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Lurasidone Meeting Meeting LurasidoneLurasidone Meeting Meeting JuneJune 12, 12, 20092009 DainipponDainippon SumitomoSumitomo PharmaPharma Co.,Co., Ltd. Ltd. 1 Lurasidone:Lurasidone: ClinicalClinical StudiesStudies SummarySummary Antony Loebel, MD Vice President, Clinical Development Dainippon Sumitomo Pharma America 2 Lurasidone Development Timeline SchizophreniaSchizophrenia Pre-NDA FirstFirst inin PrePre-NDA-NDA EOPEOP 22 FDAFDA Meeting ManMan MeetingMeeting MeetingMeeting (Japan)(Japan) BipolarBipolar DepressionDepression PhasePhase 33 1990- 1990- 20002000 20022002 20042004 20052005 20062006 20072007 20082008 20092009 20102010 20112011 19951995 Lurasidone Schizophrenia Schizophrenia Lurasidone SchizophreniaSchizophrenia SchizophreniaSchizophrenia USUS BipolarBipolar Phase 2 Phase 3 DiscoveryDiscovery PhasePhase 22 PhasePhase 33 DepressionDepression (Japan)(Japan) sNDAsNDA USUS SchizophreniaSchizophrenia Merck USUS SchizophreniaSchizophrenia INDIND Outlicensed NDANDA 3 Problems with Current Antipsychotic Agents Lack of efficacy EPS/akathisia Prolactin increase Metabolic syndrome • Weight gain • Lipid increase • Diabetes QTc prolongation Sedation Poor functioning Reduced adherence to treatment 4 ADA/APA Consensus Statement on Antipsychotic Drugs and Obesity and Diabetes Drug Weight Gain Diabetes Risk Dyslipidemia clozapine + + + + + olanzapine + + + + + risperidone + + D D quetiapine + + D D aripiprazole* +/- – – ziprasidone* +/- – – + = increased effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data. Diabetes Care/J Clin Psych, 2004 and others 5 CATIE Schizophrenia Study: Time to Discontinuation for Any Cause Olanzapine (n=330) Risperidone (n=333) 1.0 Perphenazine (n=257) Quetiapine (n=329) 0.9 Ziprasidone (n=183) 0.8 0.7 0.6 0.5 0.4 Continuing Treatment 0.3 Proportion of Patients 0.2 0.1 0.0 0 3 6 9 12 15 18 Time to Discontinuation for Any Cause (months) Lieberman JA et al. N Engl J Med. 2005;353:1209-1223. 6 Psychiatrists Perceive the Greatest Unmet Needs in the Treatment of Schizophrenia and Bipolar Disorder to Involve Better/More Consistent Efficacy Balanced with Tolerable Side Effects Unmet Needs Schizophrenia Bipolar Disorder Uniform effectiveness (balanced with side More uniformly effective for effect burden) depressed phase Treatment of positive symptoms - Drugs that work alone to treat violence, loss of self-control all stages Something to enhance cognitive Control of agitation Better Efficacy functioning of patients, improve intellectual capacity New alternatives – “There are still a number of patients who are quite sick with available medications. We need new mechanisms, an increased arsenal.” Better performance in terms of metabolic Fewer metabolic effects Fewer Side effects and weight gain (effects impact Effects Limited side effects compliance) Less expensive medications (issue for Less expensive medications Lower Cost 30% of patients) (issue for 10-20% of patients) Simple regimen, maybe a combination QD medications Simpler of meds patients typically take in a Administration single capsule DSP, data on file, 2009 7 Receptor Binding Profiles: Lurasidone and Other Agents Binding Affinities Lurasidone (Ki; nM) Risp Olanz Quet Zip Aripip Cloz D2 Antipsychotic 1.7 2.9 14 200 3 3.3 110 5-HT2A Antipsychotic/ 2.0 0.2 5.8 340 0.3 34 9.2 Attenuate EPS 5-HT1A Mood/Cognition 6.8 260 2700 320 8.5 2.1 120 5-HT7 Mood/Cognition 0.50 6.6 110 310 6.0 10 18 α2c Cognition 11 11 210 350 400 38 16 Histamine H1 Impair cognition, sedation, weight >1000 3.5 3.8 9.0 510 67 2.0 gain ACh M1 Impair cognition >1000 >1000 7.6 210 >1000 >1000 4.9 α1 Orthostatic hypotension, 48 2 19 7 2 26 7 sedation Lurasidone data on file, 2008 Bymaster,et al. Neuropsycopharmacology,1996;14:87-96 and others 8 5-HT7 Receptor Autoradiography in Rat Lurasidone Dose-Dependently Competes with [3H]SB-269970 Binding Total Non Specific Hi Th Hy Am Lurasidone 1 nM Lurasidone 10 nM Lurasidone 100 nM Lurasidone 1000 nM Am-Amygdala Hy-Hypothalamus Th-Thalamus Hi-Hippocampus 9 10 Lurasidone Reverses MK-801 Induced Learning & Memory Impairment 1 day later Inescapable shock 1 day later 1 day later + Lurasidone 11 Lurasidone Phase 2 Studies DSM-IV schizophrenia, requiring hospitalization 6-week, randomized, double-blind, placebo-controlled All studies involved US sites only Primary end point: BPRS derived from PANSS (BPRSd) Hospitalization required for 2-4 weeks 12 Study 006: PANSS Total Score (ITT-LOCF) Weeks 0123456 0 -2 -4 -6 -8 -10 -12 † -14 -16 Mean Change from Baseline Change Mean * -18 * ** -20 Placebo (n=49) Lurasidone 40 mg (n=49) Lurasidone 120 mg (n=47) †p=0.06 *p≤0.05; **p=0.01 Ogasa et al. ICOSR 2003 13 Study 196: PANSS Total Score (ITT-LOCF) Weeks 0123456Day 3 0 -2 -4 -6 * -8 -10 * -12 * Mean Change from Baseline from Change Mean -14 * * * -16 * Placebo (n=90) Lurasidone 80 mg (n=90) *p≤0.01 Nakamura M et al. J Clin Psych, 2009 14 J Clin Psychatry June 2, 2009, e1-e8 15 Depressive Symptom Change: Phase 2 Data StudiesStudies 006,006, 196196 StudyStudy 196196 PANSS MADRS Anxiety/Depression Lurasidone Anxiety Depression Placebo 80mg 0.0 0 n=135n=135 n=181n=181 n=135n=135 n=181n=181 n=83n=83 n=86n=86 -1 -0.5 -2 * -3 * * Mean Change from Baseline Change Mean Mean Change from Baseline Change Mean -1.0 -4 Baseline: Placebo 14.5, Lurasidone 14.2 LOCF at end point *p<0.05 using ANCOVA 16 PANSS Cognitive Subscale Study 196 0 n=90 n=90 -0.5 -0.5 -1 Placebo Lurasidone -1.5 Mean Change Mean -2 -2.1 -2.5 p = 0.0015 Nakamura M et al. J Clin Psych, 2009 17 Simpson Angus Scale (SAS): Pooled Phase 2 Studies* 2.5 2.0 1.5 1.24 1.0 0.49 Mean Change Change Mean 0.5 0.23 0.09 -0.05 0.04 0.0 -0.5 Placebo Lurasidone Lurasidone Lurasidone Lurasidone Haloperidol 20mg 40mg 80mg 120mg 10mg n=209 n=71 n=114 n=159 n=48 n=72 *Studies 006, 049, 196 SAS scored 0-5 on 10 items for max possible score of 50 18 Barnes Akathisia Rating Scale (BARS): Pooled Phase 2 Studies* 2.0 1.5 1.0 0.58 0.5 0.31 Mean Change Mean 0.12 0.16 0.0 -0.04 -0.06 -0.5 Placebo Lurasidone Lurasidone Lurasidone Lurasidone Haloperidol 20mg 40mg 80mg 120mg 10mg n=210 n=71 n=114 n=160 n=48 n=72 *Studies 006, 049, 196 BAS scored 0-5 on Global Clinical Assessment of akathisia; maximum score= 5 19 Serum Prolactin: Pooled Phase 2 Studies* 10 8.5 8 6 4 2 1.4 n=353n=353 n=62n=62 0 Median Change (ng/mL) Median Change n=187n=187 -2 -1.4 Placebo Lurasidone Haloperidol *Studies 006, 049, 196 20 CATIE Schizophrenia Study: Prolactin 20.0 15.4 n=262n=262 10.0 0.4 0.0 n=143n=143 n=268n=268 n=286n=286 n=212 -4.5 -6.1 -10.0 -9.3 Ziprasidone Risperidone Quetiapine Mean change from Baseline (ng/dL) -20.0 Olanzapine Perphenazine Ziprasidone Olanzapine Mean Modal Dose Ziprasidone 112.8 mg/d Risperidone 3.9 mg/d Quetiapine 543.4 mg/d Olanzapine 20.1 mg/d Lieberman JA et al. N Engl J Med 2005;353:1209-1223. Perphenazine 20.8 mg/d 21 Weight Gain: Pooled Phase 2 Studies* 2.0 1.5 1.0 0.46 0.5 Mean Change (kg) 0.16 0.10 0.0 n=208n=208 n=387n=387 n=71n=71 Placebo Lurasidone Haloperidol *Studies 006, 049, 196 22 Estimated Mean Weight Gain at 10 Weeks with Antipsychotics 6 5 4 3 Conventional Antipsychotics Second-generation Antipsychotics 2 1 0 Allison DB et al. –1 Mean Change in Body Weight (kg) –2 –3 Am J Psychiatry Placebo . 1999;156:1686-1696 Molindone Ziprasidone Fluphenazine Haloperidol Risperidone Chlorpromazine Sertindole Thioridazine Olanzapine Clozapine 23 Lipid Profile: Pooled Phase 2 Studies# Cholesterol HDL* LDL* Triglycerides 0 -5 -10 -15 -20 Mean Change (mg/dL) Mean -25 -30 n=192/381 n=78/76 n=72/70 n=192/381 Placebo Lurasidone #Studies 006, 049 and 196 *Not measured in study 049 Fasting measures obtained per protocol 24 CATIE Schizophrenia Study: Triglycerides Mean Change from Baseline (mg/dL) 42.9 19.2 8.3 n=262 n=268n=268 n=286n=286 n=212n=212 n=143 n=143 -2.6 -18.1 Ziprasidone Risperidone Quetiapine Olanzapine Perphenazine Mean Modal Dose Ziprasidone 112.8 mg/d Risperidone 3.9 mg/d Quetiapine 543.4 mg/d Olanzapine 20.1 mg/d Perphenazine 20.8 mg/d Lieberman JA et al. N Engl J Med 2005;353:1209-1223 25 AA Randomized,Randomized, Double-BlindDouble-Blind StudyStudy ComparingComparing 33 FixedFixed DosesDoses ofof LurasidoneLurasidone toto PlaceboPlacebo inin PatientsPatients WithWith AcuteAcute Schizophrenia:Schizophrenia: AA PhasePhase 33 TrialTrial Study D1050229 (PEARL 1) 26 PEARL 1: Study Design Open-Label Double-Blind Phase Extension Phase LurasidoneLurasidone 4040 mg/dmg/d n=120n=120 LurasidoneLurasidone 8080 mg/dmg/d n=120n=120 LurasidoneLurasidone 4040-120-120 mg/dmg/d Baseline Baseline Lurasidone 120 mg/d Baseline Lurasidone 120 mg/d Screening Screening Screening n=120n=120 PlaceboPlacebo n=120n=120 6 weeks 22 months 27 Key Entry Criteria DSM-IV schizophrenia • Acute exacerbation ≤2 months • ≤2 weeks hospitalization prior to screening • No significant improvement between screening and baseline Age 18-75 yrs Baseline Assessments • PANSS score ≥80; ≥4 (moderate) on at least 2 positive psychotic items •CGI-S ≥4 Medically stable Not treatment resistant • Based on failure to respond to ≥2 prior antipsychotic trials 28 Efficacy Endpoints Primary endpoint • Baseline to 6-week/endpoint change in PANSS Total Score, using mixed model repeated measures (MMRM) analysis adjusted by Hommel procedure for multiple comparisons (dose/endpoints) • ANCOVA LOCF used for sensitivity analysis Key secondary endpoint • CGI-S change 29 PANSS Total (MMRM) Wk 6 Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Endpoint 0 -5 -10 from Baseline * -15 * 0.031 * * 0.018 -20 * LS Mean Change 0.017 * 0.010 -25 * 0.011 Placebo (n=124)
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