythmic)

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Extremity Movements

6. Lower (legs, knees, ankles, toes)

e.g., lateral knee movement, foot tapping, heel dropping, foot squirming, inversion and eversion of foot.

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Trunk Movements

7. Neck, shoulders, hips e.g., rocking, twisting, squirming,

pelvic gyrations 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Global

8. Severity of abnormal movements overall 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

9. Incapacitation due to abnormal movements 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Judgments

10. Patient’s awareness of abnormal movements

Rate only patient’s report No awareness 0 Aware, no distress 1 0 0 0 0

Aware, mild distress 2 1 1 1 1

Aware, moderate distress 3 2 2 2 2

Aware, severe distress 4 3 3 3 3

4 4 4 4

Dental Status

11. Current problems with teeth and/or dentures?

No Yes No Yes No Yes No Yes

12. Are dentures usually worn? No Yes No Yes No Yes No Yes

13. Edentia? No Yes No Yes No Yes No Yes

14. Do movements disappear in sleep? No Yes No Yes No Yes No Yes

CODE

0 = None 1 = Minimal (may be extreme normal) 2 = Mild 3 = Moderate 4 = Severe

Description

The entire test can be completed in about 10 minutes. The AIMS test has a total of twelve items

rating involuntary movements of various areas of the patient's body. These items are rated on a

five-point scale of severity from 0–4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3

(moderate), 4 (severe). Two of the 12 items refer to dental care. The patient must be calm and

sitting in a firm chair that doesn't have arms, and the patient cannot have anything in his or her

mouth. The clinician asks the patient about the condition of his or her teeth and dentures, or if

he or she is having any pain or discomfort from dentures.

The remaining 10 items refer to body movements themselves. In this section of the test, the

clinician or rater asks the patient about body movements. The rater also looks at the patient in

order to note any unusual movements first-hand. The patient is asked if he or she has noticed

any unusual movements of the mouth, face, hands or feet. If the patient says yes, the clinician

then asks if the movements annoy the patient or interfere with daily activities. Next, the patient

is observed for any movements while sitting in the chair with feet flat on the floor, knees

separated slightly with the hands on the knees. The patient is asked to open his or her mouth

and stick out the tongue twice while the rater watches. The patient is then asked to tap his or

her thumb with each finger very rapidly for 10–15 seconds, the right hand first and then the left

hand. Again the rater observes the patient's face and legs for any abnormal movements.

After the face and hands have been tested, the patient is then asked to flex (bend) and extend

one arm at a time. The patient is then asked to stand up so that the rater can observe the entire

body for movements. Next, the patient is asked to extend both arms in front of the body with the

palms facing downward. The trunk, legs and mouth are again observed for signs of TD. The

patient then walks a few paces, while his or her gait and hands are observed by the rater twice.

Results

The total score on the AIMS test is not reported to the patient. A rating of 2 or higher on the

AIMS scale, however, is evidence of tardive dyskinesia. If the patient has mild TD in two areas

or moderate movements in one area, then he or she should be given a diagnosis of TD. The

AIMS test is considered extremely reliable when it is given by experienced raters.

If the patient's score on the AIMS test suggests the diagnosis of TD, the clinician must consider

whether the patient still needs to be on an antipsychotic medication. This question should be

discussed with the patient and his or her family. If the patient requires ongoing treatment with

antipsychotic drugs, the dose can often be lowered. A lower dosage should result in a lower

level of TD symptoms. Another option is to place the patient on a trial dosage of Clozapine

(Clozaril), a newer antipsychotic medication that has fewer side effects than the older

neuroleptics.

Examination Procedure

Either before or after completing the examination procedure, observe the patient unobtrusively

at rest (e.g., in the waiting room).

The chair to be used in this examination should be a hard, firm one without arms. Have the

person remove their shoes and socks.

1. Ask the patient whether there is anything in his or her mouth (such as gum or candy) and, if so, to remove it.

2. Ask about the *current* condition of the patient's teeth. Ask if he or she wears dentures. Ask whether teeth or dentures bother the patient *now*.

3. Ask whether the patient notices any movements in his or her mouth, face, hands, or feet. If yes, ask the patient to describe them and to indicate to what extent they *currently* bother the patient or interfere with activities.

4. Have the patient sit in chair with hands on knees, legs slightly apart, and feet flat on floor. (Look at the entire body for movements while the patient is in this position.)

5. Ask the patient to sit with hands hanging unsupported -- if male, between his legs, if female and wearing a dress, hanging over her knees. (Observe hands and other body areas).

6. Ask the patient to open his or her mouth. (Observe the tongue at rest within the mouth.) Do this twice.

7. Ask the patient to protrude his or her tongue. (Observe abnormalities of tongue movement.) Do this twice.

8. Ask the patient to tap his or her thumb with each finger as rapidly as possible for 10 to 15 seconds, first with right hand, then with left hand. (Observe facial and leg movements.)

9. Flex and extend the patient's left and right arms, one at a time. 10. Ask the patient to stand up. (Observe the patient in profile. Observe all body areas

again, hip included.) 11. Ask the patient to extend both arms out in front, palms down. (Observe trunk, legs, and

mouth.) 12. Have the patient walk a few paces, turn, and walk back to the chair. (Observe hands and

gait.) Do this twice.

Source: National Institute of Mental Health

D. Algorithm - Treating TD in Patients with Stable Psychiatric Diagnoses

Discontinue DRBA + follow- up AIMS in 3 months

Continue current treatment and assess severity and functional impairment of TD

Baseline EKG +Consider VMAT-2 inhibitor +

Follow-up AIMS in 1 month

Absent or minimal impairment in function

Moderate or severe impairment in function

Consider dose reduction + follow-up

AIMS in 1 month


months

Continue TD management and follow-up AIMS in 3

months

Improvement of TD?

Improvement of TD?

Add ginkgo biloba 120 mg BID OR, Amantadine 100 mg daily

+ follow-up AIMS in 1 month

Is chronic DRBA use necessary?

Yes

Yes

Yes

No

No

No

Is there value in VMAT-2 inhibitors for tardive...

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