Tardive Dyskinesia in the Psychiatric Setting: What We Know About the Risk

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4 Tardive Dyskinesia in the Psychiatric Setting: What We Know About the Risk Steven C. Stoner, PharmD, BCPP Chair and Clinical Professor UMKC School of Pharmacy Division of Pharmacy Practice and Administration Kansas City, Missouri

5 Introduction Dopamine receptor blockers (DRBs) include all antipsychotic medications (first and second generation), as well as metoclopramide. DRBs exhibit a spectrum of risk for Extrapyramidal Symptoms (EPS), including TD, depending on receptor binding affinities and individual patient susceptibility. The risk of relapse without antipsychotics for patients diagnosed with thought disorders is greater than 50%. Caroff SN. Neurol Clin.2011.

6 Introduction EPS as a complication of antipsychotic medication contributes to lack of concordance between patients expectations and clinicians expectations. The therapeutic relationship is essential for negotiating the many factors that influence a patient-centered care approach for concordance and treatment compliance. The clinical challenge: to manage psychotic illnesses with antipsychotic medications given the known risks of abnormal movements, including tardive dyskinesia.

7 Tardive Dyskinesia Chronic extrapyramidal side effect Potentially irreversible symptoms Comparison between first (FGA) and secondgeneration antipsychotics (SGA) [n=11,493] 41-study, random effects meta-analysis and metaregression Global TD prevalence = 25.3% Current: SGA 20.7% vs. FGA 30.0% (p=0.002) Lower TD prevalence in FGA-naive patients vs. SGA treated with FGA history (p<0.001) Carbon M, et al. J Clin Psychiatry

8 TD: Risk Issues All studies emphasize that rates may be an underestimation of the true risk of TD. Patient nonadherence to medications may suggest more TD side effects, as we lose these patients to follow-up and evaluation. Antipsychotics induce bradykinesia and rigidity, masking the clinical presentation of TD by increasing muscle stiffness and lowering the choreoathetotic movements associated with TD.

9 TD: Risk Issues Expanded clinical indications and use for antipsychotics (eg, bipolar, anxiety, chemotherapyinduced N/V) continue to perpetuate the risk of EPS/TD Cost concerns continue to drive use of FGAs in some health care settings

10 TD Risk Factors Increased age (higher incidence and lower remissions over age 50) African-American race History of acute EPS with antipsychotics (Parkinsonism, dystonia, akathisia) Female gender Postmenopausal Head injury Substance abuse Concurrent affective/mood disorder Concurrent medical disease (diabetes) Use of antipsychotics in high doses Exposure to antipsychotics over time Saltz BL, et al. JAMA. 1991; Ganzini L, et al. Psychopharmacol Bull. 1992; Woerner MG, et al. Am J Psychiatry. 1993; Woerner MG, et al. Am J Psychiatry. 1998; Chan HY, et al. J Clin Psychiatry. 2010; Müller T. Expert Opin Investig Drugs

11 Pharmacist-Driven Assessment of Tardive Dyskinesia

12 EPS: Tardive Dyskinesia Common clinical presentation Oral and facial abnormalities including chewing, grimacing, blinking, lip smacking Writhing movements of face, neck, back, trunk, and extremities Development of TD Remission vs. suppression of symptoms Limited treatment intervention options Practice Guideline for the Treatment of Patients with Schizophrenia. American Psychiatric Association. 2010; Caroff SN, et al. Journal of Clinical Psychiatry. 2011; Lerner V and Miodownik C. Curr Psychiatry Rep. 2011; Correll CU, Schenk EM. Curr Opin Psychiatry. 2008; Leucht S. et al. Lancet

13 Basics of Assessing Patients for Movement Disorders Establish rapport Comfortable environment Furniture Adapt the examination to the patient Distractor techniques

14 Basics of Assessing Patients for Movement Disorders Observation period Establish a personal normal Develop a consistent/fluent exam process No single standard exam process

15 Improving Your Ratings Be familiar with the neurologic basis of the syndrome Do several assessments with an experienced rater Separately complete the ratings Compare/discuss your findings Practice, practice, practice Sajatovic M, Ramirez LF, in Rating Scales in Mental Health. 2012; Hawley CJ, et al. Int J Psych Clin Pract

16 Assessing Tardive Dyskinesia Dyskinesia Identification System Condensed User Scale (DISCUS) Abnormal Involuntary Movement Scale (AIMS)

17 Dyskinesia Identification System Condensed User Scale (DISCUS) Developed in 1991 by Sprague and Kalachnik 15 items assessing 7 different regions Not diagnostic Total score of 5 or more suggests further examination and assessment needed Sprague RL and Kalachnik JE. Psychopharmacol Bull

18 Abnormal Involuntary Movement Scale (AIMS) Developed in 1976 by researchers affiliated with the Psychopharmacology Research Branch at NIMH Designed to identify dyskinesias in antipsychotic treated patients Most commonly applied scale for rating the severity of TD Guy WG. EDCEU Assessment Manual for Psychopharmacology

19 AIMS 12-item anchored scale 10 to 15 minutes to complete examination Items 1-10 are scored on 5-point scale Orofacial movements Extremity and truncal movements Global severity Items 11 and 12 address problems with teeth or dentures scored yes or no Guy WG. EDCEU Assessment Manual for Psychopharmacology

20 AIMS Severity Scale For Items 1 10 the following rating scale is used: Score of 0 = no abnormalities Score of 1 = minimal, may be extreme normal Score of 2 = mild Score of 3 = moderate Score of 4 = severe Frequency, amplitude, and quality of movement are considerations Guy WG. EDCEU Assessment Manual for Psychopharmacology

21 AIMS Severity Scale Items 11 and 12 Yes or No questions pertaining to current problems with teeth and/or dentures Identification if dentures are usually worn Assists with identification of possible false positive factors No well established or defined guidelines for scoring Activation induced movement alternative scoring Guy WG. EDCEU Assessment Manual for Psychopharmacology

22 Considerations in Assessing for Tardive Dyskinesia Schooler/Kane Criteria (AIMS) Minimum of 3 months of antipsychotic treatment Absence of contributing factors or conditions AIMS score of 2 (mild) in 2 or more body parts or a score of 3 (moderate) in 1 body region Schooler NR and Kane JM. Arch Gen Psychiatry

23 Clinical Pearls of the AIMS Examination Establish comfortable environment Comfortable, seated position Identify any confounding variables Ask the patient about the current condition of their teeth and/or dentures Ask the patient if they have noticed any abnormal movements in their face, mouth, hands, or feet

24 Clinical Pearls of the AIMS Examination Ask the patient to open their mouth and observe any abnormal movements with their tongue in their mouth and also extended* Ask for specified activation movements to allow for identification of unsuppressed movements Flex and extend each arm Ask the patient to stand Ask the patient to extend their arms Ask the patient to walk* *Repeat this observation twice.

25 Clinical Setting: Application of Assessment Tools Early identification and intervention Prevention Opportunities to enhance adherence Documentation Legal considerations Proper use requires training and retraining Bark N, et al. J Psychiatr Pract

26 Benefits of Training to Achieve a Good Rating Utilization of rating scales for clinical monitoring Good data helps make good clinical decisions Evidence based decision making Legal/documentation Validity degree to which a scale measures what it is supposed to measure Improved Reliability ability of a scale to be consistent and reproducible Testing conditions should be consistent (room, noise, furniture, etc.) Uncooperative patients yield poor results Rate up Don t think about diagnosis rate what you see

27 Using Movement Disorder Rating Scales in Clinical Practice

28 Scoring an AIMS

29 The Changing Face of Tardive Dyskinesia Treatment Options Andrew Cutler, MD Executive Vice-President and Chief Medical Officer Meridien Research Courtesy Assistant Professor of Psychiatry University of Florida Bradenton, Florida

30 Traditional Approach to Managing TD Discontinue anticholinergic medications If a dopamine receptor blocker is required, consider switching to a second generation or atypical antipsychotic Clozapine Quetiapine Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther

31 Additional Treatment Interventions for TD Agent Proposed Mechanism Evidence Gingko biloba Antioxidant Shown to improve AIMS scores over 12 weeks Amantadine Dopamine agonist Shown to improve AIMS scores in patients treated with concurrent antipsychotics Clonazepam Potentiation of GABA Improved dyskinesia scores over course of 12 weeks to 9 months Level of Evidence Moderate for use 1 Moderate for use 2 Moderate for use 3 Vitamin E Antioxidant Mixed results showing benefit Limited Data Pyridoxine Antioxidant Case reports and small studies report benefit, 26-week study showed improvement in ESRS scores Limited Data 4 Melatonin Antioxidant Questionable clinical benefit Limited Data 5 1 Zhang WF, et al. J Clin Psychiatry. 2011; 2 Pappa S, et al. Clin Neuropharmacol. 2010; 3 Thaker GK, et al. Am J Psychiatry. 1990; 4 Lerner V, et al. Am J Psychiatry. 2001; 5 Nelson K, et al. Ann Pharmacother. 2003; Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther

32 Additional Treatment Interventions for TD Agent Proposed Mechanism Evidence Level of Evidence Botulinum toxin Blocks acetylcholine release and develops axonal sprouting, reduced muscle contraction Potential benefit in orofacial TD with consistent antipsychotic dose Zonisamide Enhanced GABA release Limited data suggests improved AIMS scores Levetiracetam Binds vesicle protein 2A, N-type calcium channel blockade, reduced neurotransmitter release Branched chain amino acids Omega-3 fatty acids Increases ratio of aromatic amino acids and suppresses neurotransmitter synthesis Improved neurotransmission and neuroprotection Limited data suggests improved AIMS scores, 26-week trial demonstrated significant reductions in AIMS Mixed results, improved AIMS scores in some studies Limited data, non-significant benefit Limited Data 1 Limited data 2 Limited data 3,4 Weak evidence for use 5 Moderate evidence against use 1 Slotema CW, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 2 Iwata U, et al. J Neurol Sci. 2012; 3 Bona JR. J Clin Psychopharmacol. 2006; 4 Woods SW, et al. J Clin Psychiatry. 2008; 5 Richardson MA, et al. J Clin Psychiatry. 2004; Bhidayasiri R, et al. Neurology. 2013; Rana AQ, et al. Drug Des Devel Ther

33 Vesicular Monoamine Transporter 2 (VMAT2): Proposed Role in TD VMAT2 responsible for monoamine transport from cellular cytosol into synaptic vesicles VMAT2 inhibitors bind to distinct sites on the protein and inhibit its activity, thereby reducing monoamine concentrations in the synaptic cleft Muller T. Expert Opin Investig Drugs

34 Tetrabenazine (TBZ) VMAT2 reversible inhibitor Treatment used for schizophrenia in the 1970s; obtained FDA approval in 2009 for Huntington s disease May have therapeutic application in wide variety of hyperkinetic movement disorders Requires dosing titration and TID dosing Numerous adverse effects limit its clinical use; some serious and potentially fatal: Sedation, parkinsonism, EPS, dysphagia, hypotension, neuroleptic malignant syndrome Depression, suicidality (BOXED WARNING) Guay DR. Am J Geriatr Pharmacother

35 Deutetrabenazine

36 Deutetrabenazine VMAT2 reversible inhibitor Deutetrabenazine is a novel molecule structurally related to tetrabenazine Incorporates deuterium in lieu of hydrogen at 1 o metabolism sites Deuteration of TBZ results in a more than 2-fold increase in systemic exposure to total (α+β)-htbz, a near doubling of half-life and only minor increases in C max The increased half-life of total (α+β)-htbz allows for administration of lower doses of deutetrabenazine compared with TBZ, thus permitting comparable plasma exposure with lower peak and higher trough concentrations BID dosing Under FDA review for tardive dyskinesia (Breakthrough Therapy Designation; PDUFA 8/30/17); FDA approval for Huntington s disease on 4/4/17 Huntington Study Group. JAMA. 2016; Stamler D, et al. Neurology

37 Deutetrabenazine Clinical Trials ARM-TD (NCT ; Phase II/III) 12-wk, DBRPC study of adults 6-wk of titration plus 6-wk of maintenance AIMS responder subanalyses AIM-TD (NCT ; Phase III) 12-wk, DBRPC study Dose-finding of placebo, 12, 24, or 36 mg BID titrated over 4 wks and maintained for 8 additional wks RIM-TD (NCT ; Phase III) Open-label, 54-wk safety study DBRPC=double-blind, randomized, placebo-controlled

38 ARM-TD: Deutetrabenazine for the Treatment of Tardive Dyskinesia 12-week, randomized, double-blind, placebo-controlled, parallel group study Adult patients with moderate to severe TD using dopamine antagonists 3 months ( 1 month for patients 60 years) Baseline AIMS 6 (items 1 7) Weekly titration of study drug x 6 weeks, maintenance dose x 6 weeks Primary Outcome: Change in AIMS from baseline to Week 12 Secondary Outcome: Clinical and Patient Global Impression of Change (CGIC, PGIC) Anderson KE, et al. Presented at the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

39 ARM-TD: Baseline Demographics and Characteristics Demographic/ Characteristic 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 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 the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

40 LS Mean Change in AIMS ARM-TD: Results All patients Baseline AIMS P=.019 Deutetrabenazine Placebo -3.4 P=.027 Anderson KE, et al. Presented at the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

41 ARM-TD: Adverse Events Adverse Event Deutetrabenazine (N=58) N (%) Placebo (N=59) N (%) Any Treatment Adverse Events 41 (70.7) 36 (61.0) Somnolence 8 (13.8) 6 (10.2) Headache 4 (6.9) 6 (10.2) Fatigue 4 (6.9) 5 (8.5) Insomnia 4 (6.9) 1 (1.7) Anxiety 3 (5.2) 4 (6.8) Diarrhea 3 (5.2) 3 (5.1) Akathisia 3 (5.2) 0 (0.0) Dry Mouth 2 (3.4) 6 (10.2) Upper Respiratory Tract Infection 2 (3.4) 4 (6.8) Dizziness 2 (3.4) 3 (5.1) Rash 1 (1.7) 3 (5.1) Anderson KE, et al. Presented at the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

42 AIM-TD: Deutetrabenazine for the Treatment of TD 12-week, randomized, double-blind, placebo-controlled, parallel group, fixed-dose study Adult patients with moderate to severe TD using dopamine antagonists 3 months ( 1 month for patients 60 years) Baseline AIMS 6 (items 1 7) Dose escalation (4 weeks) to fixed dose of 12, 24, or 36 mg/day (BID) then maintained 8 weeks Primary Outcome: Change in AIMS from baseline to Week 12 Secondary Outcome: Clinical Global Impression of Change (CGIC) Anderson KE, et al. Presented at the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

43 AIM-TD: Baseline Demographics and Characteristics Demographic/ Characteristic Deutetrabenazine 12 mg/day (N=74) Deutetrabenazine 24 mg/day (N=73) Deutetrabenazine 36 mg/day (N=74) Placebo (N=72) Age, years (SD) 57.0 (10.0) 55.6 (11.3) 58.3 (11.6) 54.6 (12.1) Female, N (%) 42 (57.0) 41 (56.0) 42 (57.0) 37 (51.0) Caucasian, N (%) 58 (78) 54 (74.0) 61 (82.0) 59 (82) Weight, kg (SD) 80.8 (21.0) 86.8 (18.8) 78.5 (17.6) 82.8 (18.5) Duration of TD, years (SD) Dopamine Receptor Antagonist Use, N (%) 5.5 (5.4) 5.0 (6.0) 5.9 (5.3) 6.0 (5.4) 56 (76.0) 57 (78.0) 53 (72.0) 56 (78) Anderson KE, et al. Presented at the 2016 American Psychiatric Association Annual Meeting; May 2016; Atlanta, GA.

44 AIM-TD: Results Change in AIMS Score by Treatment Group Anderson KE, et al. Presented at the 29 th US Psychiatric and Mental Health Congress, 2016.

45 AIM-TD: Results Analysis of Change in AIMS Score at Week 12 Anderson KE, et al. Presented at the 29 th US Psychiatric and Mental Health Congress, 2016.

46 AIM-TD: Adverse Events Adverse Event Any Treatment Emergent Adverse Event Deutetrabenazine 12 mg/day (N=74), [n,%] Deutetrabenazine 24 mg/day (N=73), [n,%] Deutetrabenazine 36 mg/day (N=74), [n,%] Placebo (N=72), [n,%] 35 (47) 31 (42) 38 (51) 34 (47) Headache 5 (7) 2 (3) 5 (7) 4 (6) Diarrhea 1 (1) 3 (4) 5 (7) 2 (3) Nausea 1 (1) 1 (1) 1 (1) 7 (10) Nasopharyngitis 4 (5) 3 (4) 2 (3) 1 (1) Anxiety 3 (4) 2 (3) 3 (4) 2 (3) Fatigue 1 (1) 2 (3) 3 (4) 1 (1) Somnolence 0 1 (1) 3 (4) 3 (4) Depression 1 (1) 3 (4) 1 (1) 0 Dry Mouth 3 (4) 0 2 (3) 0 Muscle Spasms (4) 0 Hypertension (4) 1 (1) Anderson KE, et al. Presented at the 29 th US Psychiatric and Mental Health Congress, 2016.

47 Valbenazine

48 Valbenazine (VBZ) Novel, highly-selective VMAT2 inhibitor Pharmacokinetics: Orally active agent with two active metabolites also highly selective for VMAT2: NBI [(+)α-dihydrotetrabenazine] and NBI Unique pharmacokinetic profile results in reduced peak plasma concentrations and variability that may improve safety/tolerability Once daily dosing (T 1/2 =20 hours) FDA-approved for Tardive Dyskinesia on 4/11/17 Also being studied in Tourette syndrome O Brien CF, et al. Mov Disord. 2015; Valbenazine Prescribing Information.

49 Valbenazine Clinical Trials KINECT 1 (NCT ; Phase II) 6-wk, DBRPC study in adults 100 mg dose reduced symptoms on AIMS score KINECT 2 (NCT ; Phase II) 6-wk, DBRPC dose-titration study of adults on mg Psychiatric stability analysis KINECT 3 (NCT ; Phase III) 6-wk, DBRPC study of adults on 40 or 80 mg 52-week, long-term extension study KINECT 4 Open-label (with dose escalation/reduction) based on efficacy/tolerability DBRPC=double-blind, randomized, placebo-controlled

50 KINECT 2: Study Design Day -1 Week 2 Week 4 Week 6 Placebo Placebo Placebo Screening Follow-up VBZ 25 mg VBZ 25 or 50 mg VBZ 25, 50, or 75 mg Baseline AIMS Assessment Blinded central rating by 2 movement disorder neurologists scoring random sequence video AIMS Primary Endpoint AIMS Assessment O Brien CF, et al. Mov Disord

51 KINECT 2: Demographics Variable Statistic/ Category Placebo (N=49) Valbenazine (N=51) Total (N=100) Mean Age (SD), years 55.6 (9.8) 56.7 (10.8) 56.2 (10.3) Mean Age at TD Diagnosis (SD), years 49.5 (12.1) 48.9 (13.0) 49.2 (12.5) Gender (n[%]) Male 27 (55.1) 30 (58.8) 57 (57.0) Female 22 (44.9) 21 (41.2) 43 (43.0) Mean AIMS Baseline (SD) 7.9 (4.5) 8.0 (3.5) 8.0 (4.0) Disease Category Schizophrenia/ Schizoaffective Mood Disorder 30 (61.2) 28 (54.9) 58 (58.0) 18 (36.7) 20 (39.2) 38 (38.0) GI Disorder 1 (2.0) 3 (5.9) 4 (4.0) O Brien CF, et al. Mov Disord

52 KINECT 2: Results Variable Placebo (N=44) N(%) Valbenazine (N=45) N(%) P-value Mean Change AIMS (SD) -1.1 (3.7) -3.6 (3.5).0005 AIMS Response at Week 6 (MITT) Mean CGI-TD (SEM) 3.1 (0.1) 2.3 (0.1) LS Mean CGI-TD (SEM) 3.1 (0.3) 2.2 (0.3) NNT (95% CI) 8 (18.2) 22 (48.9) (2-9) CGI-TD Responder (ITT) 7 (15.9) 30 (66.7) < (2-3) Mean PGIC (SEM) 2.9 (0.1) 2.2 (0.1) LS Mean PGIC (SEM) 3.3 (0.3) 2.6 (0.3) PGIC Responders 14 (31.8) 26 (57.8) (3-17) O Brien CF, et al. Mov Disord

53 KINECT 2: Results Adverse Event Placebo (N=49) N (%) 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%) O Brien CF, et al. Mov Disord

54 KINECT 3: Study Design Screening Period Week -6 to Day-1 Randomized, Double-blind, Placebo-controlled Treatment Period Day 1 to Week 6 Placebo (n=76) Screening Valbenazine 40 mg (n=70) Patients were eligible to enter a doubleblind valbenazine treatment period (Weeks 6-48) and a follow-up period (Weeks 48-52) Valbenazine 80 mg (n=79) Baseline AIMS Week 2: AIMS Week 4: AIMS Week 6: AIMS At the Week 6 visit, subjects initially randomized to placebo were re-randomized to VBZ 40 mg or 80 mg. Subjects initially randomized to VBZ 40 mg or 80 mg remained at their current dose. Subjects initially randomized or rerandomized to VBZ 80 mg received 40 mg for the first week. Hauser R, et al. Am J Psychiatry. 2017; Hauser R, et al. Neurology. 2016; Factor SA, et al. Mov Disord

55 KINECT 3: Baseline Demographics Variable Placebo (N=76) VBZ 40 mg (N=72) VBZ 80 mg (N=79) All Subjects (N=227) Mean age (SD), years 57 (10.5) 55.3 (8.5) 56 (10.1) 56.1 (9.7) Male, N (%) 42 (55.3) 42 (58.3) 39 (49.4) 123 (54.2) Schizophrenia or Schizoaffective 50 (65.8) 48 (66.7) 52 (65.8) 150 (66.1) Disorder, N(%) Mean BPRS score at screening (SD) 29.3 (7.0) 30.6 (7.6) 29.1 (6.6) 29.7 (7.1) Mean AIMS score (SD) 9.9 (4.3) 9.7 (4.1) 10.4 (3.6) 10 (4.0) Hauser R, et al. Am J Psychiatry

56 LS Mean (SEM) Change from Baseline KINECT 3: AIMS Score Change by Study Visit *P<.05, **P<.01, ***P.001 for VBZ vs. PBO * * ** *** *** *** ITT population -4.0 Week 0 Week 2 Week 4 Week 6 Placebo (N=76) Valbenazine 40 mg (N=70) Valbenazine 80 mg (N=79) Hauser R, et al. Am J Psychiatry

57 AIMS Mean Score Change from Baseline (±SEM) KINECT 3: Long-Term Extension AIMS Score Mean Change by Study Visit (ITT Population) VE VBZ 40 mg/day DBPC Placebo DBPC VBZ 40 mg/day DBPC VBZ 80 mg/day VE VBZ 80 mg/day -2 ** -3-4 *** -5-6 BL End of DBPC Week End of Extension End of Follow-up At end of DBPC: **P<0.01; ***P<0.001 vs. placebo (statistical significance met for 80 mg/day based on the predefined fixed-sequence testing procedure); results based on least squares mean change from DBPC baseline using a mixed-effects model for repeated measures. VE and drug-free follow-up periods: results based on arithmetic mean changes, with no imputation for missing values or significance testing between dose groups. AIMS, Abnormal Involuntary Movement Scale; BL, baseline; DBPC, double-blind placebo-controlled; ITT, intent-to-treat; SEM, standard error of the mean; VBZ, valbenazine; VE, valbenazine extension. Presented at the 55 th Annual Meeting of the American College of Neuropsychopharmacology, December 2016, Hollywood, FL.

58 KINECT 3: Adverse Events Adverse Event Placebo (N=76) N(%) VBZ 40 mg (N=72) N(%) VBZ 80 mg (N=79) N(%) Any Event 33 (43.4) 29 (40.3) 40 (50.6) Any Event Leading to Discontinuation 4 (5.3) 4 (5.6) 5 (6.3) Somnolence 3 (3.9) 4 (5.6) 4 (5.1) Akathisia 1 (1.3) 3 (4.2) 2 (2.5) Suicidal Ideation 4 (5.3) 3 (4.2) 1 (1.3) Arthralgia 1 (1.3) 1 (1.4) 3 (3.8) Dry Mouth 1 (1.3) 5 (6.9) 0 (0.0) Vomiting 0 (0.0) 0 (0.0) 3 (3.8) Dyskinesia 0 (0.0) 0 (0.0) 3 (3.8) Anxiety 0 (0.0) 1 (1.4) 2 (2.5) Urinary Tract Infection 3 (3.9) 3 (4.2) 0 (0.0) Weight Increase 0 (0.0) 1 (1.4) 2 (2.5) Hauser R, et al. Am J Psychiatry

59 Valbenazine Adverse Events: Pooled Data Adverse Reactions in 3 Placebo-Controlled Studies of 6-week Treatment Duration Reported at 2% and >Placebo Adverse Reaction Placebo (N=183) VBZ (N=262) Somnolence 4.2% 10.9% Anticholinergic effects 4.9% 5.4% Balance disorders/fall 2.2% 4.1% Headache 2.7% 3.4% Akathisia 0.5% 2.7% Vomiting 0.6% 2.6% Nausea 2.1% 2.3% Arthralgia 0.5% 2.3% Valbenazine Prescribing Information, April 2017.

60 KINECT 3 Valbenazine: Psychiatric Stability Psychiatric Status Rating Scale Scores (Safety Population) At Baseline At Week 6 Placebo Valbenazine 40 mg/day Valbenazine 80 mg/day Placebo Valbenazine 40 mg/day Valbenazine 80 mg/day Psychiatric scale n Mean Score (SD) n Mean Score (SD) n Mean Score (SD) n Mean Score (SD) n Mean Score (SD) n Mean Score (SD) PANSS Negative Symptoms PANSS Positive Symptoms PANSS General Psychopathology Calgary Depression Scale for Schizophrenia Montgomery-Asberg Depression Rating Scale (4.5) (4.7) (3.9) (4.7) (4.6) (4.8) (3.3) (3.7) (4.2) (4.1) (3.6) (4.0) (5.3) (6.5) (5.5) (6.3) (5.5) (6.0) (2.2) (2.1) (2.2) (2.4) (2.4) (2.1) (2.9) (3.8) (4.0) (6.4) (4.7) (4.1) Young Mania Rating Scale (2.3) (3.0) (3.2) (3.3) (2.6) (2.2) PANSS=Positive and Negative Syndrome Scale, SD=Standard deviation Hauser R, et al. Am J Psychiatry

61 Role of the Psychiatric Pharmacist in Assessment and Management of TD Roger W. Sommi, PharmD, BCPP, FCCP Associate Dean and Professor of Pharmacy Practice and Psychiatry UMKC School of Pharmacy Center for Behavioral Medicine

62 Is Tardive Dyskinesia Still A Clinical Issue? CATIE Study suggests TD continues to be an issue Still significant utilization of first generation antipsychotics Recent meta analysis shows continued risk for TD, even with the second generation agents Caroff SN, et al. Neurol Clin. 2011; Lieberman JA, et al. N Engl J Med. 2005; Carbon M, et al. J Clin Psychiatry 2017.

63 Clinical Considerations in Managing TD Minimize risks Confirm indications for antipsychotic use and reconsider drug therapies Use conservative doses Choose low-potency agents Build concordance with clients Inform patients of the risks Caroff SN, et al. Neurol Clin. 2011; Lieberman JA, et al. N Engl J Med

64 Case Study - JL 62 year-old, lb white female diagnosed with schizoaffective disorder significant issues with depressive episodes Treated with paliperidone palmitate 117 mg IM q month for the past 3 years, combined with sertraline 100mg/d and benztropine 1 mg BID Onset of illness in early 30 s multiple hospitalizations, 2 suicide attempts most recent 3 years ago Widowed, no children, no sustained work history, receives SSI/SSD, on Medicare, lives in a board and care facility and attends social groups weekly Antipsychotic history includes multiple antipsychotics including 20 years of receiving either fluphenazine or haloperidol decanoate, several trials of oral second generation antipsychotics and more recently being psychiatrically stable on paliperidone palmitate

65 AIMS Evaluation of JL X X

66 Valbenazine Practical Issues Available May 2017 through specialty pharmacies Dose Availability: 40 mg capsule Initiate at 40 mg po daily; may increase to 80 mg po daily at one week Maintain at 40 mg if CYP2D6/3A4 poor metabolizer or hepatic impairment Take with or without food Procurement: Valbenazine Prescribing Information & Product Website, April 2017.

67 Deutetrabenazine Practical Issues FDA Approval for Huntington s Disease 4/4/17 Under FDA review for Tardive Dyskinesia, PDUFA 8/30/17 Warning for depression and suicidality Dose Availability: 6 mg, 9 mg, 12 mg tablets Initiate at 6 mg po daily, titrate up at weekly intervals by 6 mg per day to a tolerated dose that reduces chorea, up to a maximum daily dose of 48 mg In use with strong CYP2D6 inhibitors the maximum recommended dose is 36 mg per day Total daily doses of 12 mg or above should given in two divided doses Take with food Deutetrabenazine Prescribing Information & Product Website, April 2017.

68 Case Study What really happens

69