Advances in the Management of Tardive Dyskinesia

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1 Advances in the Management of Tardive Dyskinesia Supported by an educational grant from Teva Pharmaceuticals. Rakesh Jain, MD, MPH Clinical Professor Department of Psychiatry Texas Tech Health Sciences Center School of Medicine Midland, Texas Joseph P. McEvoy, MD Professor of Psychiatry and Health Behavior Clark Case Chair in Psychotic Disorders Medical College of Georgia Augusta, Georgia Faculty Disclosure Dr. Jain: Paid Speaker Addrenex, Alkermes, Allergan (Actavis/Forest), Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Rhodes Pharmaceuticals, Shionogi, Shire, Sunovion, Takeda, Tris Pharmaceuticals; Advisory Board Addrenex, Alkermes, Forum, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shionogi, Shire, Sunovion, Takeda; Research AstraZeneca, Allergan (Actavis/Forest), Lilly, Lundbeck, Otsuka, Pfizer, Shire, Takeda; Spouse: Consultant Lilly, Otsuka, Pamlab. Dr. McEvoy: Advisory Board Teva, Neurocrine; Research Grant Teva, Alkermes, Avanir, Boehringer Ingelheim, Otsuka.

2 Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing offlabel or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). The off-label or investigational use of tetrabenazine, deutetrabenazine, and valbenazine for the treatment of tardive dyskinesia will be discussed. Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance. Learning Objectives Describe the pathophysiology of tardive dyskinesia (TD), including signs, symptoms, and risk factors associated with development Apply evidence-based scales to routine practice for the timely detection, monitoring, and assessment of TD signs and symptoms Outline clinical trial data on potential therapies for the management of TD, both available and emerging Utilize the latest evidence to make informed clinical decisions for the prevention and management of TD Definition of Tardive Dyskinesia A neurological disorder characterized by involuntary uncontrollable movements especially of the mouth, tongue, trunk, and limbs and occurring especially as a side effect of prolonged use of antipsychotic drugs (such as phenothiazine) Merriam-Webster. Accessed February 22, 2017.

3 Abnormal Involuntary Movement Scale (AIMS) Preliminaries Observe the patient unobtrusively at rest, eg, in the waiting room. The chair to be used in the examination should be a hard, firm one without arms. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: Abnormal Involuntary Movement Scale (AIMS) Preliminaries Ask the patient whether there is anything in his or her mouth (such as gum or candy) and, if so, to remove it. Ask about the current condition of the patient s teeth. Ask if he or she wears dentures. Ask whether teeth or dentures bother the patient now. Ask whether the patient notices any movements in his or her mouth, face, hands, or feet. If yes, ask the patient to describe them and to indicate to what extent they currently bother the patient or interfere with activities. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: Abnormal Involuntary Movement Scale (AIMS) Examination Procedure Have the patient sit in the chair, hands on knees, legs slightly apart, and feet flat on the floor. (Look at the entire body for movements while the patient is in this position.) Ask the patient to sit with hands hanging unsupported if male, between his legs; if female and wearing a dress, hanging over her knees. (Observe hands and other body areas.) Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:

4 Abnormal Involuntary Movement Scale (AIMS) Examination Procedure Ask the patient to open his or her mouth. (Observe the tongue at rest within the mouth.) Do this twice. Ask the patient to protrude his or her tongue. (Observe abnormalities of tongue movement.) Do this twice. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: Abnormal Involuntary Movement Scale (AIMS) Examination Procedure Ask the patient to tap his or her thumb with each finger as rapidly as possible for 10 to 15 seconds, first with right hand, then with left hand. (Observe facial and leg movements.) [± activated] Flex and extend the patient s left and right arms, one at a time. Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976: Abnormal Involuntary Movement Scale (AIMS) Examination Procedure Ask the patient to stand up. (Observe the patient in profile. Observe all body areas again, hips included.) Ask the patient to extend both arms out in front, palms down. (Observe trunk, legs, and mouth.) [activated] Have the patient walk a few paces, turn, and walk back to the chair. (Observe hands and gait.) Do this twice. [activated] Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised Rockville, MD: U.S. Dept. of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976:

5 The scale is rated from: 0 (none) 1 (minimal) 2 (mild) 3 (moderate) 4 (severe) Ratings AIMS Exam Instructional Video Schooler-Kane Criteria for Tardive Dyskinesia At least 3 months of cumulative exposure to neuroleptics Absence of other conditions that might cause involuntary movements At least moderate dyskinetic movements in 1 body area ( 3 on AIMS) or mild dyskinetic movements in 2 body areas ( 2 on AIMS) Schooler NR, et al. Arch Gen Psychiatry. 1982;39(4):

6 Risk Factors for Tardive Dyskinesia Coarse extrapyramidal side effects (eg, bradykinesiarigidity, akathisia) anticholinergic drugs are not protective! Use of first-generation antipsychotic medication, especially at doses that produce coarse extrapyramidal side effects Age O Brien A. Int J Geriatr Psychiatry. 2016;31(7): Carbon M, et al. J Clin Psychiatry. 2017;[Epub ahead of print]. Tardive Dyskinesia is Still Around! Second-generation antipsychotics produce lower risk but not zero risk Legacy cases are still around The use of antipsychotic medications has expanded into additional diagnoses (eg, adjunct in treatment-resistant depression, conduct disorder) Carbon M, et al. J Clin Psychiatry. 2017;[Epub ahead of print]. Mentzel TQ, et al. J Clin Psychopharmacol. 2017;[Epub ahead of print]. Why Does Tardive Dyskinesia Matter? Stigma Dysfunction Yassa R. Acta Psychiatr Scand. 1989;80(1):64-67.

7 Focus on Treatment Implications Overview Tetrabenazine FDA approved for treatment of chorea in Huntington s disease Tetrabenazine Clinical trials in Tardive Dyskinesia (offlabel) Valbenazine Clinical trials in Tardive Dyskinesia (Not FDA approved. Granted breakthrough status by FDA.) Deutetrabenazine Clinical trials in Tardive Dyskinesia (Not FDA approved. FDA granted priority review, with a target date for approval by August 30, 2017.) The Mechanism of Action Shared by Every TD Medication Role of VMAT2 Inhibitors DOPA = dihydroxyphenylalanine; DOPAC = dihydroxyphenylacetic acid; DDC = dihydroxyphenylalanine decarboxylase; MAO = monoamine oxidase; VMAT2 = vesicular monoamine transporter-2; TH = tyrosine hydroxylase; Tyr = tyrosine. Meyer AC, et al. J Neurochem. 2013;127(2):

8 Examining Tetrabenazine Tetrabenazine Approved in 2008 as an orphan drug for the treatment of choreiform movements associated with Huntington s disease Current treatment of choice for moderate-to-severe forms of TD Patients must be thoroughly screened for depression and suicidality, as the FDA has issued a black box warning against using tetrabenazine in patients with depression Reversible and specific inhibitor of VMAT2, a transporter that packages neurotransmitters (preferentially dopamine) into vesicles for release into the synapse Use is limited due to significant side effects, short half-life Cloud LJ, et al. Neurotherapeutics. 2014;11(1): Bernstein AI, et al. Neurochemistry Int. 2014;73: Leung JG, et al. Ann Pharmacother. 2011;45(4): Citrome L. Current Psychiatry. 2014;13(5):24. Tetrabenazine Treatment for TD 2 studies have shown that tetrabenazine reduces TD symptoms by 54% to 60% Long-term observational studies support the sustained efficacy of the drug over years and decades of treatment Studies at Baylor College of Medicine have shown that up to 95% of patients with TD have moderate to marked improvement in their symptoms Tetrabenazine has a level C recommendation in the 2013 American Academy of Neurology guidelines and should be considered in treating TD Vijayakumar D, et al. Drugs. 2016;76(7): Ondo WG, et al. Am J Psychiatry. 1999;156(8): Kazamatsuri H, et al. Am J Psychiatry. 1973;130(4): Chen JJ, et al. Clin Ther. 2012;34(7): Jankovic, et al. Neurology. 1988;38(3): Shen V, et al. Tremor Other Hyperkinet Mov. 2013;3. Waln O, et al. Tremor Other Hyperkinet Mov. 2013;3. Bhidayasiri R, et al.; American Academy of Neurology. Neurology. 2013;81(5):

9 Tetrabenazine Treatment for TD Assessment by Randomized Videotape Protocol Method: 20 patients with TD (mean duration = 43.7 months) were videotaped pre- and posttreatment Randomized videotapes were scored with the motor subset of the modified AIMS by raters blind to pre- or posttreatment status Results: 1 patient did not tolerate tetrabenazine owing to sedation 19 were rated after a mean of 20.3 weeks (SD = 10.4); mean tetrabenazine dose = 57.9 mg/day (SD = 22.8) Mean score on the AIMS motor subset improved 54.2% From 17.9 (SD = 4.4) to 8.2 (SD = 5.3) (two-tailed Wilcoxon signed rank, P <.001) Subjective scores improved 60.4% From a mean of 9.1 (SD = 1.5) to 3.6 (SD = 1.5) (two-tailed Wilcoxon signed rank, P <.001) 11 patients rated themselves as markedly improved, 6 as moderately improved, and 2 as mildly improved All 19 patients continued to take tetrabenazine after the study Conclusions: Tetrabenazine was well tolerated and resulted in significant improvements in AIMS scores for patients with refractory TD Ondo WG, et al. Am J Psychiatry. 1999;156(8): Valbenazine Valbenazine A novel, highly selective, VMAT2 inhibitor Orally active compound with 2 active metabolites: (+)α- DHTBZ and the oxidative metabolite of (+)α-dhtbz, all 3 have VMAT2 binding Designed to deliver the active metabolites in a controlled fashion Designed to limit off-target receptor binding Half-life of 20 hours allowing QD dosing Breakthrough therapy designation from the FDA for the treatment of TD DHTBZ = dihydrotetrabenazine. O Brien CF, et al. Mov Disord. 2015;30(12):

10 Valbenazine for TD: Participants Randomized (n = 102) Allocated to placebo (n = 51) Received placebo (n = 51) Allocation Allocated to valbenazine (n = 51) Received valbenazine (n = 51) Discontinued intervention (n = 5) - Adverse event (n = 2) - Noncompliance (n = 2) - Withdrawal of consent (n = 1) Follow-up Discontinued intervention (n = 5) - Noncompliance (n = 2) - Withdrawal of consent (n = 3) Analyzed (n = 44) Excluded from analysis (n = 7) - Did not have post-treatment AIMS (n = 7) mitt Analysis Analyzed (n = 45) Excluded from analysis (n = 6) - Did not have post-treatment AIMS (n = 6) Analyzed (n = 44) Excluded from analysis (n = 7) - Did not meet ITT analysis (n = 7) PP Analysis Analyzed (n = 32) Excluded from analysis (n = 19) - Did not meet ITT analysis (n = 6) - No quantifiable plasma concentration at Week 6 (n = 12) - Discontinued psychiatric meds, protocol deviation (n = 1) O Brien CF, et al. Mov Disord. 2015;30(12): Valbenazine for TD: Demographics and Baseline Characteristics Variable Statistic or Category O Brien CF, et al. Mov Disord. 2015;30(12): Placebo (n = 49) Valbenazine (n = 51) Age (y) Mean (SD) 55.6 (9.8) 56.7 (10.8) Age at TD diagnosis (y) Mean (SD) 49.5 (12.1) 48.9 (13.0) Gender (n [%]) Male 27 (55.1) 30 (58.8) AIMS at baseline Disease category (n [%]) Female 22 (44.9) 21 (41.2) Mean (SD) 7.9 (4.5) 8.0 (3.5) Schizophrenia or schizoaffective disorder 30 (61.2) 28 (54.9) Mood disorder 18 (36.7) 20 (39.2) Gastrointestinal disorder 1 (2.0) 3 (5.9) Valbenazine for TD: Results AIMS Change from Baseline at Week 6 (mitt) Placebo (n = 44) Valbenazine (n = 45) Mean (SD) -1.1 (3.7) -3.6 (3.5) Median LS mean (SEM) -0.2 (1.1) -2.6 (1.2) 95% CI (-2.4, 2.0) (-4.9, -0.3) LS mean difference (SEM) -2.4 (0.7) 95% CI (-3.7, -1.1) P Value O Brien CF, et al. Mov Disord. 2015;30(12):

11 Valbenazine for TD: Results Summary of CGI-TD and PGIC Scores and Response Rates by Treatment Group at Week 6 (mitt) Assessment Statistic CGI-TD = Clinical Global Impression of Change-TD scale; PGIC = Patient Global Impression of Change. O Brien CF, et al. Mov Disord. 2015;30(12): Placebo (n = 44) Valbenazine (n = 45) CGI-TD score Mean (SEM) 3.1 (0.1) 2.3 (0.1) LS mean (SEM) 3.1 (0.3) 2.2 (0.3) LS mean difference (SEM) -0.8 (0.2) 95% CI (-1.2, -0.5) P Value < CGI-TD response: N (%) 7 (15.9) 30 (66.7) Very much improved or Much Improved PGIC score Mean (SEM) 2.9 (0.1) 2.2 (0.1) LS mean (SEM) 3.3 (0.3) 2.6 (0.3) LS mean difference (SEM) -0.7 (0.2) 95% CI (-1.1, -0.3) P Value PGIC response: n (%) 14 (31.8) 26 (57.8) Very much improved or Much improved Valbenazine for TD: Side Effects Incidence of TEAEs Experienced by 2 Participants Adverse Event Placebo (n = 49) n (%) TEAE = treatment-emergent adverse event. O Brien CF, et al. Mov Disord. 2015;30(12): Valbenazine (n = 51) n (%) Fatigue 2 (4.1%) 5 (9.8%) Headache 2 (4.1%) 5 (9.8%) Decreased appetite 0 4 (7.8%) Nausea 2 (4.1%) 3 (5.9%) Somnolence 1 (2.0%) 3 (5.9%) Dry mouth 0 3 (5.9%) Vomiting 0 3 (5.9%) Constipation 3 (6.1%) 2 (3.9%) Urinary tract infection 3 (6.1%) 2 (3.9%) Sedation 1 (2.0%) 2 (3.9%) Back pain 0 2 (3.9%) Dizziness 2 (4.1%) 0 Valbenazine for TD: Study Conclusions Valbenazine 25 mg to 75 mg once daily for 6 weeks marked reduction in TD severity as assessed by AIMS and CGI-TD as well as supported by PGIC Improvement in dyskinesia (LS mean change from baseline of -2.6 points on valbenazine vs -0.2 points on placebo; mitt) reflect > 30% reduction in AIMS score The magnitude of effect is clinically meaningful > 50% reduction in AIMS and the corresponding CGI- TD scores of 2 or 1, reflect the categories of much improved or very much improved O Brien CF, et al. Mov Disord. 2015;30(12):

12 Valbenazine for TD Phase 3 Trial (KINECT 3, NCT ) 6-week, double-blind, placebo-controlled, parallel, fixed-dose study of valbenazine 40 mg and 80 mg Participants eligible to continue for an additional 42 weeks (participants on placebo re-randomized to 40 mg or 80 mg) 234 moderate to severe TD patients with schizophrenia, schizoaffective disorder, bipolar or major depressive disorder Study completion rate 89%, valbenazine 80 mg; 83%, valbenazine 40 mg; and 91%, placebo Primary efficacy endpoint change in AIMS from baseline at week 6 in the 80 mg once-daily dosing group compared to placebo as assessed by central blinded video raters Results: AIMS score (LS mean change from baseline to week 6, MMRM): valbenazine 80 mg, -3.2; placebo, -0.1; P <.0001; effect size, d =.90 Hauser RA, et al. Presented at: American Academy of Neurology Annual Meeting; April 15-21, 2016; Vancouver, BC, Canada. Marder SR, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Deutetrabenazine Deuterated Tetrabenazine Tetrabenazine Deutetrabenazine CH 3 O CD 3 O O CH 3 H N O CD 3 H N O O Deuterium (D) is a naturally-occurring, stable, non-radioactive isotope of hydrogen

13 Drug Deuteration: Possible Clinical Implications Longer duration of action Less frequency of dosing Less side effects Similar efficacy Drug Deuteration: Pharmacological Expressions 1. Safety/Efficacy 2. Tolerability/Efficacy 3. Bioavailability/Tolerability Deuterated Drug Drug Concentration Drug Concentration C MAX Metabolism C MAX Inhibit Formation Enhance Formation AUC AUC Toxic/Reactive Metabolite Active Metabolite Harbeson SL, et al. MEDCHEMNEWS. 2014;2: /12/MedChemNews-0514.pdf. Accessed February 24, Barratt MJ, et al (Eds). Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. Hoboken, NJ: John Wiley & Sons, Inc.; 2012:322. Deuterated Tetrabenazine Mean Plasma Concentrations Total alpha + beta (n = 24 25) Plasma Concentration (ng/ml) Time Post Dose (hours) Deutetrabenazine 15 mg, Fed Deutetrabenazine 15 mg, Fasted Tetrabenazine 25 mg, Fasted Stamler DA, et al. The pharmacokinetics of extended release SD-809, a deuterium-substituted analogue of tetrabenazine [abstract]. Movement Disorders. 2013;28 Suppl 1:765.

14 Deutetrabenazine for TD: ARM-TD (Aim to Reduce Movements in TD) Patient Disposition Patients screened N = 202 Patients randomized N = 117 Failed screening n = 85 Failed inclusion criteria n = 57 Failed exclusion criterial n = 23 Withdrew consent n = 2 Lost to follow-up n = 2 Adverse event n = 1 Withdrawals Withdrew consent n = 3 Adverse event n = 1 Lost to follow-up n = 1 Non-compliance n = 1 Deutetrabenazine n = 58 Placebo n = 59 Withdrawals Withdrew consent n = 2 Adverse event n = 2 Protocol violation n = 2 Lost to follow-up n = 1 Efficacy analyses n = 56 Safety analyses n = 58 Efficacy analyses n = 57 Safety analyses n = 59 Completed n = 52 (89.7%) Completed n = 52 (88.1%) Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; Deutetrabenazine for TD: ARM-TD Patient Baseline Characteristics Patient Demographics Deutetrabenazine n = 56 Placebo n = 57 All N = 113 P value Age, years (SD) 56.9 (8.5) 53.0 (10.7) 54.9 (9.8).035 Female, n (%) 28 (50.0) 31 (54.4) 59 (52.2).641 Caucasian, n (%) 37 (66.1) 42 (73.7) 79 (69.9).628 Patient Clinical Characteristics Weight, kg (SD) 87.3 (24.4) 85.6 (20.9) 86.4 (22.6).682 Duration of TD, months (SD) 75.0 (82.1) 75.0 (82.5) 75.0 (81.9).999 Dopamine receptor antagonist use, n (%) 43 (76.8) 48 (84.2) 91 (80.5).319 AIMS, items 1 7 (SD) 9.7 (4.1) 9.6 (3.8) 9.6 (3.9).932 AIMS Score 6, n (%) 48 (85.7) 49 (86.0) 97 (85.8).970 Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; Deutetrabenazine for TD: ARM-TD Phase 2/3, double-blind, randomized, placebo controlled trial of deutetrabenazine in 117 patients with TD Titration from 12 mg/day (6 mg BID) to max dose of 48 mg/day (24 mg BID) (if on CYP2D6 inhibitor, 36 mg/day) Primary Outcome Measure: Change in AIMS at end of 12 weeks from baseline Secondary Outcome Measure: CGIC at Week 12 Main Results: Deutetrabenazine significantly reduced AIMS over placebo (3 points vs 1.6 points in placebo) P =.0188 Well tolerated CGIC = Clinical Global Impression of Change. Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; 2016.

15 Deutetrabenazine for TD: ARM-TD Mean Change in AIMS Score Mean Change in AIMS Score * ** Deutetrabenazine Placebo -4 Baseline Weeks *P =.0067; **P = Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; Deutetrabenazine for TD: ARM-TD Adverse Events by Treatment Group Any TEAE Serious TEAE Deutetrabenazine (n = 58) n (%) 41 (70.7) 4 (6.9) Placebo (n = 59) n (%) 36 (61.0) 6 (10.2) Treatment-related TEAEs 28 (48.3) 21 (35.6) TEAE leading to dose reduction TEAE leading to dose suspension TEAE leading to discontinuation 6 (10.3) 3 (5.2) 1 (1.7) 3 (5.1) 5 (8.5) 2 (3.4) Deaths 0 0 Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; Deutetrabenazine for TD: ARM-TD Treatment over 12 weeks significant reduction in abnormal involuntary movements in patients with moderate to severe TD compared with placebo, as assessed by AIMS score Efficacy was enhanced in participants with a centrally read AIMS score 6 at baseline à appropriate target population Similar incidence of overall TEAEs and low rates of dose reductions, suspensions, and withdrawals due to TEAEs between treatment groups à tolerability of deutetrabenazine in patients with TD In contrast, dose escalation was discontinued or dosage of study drug was reduced in 52% of patients with Huntington s disease treated with tetrabenazine due to AEs No reports of depression or suicidal ideation; low rates of other psychiatric AEs (ie, anxiety, insomnia) à reported with tetrabenazine in patients with Huntington s disease Anderson KE, et al. Presented at: American Psychiatric Association Annual Meeting; May 14-18, 2016; Atlanta, GA. Data on file. Teva Pharmaceuticals; 2016.

16 Deutetrabenazine for TD: AIM-TD (Addressing Involuntary Movements) Phase 3, double-blind, randomized, placebo-controlled fixeddose trial of deutetrabenazine in TD 288 participants 12 mg/day (6 mg BID); 24 mg/day (12 mg BID); 36 mg/day (18 mg BID); placebo titrated over 4 weeks and maintained for 8 additional weeks Primary Outcome Measure: Change in AIMS from baseline to week 12 At week 12, the AIMS rating improved from baseline by -3.3 points for 36 mg (P =.001), -3.2 points for 24 mg (P =.003), and -2.1 for 12 mg (P = NS), compared to -1.4 in placebo Secondary Outcome Measure: CGIC at Week 12 Mean scores on the CGIC improved by -0.5 for 36 mg (P =.011) and by -0.6 for 24 mg (P =.002) based on the mitt population ClinicalTrials.gov Identifier: NCT BusinessWire. September 22, Accessed February 24, Anderson KE, et al. Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD): A Randomized, Double- Blind, Placebo-Controlled, Fixed-Dose Study of Deutetrabenazine for the Treatment of Moderate to Severe Tardive Dyskinesia (TD). Presented at: 29th Annual US Psychiatric and Mental Health Congress; October 21-24, 2016; San Antonio, TX. Poster #206. Deutetrabenazine for TD: AIM-TD Results Anderson KE, et al. Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD): A Randomized, Double- Blind, Placebo-Controlled, Fixed-Dose Study of Deutetrabenazine for the Treatment of Moderate to Severe Tardive Dyskinesia (TD). Presented at: 29th Annual US Psychiatric and Mental Health Congress; October 21-24, 2016; San Antonio, TX. Poster #206. VMAT2 Inhibitors for Tardive Dyskinesia: Summary and Conclusions Increasing data for use of tetrabenazine and derivatives for chorea, TD (and other involuntary movements) Still not an FDA-approved indication Tetrabenazine should be considered for TD Variants of tetrabenazine may offer attractive alternatives in the near future

17 Learning Points for Us Clinicians Do not prescribe a typical or atypical antipsychotic medication unless there is a clear indication If you prescribe it, obtain informed consent after discussion of the risk for TD and what you will do to limit the risk and monitor for the signs of TD If you prescribe it, use the lowest maintenance doses possible If you prescribe it, monitor the patient regularly with the AIMS examination, or at least a brief screen (every 6 months, or every 3 months in patients > 50 years of age) In Conclusion: What have we learned together today? Part 1 of 2 1. TD is often forgotten as a problem in this age of atypical antipsychotics, but it is still a very real challenge 2. Our understanding of the pathophysiology of TD has evolved and is now better understood 3. The consequences of TD on human life are considerable In Conclusion: What have we learned together today? Part 2 of 2 4. Screening proactively, routinely, and systematically for TD in patients on atypical and typical antipsychotics is a mandate for all clinicians 5. Innovative alterations of tetrabenazine (such as deutetrabenazine and valbenazine) are expected to serve patient s needs better 6. Significant, promising research activity on control of TD symptoms is occurring with multiple VMAT2 inhibitors. It behooves us clinicians to keep abreast of important new developments in this field