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

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June 12, 2009 Dainippon Sumitomo Pharma Co., Ltd. June 12, 2009 Dainippon Sumitomo Pharma Co., Ltd.

Lurasidone Meeting Lurasidone Meeting

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Lurasidone: Clinical Studies Summary Lurasidone: Clinical Studies Summary

Antony Loebel, MD Vice President, Clinical Development Dainippon Sumitomo Pharma America

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Lurasidone Development Timeline

2008 2008 2009 2009 1990- 1995 1990- 1995 2007 2007 2002 2002 2000 2000 2004 2004 2005 2005 2006 2006

First in Man (Japan) First in First in Man Man (Japan) (Japan) US Schizophrenia IND US Schizophrenia US Schizophrenia IND IND US Schizophrenia NDA US Schizophrenia US Schizophrenia NDA NDA Schizophrenia Phase 3 Schizophrenia Schizophrenia Phase 3 Phase 3 Schizophrenia Phase 2 Schizophrenia Schizophrenia Phase 2 Phase 2 Schizophrenia Pre-NDA Meeting Schizophrenia Schizophrenia Pre Pre-

• NDA

NDA Meeting Meeting

Bipolar Depression Phase 3 Bipolar Bipolar Depression Phase 3 Depression Phase 3

EOP 2 FDA Meeting EOP 2 FDA EOP 2 FDA Meeting Meeting Lurasidone Discovery (Japan) Lurasidone Lurasidone Discovery Discovery (Japan) (Japan)

2010 2010 2011 2011

US Bipolar Depression sNDA US Bipolar US Bipolar Depression Depression sNDA sNDA

Merck Outlicensed

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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

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ADA/APA Consensus Statement

• n Antipsychotic Drugs and

Obesity and Diabetes

– – +/- ziprasidone* – – +/- aripiprazole* D D + + quetiapine D D + + risperidone + + + + +

• lanzapine

+ + + + + clozapine

Dyslipidemia Diabetes Risk Weight Gain Drug

+ = increased effect; - = no effect; D = discrepant results. *Newer drugs with limited long-term data. Diabetes Care/J Clin Psych, 2004 and others

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Olanzapine (n=330) Risperidone (n=333) Ziprasidone (n=183) Quetiapine (n=329) Perphenazine (n=257) 0.8 0.9 0.7 0.6 0.4 0.3 0.1 0.5 0.2 0.0 3 6 9 12 15 18 1.0 Time to Discontinuation for Any Cause (months) Proportion of Patients Continuing Treatment

CATIE Schizophrenia Study: Time to Discontinuation for Any Cause

Lieberman JA et al. N Engl J Med. 2005;353:1209-1223.

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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

Less expensive medications

(issue for 10-20% of patients)

Less expensive medications (issue for

30% of patients) Lower Cost

QD medications Simple regimen, maybe a combination

• f meds patients typically take in a

single capsule Simpler Administration

Fewer metabolic effects Limited side effects Better performance in terms of metabolic

effects and weight gain (effects impact compliance) Fewer Side Effects

More uniformly effective for

depressed phase

Drugs that work alone to treat

all stages

Control of agitation Uniform effectiveness (balanced with side

effect burden)

Treatment of positive symptoms -

violence, loss of self-control

Something to enhance cognitive

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 Efficacy Bipolar Disorder Schizophrenia Unmet Needs

DSP, data on file, 2009

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Receptor Binding Profiles: Lurasidone and Other Agents

26 >1000 67 38 10 2.1 34 3.3

Aripip

7 4.9 2.0 16 18 120 9.2 110

Cloz

7 210 9.0 350 310 320 340 200

Quet

2 >1000 510 400 6.0 8.5 0.3 3

Zip

19 2 48

α1 Orthostatic hypotension, sedation

210 11 11

α2c Cognition

110 6.6 0.50

5-HT7 Mood/Cognition

2700 260 6.8

5-HT1A Mood/Cognition

7.6

>1000

>1000

ACh M1 Impair cognition

3.8 3.5 >1000

Histamine H1 Impair cognition, sedation, weight gain

5.8 0.2 2.0

5-HT2A Antipsychotic/ Attenuate EPS

14 2.9 1.7

D2 Antipsychotic

Olanz Risp

Lurasidone

Binding Affinities (Ki; nM)

Lurasidone data on file, 2008 Bymaster,et al. Neuropsycopharmacology,1996;14:87-96 and others

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Lurasidone Dose-Dependently Competes with [3H]SB-269970 Binding

5-HT7 Receptor Autoradiography in Rat

Lurasidone 100 nM Lurasidone 1000 nM

Th Hy Am

Lurasidone 1 nM Lurasidone 10 nM Am-Amygdala Hy-Hypothalamus Th-Thalamus Hi-Hippocampus Total Non Specific

Hi

10

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Lurasidone Reverses MK-801 Induced Learning & Memory Impairment

Inescapable shock + Lurasidone

1 day later 1 day later 1 day later

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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

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Study 006: PANSS Total Score (ITT-LOCF)

†p=0.06 *p≤0.05; **p=0.01 Ogasa et al. ICOSR 2003

• 20
• 18
• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

1 2 3 4 5 6 Weeks Mean Change from Baseline Placebo (n=49)

†

Lurasidone 40 mg (n=49)

* * **

Lurasidone 120 mg (n=47)

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• 16
• 14
• 12
• 10
• 8
• 6
• 4
• 2

1 2 3 4 5 6 Weeks Mean Change from Baseline

Study 196: PANSS Total Score (ITT-LOCF)

* * * * * * *

Day 3

*p≤0.01 Nakamura M et al. J Clin Psych, 2009 Placebo (n=90) Lurasidone 80 mg (n=90)

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

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Depressive Symptom Change: Phase 2 Data

Anxiety Depression

PANSS Anxiety/Depression MADRS

* *

n=135 n=135 n=135 n=135 n=181 n=181 n=181 n=181

• 1.0
• 0.5

0.0 Mean Change from Baseline Placebo *

n=83 n=83 n=86 n=86

• 4
• 3
• 2
• 1

Mean Change from Baseline

Studies 006, 196 Studies 006, 196 Studies 006, 196 Study 196 Study 196 Study 196

Baseline: Placebo 14.5, Lurasidone 14.2 LOCF at end point *p<0.05 using ANCOVA

Lurasidone 80mg

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PANSS Cognitive Subscale

Nakamura M et al. J Clin Psych, 2009

Study 196

• 0.5
• 2.1
• 2.5
• 2
• 1.5
• 1
• 0.5

Mean Change

Placebo Lurasidone p = 0.0015

n=90 n=90

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Simpson Angus Scale (SAS): Pooled Phase 2 Studies*

0.23 0.04 1.24

• 0.05

0.49 0.09

• 0.5

0.0 0.5 1.0 1.5 2.0 2.5

Placebo Lurasidone 20mg Lurasidone 40mg Lurasidone 80mg Lurasidone 120mg Haloperidol 10mg

Mean Change

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

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Barnes Akathisia Rating Scale (BARS): Pooled Phase 2 Studies*

*Studies 006, 049, 196

BAS scored 0-5 on Global Clinical Assessment of akathisia; maximum score= 5

0.16 0.31 0.58 0.12

• 0.06
• 0.04
• 0.5

0.0 0.5 1.0 1.5 2.0

Placebo Lurasidone 20mg Lurasidone 40mg Lurasidone 80mg Lurasidone 120mg Haloperidol 10mg

Mean Change

n=210 n=71 n=114 n=160 n=48 n=72

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Serum Prolactin: Pooled Phase 2 Studies*

• 1.4

1.4 8.5

• 2

2 4 6 8 10 Placebo Lurasidone Haloperidol

Median Change (ng/mL)

n=187 n=187 n=62 n=62 n=353 n=353

*Studies 006, 049, 196

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CATIE Schizophrenia Study: Prolactin

• 4.5

15.4

• 9.3
• 6.1

0.4

• 20.0
• 10.0

0.0 10.0 20.0 Ziprasidone Risperidone Quetiapine Olanzapine Perphenazine

Mean change from Baseline (ng/dL)

Ziprasidone Olanzapine

n=143 n=143 n=262 n=262 n=268 n=268 n=286 n=286 n=212

Lieberman JA et al. N Engl J Med 2005;353:1209-1223. 20.1 mg/d Olanzapine 20.8 mg/d Perphenazine 543.4 mg/d Quetiapine 3.9 mg/d Risperidone 112.8 mg/d Ziprasidone Mean Modal Dose

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Weight Gain: Pooled Phase 2 Studies*

0.16 0.46 0.10 0.0 0.5 1.0 1.5 2.0 Placebo Lurasidone Haloperidol

Mean Change (kg)

n=208 n=208

n=71 n=71

n=387 n=387

*Studies 006, 049, 196

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Placebo Molindone Ziprasidone Fluphenazine Haloperidol Risperidone Chlorpromazine Sertindole Thioridazine Olanzapine Clozapine –3 –2 –1 1 2 3 4 5 6 Mean Change in Body Weight (kg) Conventional Antipsychotics Second-generation Antipsychotics

Estimated Mean Weight Gain at 10 Weeks with Antipsychotics

Allison DB et al. Am J Psychiatry. 1999;156:1686-1696

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• 30
• 25
• 20
• 15
• 10
• 5

Cholesterol HDL* LDL* Triglycerides Mean Change (mg/dL) Placebo Lurasidone

Lipid Profile: Pooled Phase 2 Studies#

n=192/381 n=78/76 n=72/70 n=192/381

#Studies 006, 049 and 196

*Not measured in study 049 Fasting measures obtained per protocol

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• 18.1
• 2.6

19.2 42.9 8.3

CATIE Schizophrenia Study: Triglycerides

Ziprasidone Risperidone Quetiapine Olanzapine Perphenazine

n=143 n=143 n=262 n=268 n=268 n=286 n=286 n=212 n=212

20.8 mg/d Perphenazine 20.1 mg/d Olanzapine 543.4 mg/d Quetiapine 3.9 mg/d Risperidone 112.8 mg/d Ziprasidone Mean Modal Dose

Lieberman JA et al. N Engl J Med 2005;353:1209-1223

Mean Change from Baseline (mg/dL)

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

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PEARL 1: Study Design

Open-Label Extension Phase Double-Blind Phase 6 weeks 22 months Screening Screening Screening Baseline Baseline Baseline Lurasidone 40 mg/d n=120 Lurasidone 40 mg/d Lurasidone 40 mg/d n=120 n=120 Placebo n=120 Placebo Placebo n=120 n=120 Lurasidone 80 mg/d n=120 Lurasidone 80 mg/d Lurasidone 80 mg/d n=120 n=120 Lurasidone 120 mg/d n=120 Lurasidone 120 mg/d Lurasidone 120 mg/d n=120 n=120 Lurasidone 40-120 mg/d Lurasidone 40 Lurasidone 40-

• 120 mg/d

120 mg/d

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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

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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

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PANSS Total (MMRM)

• 25
• 20
• 15
• 10
• 5

Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Endpoint Placebo (n=124) 40 mg Lurasidone (n=118) 80 mg Lurasidone (n=123) 120 mg Lurasidone (n=121) LS Mean Change from Baseline

*

0.031

*

0.018

*

0.017

*

0.010

*

0.011

* *

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PEARL 1: PANSS Total ≥30% Responder Analysis

38% 50% 52% 46% 0% 10% 20% 30% 40% 50% 60% 70% Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo Percentage of Subjects n=122 n=119 n=124 n=124

*

p=0.058

†

P=0.028

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• 30
• 25
• 20
• 15
• 10
• 5

PANSS Total: Per Protocol Population

LS Mean Change (LOCF)

n=19 n=26 n=13 n=29

n=100 n=89 n=94 n=102

* *

p=0.004

Lur 40 mg Lur 80 mg Placebo Lur 120 mg

p=0.032

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PANSS Positive Subscale (MMRM)

• 10
• 5

Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Endpoint Placebo (n=124) 40 mg Lurasidone (n=118) 80 mg Lurasidone (n=123) 120 mg Lurasidone (n=121) LS Mean Change from Baseline

* *** *** *** *** *** *** *** *** *** ** ** ** * *

*p<0.05 **p<0.01 ***p<0.001

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CGI-S (MMRM)

• 1.5
• 1.2
• 0.9
• 0.6
• 0.3

0.0 Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6 Endpoint Placebo (n=124) 40 mg Lurasidone (n=122) 80 mg Lurasidone (n=119) 120 mg Lurasidone (n=124)

*

0.025

*

0.029

*

0.009

*

0.006

*

0.005

* 0.048 * 0.029

LS Mean Change from Baseline

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0.3 0.0 0.0 0.5 1.0 1.5 Lurasidone Placebo

PEARL 1: Weight Change (LOCF)

Median Change from Baseline (kg) (N=124) n=364

36 SAS scored 0-5 on 9 items for max possible score of 45

PEARL 1: Simpson Angus Scale (SAS)

• 0.01

0.06 0.01 0.03

• 0.05

0.00 0.05 0.10 0.15 0.20 Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo LS Mean Change n=122 n=119 n=124 n=124

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PEARL 1: Barnes Akathisia Rating Scale (BAS)

BAS scored 0-5 on Global Clinical Assessment of akathisia for a maximum possible score of 5

0.0 0.3 0.1 0.1 0.0 0.5 1.0 Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo LS Mean Change n=124 n=122 n=119 n=124

Global Clinical Assessment

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0.70 0.35 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Lurasidone Placebo Median Change (ng/mL)

PEARL 1: Serum Prolactin

n=361 n=361 n=122 n=122

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• 14
• 12
• 10
• 8
• 6
• 4
• 2

Cholesterol HDL LDL Triglycerides Median Change (mg/dL) Placebo Lurasidone

PEARL 1: Lipid Profile

n=108/343 n=108/343 n=108/343 n=108/343

LOCF endpoint values; fasting per protocol; includes all subjects

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2.1 1.9 1.2 1.8 0.0 2.0 4.0 6.0 8.0 10.0

Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo

PEARL 1: QTcF Interval Change (LOCF)

Mean Change (msec)

n=120 n=120 n=122 n=122 n=117 n=117 n=120 n=120

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6.2% 6.5% 4.7% 4.1% 11.2% 10.8% 8.7% 11.2% 12.8% 12.8% 10.6% 14.9% 11.6% 6.5% 13.3% 21.4% Sedation Nausea Somnolence Akathisia Placebo (n=339) Lurasidone 40 mg (n=241) Lurasidone 80 mg (n=282) Lurasidone 120 mg (n=173)

Treatment-Emergent Adverse Event Rates (Incidence ≥10%)

Phase 2 and 3 Data Studies 006/049/196/PEARL 1

Cucchiaro J, et al. Efficacy and Safety of Lurasidone in Phase 2/3 Acute Schizophrenia Trials. Poster. American Psychiatric Association, San Francisco, CA, May 16-21, 2009,

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Lurasidone Efficacy: Summary

Consistent efficacy 40, 80 and 120 mg/d shown effective across 3 placebo-controlled trials Rapid onset (day 3 or 4) with subsequent sustained improvement noted in placebo-controlled trials Potential for improvement of cognitive deficits, based

• n preclinical and clinical data

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Lurasidone Safety: Summary

Lurasidone is well tolerated Low rates of EPS and akathisia Minimal prolactin change Neutral effects on weight, lipids and glucose Modest change in QTc interval Self-reported AEs are generally mild and transient Potential for Ongoing Adherence to Treatment Potential for Ongoing Adherence to Treatment Potential for Ongoing Adherence to Treatment

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Lurasidone Development Program Lurasidone Development Program

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PEARL 1 and 2 Trials: Lurasidone in Acute Schizophrenia

Lurasidone 40 mg Lurasidone 40 mg Lurasidone 40 mg Lurasidone 80 mg Lurasidone 80 mg Lurasidone 80 mg Lurasidone 120 mg Lurasidone 120 mg Lurasidone 120 mg Placebo Placebo Placebo Lurasidone 40-120 mg Lurasidone 40 Lurasidone 40-

• 120 mg

120 mg Open-label, 2 years

Study 229 PEARL #1 Study 229 Study 229 PEARL #1 PEARL #1

Double-blind, 6 weeks Lurasidone 40 mg Lurasidone 40 mg Lurasidone 40 mg Lurasidone 120 mg Lurasidone 120 mg Lurasidone 120 mg Olanzapine 15 mg Olanzapine 15 mg Olanzapine 15 mg Placebo Placebo Placebo Lurasidone 40-120 mg Lurasidone 40 Lurasidone 40-

• 120 mg

120 mg Open-label, 6 months

Study 231 PEARL #2 Study 231 Study 231 PEARL #2 PEARL #2

Double-blind, 6 weeks

N=480/study Lurasidone: QD dosing schedule

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PEARL 3: Lurasidone in Acute Schizophrenia

Lurasidone 80 mg Lurasidone 80 mg Lurasidone 80 mg Lurasidone 160 mg Lurasidone 160 mg Lurasidone 160 mg Quetiapine XR 600 mg Quetiapine XR 600 mg Quetiapine XR 600 mg Placebo Placebo Placebo Lurasidone 40-160 mg Lurasidone 40 Lurasidone 40-

• 160 mg

160 mg Quetiapine XR 200-800 mg Quetiapine XR 200 Quetiapine XR 200-

• 800 mg

800 mg Double-blind, flexible dose, 1 year

Studies 233/234 PEARL #3 Studies Studies 233/234 233/234 PEARL #3 PEARL #3

Double-blind, 6 weeks

N=480/study Lurasidone: QD dosing schedule

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Open-Label Continuation Phase Double-Blind Phase

12 months 6 months Screening Screening Screening Baseline Baseline Baseline Lurasidone 40-120mg/d N=400(200 for sub-study) Lurasidone 40 Lurasidone 40-

• 120mg/d

120mg/d N= N=4 400 00(200 for sub (200 for sub-

• study)

study) Risperidone 2-6mg/d N=200(100 for sub-study) Risperidone 2 Risperidone 2-

• 6mg/d

6mg/d N= N=2 200 00(100 for sub (100 for sub-

• study)

study) Lurasidone 40-120mg/d Lurasidone Lurasidone 40 40-

• 120mg/d

120mg/d

Long-Term Safety Study With Cognitive Sub-Study

6 Months

MCCB UPSA-B

Cognition Sub-Study

MCCB: MATRICS Consensus Cognitive Battery UPSA-B: UCSD Performance-Based Skills Assessment - Brief Version

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Atypical Use Has and Will Continue to Expand

Acute Mania Acute Mania Maintenance Maintenance Treatment- Resistant Depression Treatment- Resistant Depression Depression/ Anxiety Depression/ Anxiety Bipolar Depression Bipolar Depression

Depression Schizophrenia Bipolar

Atypicals Atypicals Antidepressants Antidepressants Mood Stabilizers Mood Stabilizers

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PREVAIL: Lurasidone in Bipolar Depression

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PREVAIL Add-On Design (Study 235) PREVAIL Monotherapy Design (Study 236)

PREVAIL Extension Study PREVAIL PREVAIL Extension Extension Study Study

Placebo + Lithium or Valproate Placebo Placebo + Lithium or + Lithium or Valproate Valproate Lurasidone 20-120 mg/d + Lithium or Valproate Lurasidone 20 Lurasidone 20-

• 120 mg/d

120 mg/d + Lithium or + Lithium or Valproate Valproate

Screening Screening Screening Baseline Baseline Baseline

3-28 days Day 0

Double-Blind Phase

6 weeks Enrollment Initiated 2Q ’09 Enrollment Initiated 2Q ’09

PREVAIL Extension Study PREVAIL PREVAIL Extension Extension Study Study

Placebo Placebo Placebo

Screening Screening Screening

Lurasidone 20-60 mg/d Lurasidone 20 Lurasidone 20-

• 60 mg/d

60 mg/d

3-28 days Day 0

Lurasidone 80-120 mg/d Lurasidone 80 Lurasidone 80-

• 120 mg/d

120 mg/d

n=504 （Study 235） （Study 236）

Total n=504 (n=168/arm). Total n=340 (n=170/arm).

Baseline Baseline Baseline

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Lurasidone Commercial Overview Lurasidone Commercial Overview

Joseph Yen Lin Vice President, Marketing Dainippon Sumitomo Pharma America

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Agenda

• I. Market and Disease State Overview
• II. Competitive Landscape

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$0 $2 $4 $6 $8 $10 $12 $14

Market Overview Overall Growth

Sales ($Billions)

Source: IMS NSP Data, 2004-2008

The atypical antipsychotic market is large and continues to grow at a robust rate

$14.1B $12.7B $11.3B $10.1B $9.3B +8.6% +11.9% +12.4% +11.0%

2004 2005 2006 2007 2008

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$2.9 $3.6 $3.2 $3.4 $3.8 $0.6 $0.4 $0.6 $0.6 $0.6 $1.4 $1.3 $1.3 $1.5 $1.3 $2.1 $2.2 $2.8 $2.8 $3.3 $2.3 $2.6 $3.4 $4.4 $5.0 $0 $2 $4 $6 $8 $10 $12 $14

Market Overview Growth by Diagnosis

Sales ($Billions)

$14.1B $12.7B $11.3B $10.1B $9.3B

Source: Estimated from IMS NSP Data, 2004-2008 and NDTI 2004 to 2008

Growth in the atypical antipsychotic category is being driven by use in bipolar disorder and schizophrenia

2004 2005 2006 2007 2008 Bipolar Disorder Schizophrenia Depression Anxiety Other

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Schizophrenia Disease State Overview Patient Flow

U.S. lifetime prevalence of schizophrenia is 1%; approximately 2.5 million affected

Origination Diagnosis/ Evaluation Treatment Continuation

High rates of patient discontinuation and switching

• Lack of efficacy
• Side effects
• Need for new treatment options

High rates of diagnosis (80%) and treatment (85%) Atypical antipsychotics considered the gold standard for schizophrenia

56

Schizophrenia Disease State Overview Landmark CATIE Trial

“…patients with chronic schizophrenia in this study discontinued their antipsychotic study medications at a high rate, indicating substantial limitations in the effectiveness of the drugs.”

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Marvin S. Swartz, M.D., Robert A. Rosenheck, M.D., Diana O. Perkins, M.D., M.P.H., Richard S.E. Keefe, Ph.D., Sonia M. Davis, Dr.P.H., Clarence E. Davis, Ph.D., Barry D. Lebowitz, Ph.D., Joanne Severe, M.S., John K. Hsiao, M.D., for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators

57

Bipolar Disease State Overview Patient Flow

U.S. lifetime prevalence of bipolar disorder is 2.6%; over 6 million affected Origination Diagnosis/ Evaluation Treatment Continuation Relatively lower rates of diagnosis (45%) and treatment (80%) as compared to schizophrenia Multiple agents currently used in treatment – lithium, antiepileptic agents Atypicals increasingly used to treat bipolar depression Only 1 atypical currently approved for bipolar depression (Seroquel)

58

Key Takeaways

Large, growing market for atypical antipsychotics High rate of dissatisfaction and switch; need for new treatment options Increasing use for the treatment of bipolar disorder is a significant driver of atypical antipsychotic market growth Challenges Opportunities

59

Agenda

• I. Market and Disease State Overview
• II. Competitive Landscape

60 0% 5% 10% 15% 20% 25% 30% 35% 40% Jan-03 Jul-03 Jan-04 Jul-04 Jan-05 Jul-05 Jan-06 Jul-06 Jan-07 Jul-07 Jan-08 Jul-08

Atypical Antipsychotic Market Current Competitive Environment

SEROQUEL RISPERIDONE ABILIFY ZYPREXA GEODON CLOZARIL INVEGA RIS CONSTA

Seroquel is the clear market leader; impact of generic risperidone not yet evident

Source: IMS DataView TRx Share

61

Atypical Antipsychotic Market Perceptual Mapping in Schizophrenia

Safety/Tolerability Efficacy

Better-Tolerated Medications (i.e. limited weight gain, metabolic issues); Less Efficacious More Efficacious Medications; Less Well-tolerated (i.e. weight gain, metabolic issues, EPS)

Cognitive Functioning

New product

• pportunity

62

APS Market Evolution: New Competitors, Generic Entries

2009 2010 2012 2013 2014 2011

Fanapt (iloperidone) Saphris (asenapine) Serdolect (sertindole)

New Competitors Up to 3 new competitors within the next 12 months

Generic Olanzapine Generic Quetiapine Generic Ziprasidone Generic Paliperidone

Generic Entries Large brands turning generic 2011-2013

63

Antipsychotic Payer Mix

Dual Eligibles 7% Medicaid 23% Medicare Part D 17% Commercial Managed Care 39%

Public and private payers likely to increase control over utilization of branded products when more generics become available

Source: IMS Other 14% Manage access through tiered co-payments (higher co-pay for more restricted medications) Manage access through preferred drug lists (PDLs); manufacturers provide supplemental rebates to gain access to PDL

64

Key Takeaways

Highly competitive market with large brands New competitor launches pending Genericization of market beginning in 2011 will change market dynamics payers more likely to control utilization

• f branded products

Large, growing market for atypical antipsychotics High rate of dissatisfaction and switch; need for new treatment

• ptions

Increasing use for the treatment

• f bipolar disorder is a

significant driver of atypical antipsychotic market growth Market opportunity for more efficacious, better tolerated medications Challenges Opportunities

65

Disclaimer Regarding Forward- looking Statements

The statements made in this presentation material are forward- looking statements based on management’s assumptions and beliefs in light of information available up to the day of announcement, and involve both known and unknown risks and uncertainties. Actual financial results may differ materially from those presented in this document, being dependent on a number of factors. Information concerning pharmaceuticals (including compounds under development) contained within this material is not intended as advertising or medical advice.