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 Conventional Antipsychotics 5 Second-generation Antipsychotics 4 3 2 1 0 –1 –2 Mean Change in Body Weight (kg) Weight Body in Change Mean –3 o e e e l e e e e e e b n n n o n n l n n i d o i o i i in e o o z ri z d z p p c d id a e id a n a a a la n n r i d z z li s p e m t i P a e o o r r n lo r h l p r e o la Mo p p a S i C i is rp h O Z lu H R T F lo h C

Allison DB et al. Am J Psychiatry. 1999;156:1686-1696 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) 40 mg Lurasidone (n=118) 80 mg Lurasidone (n=123) 120 mg Lurasidone (n=121)

30 PEARL 1: PANSS Total ≥30% Responder Analysis

70% P=0.028 p=0.058 60% * † 52% 50% 50% 46%

40% 38%

30%

20% Percentage of Subjects Subjects of Percentage 10% n=122 n=119 n=124 n=124 0% Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo

31 PANSS Total: Per Protocol Population

Lur 40 mg Lur 80 mgLur 120 mg Placebo 0 n=100 n=89 n=94 n=102 -5

-10

-15

-20 LS Mean Change (LOCF) Change LS Mean -25 p=0.032* p=0.004* n=19 n=26 n=13 n=29 -30

32 PANSS Positive Subscale (MMRM)

Wk 6 Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Endpoint 0

* ** ** *** from Baseline -5 *** *** *** *** *** ** ** ***

LS Mean Change *** *** -10

Placebo (n=124) 40 mg Lurasidone (n=118) *p<0.05 80 mg Lurasidone (n=123) 120 mg Lurasidone (n=121) **p<0.01 ***p<0.001 33 CGI-S (MMRM)

Wk 6 Baseline Day 4 Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Endpoint 0.0

-0.3

-0.6 from Baseline * -0.9 0.025 * * 0.048 0.029 * 0.029 -1.2 *

LS Mean Change 0.009 * 0.006 -1.5 * 0.005 Placebo (n=124) 40 mg Lurasidone (n=122) 80 mg Lurasidone (n=119) 120 mg Lurasidone (n=124)

34 PEARL 1: Weight Change (LOCF)

1.5

1.0

0.5 0.3

0.0 n=364 Median Change from Baseline (kg) 0.0 Lurasidone Placebo (N=124)

35 PEARL 1: Simpson Angus Scale (SAS)

0.20

0.15

0.10 0.06 0.05 0.03

LS Mean Change LS Mean 0.01 n=124 0.00 n=122 n=119 n=124 -0.01 -0.05 Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo

SAS scored 0-5 on 9 items for max possible score of 45 36 PEARL 1: Barnes Akathisia Rating Scale (BAS)

Global Clinical Assessment

1.0

0.5

0.3 LS Mean Change Mean LS

0.1 0.1 0.0 0.0 Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo n=124 n=122 n=119 n=124

BAS scored 0-5 on Global Clinical Assessment of akathisia for a maximum possible score of 5 37 PEARL 1: Serum Prolactin

3.0

2.5

2.0

1.5

1.0 0.70

0.5 0.35 Median Change (ng/mL) Change Median

n=361n=361 n=122 0.0 n=122 Lurasidone Placebo

38 PEARL 1: Lipid Profile

Cholesterol HDL LDL Triglycerides 0

-2

-4

-6

-8

-10

Median Change (mg/dL) Median -12

-14 n=108/343 n=108/343 n=108/343 n=108/343

Placebo Lurasidone

LOCF endpoint values; fasting per protocol; includes all subjects 39 PEARL 1: QTcF Interval Change (LOCF)

10.0

8.0

6.0

4.0

1.9 2.1

Mean Change (msec) Change Mean 1.8 2.0 1.2

n=120n=120 n=117n=117 n=122n=122 n=120n=120 0.0 Lur 40 mg/d Lur 80 mg/d Lur 120 mg/d Placebo

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

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

6.2% Placebo (n=339) 11.2% Lurasidone 40 mg (n=241) Sedation 12.8% Lurasidone 80 mg (n=282) 11.6% Lurasidone 120 mg (n=173)

6.5% 10.8% Nausea 12.8% 6.5%

4.7% 8.7% Somnolence 10.6% 13.3%

4.1% 11.2% Akathisia 14.9% 21.4%

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, 41 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 on preclinical and clinical data

42 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

PotentialPotential forfor OngoingOngoing AdherenceAdherence toto TreatmentTreatment

43 LurasidoneLurasidone DevelopmentDevelopment ProgramProgram

44 PEARL 1 and 2 Trials: Lurasidone in Acute Schizophrenia

LurasidoneLurasidone 4040 mgmg

LurasidoneLurasidone 8080 mgmg StudyStudy 229229 LurasidoneLurasidone 4040-120-120 mgmg LurasidoneLurasidone 120120 mgmg PEARLPEARL #1#1 Open-label, 2 years PlaceboPlacebo

Double-blind, 6 weeks

LurasidoneLurasidone 4040 mgmg

LurasidoneLurasidone 120120 mgmg StudyStudy 231231 LurasidoneLurasidone 4040-120-120 mgmg OlanzapineOlanzapine 1515 mgmg PEARLPEARL #2#2 Open-label, 6 months PlaceboPlacebo

Double-blind, 6 weeks

N=480/study Lurasidone: QD dosing schedule 45 PEARL 3: Lurasidone in Acute Schizophrenia

LurasidoneLurasidone 8080 mgmg

StudiesStudies LurasidoneLurasidone 160160 mgmg LurasidoneLurasidone 4040-160-160 mgmg 233/234233/234 Quetiapine XR 600 mg PEARLPEARL #3#3 Quetiapine XR 600 mg QuetiapineQuetiapine XRXR 200200-800-800 mgmg

PlaceboPlacebo Double-blind, flexible dose, 1 year Double-blind, 6 weeks

N=480/study Lurasidone: QD dosing schedule 46 Long-Term Safety Study With Cognitive Sub-Study

Open-Label Double-Blind Phase Continuation Phase

LurasidoneLurasidone 4040-120mg/d-120mg/d N=N=400(200400(200 forfor subsub-study)-study)

LurasidoneLurasidone 4040-120mg/d-120mg/d Baseline Baseline Baseline Screening Screening Screening RisperidoneRisperidone 22-6mg/d-6mg/d N=N=200(100200(100 forfor subsub-study)-study)

6 Months ‹ MCCB ‹ UPSA-B

12 months 6 months

Cognition Sub-Study

MCCB: MATRICS Consensus Cognitive Battery UPSA-B: UCSD Performance-Based Skills Assessment - Brief Version 47 Atypical Use Has and Will Continue to Expand

Schizophrenia Bipolar Depression

Treatment-Treatment- AcuteAcute BipolarBipolar Depression/Depression/ MaintenanceMaintenance ResistantResistant ManiaMania DepressionDepression AnxietyAnxiety DepressionDepression

AtypicalsAtypicals

MoodMood StabilizersStabilizers

AntidepressantsAntidepressants

48 PREVAIL: Lurasidone in Bipolar Depression

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

Double-Blind Phase

（Study 235） LurasidoneLurasidone 2020-120-120 mg/dmg/d ++ LithiumLithium oror ValproateValproate PREVAILPREVAIL ScreeningScreening ExtensionExtension StudyStudy Baseline Baseline 3-28 days Baseline PlaceboPlacebo ++ LithiumLithium oror ValproateValproate Day 0 Total n=340 (n=170/arm).

（Study 236） LurasidoneLurasidone 2020-60-60 mg/dmg/d PREVAILPREVAIL ScreeningScreening LurasidoneLurasidone 8080-120-120 mg/dmg/d ExtensionExtension Study Baseline Baseline Study 3-28 days Baseline PlaceboPlacebo n=504 Day 0 Total n=504 (n=168/arm). 6 weeks EnrollmentEnrollment InitiatedInitiated 2Q2Q ’09’09 50 LurasidoneLurasidone Commercial Commercial OverviewOverview

Joseph Yen Lin Vice President, Marketing Dainippon Sumitomo Pharma America

51 Agenda

I. Market and Disease State Overview

II. Competitive Landscape

52 Market Overview Overall Growth

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

+11.0% $14 +12.4% $14.1B +11.9% $12 +8.6% $12.7B $10 $11.3B $10.1B $8 $9.3B

$6 Sales ($Billions)

$4

$2

$0 2004 2005 2006 2007 2008

Source: IMS NSP Data, 2004-2008

53 Market Overview Growth by Diagnosis

Growth in the atypical antipsychotic category is being driven by use in bipolar disorder and schizophrenia $14.1B

$14 $12.7B $11.3B $12 Bipolar $10.1B $5.0 Disorder $9.3B $4.4 $10 $3.4 $2.6 $8 $2.3 $3.3 Schizophrenia $2.8 $2.2 $2.8 $6 $2.1 Sales ($Billions) $1.3 Depression $1.3 $1.3 $1.5 $4 $1.4 $0.6 Anxiety $0.4 $0.6 $0.6 $0.6 Other $2 $3.6 $3.8 $2.9 $3.2 $3.4

$0 2004 2005 2006 2007 2008

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

54 Schizophrenia Disease State Overview Patient Flow

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

Diagnosis/ Evaluation ‹ High rates of diagnosis (80%) and treatment (85%) ‹ Atypical antipsychotics considered Treatment the gold standard for schizophrenia

Continuation ‹ High rates of patient discontinuation and switching • Lack of efficacy • Side effects • Need for new treatment options

55 Schizophrenia Disease State Overview Landmark CATIE Trial

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

“…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.”

56 Bipolar Disease State Overview Patient Flow

‹ U.S. lifetime prevalence of bipolar Origination disorder is 2.6%; over 6 million affected

Diagnosis/ ‹ Relatively lower rates of diagnosis Evaluation (45%) and treatment (80%) as compared to schizophrenia ‹ Multiple agents currently used in Treatment treatment – lithium, antiepileptic agents ‹ Atypicals increasingly used to treat bipolar depression Continuation ‹ Only 1 atypical currently approved for bipolar depression (Seroquel)

57 Key Takeaways

Opportunities Challenges

‹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

58 Agenda

I. Market and Disease State Overview

II. Competitive Landscape

59 Atypical Antipsychotic Market Current Competitive Environment

Seroquel is the clear market leader; impact of generic risperidone not yet evident 40%

35% SEROQUEL

30%

25% RISPERIDONE

20% TRx Share

15% ABILIFY ZYPREXA 10%

GEODON 5% CLOZARIL INVEGA 0% RIS CONSTA

3 3 4 4 5 5 6 6 7 7 8 8 -0 0 -0 0 -0 0 -0 0 0 0 0 0 n l- n l- n l- n l- n- l- - l- a u a u a u a u a u an u J J J J J J J J J J J J

Source: IMS DataView

60 Atypical Antipsychotic Market Perceptual Mapping in Schizophrenia Cognitive Functioning

Better-Tolerated New product Medications (i.e. opportunity

limited weight gain, y

t metabolic issues);

i

l i

b Less Efficacious

a

r

e

l

o T

/ More Efficacious

y t

e Medications; Less f

a Well-tolerated (i.e. S weight gain, metabolic issues, EPS)

Efficacy

61 APS Market Evolution: New Competitors, Generic Entries

Saphris (asenapine) Up to 3 new competitors Fanapt Serdolect within the next 12 months (iloperidone) (sertindole) New Competitors 2009 20102011 2012 2013 2014

Large brands turning Generic Generic Olanzapine Paliperidone generic 2011-2013 Generic Generic

Generic Entries Quetiapine Ziprasidone

62 Antipsychotic Payer Mix

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

Dual Eligibles 7%

Medicare Part D Medicaid 17% 23% Manage access through preferred drug lists (PDLs); Manage access through manufacturers provide tiered co-payments supplemental rebates to (higher co-pay for more gain access to PDL restricted medications)

Other Commercial 14% Managed Care 39%

Source: IMS

63 Key Takeaways

Opportunities Challenges

‹Large, growing market for ‹Highly competitive market with atypical antipsychotics large brands ‹High rate of dissatisfaction and ‹New competitor launches switch; need for new treatment pending options ‹Genericization of market ‹Increasing use for the treatment beginning in 2011 will change of bipolar disorder is a market dynamics Æ payers significant driver of atypical more likely to control utilization antipsychotic market growth of branded products ‹Market opportunity for more efficacious, better tolerated medications

64 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.

65