Lurasidone Meeting Lurasidone Meeting June 12, 2009 June 12, 2009 - PowerPoint PPT Presentation

Lurasidone Meeting Lurasidone Meeting June 12, 2009 June 12, 2009 Dainippon Sumitomo Pharma Co., Ltd. Dainippon Sumitomo Pharma Co., Ltd. 1

Lurasidone: Clinical Studies Lurasidone: Clinical Studies Summary Summary Antony Loebel, MD Vice President, Clinical Development Dainippon Sumitomo Pharma America 2

Lurasidone Development Timeline Schizophrenia Schizophrenia Schizophrenia Pre- -NDA NDA Pre First in Pre-NDA First in First in EOP 2 FDA EOP 2 FDA EOP 2 FDA Meeting Meeting Man Meeting Man Man Meeting Meeting Meeting (Japan) (Japan) (Japan) Bipolar Bipolar Bipolar Depression Phase 3 Depression Phase 3 Depression Phase 3 1990- 1990- 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 1995 1995 Lurasidone Lurasidone Schizophrenia Schizophrenia Schizophrenia Schizophrenia Lurasidone Schizophrenia Schizophrenia US Bipolar US Bipolar US Bipolar Phase 3 Discovery Discovery Phase 2 Phase 2 Phase 3 Phase 3 Discovery Phase 2 Depression Depression Depression (Japan) (Japan) sNDA (Japan) sNDA sNDA Merck US Schizophrenia US Schizophrenia US Schizophrenia US Schizophrenia US Schizophrenia US Schizophrenia IND NDA IND NDA Outlicensed IND NDA 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) Ziprasidone (n=183) 0.9 Proportion of Patients Continuing Treatment 0.8 0.7 0.6 0.5 0.4 0.3 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 � Limited side effects 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 Risp Olanz Quet Zip Aripip Cloz Lurasidone (Ki; nM) D 2 1.7 2.9 14 200 3 3.3 110 Antipsychotic 5-HT 2A 2.0 0.2 5.8 340 0.3 34 9.2 Antipsychotic/ Attenuate EPS 5-HT 1A 6.8 260 2700 320 8.5 2.1 120 Mood/Cognition 5-HT 7 0.50 6.6 110 310 6.0 10 18 Mood/Cognition α 2c 11 11 210 350 400 38 16 Cognition Histamine H1 Impair cognition, >1000 3.5 3.8 9.0 510 67 2.0 sedation, weight gain ACh M1 >1000 >1000 7.6 210 >1000 >1000 4.9 Impair cognition α 1 Orthostatic 48 19 7 2 26 7 2 hypotension, sedation Lurasidone data on file, 2008 Bymaster,et al. Neuropsycopharmacology,1996;14:87-96 and others 8

5-HT 7 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

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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 0 1 2 3 4 5 6 0 -2 Mean Change from Baseline -4 -6 -8 -10 -12 † -14 -16 * -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 Day 3 0 1 2 3 4 5 6 0 -2 Mean Change from Baseline -4 -6 * -8 * -10 * -12 -14 * * * * -16 Placebo (n=90) Lurasidone 80 mg (n=90) *p ≤ 0.01 Nakamura M et al. J Clin Psych, 2009 14

15 J Clin Psychatry June 2, 2009, e1-e8

Depressive Symptom Change: Phase 2 Data Studies 006, 196 Study 196 Studies 006, 196 Study 196 Studies 006, 196 Study 196 PANSS MADRS Anxiety/Depression Lurasidone Anxiety Depression Placebo 80mg 0 0.0 Mean Change from Baseline Mean Change from Baseline n=135 n=181 n=135 n=181 n=181 n=83 n=86 n=135 n=181 n=135 n=83 n=86 -1 -0.5 -2 -3 * * * -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 Mean Change Placebo -1 Lurasidone -1.5 -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 Mean Change 1.5 1.24 1.0 0.49 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 Mean Change 1.0 0.58 0.5 0.31 0.16 0.12 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 Median Change (ng/mL) 8 6 4 1.4 2 n=353 n=62 n=353 n=62 0 n=187 n=187 -2 -1.4 Placebo Lurasidone Haloperidol *Studies 006, 049, 196 20

CATIE Schizophrenia Study: Prolactin 20.0 Mean change from Baseline (ng/dL) 15.4 n=262 n=262 10.0 0.4 0.0 n=143 n=268 n=286 n=143 n=268 n=286 n=212 -4.5 -6.1 -10.0 -9.3 Ziprasidone Risperidone Quetiapine -20.0 Olanzapine Perphenazine Ziprasidone Olanzapine Mean Modal Dose Ziprasidone 112.8 mg/d Risperidone 3.9 mg/d Quetiapine 543.4 mg/d 20.1 mg/d Olanzapine 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 Mean Change (kg) 1.5 1.0 0.46 0.5 0.16 0.10 n=208 n=387 n=208 n=387 n=71 n=71 0.0 Placebo Lurasidone Haloperidol *Studies 006, 049, 196 22

Estimated Mean Weight Gain at 10 Weeks with Antipsychotics 6 Conventional Antipsychotics Mean Change in Body Weight (kg) Second-generation Antipsychotics 5 4 3 2 1 0 –1 –2 –3 Placebo Molindone Ziprasidone Fluphenazine Haloperidol Risperidone Chlorpromazine Sertindole Thioridazine Olanzapine Clozapine Allison DB et al. Am J Psychiatry . 1999;156:1686-1696 23

Lipid Profile: Pooled Phase 2 Studies # Cholesterol HDL* LDL* Triglycerides 0 -5 Mean Change (mg/dL) -10 -15 -20 -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=268 n=286 n=212 n=268 n=286 n=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

A Randomized, Double-Blind Study Comparing 3 A Randomized, Double-Blind Study Comparing 3 Fixed Doses of Lurasidone to Placebo in Patients Fixed Doses of Lurasidone to Placebo in Patients With Acute Schizophrenia: A Phase 3 Trial With Acute Schizophrenia: A Phase 3 Trial Study D1050229 (PEARL 1) 26