Utah Medicaid Dur Report January 2019 Vesicular Monoamine Transporter 2 Inhibitors for Huntington's Disease and Tardive Dyskin

UTAH MEDICAID DUR REPORT JANUARY 2019

VESICULAR MONOAMINE TRANSPORTER 2 INHIBITORS FOR HUNTINGTON’S DISEASE AND TARDIVE DYSKINESIA

Deutetrabenazine (Austedo) Tetrabenazine (Xenazine, generic) Valbenazine (Ingrezza)

Report finalized: December 2018

Drug Regimen Review Center

Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

Contents Background ...... 3 Methods ...... 3 Disease Overview and Guideline Recommendations ...... 4 Huntington’s Disease ...... 4 Table 1. Clinical Practice Guideline Recommendations for the Treatment of Chorea in Huntington’s Disease ...... 5 Tardive Dyskinesia ...... 6 Table 2. Description of Selected Tardive Syndromes ...... 6 Table 3. Agents That Can Cause Tardive Syndromes ...... 7 Table 4. Clinical Practice Guideline Recommendations for Tardive Syndromes ...... 9 Vesicular Monoamine Transporter 2 Inhibitors ...... 11 Table 5. FDA-Approved Vesicular Monoamine Transporter 2 Inhibitors ...... 11 Mechanism of Action ...... 12 Pharmacokinetics ...... 12 Off-label Use of Tetrabenazine ...... 12 Safety ...... 13 Table 6. Adverse Events and Warnings for Vesicular Monoamine Transporter 2 Inhibitors ...... 15 Systematic Review Evidence ...... 16 Table 7. Strength of Recommendations for Agents in Treating Tardive Syndromes ...... 17 Table 8. Clinical Practice Algorithm for the Management of Tardive Dyskinesia ...... 18 Expert Opinion Evidence ...... 19 Clinical Trial Evidence ...... 19 Table 9. Results from Placebo-Controlled Trials Including Deutetrabenazine or Valbenazine for Tardive Dyskinesia ...... 23 Utah Medicaid Utilization Data ...... 24 Table 10. Total ACO Pharmacy Data for VMAT-2 Inhibitors (2016-2018) ...... 24 Table 11. Total FFS Pharmacy Data for VMAT-2 Inhibitors (2016-2018) ...... 24 Table 12. Total FFS Patients with Diagnosis Codes Submitted for HD and TD (2016-2018) ...... 24 Discussion Topics and Potential Prior Authorization Criteria for VMAT-2 Inhibitors ...... 25 Summary ...... 28 References ...... 30 Appendix A: Literature Search Strategies ...... 34 Appendix B: Relevant Diagnosis Codes ...... 35 Appendix C: Key Findings in Cochrane Reviews and Other Systematic Reviews for Tardive Dyskinesia ... 36 Appendix D: Key Findings in Cochrane Reviews for Huntington’s Disease ...... 38 Appendix E: Key Findings in Published Placebo-Controlled Trials ...... 39

Background Movement disorders are neurological conditions characterized by abnormal voluntary and involuntary movements.1 These disorders can affect activities of daily living and quality of life of patients and their caregivers. Movement disorders include several conditions such as Huntington’s disease, tardive dyskinesia, parkinsonism, Parkinson’s disease, Wilson’s disease, tics, essential tremor, dystonia, and Tourette syndrome, among others.1-3

Three vesicular monoamine transporter type 2 (VMAT-2) inhibitors are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of chorea associated with Huntington’s disease (HD) and tardive dyskinesia (TD): deutetrabenazine (Austedo), tetrabenazine (Xenazine), and valbenazine (Ingrezza).4-6 Deutetrabenazine and tetrabenazine are approved orphan drugs for the treatment of chorea associated with HD.4,5 Deutetrabenazine and valbenazine are the first drugs to be approved for the treatment of TD in adult patients.4,6 Tetrabenazine has an additional orphan drug designation for the treatment of moderate/severe tardive dyskinesia;7 however it is not yet FDA- approved for that indication. In addition, the 3 VMAT-2 inhibitor agents have orphan drug designations for the treatment of Tourette syndrome in pediatric patients;7 however, no FDA approval is granted for such indication. Each of the VMAT-2 inhibitors is available as an oral formulation.4-6 Dosing should be individualized to each patient and gradually up-titrated based on a reduction of symptoms and tolerability.4-6

There are no current prior authorization criteria in place for VMAT-2 inhibitors. The purpose of this review is to provide evidence that can assist the Medicaid Drug Utilization Review (DUR) Board in assuring appropriate use of the VMAT-2 inhibitors in patient populations most likely to benefit. Methods A literature search for systematic reviews addressing the efficacy and safety of the 3 VMAT-2 inhibitors was conducted in the Cochrane Library and Ovid Medline. References of relevant search results were screened. Search strategies are provided in Appendix A. In addition, searches in The National Institute for Health and Care Excellence (NICE) website were performed. Information concerning product labeling and FDA clinical review documents were searched in the FDA website. Additional information was found in Micromedex, Lexicomp, and Up To Date. Treatment guidelines for the management of Huntington’s disease and tardive dyskinesia were identified by searching in The American Academy of Neurology (AAN) website and checking the reference lists of relevant systematic reviews.

Relevant information from the Utah Medicaid Pharmacy and Therapeutics Committee Drug Class Review: Vesicular Monoamine Transporter 2 Inhibitors and Anticholinergic Agents for Movement Disorders (March 2018) was incorporated into this report. Reimbursement documents, health plan documents including prior authorization documents, and any relevant diagnosis coding documents were reviewed for information regarding billing to inform data extraction (claims data). Appendix B includes the International Classification of Diseases (ICD)-9 and ICD- 10 codes for HD and TD.

Disease Overview and Guideline Recommendations Movement disorders are neurological conditions caused by basal ganglia dysfunction.1 Basal ganglia are a group of subcortical gray matter nuclei, located in the brain, and principally responsible for motor control.1 The etiology of movement disorders includes certain drugs (eg, antipsychotics), genetic factors, injuries, stroke, infections, and unknown origins.1,3,8,9 Examples of movement disorders include tremor, dystonia, athetosis, chorea, myoclonus, tics, tardive dyskinesia, and Parkinson’s disease.1,3

1. Huntington’s Disease Huntington’s disease, formerly known as Huntington’s chorea,3 is a fatal, progressive, autosomal dominant neurodegenerative disorder caused by a mutation (a CAG segment repetition ≥36) in the huntingtin gene.10,11 It is characterized by motor, cognitive, and psychiatric impairment.1,3,12 Histopathologic abnormalities include striatal medium-sized spiny neuron loss, which may cause dopaminergic hyperactivity.12 Huntington’s disease onset is usually between 25 and 45 years old and survival length typically ranges from 10 to 20 years after diagnosis.13 Typical early symptoms include rapid, involuntary choreiform movements (ie, chorea or “uncontrollable dance-like movements”12).10 Voluntary movements are additionally impaired causing “…reduced manual dexterity, slurred speech, swallowing difficulties, problems with balance, and falls.”13 Other symptoms such as behavioral disturbances and dementia appear as the disease progresses.3,12 The progression of HD can be classified into 3 stages: 1) early stage with minor involuntary movements and independent life (functional capacity slightly affected), 2) middle stage when motor and functional capacity are more compromised, and 3) late stage with chorea that is severe and complete assistance in all activities of daily living is required.13 Epidemiology

According to the Huntington Study Group and the Huntington’s Disease Society of America, around 30,000 North Americans live with Huntington’s disease.14,15 Diagnosis

Clinical diagnosis of HD may be determined by family history, presence of typical movement disorders, and genetic testing.10,13 In case of negative family history or presence of atypical symptoms, genetic testing is useful to confirm the presence of a mutation in the huntingtin gene.13 Motor symptoms and functional abilities can be measured using the appropriate scales in the validated Unified Huntington’s Disease Rating Scale (UHDRS).13,16

Huntington’s Disease Society of America (HDSA) currently has 43 Centers of Excellence in the US, including the University of Utah Center of Excellence for Huntington’s Care.17 Treatment Strategies and Guideline Recommendations

Huntington’s disease is a chronic disease with no treatment to delay or stop its progression. Current treatment strategies are aimed to treat symptoms (eg, movement and behavioral impairment), increase function, and improve quality of life.13 Tetrabenazine and deutetrabenazine are VMAT-2 inhibitors that decrease dopaminergic activity and reduce abnormal movements.1,4,5 They are currently approved for the treatment of chorea associated with HD.4,5 In addition, antidepressant, antianxiety, and

antipsychotic drugs may be appropriate for the treatment of psychiatric and behavioral disorders in patients with HD.10 The 2012 American Academy of Neurology (AAN) guideline for Huntington’s disease recommends the use of tetrabenazine, amantadine, or riluzole as “likely effective” agents for the treatment of choreic movements based on moderately strong evidence.18 Deutetrabenazine was approved in 2017 and is not yet mentioned in this guideline. See Table 1 for a summary of guideline recommendations.

Table 1. Clinical Practice Guideline Recommendations for the Treatment of Chorea in Huntington’s Disease Guideline Recommendationa,b Evidence-based guideline: If patients with chorea associated with HD require treatment, clinicians should Pharmacologic treatment of prescribe: chorea in Huntington - Tetrabenazine (up to 100 mg/day) (Level B recommendation based on 1 disease. Report of the Class I study and 1 Class II study) Guideline Development - Amantadine (300–400 mg/day) (Level B recommendation based on 1 Class I Subcommittee of the and 1 Class II studies), OR American Academy of - Riluzole (200 mg/ day) (Level B recommendation based on 1 Class I RCT) Neurology, 2012 (reaffirmed in July 2015)18 Note: “TBZ likely has very important antichoreic benefits, and riluzole 200 mg/day likely has moderate benefits (Level B). The degree of benefit for amantadine is unknown. Clinicians should discuss possible adverse events with patients with HD and monitor for their occurrence, particularly parkinsonism and depression/suicidality with TBZ and elevated liver enzymes with riluzole.” Abbreviations: AAN, American Academy of Neurology; HD, Huntington disease; RCT, randomized controlled trial a Levels of recommendation according to the 2017 AAN’s Clinical Practice Guideline Process Manual19: • Level A (Strong recommendation): The agent is established as effective based on at least 2 consistent class I studies (strong evidence) and MUST be recommended • Level B (Moderately strong recommendation): The agent is probably effective based on at least 1 class I study or 2 consistent class II studies (moderate evidence) and SHOULD be recommended • Level C (Weak recommendation): The agent is possibly effective based on at least 1 class II study and 2 consistent class III studies (weak evidence) and MAY be recommended • Level U (Insufficient evidence): Evidence is insufficient to support or refute the efficacy of drugs in the treatment of the disease b Study Classification according to the 2017 AAN’s Clinical Practice Guideline Process Manual19 (Criteria for rating therapeutic studies): • Class I: RCT in a representative population, triple-masked studies, and other additional Class I criteria • Class II: eg, RCT that lacks one or two Class I criteria • Class III: eg, controlled studies, crossover trial missing specific criteria, etc. • Class IV: Studies not meeting Class I, II, or III criteria

2. Tardive Dyskinesia Tardive syndromes (TS) are a group of heterogeneous disorders characterized by persistent, repetitive, rhythmic, abnormal involuntary movements after chronic exposure to dopamine-receptor blocking agents (DRBAs).20,21 Tardive syndromes include several disorders such as tardive dyskinesia, tardive dystonia, tardive akathisia, tardive myoclonus, tardive stereotypy, tardive tics, tardive tremor, and withdrawal-emergent dyskinesia.22 As TS are heterogeneous conditions, classification, recognition, and treatment of TS are challenging.23 See Table 2 for further description concerning selected types of TS. The term “tardive” refers to symptoms that usually develop late after a prolonged use of DRBAs. However, symptoms may also appear soon (within days) following treatment initiation with DRBAs.21 The 2 main features of TS are prolonged exposure to DRBA (although spontaneous dyskinesia has been also reported in older patients23) and persistence of symptoms even after stopping treatment with DRBA.21 This last feature is useful to distinguish tardive syndromes from acute syndromes (eg, acute dystonia), which usually disappear after the DRBA is stopped.21

The 2013 AAN guideline states that tardive syndromes should fulfill the following 3 criteria24,25:

1. A “history of at least 3 months’ total cumulative neuroleptic exposure during which the exposure can be continuous or discontinuous” 2. “Presence of at least “moderate” abnormal involuntary movements in one or more body areas or at least “mild” movements in 2 or more body areas.” To evaluate abnormal movements, Schooler and Kane (1982) recommended using a standardized rating scale such as the Abnormal Involuntary Movement Scale (AIMS)25 3. “Absence of other conditions that might produce abnormal involuntary movements”24

Table 2. Description of Selected Tardive Syndromes26,27 Syndrome Characteristics of abnormal movements

Abnormal and random face movements (tongue, lips, jaw). Arms, legs, fingers, toes, Tardive dyskinesia or hips can also be affected

Tardive akathisia Restlessness or jittery sensation (frequently in legs or trunk)

Recurrent muscle contractions leading to abnormal posture. Face, neck, arms, or Tardive dystonia trunk are typically affected

Tardive tics Repeated brief movements (muscle tics) or sounds (voice tics)

Tardive myoclonus Uncontrolled and quick shaking of muscles (often in arms, fingers, and legs)

Tardive tremor Shaking movements (often in hands and arms, but it can affect any part of the body)

DRBAs that may cause TS include typical and atypical antipsychotic drugs (eg, haloperidol and clozapine) and antiemetics (eg, metoclopramide), among others.21,27 Table 3 lists the agents that can cause TS.8,27

Table 3. Agents That Can Cause Tardive Syndromes8,27a Typical Antipsychotics Atypical Antipsychotics - Phenothiazines: chlorpromazine, fluphenazine, - Dibenzodiazepine: clozapine, quetiapine perphenazine, prochlorperazine, thioridazine, - Substitute benzamide: sulpiride, remoxipride, trifluoperazine, perazine, triflupromazine, levosulpiride, tiapride, amisulpride levomepromazine, mesoridazine - Benzisoxazole: iloperidone - Thioxanthene: chlorprothixene, thiothixene, - Dibenzazepine: asenapine flupentixol, zuclopentixol - Benzisothiazole: ziprasidone - Dibenzazepine: loxapine - Thienobenzodiazepine: olanzapine - Butyrophenones: haloperidol, droperidol - Pyrimidinone: risperidone, paliperidone - Diphenylbutylpiperidine: pimozide - Quinolinone: aripiprazole - Dihydroindolone: molindone - Other: lurasidone Antiemetics Calcium Channel Blockers Metoclopramide, clebopride, cisapride Cinnarizine, flunarizine Serotonin Norepinephrine Reuptake Inhibitors Tricyclic Antidepressants Duloxetine, citalopram Amoxapine Central Monoamine Oxidase Inhibitors Anti-manic Agents Reserpine - Lithium - Substitute benzamides: sulpiride, veralipride First Generation Antihistamines Promethazine a Information mainly extracted from Vijayakumar and Jankovic 201627

Tardive dyskinesia (TD) or “classic” dyskinesia is probably the most common type of tardive syndrome.28 It is also called oral-buccal-lingual (O-B-L) dyskinesia because it is characterized by repeated and rapid involuntary movements of the tongue, jaw, and mouth.22,28 Other parts of the body such as limbs, trunk, and upper face may also be affected.22,28 It typically occurs after a prolonged use of DRBAs for at least 3 months (or only 1 month for elderly patients) and is rarely reversible after DRBA withdrawal.19,22 The Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) defines tardive dyskinesia as a movement disorder induced by the use of DRBAs for at least a few months (or shorter in elderly patients).29 In some cases, abnormal movements may appear after neuroleptic withdrawal, switch, or dose reduction, also called “neuroleptic withdrawal-emergent dyskinesia.”29 This type of dyskinesia usually lasts 4 to 8 weeks.29 Dyskinesia that lasts more than 8 weeks is considered tardive dyskinesia according to DSM -5.29 Tardive dyskinesia appears more frequently in patients with schizophrenia and other mental illness disorders who require chronic treatment with antipsychotics.1 Risk factors associated with the occurrence of TD include advanced age, female sex, diabetes mellitus, history of dementia and depression, and an extended treatment duration of DRBAs.22,30 Age is strongly associated with the development, severity, and low spontaneous remission rate of TD.22 The pathophysiology of TD remains uncertain.22 Some hypotheses include “dopamine hypersensitivity, depletion of gamma-aminobutyric acid or acetylcholine, oxidative stress, and synaptic plasticity.”22 TD may be mild, moderate, or severe.27 In some moderate to severe cases, TD can be extremely distressing and may lead to negative consequences such as social stigma linked to mental illness and

isolation.27,31 In addition, TD may affect a patient’s activities of daily living and the quality of life.31 Thus, effective treatment is highly important.31 Epidemiology Although evidence suggests that exposure to DRBA is likely related to TD, epidemiology of TD is unclear and not well-defined.23 TD is a major concern in patients treated with any class of antipsychotics (typical or atypical antipsychotics); however, the incidence of TD is lower with atypical antipsychotics compared to typical antipsychotics.22,26,31,32 A meta-analysis performed in 2017 by Carbon et al showed a prevalence of TD of 30% with typical antipsychotics and 21% with atypical antipsychotics.26 However, in the subgroup of patients treated with atypical antipsychotics but without prior exposure to typical antipsychotics, the prevalence of TD was 7.2% compared to 23.4% in the subgroup of patients with likely prior exposure to typical antipsychotics.26 In addition, other authors reported an increased cumulative incidence of TD with extended duration of antipsychotic drug therapy (5%, 27%, 43%, and 52% after 1 year, 5 years, 10 years, and 15 years of treatment with antipsychotic therapy, respectively).30 The risk of TD in patients treated with metoclopramide is less than 1%, probably due to its use for shorter periods of time compared to antipsychotic therapy.23 Epidemiology of TD with other causative drugs is uncertain and not well understood.23 Diagnosis and Prevention Diagnosis of TD is based on medication history (prolonged exposure to DRBAs) and presence of abnormal movements.22,31 To measure TD symptoms, several rating scales can be used such as AIMS and Extrapyramidal Symptom Rating Scale (ESRS).22,31,33 AIMS is a validated rating scale commonly used in clinical and research settings.31,34 Adequate training in use of the AIMS is required to ensure reliable scores.31 AIMS includes 12 items to evaluate TD symptoms, severity of abnormal movements over time, and effects of treatment.31,35 Items 1 to 7 of AIMS measure the severity of involuntary motor movements in several body parts (face, extremities, and trunk). Each of the 7 items is scored on a 0 (no dyskinesia) to 4 (severe dyskinesia) scale.6 AIMS (items 1 to 7) scores are usually assessed as the primary endpoint in clinical trials for TD.4,6,35 Preventive measures and early diagnosis are important.36 Prevention of TD can only be effective by avoiding the administration of DRBAs, especially to older patients because they are at higher risk for TD, and avoiding the prolonged use of these agents, if possible.36 Treatment Strategies and Guideline Recommendations Deutetrabenazine and valbenazine are the first FDA-approved agents for the treatment of TD since 2017.4,6 Tetrabenazine and other agents including clonazepam, ginkgo biloba, and amantadine may be used off-label in patients with TD and are listed as therapeutic options for the management of TD in the 2013 AAN evidence-based guideline for the management of tardive syndromes.22,24 Other treatment options for TD may include reducing the dose of antipsychotics, switching to other antipsychotics with less potential to induce TD, or withdrawing antipsychotics if clinically possible. However, little evidence is available regarding these interventions.24,35,37 The 2013 AAN evidence-based guideline for the management of tardive syndromes24 developed a list of agents for the treatment of TS or TD based on the strength of evidence supporting their use. Concerning the agents of interest for this report, the AAN guideline states that tetrabenazine is possibly effective in

decreasing TS symptoms and may be considered as a therapeutic option for TS (Level C or weak recommendation based on low quality evidence).24 Authors mention that long-term use of tetrabenazine may cause parkinsonism.24 The guideline predated FDA approvals for deutetrabenazine and valbenazine.24 Regarding other strategies for the management of TS such as withdrawal of DRBAs or switching from typical to atypical DRBAs, the 2013 AAN guideline states that there is insufficient evidence to support or refute the management of TS by implementing these interventions.24 The 1992 American Psychiatric Task Force (APTF) on Tardive Dyskinesia recommends withdrawing antipsychotics if patients can tolerate it; however, authors state that this may cause acute worsening of TD or relapse of psychotic symptoms.29 If continuation of treatment is needed (eg, in schizophrenia or gastroparesia19), it may be an appropriate attempt to gradually reduce the dose of DRBAs to avoid “neuroleptic withdrawal- emergent dyskinesia” or deterioration of TD.22,29 In addition, the APTF considers switching from typical to atypical antipsychotics a potential therapeutic approach; however, this is not adequately supported by controlled trials.29 Regarding the use of metoclopramide, the 2013 American College of Gastroenterology guideline for the management of gastroparesis recommends metoclopramide as first-line prokinetic therapy in patients with gastroparesis.38 Metoclopramide should not be used longer than 3 months due to the increased risk of experiencing TD and should be discontinued if TD appears (black box warning).38,39 Table 4 includes a summary of guideline recommendations for TS.

Table 4. Clinical Practice Guideline Recommendations for Tardive Syndromes Guideline Recommendationa Evidence-based - Clonazepam “probably improves” tardive dyskinesia (Level B) guideline: Treatment of - Ginkgo biloba “probably improves” tardive syndromes (Level B) tardive syndromes. - Amantadine may be considered for the treatment of tardive syndromes (Level C) Report of the Guideline - Tetrabenazine “possibly reduces tardive syndromes symptoms” and may be Development considered in treating tardive syndromes (Level C - Possibly effective based on 2 consistent Class III studies): Subcommittee of the “One Class III study compared haloperidol use with tetrabenazine use (100 American Academy of o mg/day for 14 weeks)” Neurology, 201324 o One “Class III, nonrandomized, single-blind study compared tetrabenazine efficacy using a randomized videotape protocol pre- and posttreatment” - Second-generation antipsychotics (eg, risperidone and olanzapine) may improve TD symptoms; however, these drugs cannot be recommended for TD treatment because they can cause TD by themselves and mask its symptoms - Diltiazem should not be considered (Level B) - Galantamine and eicosapentaenoic acid may not be considered (Level C) - There is insufficient evidence to support or refute treatment of tardive syndromes “by withdrawing causative agents or switching from typical to atypical DRBAs (Level U)” - There is insufficient evidence to support or refute the use of acetazolamide, bromocriptine, thiamine, baclofen, vitamin E, vitamin B6, selegiline, clozapine, olanzapine, melatonin, nifedipine, fluperlapine, sulpiride, flupenthixol, thiopropazate, haloperidol, levetiracetam, quetiapine, ziprasidone, sertindole, aripiprazole, buspirone, yi-gan san, biperiden discontinuation, botulinum toxin type A, electroconvulsive therapy, α-methyldopa, reserpine, and pallidal deep brain stimulation as TS treatments (Level U)

Table 4. Clinical Practice Guideline Recommendations for Tardive Syndromes Guideline Recommendationa Treatment - Treatment recommendations for tardive dyskinesia: recommendations for o Discontinue antipsychotic therapy. If this is not possible, consider reducing extrapyramidal side the antipsychotic dose effects associated with o Withdrawal of any anticholinergic drugs second-generation o Switching antipsychotic therapy to clozapine may be appropriate because it antipsychotic use in may improve TD symptoms (LOE low) Agents that may potentially improve TD include tetrabenazine (LOE very low), children and youth o clonazepam (LOE high), levetiracetam (LOE high) (CAMESA group, 2011)40 The Maudsley - Treatment recommendations for tardive dyskinesia: Prescribing Guidelines o Discontinue anticholinergic if prescribed (10th Edition). London: o Reduce antipsychotic dose Informa Healthcare, o Discontinue antipsychotic and substitute by another drug (eg, clozapine, 200941 olanzapine, risperidone, aripiprazole) o “Switching or withdrawing antipsychotics is not always effective and so additional agents are often used” (eg, tetrabenazine and benzodiazepines such as clonazepam) American Psychiatric - Treatment options for TD: Association Practice o “Switching to a second-generation antipsychotic (symptoms of TD may Guideline for the increase) or reducing the dose of the first-generation antipsychotic” Treatment of Patients o “…despite mild tardive dyskinesia, a risk-benefit analysis favored continued With Schizophrenia maintenance of antipsychotic treatment to prevent the likelihood of relapse” Second Edition, 200442 o Drugs that may potentially reduce TD symptoms (with few positive results): vitamin E, benzodiazepines, anticholinergic agents, calcium channel blockers, γ-amino butyric acid receptor agonists, essential fatty acids, estrogen, and insulin American Psychiatric - If feasable, neuroleptic discontinuation may be an option in patients with TD. Task Force on Tardive However, neuroleptic withdrawal may cause acute worsening of TD or relapse of Dyskinesia, Tardive psychotic symptoms Dyskinesia-A Task - If continuation of neuroleptic treatment is required (eg, chronic schizophrenia), it Force Report of the may be appropriate to try to reduce the neuroleptic dose gradually American Psychiatric - Switching from one class to another class of neuroleptic may be appropriate; however, there are no controlled trials Association, American - The majority of TD cases are mild and do not need additional treatment (“apart Psychiatric Press, 29 from neuroleptic dose reduction or withdrawal, if feasable”) Washington DC, 1992 - Suppressant agents: eg, tetrabenazine has been extensively studied and it is a “useful therapeutic agent” for TD. Other agents with a potential effect in TD include reserpine and oxypertine; however, further evidence is needed - Recommendations: o “Review indications for neuroleptic drugs, and consider alternative treatment when available” o Use “the minimum effective dosage for chronic treatment” o If TD worsen, “consider discontinuing the neuroleptic or switching to a new neuroleptic.” At present, clozapine may hold some promise but more evidence is needed Abbreviations: AAN, American Academy of Neurology; CAMESA, Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children; DRBA, dopamine receptor blocking agents; LOE, level of evidence; TD, tardive dyskinesia; TS, tardive syndrome a See AAN levels of recommendation and study classification in Table 1

Vesicular Monoamine Transporter 2 Inhibitors

Table 5. FDA-Approved Vesicular Monoamine Transporter 2 Inhibitors Generic Name & Preparations Indication & Dosage Brand Name

Deutetrabenazine Oral tablet: Treatment of chorea associated with Huntington’s disease and tardive • 6 mg dyskinesia in adults • 9 mg Patients who are not being switched from tetrabenazine: • 12 mg 1. Chorea associated with Huntington’s disease: Initial dose: 6 mg QD;

titrate up at weekly intervals by 6 mg per day up to a maximum

recommended daily dosage of 48 mg

2. Tardive dyskinesia in adults: Initial dose: 6 mg BID; may increase by

6 mg/day at weekly intervals to a maximun of 48 mg/day

• Administer total daily dosages ≥ 12 mg in 2 divided doses

• If doses > 24 mg/day are needed, monitor QT interval in patients at risk for

QT prolongation before and after increasing the dose

• If patients are poor CYP2D6 metabolizers or are taking strong CYP2D6 Austedo4 inhibitors, Austedo should not exceed 36 mg (18 mg/single dose) (April 2017) Switching patients from tetrabenazine to Austedo: • Discontinue tetrabenazine and initiate Austedo the next day (see dosing recommendations in the package insert). Dose adjusted at weekly intervals

Tetrabenazine Oral tablet: Treatment of chorea associated with Huntington’s disease • 12.5 mg Dosing Recommendations (up to 50 mg/day) • 25 mg • 1st week: 12.5 mg QD

• 2nd week: 25 mg daily (12.5 mg BID); then slowly titrate up at weekly Generic intervals by 12.5 mg to a tolerated dose that reduces chorea available • If daily doses of 37.5 mg to 50 mg are needed, they should be divided into

3 doses (maximum single dose: 25 mg)

Dosing Recommendations (> 50 mg/day) • Patients requiring doses > 50 mg/day should be genotyped for CYP2D6: o Extensive/intermediate CYP2D6 metabolizers: . Doses > 50 mg/day should be divided into 3 doses. Maximum daily dose: 100 mg; 37.5 mg/single dose o Poor CYP2D6 metabolizers: Xenazine5 . Maximum daily dose: 50 mg; 25 mg/single dose (August 2008) Unlabeled indications: Tardive dyskinesia and Tourette syndrome

Valbenazine Oral capsule: Treatment of tardive dyskinesia in adults • 40 mg • Initial dose: 40 mg QD. After 1 week, increase dose to 80 mg QD • 80 mg • Dose reduction in patients with moderate or severe hepatic impairment, Ingrezza6 CYP2D6 poor metabolizers, and patients taking concomitantly a strong (April 2017) CYP2D6 or CYP3A4 inhibitor Abbreviations: BID, twice daily; CYP, cytochrome P450; QD, once daily

Mechanism of Action

Tetrabenazine, deutetrabenazine, and valbenazine reversibly block VMAT-2 decreasing the uptake of dopamine into the presynaptic vesicles and causing dopamine storage depletion in the central nervous system.8,9,43-45 Each agent is metabolized to active metabolites. The principal active metabolite of VMAT-2 inhibitors is dihydrotetrabenazine (HTBZ), which exhibits the major pharmacological effect.46

Pharmacokinetics

Tetrabenazine has short half-life44,46 and it requires a multiple daily administration schedule (2 to 3 times daily).44,46 Doses should be carefully individualized according to the observed response and adverse events.44 Tetrabenazine is rapidly metabolized to several metabolites by hepatic carbonyl reductase and its plasma concentrations are very low.44,47 The main active metabolites (α-HTBZ and β-HTBZ) have high bioavailability, show similar activity to tetrabenazine, and are primarily metabolized by cytochrome P450 2D6 (CYP2D6).9,44,47 High peak plasma concentrations of active metabolites may occur within 1 hour after tetrabenazine administration, probably contributing to the occurrence of adverse events.48 Tetrabenazine and its 2 main active metabolites block VMAT-2, producing the desired effects. However, they also have affinity for other receptors (e.g. adrenergic, dopaminergic, muscarinic receptors),47 causing adverse events.49 Doses of tetrabenazine ranging from 12.5 mg to 100 mg daily can be used; however, patients requiring more than 50 mg daily should be genotyped for a genetic variant of cytochrome P450 (CYP) 2D6, the hepatic enzyme responsible for metabolizing tetrabenazine, to identify their CYP2D6 metabolizer status (extensive, intermediate, or poor).44 For poor CYP2D6 metabolizers, the recommended maximum daily dose is 50 mg daily.44

Deutetrabenazine is an analog of tetrabenazine, with 6 hydrogen atoms substituted by deuterium atoms (nontoxic forms of hydrogen).13 Because deuterium atoms bind to carbon stronger than hydrogen, deutetrabenazine exhibits increased resistance to CYP2D6 metabolism and a prolonged plasma half- life.9,50 Less frequent administration and lower recommended doses of deutetrabenazine are required to achieve the desired effect compared to tetrabenazine.9,43 Labeling for deutetrabenazine does not require genotyping for CYP2D6; however, the maximum recommended dose is 36 mg daily for poor CYP2D6 metabolizers and patients taking strong CYP2D6 inhibitors.4 The slower metabolism of deutetrabenazine and lower peak plasma concentrations compared to tetrabenazine may be theoretically associated with a less incidence of adverse events.9,50,51

Valbenazine has a longer plasma half-life than tetrabenazine and deutetrabenazine supporting once- daily administration.49 Valbenazine has high VMAT-2 selectivity. The results of a study comparing the pharmacological profile of tetrabenazine and valbenazine suggest that valbenazine has a “higher potency, selectivity, and specificity of VMAT2 binding”9 than tetrabenazine due to its principal, active metabolite, (+)-α-HTBZ. This metabolite is the most highly selective VMAT-2 when compared to tetrabenazine, valbenazine, and other metabolites of these agents.9 Additionally, given the absence of affinity for other receptors a lower incidence of adverse events is expected.49 Labeling for valbenazine does not require genotyping for CYP2D6; however, dose reductions are required for poor CYP2D6 metabolizers or patients taking a strong CYP2D6 or CYP3A4 inhibitor.6 Off-label Use of Tetrabenazine Tetrabenazine has been commonly used off-label for tardive dyskinesia in the US, although not specifically approved for this indication by the FDA.49,52 Other off-label uses of tetrabenazine include 12

dystonia, tics, and Tourette syndrome.47 Evidence supporting its off-label uses comes from poor-quality trials and retrospective studies.47 Some authors consider tetrabenazine a therapeutic alternative for these indications based on this limited, positive evidence.47 In the setting of TD, although there is a lack of well-conducted RCTs in patients with TD, the AAN evidence-based guideline considers tetrabenazine as possibly effective for TD based on 2 low-quality studies.24 A systematic review including 8 studies (1 double-blind, cross-over study and 7 open-label trials) of tetrabenazine for TD concluded that tetrabenazine improves TD and is well-tolerated.49 Limitations of the evidence include the absence of randomized and placebo-controlled trials, differences in population characteristics and dosing, small sample sizes, and different outcome assessment tools.49 Supported off-label uses for deutetrabenazine and valbenazine have not been established.53 Safety Common Adverse Events In patients with HD, the most common AEs related to tetrabenazine (frequency >10% and difference from placebo ≥5%) include sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea.5 Adverse events most commonly reported with deutetrabenazine (frequency >8%) include somnolence, diarrhea, dry mouth, and fatigue.4 In placebo-controlled trials including patients with tardive dyskinesia, somnolence, anticholinergic effects, balance disorder/fall, and headache were the most frequently reported adverse event (frequency ≥3% and greater than placebo) with valbenazine treatment.6 Nasopharyngitis, insomnia, depression/dysthymic disorder, and akathisia/agitation/restlessness were the most common adverse events reported (frequency >2% and greater than placebo) with deutetrabenazine.4 Contraindications Tetrabenazine and deutetrabenazine are contraindicated in patients with HD who have thoughts of suicide or those who have untreated or uncontrolled depression.4,5 In addition, these agents are contraindicated in patients with hepatic impairment or taking monoamine oxidase inhibitors (MAOIs), reserpine, or other VMAT-2 inhibitors.4,5 No contraindications are labeled for valbenazine.6 Warnings and Precautions - Depression and Suicidality The main safety concern related to tetrabenazine and deutetrabenazine use in patients with HD is the increased risk of depression and suicidal thoughts and behaviors.4,5 In a 12-week placebo-controlled trial including patients with HD, events of depression or worsening of depression were reported in 19% of patients receiving tetrabenazine compared to 0% in the placebo group.5 Regarding deutetrabenazine, a 12-week placebo-controlled trial in HD reported suicidal ideation in 2% of patients receiving deutetrabenazine compared to 0% in the placebo group.4 Depression was reported in 4% of patients taking deutetrabenazine.4 Thus, tetrabenazine and deutetrabenazine carry a black box warning regarding the increased risk of depression and suicidality in patients with HD.4,5

In the setting of tardive dyskinesia, data from clinical trials assessing deutetrabenazine or valbenazine in TD patients did not appear to show an increased risk for depression and suicidal ideation.34,54 Thus, the FDA decided not to include a black box warning regarding depression and suicidality in patients with TD.4,6 - Akathisia, Agitation, Restlessness, Parkinsonism, and Neuroleptic Malignant Syndrome Labeling for tetrabenazine and deutetrabenazine includes warnings and precautions concerning the risk of akathisia, agitation, restlessness, parkinsonism, and neuroleptic malignant syndrome (potentially fatal).4-6 Dose reduction or drug discontinuation may be required if these events occur.4,5 - QT Prolongation VMAT-2 inhibitors may cause QT prolongation that may be clinically significant in some cases.4-6 VMAT-2 inhibitors should not be used in patients with hereditary long QT syndrome or a history of cardiac arrythmias.4,5 Co-administration of VMAT-2 inhibitors with other drugs that prolong the QT interval (eg, antipsychotic drugs such as chlorpromazine and haloperidol, Class 1A antiarrhythmic, and moxifloxacin5) should be avoided.4-6 - Somnolence Each VMAT-2 inhibitor may cause sedation/somnolence and the ability to drive or operate hazardous machinery may be impaired.4-6 Drud-drug Interactions The use of tetrabenazine and deutetrabenazine is contraindicated in combination with MAOIs, reserpine, and other VMAT-2 inhibitors.4,5 Valbenazine should not be co-administered with MAOIs and strong CYP3A4 inducers.6 Dose reductions may be necessary when combining VMAT-2 inhibitors with strong CYP2D6 inhibitors (see product labeling for further information).4-6 Risk Evaluation and Mitigation Strategy for Tetrabenazine An approved Risk Evaluation and Mitigation Strategy (REMS) is available for tetrabenazine. This program is intended to inform healthcare professional about the risk of depression and suicide thoughts, appropriate dose titration and dosing, and potential for drug interactions with strong CYP2D6 inhibitors.55 Indirect Safety Comparison in Patients with Huntington’s Disease Claassen et al56 (2017) conducted indirect tolerability comparisons between tetrabenazine and deutetrabenazine in patients with Huntington’s disease. Results suggested a significantly lower incidence of overall adverse events, moderate to severe adverse events, and neuropsychiatric adverse events such as agitation, akathisia, depression, drowsiness/somnolence, insomnia, and parkinsonism with deutetrabenazine compared to tetrabenazine. Significantly lower rates of dose reduction and dose reduction/suspension due to adverse events were reported with deutetrabenazine compared to tetrabenazine. Authors explained the apparent favorable safety profile of deutetrabenazine may be related to its pharmacokinetic profile. Indirect comparisons are considered low-quality evidence and should be interpreted cautiously. Well-conducted head-to-head studies are needed to confirm safety differences between these 2 agents.

Table 6. Adverse Events and Warnings for Vesicular Monoamine Transporter 2 Inhibitors4-6,8,53 Agent Warnings Adverse Events Black box warning: >10%: Depression and suicidality in patients CNS: Drowsiness (11%) with HD 1% to 10%: Other warnings: CNS: Fatigue (9%), insomnia (4% to 7%), anxiety (4%), • Akathisia depression (≤4%), agitation (≤4%), akathisia (≤4%), • CNS depression restlessness (≤4%), suicidal ideation (2%) • Hyperprolactinemia GI: Diarrhea (9%), xerostomia (9%), constipation (4%)

Deutetrabenazine • Neuroleptic malignant syndrome GU: Urinary tract infection (7%) • Ophthalmic effects Hema&onco: Bruise (4%) • Parkinsonism Resp: Nasopharyngitis (4%) • QTc prolongation >10%: • CYP2D6 poor metabolizers CNS: Drowsiness (≤17% to ≤57%), sedation (≤17% to ≤57%), • Hyperprolactinemia depression (19% to 35%), extrapyramidal reaction (15% to • Binding to melanin-containing tissue 33%), fatigue (22%), insomnia (22%), akathisia (19% to 20%), of the eye anxiety (15%), falling (15%) • Worsening of mood, cognition, rigidity, and functional capacity in GI: Nausea (13%) patients with HD Resp: Upper respiratory tract infection (11%)

Additional warnings for tetrabenazine 1% to 10%: • Esophageal dysmotility/aspiration CNS: Drug-induced Parkinson's disease (3% to 10%), • Orthostatic hypotension equilibrium disturbance (9%), irritability (9%), abnormal gait (4%), dizziness (4%), dysarthria (4%), headache (4%), obsessive

Tetrabenazine rumination (4%) GI: Dysphagia (4% to 10%), vomiting (6%), decreased appetite (4%), diarrhea (2%) GU: Dysuria (4%) Hema&onco: Bruise (6%) NMS: Bradykinesia (9%) Resp: Bronchitis (4%), dyspnea (4%) Miscellaneous: Laceration (6%, head) No black box warnings >10%: Other warnings: CNS: Drowsiness (≤11%), fatigue (≤11%), sedation (≤11%) • Somnolence 1% to 10%: • QT prolongation CNS: Abnormal gait (≤4%), dizziness (≤4%), equilibrium

• Use with caution in patients with disturbance (≤4%), falling (≤4%), akathisia (≤3%), restlessness moderate/severe hepatic (≤3%), anxiety (≥1% to <2%), drooling (≥1% to <2%), impairment extrapyramidal reaction (≥1% to <2%), insomnia (≥1% to <2%)

Valbenazine • Use not recommended in patients Endo&meta: Increased serum glucose (≥1% to <2%), weight with severe renal impairment gain (≥1% to <2%) • CYP2D6 poor metabolizers GI: Vomiting (3%) NMS: Arthralgia (2%), dyskinesia (≥1% to <2%) Resp: Respiratory tract infection (≥1% to <2%) Abbreviations: CNS, central nervous system; CV, cardiovascular; Derma, dermatologic; endo&meta: endocrine & metabolic; GI, gastrointestinal; GU, genitourinary; HD, Huntington’s disease; hema&onco; hematologic & oncologic; NMS, neuromuscular & skeletal; Ophth, Ophthalmic; Resp, respiratory

Systematic Review Evidence

Appendixes C and D contain information from relevant systematic reviews identified in the Cochrane Library and Ovid Medline.

1. Huntington’s Disease A Cochrane review, published before deutretrabenazine was approved, reported that tetrabenazine was the only agent efficacious for the treatment of chorea associated with HD based on good quality evidence.57 Additional relevant systematic reviews assessing tetrabenazine or deutetrabenazine for Huntington´s disease were not identified.

2. Tardive Dyskinesia A Cochrane review published in 2018 evaluated the effect of withdrawing or reducing the dose of antipsychotics in the treatment of TD.58 Conclusions indicated that there is limited and poor quality evidence to support or refute the use of these strategies in the treatment of TD.58

A 2018 systematic review (SR) by Bhidayasiri et al was designed to update the 2013 AAN guideline for the treatment of TS.28 Five main research questions, originally proposed in the 2013 AAN guideline, were addressed in the 2018 SR28: 1. “Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2. Does switching from typical to atypical DRBAs reduce TS symptoms? 3. What is the efficacy of pharmacologic agents in treating TS? 4. Do patients with TS benefit from chemodenervation with botulinum toxin? 5. Do patients with TS benefit from surgical therapy?”28

Evidence-based recommendations stated that deutetrabenazine and valbenazine are “established as effective treatments” for TD and must be suggested as first-line agents (Level A or strong recommendation based on high quality evidence).28 Clonazepam and Ginkgo biloba were classified as “probably effective” and should be considered as a therapeutic option for TD (Level B or moderately strong recommendation based on moderate quality evidence).28 Tetrabenazine was classified as “possibly effective” and might be considered for the treatment of TD (Level C or weak recommendation based on low quality evidence).28 Other therapies may be considered including combinations with amantadine if TS symptoms are still problematic or globus pallidus interna deep brain stimulation (GPi DBS) for patients with refractory TD (Level C or weak recommendation).28

Additional information concerning the strength of evidence and recommendations in response to the aforementioned 5 questions are outlined in Table 7. Information was extracted from the 2018 SR mentioned above (Bhidayasiri, 2018)28 and the 2017 AAN Clinical Practice Guideline Process Manual.19 Agents related to question 2 and 3 are listed based on the strength of evidence (from Level A - strongest recommendation to Level U - evidence is insufficient to support or refute the efficacy of drugs in the treatment of TS).28

Table 7. Strength of Recommendations for Agents in Treating Tardive Syndromes19,28 b Agent Evidence Summarya Strength of Recommendation 1. Is withdrawal of DRBAs an effective TS treatment? Neuroleptic withdrawal or switching No studies Level U (insufficient evidence) 2. Does switching from typical to atypical DRBAs reduce TS symptoms? Risperidone 2 Class II and 1 Class III studies Level B (probably effective) Olanzapine 2 Class III studies Level C (possibly effective) Clozapine No studies Level U (insufficient evidence) Quetiapine No studies Level U (insufficient evidence) 3. What is the efficacy of pharmacologic agents in treating TS? Deutetrabenazine 2 Class I studies Level A (established efficacy) Valbenazine 2 Class I studies Level A (established efficacy) Clonazepam 1 Class I study Level B (probably effective) Ginkgo biloba 1 Class I study in patients Level B (probably effective) hospitalized with schizophrenia Amantadine with neuroleptics 1 Class II and 2 Class III (short- Level C (possibly effective) term) studies Haloperidol 2 Class II and 4 Class III studies Level C (possibly effective) Tetrabenazine 2 Class III and 1 Class IV studies Level C (TD) (possibly effective) Acetazolamide and thiamine, alpha- Insufficient evidence Level U (insufficient evidence) methyldopa, baclofen, biperiden discontinuation, bromocriptine, buspirone, fluperlapine, levetiracetam, melatonin, piracetam, reserpine, selegiline, vitamin B6, vitamin E, Yi-gan san, zonisamide, combined treatment 4. Do patients with TS benefit from chemodenervation with botulinum toxin? Botulinum toxin No studies Level U (insufficient evidence) 5. Do patients with TS benefit from surgical therapy? Bilateral GPi DBS 1 Class II study Level C (possibly effective) Abbreviations: AAN, American Academy of Neurology; DRBA, dopamine receptor blocking agent; GPi DBS, globus pallidus interna deep brain stimulation; RCT, randomized controlled trial; TD, tardive dyskinesia; TS, tardive syndrome a Study Classification according to the 2017 AAN’s Clinical Practice Guideline Process Manual19 (Criteria for rating therapeutic studies): • Class I: RCT in a representative population, triple-masked studies, other additional Class I criteria • Class II: eg, RCT that lacks one or two Class I criteria • Class III: eg, controlled studies, crossover trial missing specific criteria, etc. • Class IV: Studies not meeting Class I, II, or III criteria b Levels of recommendation according to the 2017 AAN’s Clinical Practice Guideline Process Manual19: • Level A (Strong recommendation): The agent is established as effective based on at least 2 consistent class I studies (strong evidence) and MUST be recommended • Level B (Moderately strong recommendation): The agent is probably effective based on at least 1 class I study or 2 consistent class II studies (moderate evidence) and SHOULD be recommended • Level C (Weak recommendation): The agent is possibly effective based on at least 1 class II study and 2 consistent class III studies (weak evidence) and MAY be recommended • Level U (Insufficient evidence): Evidence is insufficient to support or refute the efficacy of drugs in the treatment of TS

Bhidayasiri et al provided a practical treatment algorithm for the treatment of TD (see Table 8) based on the evidence currently available.28

Table 8. Clinical Practice Algorithm for the Management of Tardive Dyskinesia19,28

STEP 1: Check if 1) antipsychotic therapy is indicated* and if a Evaluation of TD 2) troublesome TD symptoms are present**

If 1 AND 2 assessments of step 1 are confirmed, use the minimum STEP 2: effective dose of antipsychotics (there is limited evidence Dosage assessment available regarding withdrawing or switching antipsychotics)

TD persists

Suppressive oral agents should be considered if TD persists***: - First-line agents (level A): VAL or DEU. TBZ should be STEP 3: Need for considered if VAL or DEU are not available (level C) suppressive agent? - Second-line agents (level B): Clonazepam or Gingko biloba - Third-line agents: TBZ or amantadine (level C) may be considered in combination with the above agents

* If antipsychotic therapy is not indicated: review by specialist for potential alternatives and assess the patient ** If mild TD (non-troublesome symptoms) is present, use the minimal effective dose of antipsychotics and observe/assess the patient (administration of suppressive agents is not recommended) *** If TD persists with suppressive oral agents, GPi DBS may be considered (Leve C) Abbreviations: DEU, deutetrabenazine; GPi DBS, globus pallidus interna deep brain stimulation; TBZ, tetrabenazine; TD, tardive dyskinesia; VAL, valbenazine a Symptoms that impair a patient’s activities of daily living or the quality of life Note: See AAN levels of recommendation and study classification in Table 1 and 7

Expert Opinion Evidence

Experts from UpToDate include the following treatment recommendations for patients with TD36:

- Immediate discontinuation or dose reduction of the DRBAs causing TD (eg, antipsychotics and metoclopramide) is recommended, if feasible. However, limited evidence regarding these strategies is available. In the case of antipsychotic withdrawal or dose reduction, worsening of the underlying psychotic disease is possible. - In patients with TD and psychosis, atypical antipsychotics (clozapine is preferred, followed by low- dose quetiapine) are recommended over typical antipsychotics. - In patients with “disturbing and intrusive TD”, treatment with valbenazine or tetrabenazine is suggested. - In patients with mild and not disturbing TD, treatment for TD may not be required. Clinical Trial Evidence

Appendix E outlines the efficacy results from placebo-controlled trials evaluating VMAT-2 inhibitor agents.

1. Huntington’s Disease Placebo-controlled Trials

Tetrabenazine and deutetrabenazine were FDA approved based on 12-week, phase III, placebo- controlled trials (TETRA-HD32 study with tetrabenazine and FIRST-HD59 study with deutetrabenazine) for the management of chorea associated with HD.59,60 Both trials included patients diagnosed with HD as confirmed by family history, neurologic exam (eg, presence of chorea movements), and genetic testing (≥36 CAG repeats in the HD gene59,60).4,5

- Tetrabenazine

Tetrabenazine was approved in 2008 as the first drug with a positive effect on the chorea movements associated with HD. TETRA-HD study included patients between 25 and 77 years of age and the primary efficacy endpoint was the mean change from baseline to week 9-12 in the total maximal chorea (TMC) score of the Unified Huntington’s Disease Rating Scale (UHDRS). Total maximal chorea score is the sum of scores for 7 body regions and ranges from 0 (no chorea) to 28 (maximal chorea).16 Results showed a 5-point reduction from baseline in chorea severity with tetrabenazine compared to 1.5-point reduction with placebo; the treatment effect difference of -3.5 reached statistical significance.60 The secondary endpoint (ie, physician-rated Clinical Global Impression) showed statistically significance in favor of tetrabenazine.5

- Deutetrabenazine

Deutetrabenazine was approved in 2017 mainly based on a 12-week, phase III, placebo-controlled RCT (FIRST-HD) in patients with HD (23-74 years of age).4 The primary endpoint was the same as in the tetrabenazine phase III study. Results showed a chorea severity reduction of 4.4 units with deutetrabenazine compared to 1.9 units with placebo; the treatment effect difference of -2.5 reached statistical significance.4,59 After deutetrabenazine discontinuation at week 13, the TMC score returned to baseline.4 Three of the 4 secondary endpoints (Patient Global Impression of Change, Clinical Global

Impression of Change, and SF-36 survey for physical functioning) showed a statistically significance difference in favor of deutetrabenazine.59

Head-to-head Studies

No head-to-head efficacy or safety comparisons between tetrabenazine and deutetrabenazine are currently available in HD population. No other drugs are currently FDA approved for the treatment of chorea in patients with Huntington’s disease.

2. Tardive Dyskinesia Placebo-controlled Trials

Deutetrabenazine and valbenazine have been recently approved by the FDA for the treatment of tardive dyskinesia based on randomized, double-blind, placebo-controlled trials.61

- Deutetrabenazine

The efficacy and safety of deutetrabenazine are supported by two 12-week phase II/III RCTs (ARM-TD62 and AIM-TD trials61) in adult patients with moderate to severe TD and schizophrenia, schizoaffective disorder, or mood disorder.4 To enter in these trials, patients were required to meet the following criteria37:

• Age: 18 to 80 years • A history of using a DRBA for at least 3 months or at least 1 month in elderly patients ≥ 60 years37 • A “clinical diagnosis of TD with symptoms for at least 3 months prior to screening”37 • “Patient’s TD symptoms had to be bothersome to the patient or cause functional impairment”37 • Moderate to severe symptoms based on item 8 (“severity of abnormal movements overall”) of the AIMS37 • A total motor AIMS score ≥6 based on items 1-7 of the AIMS37 • “Psychiatrically stable with no change in psychoactive medications for ≥30 days before screening (45 days for antidepressants)”37 • “Patients on long-acting (depot) medications were required to be on stable therapy (dose, frequency) for ≥3 months before screening”37

Regarding baseline characteristics, patients included in the 2 pivotal trials had a mean total motor AIMS score at baseline ranging from 9.4 to 10.7.34 With respect to concomitant medication allowed in the 2 RCTs, approximately 64% of patients were taking atypical antipsychotics, 12% were taking typical or combination antipsychotics, and 24% were not taking antipsychotics.4 Patients receiving other agents such as tetrabenazine, reserpine, metoclopramide, promethazine, and stimulants 30 days prior to screening were excluded.34

The primary efficacy endpoint was the change in total motor AIMS score from baseline to week 12. AIMS includes 12 items to evaluate the severity of TD symptoms. Items 1 to 7 of the AIMS, which are associated with involuntary movements in the orofacial region, trunk, and extremities, were assessed in clinical trials.34 Scores for each item were assessed by blinded central video rating and ranged from 0 (no dyskinesia) to 4 (severe dyskinesia).34 Maximum total score is 28 (maximal severity of TD). The key

secondary endpoint was the percentage of patients achieving treatment success (defined as “Much Improved or Very Much Improved”34) at week 12, based on the Clinical Global Impression of Change (CGIC) scale for TD symptoms.34 CGIC is a scale ranging from “very much improved” to “very much worse” and is used by the investigator to evaluate the potential benefits of treatment at week 12 compared to baseline.34

Efficacy and safety results from relevant studies are summarized as follows:

• ARM-TD trial was a flexible-dose trial comparing deutetrabenazine (12-48 mg/day; average dose: 38.3 mg/day) with placebo.4 The mean change in total motor AIMS score from baseline to week 12 (primary endpoint) was significantly reduced with deutetrabenazine (-3.0 units) compared to placebo (-1.6 units).34 The secondary endpoint of CGIC did not meet statistical significance (p=0.40) and additional endpoints were considered exploratory according to the hierarchy of the statistical analysis plan.37 • AIM-TD trial was a fixed-dose trial evaluating 3 different target doses of deutetrabenazine (12 mg, 24 mg, or 36 mg per day) versus placebo. The primary efficacy endpoint (ie, the change in total motor AIMS score from baseline to week 12 in the 36 mg/day treatment group34,37) showed a significant improvement in TD severity with deutrabenazine 36 mg/day (-3.3 units) compared to placebo (-1.4 units). The AIMS result for deutetrabenazine 24 mg/day compared to placebo was also statistically significant; however, this result was considered exploratory according to the hierarchical statistical method specified.34 Regarding the secondary endpoint of CGIC, a higher percentage of patients receiving deutetrabenazine 36 mg/day (44%) achieved treatment success at week 12 compared to placebo (26%). These results were clinically meaningful but not statistically significant.34 The remaining efficacy endpoints were considered exploratory due to the hierarchical statistical method implemented.34

• A long-term, ongoing extension study provided results up to 54 weeks. Results of total motor AIMS scores in patients treated with deutetrabenazine indicated no loss of efficacy over time and a 5-point reduction from baseline to week 54.34,37

• In summary, deutetrabenazine at doses of 24 mg/day or greater were efficacious and well- tolerated for the management of moderate to severe TD.34,37,63 A recommended maintenance dose is not specifically stated in the labeling. Starting dose is 12 mg/day. Up-titration should be performed based on efficacy and tolerability.4

- Valbenazine

The efficacy and safety of valbenazine are supported by a 6-week phase II RCT (KINECT 264) and a 6-week phase III RCT (KINECT 365) in adult patients with moderate to severe TD and stable schizophrenia, schizoaffective disorder, or mood disorder.6 To enter in these trials, patients were required to meet the following criteria, among others54:

• Age: 18-85 years • “Meet clinical diagnoses of schizophrenia, schizoaffective disorder, mood disorder, and neuroleptic-induced TD for at least 3 months prior to screening, with TD assessed as moderate or severe by AIMS Item 8”54

• Maintenance medication for underlying disorders should be stable for ≥30 days before screening54 • Stable psychiatric status54

Regarding baseline characteristics, patients included in the 2 pivotal trials had a mean total motor AIMS score at baseline ranging from 8 to 10.4. With respect to concomitant medication allowed in the 2 RCTs, approximately 70% of patients were taking atypical antipsychotics, 14% were taking typical or combination antipsychotics, and 16% were not taking antipsychotics.6 Patients receiving other agents such as tetrabenazine, reserpine, metoclopramide, promethazine, and stimulants 30 days prior to screening were excluded.54

The primary efficacy endpoint was the change in AIMS total motor score from baseline to week 6 using items 1-7 of AIMS.54 The key secondary endpoint was the CGIC.54

Efficacy and safety results from relevant studies are summarized as follows:

• Both KINECT 2 and KINECT 3 studies reported substantial improvements in the AIMS total motor score from baseline to week 6 (primary efficacy endpoint) with valbenazine treatment compared to placebo.

o KINECT 2 study showed a significant reduction in total motor AIMS score with valbenazine 25-75 mg/day (-2.6 units) compared to placebo (-0.2 units).54

o KINECT 3 study showed a greater reduction in total motor AIMS score with valbenazine 40 mg or 80 mg compared to placebo.54 The result was statistically significant for valbenazine 80 mg/day (-3.2 units) compared to placebo (-0.1 units); however, the result for valbenazine 40 mg/day (- 1.9 units) compared to placebo (-0.1 units) was nominally significant but not statistically significant according to the hierarchical statistical method specified.54 Results for the key secondary endpoint of CGI-TD were numerically higher with valbenazine 40 mg or 80 mg/day compared to placebo; however, they were not statistically significant.54 In summary, as valbenazine 80 mg showed a significant improvement in the AIMS score over valbenazine 40 mg, the 80 mg dose was suggested to be considered the target dose for the majority of patients.54

• KINECT 3 extension study was an open-label study from week 6 of KINECT 3 study to week 48, in which all patients received valbenazine 40 mg or 80 mg. Long-term results indicated a progressive reduction in TD symptoms (measured by AIMS change from baseline) up to week 48. Following valbenazine withdrawal (after week 48), AIMS score returned to baseline.54

Table 9 includes the primary endpoint results from placebo-controlled trials evaluating deutetrabenazine and valbenazine.

Table 9. Results from Placebo-Controlled Trials Including Deutetrabenazine or Valbenazine for Tardive Dyskinesia Primary Efficacy Endpoint Least Square Mean Change from Study Treatment Group Treatment Effect Difference Baseline in the AIMS Total Score vs. Placebo (95% CI) to treatment endpoint Deutetrabenazine Deu 36 mg -3.3 -1.9 (-3.09, -0.79) Deu 24 mg -3.2 -1.8 (-3.00, -0.63) Study 1 (AIM-TD) Deu 12 mg -2.1 -0.7 (-1.84, 0.42) Placebo -1.4 Study 2 (ARM- Deu (12 to 48 mg/day) -3.0 -1.4 (-2.6, -0.2) TD) Placebo -1.6 Valbenazine Val 25-75 mg -2.6 -2.4 (p = 0.001) KINECT 2 Placebo -0.2 Val 40 mg -1.9 -1.8 (-3.0, -0.7) KINECT 3 Val 80 mg -3.2 -3.1 (-4.2, -2.0) Placebo -0.1 Abbreviations: AIMS, Abnormal Involuntary Movement Scale; Deu, deutetrabenazine; CI, confidence interval; Val, valbenazine

Head-to-head studies

No direct evidence comparing deutetrabenazine versus valbenazine was identified; thus, there is insufficient evidence available to establish efficacy and safety differences between these agents regarding improvements in TD severity.

Utah Medicaid Utilization Data The utilization data for the 3 VMAT-2 inhibitors for the last 3 years (January 2016 to November 2018) is presented as follows:

A. Total pharmacy claims and accountable care organization (ACO) patients from January 2016 to November 2018

Table 10. Total ACO Pharmacy Data for VMAT-2 Inhibitors (2016-2018) 2016 2017 2018 Total Claims Patients Claims Patients Claims Patients Claims Patients Deutetrabenazine 0 0 0 0 8 <5 8 <5 Tetrabenazine 26 <5 21 5 12 <5 59 8 Valbenazine Tosylate 0 0 2 <5 6 <5 8 <5 Total 9 Abbreviations: ACO, accountable care organization; VMAT-2, vesicular monoamine transporter-2

B. Total pharmacy claims and fee-for-service (FSS) patients from January 2016 to November 2018

Table 11. Total FFS Pharmacy Data for VMAT-2 Inhibitors (2016-2018) 2016 2017 2018 Total Claims Patients Claims Patients Claims Patients Claims Patients Deutetrabenazine 0 0 0 0 <5 <5 <5 <5 Tetrabenazine 9 <5 <5 <5 21 4 33 6 Valbenazine Tosylate 0 0 6 <5 10 <5 16 <5 Total 8 Abbreviations: FFS, fee-for-service; VMAT-2, vesicular monoamine transporter-2

C. Age distribution for whom there were claims for a VMAT-2 inhibitor (only FFS patients)

The majority of FFS patients receiving VMAT-2 inhibitors were between 18 and 64 years old. There were less than 5 FFS pediatric patients.

D. Patients with diagnosis codes submitted for HD and TD

Among the 8 FFS patients that received a VMAT-2 inhibitor, less than 5 patients receiving tetrabenazine had diagnosis codes submitted for HD and less than 5 patients receiving either deutetrabenazine, valbenazine, or tetrabenazine had diagnosis codes submitted for TD (see appendix B for detailed information regarding diagnosis codes). Less than 5 patients receiving tetrabenazine had diagnosis codes submitted different from the diagnosis codes included in Appendix B.

Table 12. Total FFS Patients with Diagnosis Codes Submitted for HD and TD (2016-2018) Patients with Patients with diagnosis Patients with diagnosis codes diagnosis codes Agent codes submitted for HD submitted for TD submitted not (3334 or G10) (33385 or G2401) included in Appendix B Deutetrabenazine 0 <5 0 Tetrabenazine <5 <5 <5 Valbenazine Tosylate 0 <5 0 Abbreviations: FFS, fee-for-service; HD, Huntington’s disease; TD, tardive dyskinesia

Discussion Topics and Potential Prior Authorization Criteria for VMAT-2 Inhibitors

Indication

• Tetrabenazine or deutetrabenazine are prescribed for the FDA-approved indication of “treatment of chorea associated with Huntington’s disease”

o Documentation for diagnosis of Huntington’s disease

o If age limits are included, consider limiting to patients 18 years old or older because product labeling states that efficacy and safety have not been established in the pediatric population. In addition, the phase III trial evaluated for tetrabenazine approval included only patients from 25 to 77 years old

• Deutetrabenazine and valbenazine are prescribed for the FDA-approved indication of tardive dyskinesia. These agents should not be employed for the prophylaxis of TD

For prescribers seeking eligibility to treat this disorder, we recommend that the patient meets the following criteria:

o Patient is 18 years old or older

o Patient is diagnosed with tardive dyskinesia that is bothersome or causing functional deficiency

Additional considerations:

o The 2013 AAN guideline states that tardive syndromes should fulfill the following 3 criteria24:

. A “history of at least 3 months’ total cumulative neuroleptic exposure during which the exposure can be continuous or discontinuous”

. “Presence of at least “moderate” abnormal involuntary movements in one or more body areas or at least “mild” movements in 2 or more body areas.”

. “Absence of other conditions that might produce abnormal involuntary movements”24

o DSM-5 defines TD as follows: . Involuntary athetoid or choreiform movements induced by the use of a DRBA for at least a few months (or shorter in elderly patients)

o Clinical trials only included patients with moderate to severe TD (AIMS item 8 ≥ 3) and schizophrenia, schizoaffective disorder, or mood disorder. Most patients (≥ 75%) were receiving antipsychotics at study entry. Patients receiving other agents such as metoclopramide, promethazine, tetrabenazine, reserpine, and stimulants 30 days prior to screening were excluded

o Discontinuation of DRBAs, dosage reduction, or switching to agents with less potential to induce TD symptoms (eg, switching from typical to atypical antipsychotics) may be alternative strategies to treat TD before prescribing deutetrabenazine or valbenazine; however, these strategies are not well-supported according to several systematic reviews and clinical guidelines

o Tetrabenazine has some evidence supporting off-label use for rare disorders such as dystonia, tics, Tourette syndrome, and tardive dyskinesia

Dosing

• Dosing should be in accordance with the FDA approved labeling:

o If a patient requires tetrabenazine at doses ≥ 50 mg daily, genetic testing to evaluate the patient’s CYP2D6 metabolizer status should be performed before prescribing the medication. For CYP2D6 poor metabolizers, the maximum recommended dose of tetrabenazine is 50 mg daily

o Labeling for deutetrabenazine or valbenazine does not require genotyping for CYP2D6; however, for CYP2D6 poor metabolizers the maximum recommended dose for deutetrabenazine is 36 mg daily (18 mg twice daily) and dose reductions are specified with valbenazine

o In patients with moderate or severe hepatic impairment, a valbenazine dosage of 40 mg once daily is recommended

Educational Notes • May consider safety concerns and drug-drug interaction limitations:

o Depression and suicidality in patients with HD: Patients eligible for receiving tetrabenazine or deutetrabenazine should not have thoughts of suicide or untreated or uncontrolled depression. Tetrabenazine and deutetrabenazine may increase the risk of depression and suicidal thoughts and behaviors, and are contraindicated in patients with HD who have thoughts of suicide or those who have untreated or uncontrolled depression (black box warning)

o QTc prolongation: . Patients eligible for receiving VMAT-2 inhibitors should not have congenital long QT syndrome or a history of cardiac arrhythmias . VMAT-2 inhibitors may cause QT prolongation, which may be clinically relevant in some cases (eg, patients who are CYP2D6 poor metabolizers, take strong CYP2D6 inhibitors, or take other drugs that prolong QT interval)

o The use of tetrabenazine or deutetrabenazine is contraindicated in patients with any type of hepatic impairment

o The use of tetrabenazine or deutetrabenazine in combination with MAOI, reserpine, and other VMAT-2 inhibitors should be avoided

o The use of valbenazine in combination with MAOI and strong CYP3A4 inducers should be avoided

o Maximum doses are specified for patients taking tetrabenazine or deutetrabenazine with strong CYP2D6 inhibitors

o Dose reductions may be necessary for patients taking valbenazine with strong inhibitors of CYP2D6 or CYP3A4

Re-authorization Criteria Re-authorization approval may be established based on symptom improvement. If the AIMS is suggested as the assessment tool to evaluate improvements in TD symptoms, the following limitations should be considered:

o There is not a standard definition for a clinically meaningful AIMS score reduction. The FDA clinical review for valbenazine highlights that “there are no accepted criteria as to what represents a clinically meaningful change in AIMS score”54

o The FDA clinical review for deutetrabenazine suggested that at least a 1 to 2 point reduction from baseline in AIMS total motor score (items 1-7) may be clinically significant.34 The valbenazine FDA clinical review stated that “it seems reasonable that a 3 to 4 decrease in the AIMS total dyskinesia score would represent a clinically meaningful change in TD symptoms54

o In the clinical trials, treatment with either valbenazine or deutetrabenazine reduced the AIMS total motor score from baseline by 1.9 to 3.3 points depending on the dose34,54

o The Tardive Dyskinesia Assessment Working Group reported in an article elaborated by Kane et al (2018) that “no minimal clinically important difference (MCID) for the AIMS has been established for TD.”31 Results from a pooled analysis of placebo-controlled trials with valbenazine suggested that a 2 or 3 point reduction in the total motor AIMS score may be considered as the MCID. However, the Working Group considers that further analyses are required.31

Summary

Huntington’s Disease

Huntington’s disease is a progressive genetic disorder characterized by motor, cognitive and behavioral dysfunction. It affects approximately 30,000 people in the US.

Tetrabenazine and deutetrabenazine are the only drugs approved by the FDA for the treatment of chorea associated with HD. Both agents have demonstrated significant improvements in chorea control after 12 weeks of treatment in clinical trials including patients with HD. Some important adverse events reported with both agents in patients with HD include an increased risk of depression and suicidality (black box warning). Deutetrabenazine shows pharmacologic advantages compared to tetrabenazine, including increased resistance to metabolism, a longer half-life, and a reduced dosing frequency.

The 2012 AAN guideline on chorea management in Huntington’s disease recommends the use of tetrabenazine, amantadine, or riluzole as “likely effective” agents for the treatment of choreic movements (Level B or moderately strong recommendation). Recommendations for deuterabenazine are not yet incorporated into clinical guidelines.

The Utah Medicaid utilization data for the FFS population documented less than 5 patients receiving tetrabenazine and no patients receiving deutetrabenazine with diagnosis codes submitted for HD. To encourage appropriate prescribing of VMAT-2 inhibitors for the treatment of chorea associated with HD, prior authorization criteria may include FDA-approved indication and dosage, confirmation of diagnosis for HD, contraindications, and warnings.

Tardive Dyskinesia

Tardive dyskinesia is a chronic and serious condition that may affect patients with or without psychiatric disorders. It typically occurs after prolonged use of DRBAs and is rarely reversible after DRBA withdrawal. TD is most commonly diagnosed in patients with mental illnesses (eg, schizophrenia and bipolar disorder) receiving typical or atypical antipsychotics. Evidence suggests that up to 30% of patients treated with antipsychotics and approximately 1% of patients taking metoclopramide may develop tardive dyskinesia. The incidence of TD in patients taking other DRBAs is uncertain and not well- defined.

In clinical practice, withdrawing, reducing the dose, or switching the offending DRBA to another medication with less potential to induce TD is often not feasible due to the underlying medical condition(s). In addition, these strategies may worsen TD symptoms or cause a recurrence of the underlying health problem(s). Thus, suppressive agents to manage TD symptoms are indicated.

Deutetrabenazine at doses of 24 to 36 mg/day and valbenazine at doses of 40 to 80 mg/day have demonstrated efficacy in reducing involuntary movements in the orofacial region, trunk, and extremities, as measured by the AIMS. No concerns arose during clinical trials regarding a higher risk of depression or suicidality in patients with TD receiving deutetrabenazine or valbenazine and therefore, no black box warning in the TD population is included in the product labeling. Tetrabenazine can be used off-label for TD or other hyperkinetic rare diseases; however, it is not FDA-approved for such indications.

The 2013 AAN evidence-based guideline recommends tetrabenazine as possibly effective in decreasing TS symptoms and it may be considered as a therapeutic option for the treatment of TS (Level C or weak recommendation based on low quality evidence). Novel therapies (ie, deutetrabenazine and valbenazine) are not yet included in the 2013 AAN guideline. Regarding other strategies for the management of TS such as withdrawal of DRBAs or switching to agents with less potential to induce TD (eg, switching from typical to atypical antipsychotics), the 2013 AAN guideline states that there is insufficient evidence to support or refute the management of TS by implementing these interventions. The 2018 systematic review performed by Bhidayasiri et al suggests deutetrabenazine or valbenazine are effective therapeutic options for the treatment of TD based on high-quality evidence. Authors state that other agents such as clonazepam, ginkgo biloba, amantadine, and tetrabenazine are considered possibly or probably effective for the treatment of TD based on limited and lower-quality evidence. Insufficient evidence is available regarding the treatment of TD by withdrawing antipsychotics or switching from typical to atypical antipsychotics.

The Utah Medicaid utilization data for the FFS population documented fewer than 5 patients receiving a VMAT-2 inhibitor with diagnosis codes submitted for TD. To encourage appropriate prescribing of VMAT-2 inhibitors for the treatment of TD, prior authorization criteria may include FDA-approved indication and dosage, confirmation of TD diagnosis, contraindications, and warnings. Evidence from relevant systematic reviews suggests using the lowest effective antipsychotics dosage before administering suppressive agents. In addition, some experts recommend discontinuation of the offending DRBA or switching to other agents with less potential to induce TD; however, these strategies are not well-supported.

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Appendix A: Literature Search Strategies

Table 1. Cochrane Library Search Strategy Search Date: November, 13 2018 #1 (tetrabenazine OR deutetrabenazine OR valbenazine):ti,ab,kw (Word variations have been searched) 123 #2 MeSH descriptor: [Tetrabenazine] this term only 42 #3 ("tardive dyskinesia"):ti,ab,kw (Word variations have been searched) 582 #4 MeSH descriptor: [Tardive Dyskinesia] this term only 15 #5 ("tardive syndrome"):ti,ab,kw (Word variations have been searched) 4 #6 (huntington*):ti,ab,kw (Word variations have been searched) 544 #7 MeSH descriptor: [Huntington Disease] this term only 225 #8 #1 OR #2 123 #9 #3 OR #4 OR #5 OR #6 OR #7 1116 #10 #8 AND #9 93 (90 trials and 3 Cochrane reviews)

Table 2. Ovid Medline Literature Search Strategy for Systematic Reviews Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to November 15, 2018> Search Strategy: ------1 TETRABENAZINE/ (1166) 2 (valbenazin$ or deutetrabenazin$ or tetrabenazin$).ti,ab,kw,kf. (963) 3 (Vesicular Monoamine Transport$ adj2 (inhibitor? or blocker?)).ti,ab,kw,kf. (57) 4 Vesicular Monoamine Transport Proteins/ (1014) 5 huntington disease/ or dyskinesia, drug-induced/ or tardive dyskinesia/ (17879) 6 tardive dyskinesia$.ti,ab,kw,kf. (4209) 7 huntington disease.ti,ab,kw,kf. (2668) 8 (huntington? adj10 chorea$).ab,kw,kf. or (huntington? and (chorea$ or disease? or disorder? or syndrom$)).ti. (9162) 9 tardive syndrome$.ti,ab,kw,kf. (81) 10 ((VMAT or VMAT2 or VMAT-2) adj2 (inhibitor? or antagonist? or blocker?)).ti,ab,kw,kf. (122) 11 Meta-Analysis/ (94254) 12 (metaanaly$ or meta-analy$).ti,ab,kw,kf. (138654) 13 (cochrane$ or systematic review?).jw. (15985) 14 (systematic adj3 review).ti,ab,kw,kf. (126355) 15 (MEDLINE or systematic review).tw. or meta analysis.pt. (225046) 16 1 or 2 or 3 or 4 or 10 (2384) - Agents and drug class 17 5 or 6 or 7 or 8 or 9 (21271) - Indications 18 11 or 12 or 13 or 14 or 15 (272225) - Systematic review filter 19 16 and 17 and 18 (24) - Total number of systematic reviews a Search filter for “Reviews” (Maximizes specificity) in Ovid Medline from McMaster University (https://hiru.mcmaster.ca/hiru/hiru_hedges_medline_strategies.aspx)

Appendix B: Relevant Diagnosis Codes

Huntington’s disease

ICD-9 diagnosis codes ICD Diagnosis 3334 HUNTINGTON'S CHOREA

ICD-10 diagnosis codes ICD Diagnosis G10 HUNTINGTON'S DISEASE

Tardive Dyskinesia

ICD-9 diagnosis codes ICD Diagnosis 33385 SUBACUTE DYSKINESIA DUE TO DRUGS 33382 OROFACIAL DYSKINESIA 33389 FRAGM TORSION DYSTON NEC E9392 ADV EFF BUTYROPHEN TRANQ 7810 ABNORMAL INVOLUNTARY MOVEMENTS (SPASM) NEC

ICD-10 diagnosis codes ICD Diagnosis G2401 DRUG INDUCED SUBACUTE DYSKINESIA G244 IDIOPATHIC OROFACIAL DYSTONIA G248 OTHER DYSTONIA T434X5A ADVERSE EFFECT OF BUTYROPHEN/THIOTHIXEN NEUROLEPTI R258 OTHER ABNORMAL INVOLUNTARY MOVEMENTS

Appendix C: Key Findings in Cochrane Reviews and Other Systematic Reviews for Tardive Dyskinesia

Table 1. Systematic Reviews in the Management of Tardive Dyskinesia Reference Objective(s) Results and Recommendations - Included studies: 13 RCTs To determine whether a reduction - Key results: “Due to the poor quality, small size, and limited Bergman, 201858 or cessation of antipsychotic drugs data from the 13 studies, there is limited evidence. It is not (Cochrane is associated with a reduction in known if strategies such as dose reduction, ‘drug holidays’, Systematic TD for people with schizophrenia and stopping medication are helpful in the treatment of Review) (or other chronic mental illnesses) tardive dyskinesia. There is limited evidence on specific who have existing TD antipsychotic drugs in the treatment of tardive dyskinesia.” To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: - DEU and VAL MUST be recommended for the treatment of TD Bhidayasiri, 1. Is withdrawal of DRBAs an (Level A – established efficacy for TD based on 2 Class I 201828 effective TS treatment? studies for each agent)

2. Does switching from typical to - Clonazepam and Ginkgo biloba SHOULD be considered for TD - Literature atypical DRBAs reduce TS (Level B – probably effective) search from symptoms? - Amantadine and TBZ MIGHT be considered for TD (Level C – January 2012 3. What is the efficacy of possibly effective; based on low quality studies) to pharmacologic agents in - “There is insufficient evidence to support or refute TS September treating TS? treatment by withdrawing causative agents or switching from 2017 4. Do patients with TS benefit typical to atypical DRBA (Level U)” from chemodenervation with botulinum toxin? 5. Do patients with TS benefit from surgical therapy? - Included studies: 31 RCTs of 24 interventions. - 5 trials are awaiting classification (1 of DEU and 2 of VAL) and 7 trials are ongoing - Results: 19 studies including several interventions reported “no Soares-Weiser, To determine whether drugs, o clinically important improvement in TD symptoms” 201866 hormone-, dietary, or herb- 2 small studies reported moderate-quality evidence of a (Cochrane supplements not covered in other o significant benefit of VAL or Ginkgo biloba vs. PLA: Systematic Cochrane reviews on TD  VAL (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n =92) Review) treatments, surgical interventions,  extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 electroconvulsive therapy, and RCT, n =157) - Literature mind-body therapies were - The remaining studies showed low- to very low-quality search from effective and safe for people with evidence with inconclusive conclusions July 2015 to antipsychotic-induced - Conclusions: “This review has found that the use of April 2017 TD. valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results.”

Table 1. Systematic Reviews in the Management of Tardive Dyskinesia Reference Objective(s) Results and Recommendations El-Sayeh, 201832 To determine the effects several - Included studies: 18 studies (Cochrane drugs (Dopamine receptor - One small study comparing TBZ vs. haloperidol for TD reported Systematic agonists, dopamine receptor no differences on clinically important improvement in TD Review) antagonists, dopamine-depletor symptoms between groups

drugs, etc.) for antipsychotic- - No studies included VAL or DEU - Literature induced TD in people with - Conclusion: “The review provides little usable information for search from schizophrenia or other chronic service users or providers and more well-designed and well- July 2015 to mental illnesses reported studies are indicated.” April 2017 - Included studies: 11 studies o 3 studies with VAL: KINECT 2, KINECT 3, KINECT 3 extension study (“Valbenazine efficacy was demonstrated in rigorously Caroff, 201849 designed clinical trials that meet the guidelines for AAN To update the evidence for TD Class I evidence”) - Literature treatment, comparing two 8 studies with tetrabenazine: search from vesicular monoamine transporter o . 1 double-blind, crossover study (n=12) January 1980 2 (VMAT2) inhibitors, . 7 open-label studies (n=381) to March tetrabenazine and valbenazine . Result: TBZ was effective and well tolerated in TD 2017 (“Due to differences in study designs and a lack of standardized and controlled trials with tetrabenazine, a formal meta-analysis comparing the agents was not possible”) - Included studies: 112 RCTs (9 Cochrane reviews) and 8 prospective cohort studies Bergman, 201767 - 3 main questions: 1. Reducing antipsychotic dose (2 small trials) Health o Result: reducing antipsychotic dose has no clear effect on Technology TD symptoms, based on very low quality evidence Assessment of (Combined effect of 2 RCTs: RR 0.42, 95% CI 0.17 to 1.04) the of the 2. Switching antipsychotic drug National Result: 2 low-quality trials reported “TD symptoms To summarize the clinical o Institute for improved to a clinically important extent” when switching effectiveness and safety of Health Research from an antipsychotic drug to risperidone (1 trial) or to treatments for TD by updating quetiapine or haloperidol (1 trial) past Cochrane reviews with new - Literature 3. Adjunctive treatment in addition to antipsychotic drug: evidence and improved methods search up to o Very low quality evidence. No trials with DEU or VAL. “TBZ July 2015 (for has been suggested as a treatment for TD” Cochrane) - Conclusions: “Although it seems prudent to use the lowest and January effective dosage of antipsychotic drug possible (within the 2017 (for licensed range) for individual patients, there is no evidence Embase and that antipsychotic discontinuation will improve TD symptoms” Medline) - “Current treatments for TD are prescribed in the hope that they will have an impact on TD, but do not have a strong evidence base” Abbreviations: DEU, deutetrabenazine; DRBA, dopamine receptor blocking agents; CI, confidence interval; PLA, placebo; RCT, randomized controlled trial; RR, relative risk; TBZ, tetrabenazine; TD, tardive dyskinesia; TS, tardive syndromes; VAL, valbenazine

Appendix D: Key Findings in Cochrane Reviews for Huntington’s Disease

Table 1. Systematic Reviews in the Management of Huntington’s Disease Reference Objective(s) Results and Recommendations Mestre, 200957 (Cochrane - Included studies: 22 Systematic - Results: “Only tetrabenazine showed a Review) To evaluate the effectiveness of the clear efficacy for the control of chorea”

available interventions for the (TETRA-HD trial) - Literature symptomatic treatment of HD - Conclusion: “Tetrabenazine is the anti- search up choreic drug with the best quality data to available” December 2007 Abbreviations: HD, Huntington´s disease

Appendix E: Key Findings in Published Placebo-Controlled Trials

Study Group, double-blind, baseline to week 9-12 in UHDRS TMC scorea 200660 placebo N=84 patients (25 to controlled 77 years old, TMC Treatment effect difference: 3.5-unit reduction TETRA-HD, score ≥10, UHDRS total in UHDRS chorea score (-5.0±0.5 TBZ vs - HSG (2006) TBZ 100 mg/day functional capacity 1.5±0.7 PLA; p=0.0001). (Significant Tetrabenazine vs. pla score ≥ 5, family improvement in favor of TBZ) history)

Frank, Randomized, 12 weeks Primary efficacy endpoint: Change from 201659 double-blind, baseline to week 9-12 in UHDRS TMC score placebo N=90 (TMC score ≥8 FIRST-HD, controlled and UHDRS Treatment effect difference: 2.5-unit reduction HSG (2016) total functional in UHDRS chorea score (p<0.0001) (Significant DEU 6-48 mg/day capacity score ≥ 5) improvement in favor of DEU) Deutetrabenazine vs. PLA Tardive Dyskinesia Fernandez, Randomized, 12 weeks Primary efficacy endpoint: Change in AIMSb 201762 double-blind, score (items 1–7) from baseline to week 12: placebo- N= 113 patients (18 to Study 2 controlled, multi- 75 years old) with LS mean AIMS score: (ARM-TD center trial history of using a DRBA • -3.0 units for DEU vs. -1.6 for PLA study) (Phase II/III trial) for ≥ 3 months; clinical Treatment difference: -1.4 units (95% diagnosis of TD and has CI: -2.6, -0.2) (Significant improvement in DEU 12- had symptoms for ≥ favor of DEU) 48 mg/day vs. 3 months prior to

PLA screening Anderson, Randomized, 12 weeks Primary efficacy endpoint: Change in AIMSb 201761 double-blind, score (items 1–7) from baseline to week 12 placebo- N=298 patients (18 to Study 1 controlled, multi- 75 years) with TD for ≥ LS mean AIMS score: (AIM-TD, center trial 3 months, use of DRBA • Deutetrabenazine -3.3 units for DEU 36 mg vs. -1.4 for PLA: 2017) (Phase III trial) for ≥ 3 months (or 1 Treatment difference: -1.9 unit reduction month in ≥60 years), (95% CI: -3.09, -0.79) (Significant 3 fixed-doses of AIMS score (items 1- improvement in favor of DEU) DEU were 7)≥6, stable underlying • -3.2 units for DEU 24 mg vs. -1.4 for PLA: assessed: 12, 24, psychiatric illness, no Treatment difference: -1.8 unit reduction and 36 mg/day change of psychiatric (95% CI:-3.00, -0.63) vs. PLA medication for ≥30 • -2.1 units for DEU 12 mg vs. -1.4 for PLA days or 45 days Treatment difference: -0.7-unit reduction (antidepressants) (95% CI:-1.84, 0.42)

O'Brien, Randomized, 6 weeks Primary efficacy endpoint: Change in the 201564 double-blind, AIMSb total score (items 1–7) from baseline to placebo- N= 100 adults with TD week 6: KINECT 2 controlled (Phase and stable • -0.2 placebo, -2.6 VAL (p = 0.001); mean II study) schizophrenia,

Valbenazine differences between VAL and PLA = -2.4 schizoaffective (Significant improvement in favor of VAL)

Table 1. Placebo-Controlled Trials with Vesicular Monoamine Transporter-2 Inhibitors Reference/ Study Design/ Study Duration/ Clinical Results for Primary Endpoint Intervention Participants Study VAL dose: 25- disorder, or mood Secondary endpoint: % of participants 75 mg/day vs. disorder achieving a rigorous AIMS response threshold PLA (≥50% total score improvement from baseline): 49 vs 18%; p < 0.05) Hauser, Randomized, 6 weeks Primary efficacy endpoint: Change in the 201765 double-blind, AIMSb total score (items 1–7) from baseline to placebo- N= 227 adults with TD week 6: KINECT 3 controlled and stable (2017) (Phase III trial) schizophrenia, • -0.1 placebo, -1.9 (VAL 40 mg/day; schizoaffective p=0.002), -3.2 (VAL 80 mg/day; p< 0.001); VAL 40 or disorder, or mood (Significant improvement in favor of VAL) 80 mg/day disorder compared to PLA Secondary endpoint: % of participants achieving a rigorous AIMS response threshold (≥50% total score improvement from baseline): 40% [80 mg/day] and 24% [40 mg/day] vs 9%; p < 0.05) Factor, Double-blind Up to 48 weeks plus 4- Primary efficacy endpoint: Change in the 201768 extension of week AIMSb total score (items 1–7) from baseline to KINECT 3 Washout week 48: (KINECT 3 extension VAL 40 or N=198 adults with TD • -4.8 VAL 80 mg, -3.0 VAL 40 mg study) 80 mg/day and stable (statistically significant improvements in compared to schizophrenia, favor of VAL relative to baseline in both baseline schizoaffective dose groups) disorder, or mood disorder Abbreviation: AIMS, Abnormal Involuntary Movement Scale; CI, confidence interval; DEU, deutetrabenzazine; LS, least square; PLA, placebo; TD, tardive dyskinesia; TBZ, tetrabenazine; TMC, total maximal chorea; UHDRS, Unified Huntington's Disease Rating Scale; VAL, valbenazine Notes: a UHDRS: Unified Huntington's Disease Rating Scale (comprehensive scale including 4 components that evaluate motor function, cognition, behavior, and functional abilities)16 b AIMS: Abnormal Involuntary Movement Scale. 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity)