R&D Meeting...2013/03/25 · Source：Byerly.M.: the 41 st annual meeting of the American College of Neuropsychopharmacology, Dec. 10, 2002 Adherence Issue with Antipsychotics 3 61.9%

0

R&D Meeting

March 21, 2013

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1

Source：Byerly.M.: the 41st annual meeting of the American College of Neuropsychopharmacology, Dec. 10, 2002

Adherence Issue with Antipsychotics

3

61.9%

5.3% 0%

10%

20%

30%

40%

50%

60%

70%

チップによる集計で飲んでいないと判定された患者さん

医師が飲んでいないと判断した患者さん

Patients assessed as non-adherence by doctor

Assessment of the antipsychotic adherence by an electronic monitoring device (called the MEMS(R) cap), which recorded how often the container of medicine, was opened and at what time of day.

Definition of non-adherence: Taking of <70% of prescribed antipsychotics

Valenstein, M., et al.: Med. Care,40,630-639,2002

31.7 29.5 28.1

25.9 23.4

18.5 17.0 13.4

11.2 8.3

05

10152025303540

10 20 30 40 50 60 70 80 90 100

MPR（Medication Possession Ratio)＝Prescribed days／treatment days

• Relapse rate of schizophrenia gets higher with poor adherence

• When medication discontinued, 60% of the patients relapsed within 1 year

（Johnson, D.A.W.: J. Clin. Psychiatry, 45（5）, 13-21, 1984）

Poor Adherence Good

Relationship between re-hospitalization rate and adherence （N=48,148）

Cohort study by Veterans Health Administration

Def

ined

as

non-

adhe

renc

e (%

)

Patients assessed as non-adherence by MEMS

Re-

hosp

italiz

atio

n ra

tio fo

r 1 y

ear (

%)

MPR (%)

Current estimate of

patients treated: 70,000

Among them, 10% need treatment due to symptom deterioration:

Approx. 200,000 patients

Launch of ABILIFY MAINTENA

4

アリピプラゾール持効性注射剤（IMデポ製剤）

65% of them stop medication due to poor adherence:

1.95 million patients

Treated with oral schizophrenia drugs: 3 million patients (US)

Room for market

expansion up to 200,000

4

Treatment with depot formulation

1,425 1,500 1,588

21 134

579 180

224

4 54

238

474

849

1,128 1,309

1,446

1,814

2,391

0

500

1,000

1,500

2,000

2,500

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

ZYPREXA RELPREVV

INVEGA SUSTENNA

RISPERDAL CONST

$ Mil

Atypical antipsychotics depot market (global)

• Global depot market ：$ 2,391Mil - CAGR(2007-2011）： 20.7% - RISPERDAL CONSTA : 8.9%

Source：Annual report of each company

A

Launch of ABILIFY MAINTENA

アリピプラゾール持効性注射剤（IMデポ製剤） ABILIFY MAINTENA（IM depot）

Indication: Maintenance phase of schizophrenia in adults Dosage and administration: Administered into gluteus

muscle once in 4 weeks. At the initial injection, oral aripiprazole or other oral antipsychotics is concomitantly used for 2 weeks. Thereafter, depot monotherapy starts.

Reconstitute before use：Reconstitute the lyophilized powder with sterile water（2ml）

Most commonly observed adverse event: akathisia Differentiation from existing drugs

– High tolerability suggested by its safety profile – Administration frequency: once monthly (IM) – Room-temperature storage – 21G injection needle, limited discomfort to patients – Formulation patents: October, 2024 (Japan, US, EU)

Aripiprazole: Highly evaluated safety profile

self-developed formulation technology (administered

once monthly)

Depot formulation with excellent adherance and

long-term safety ＝ +

5

kit includes: Syringe with pre-attached needle,

vial of Abilify Maintena, etc.

Kit Package （400mg、300mg）

ABILIFY MAINTENA

Development History (US) - October 2010: Independent Data-Monitoring Committee’s interim analysis results for

Phase 3 study (placebo-controlled for schizophrenia) met efficacy and safety criteria for termination. The early study termination was recommended.

- September 2011: NDA submission - February 28, 2013: Approval - March 18, 2013: Launch Development History (EU) - Phase 3 study (non-Inferiority to oral Abilify for schizophrenia): completed - December 2012: EMA submission Development History (Japan) - Phase 3 study (non-Inferiority to oral Abilify for schizophrenia): ongoing Other indications - Bipolar disorder: Phase 3 (US & EU)

6

Formulation Technology

100

200

300

400

plasma concentration

（ng/ml）

Week 1 Week 2 Week 3 Week 4

No. of PK samples: 14 1)Abilify 30mg oral

tablet :Cmax 424ng/ml, trough 286ng/ml,

2) Abilify 10mg oral tablet: Cmax: 147ng/ml, trough 94ng/ml

Abilify 30mg oral tablet 1)

Abilify 10mg oral tablet2)

Pharmacokinetics parameter

ARI-ERIS- 400

(N=12）

ARI-ERIS- 300

（N=8)

ARI-ERIS- 200

（N=4)

Css,max ng/mL(SD) 316(160) 269(128) 100(68.4)

tmax day(median) 7.1(3.0-11.2) 6.5(0.5-21.2) 5.0(4.0-27.9)

AUC, mg-h/mL(SD) 163(88.8) 140(58.4) 54.5(39.4)

t1/2,Z day(SD) 46.5(10.8) 29.9(8.0) ND

Css,min ng/ml(SD) 212(113) 156(67.7) 95.0(86.2)

Pharmacokinetic Study

Source：Pharmacokinetic Study of Once-Monthly Aripiprazole Extended-Release Injectable Suspension in Adult Patients with Schizophrenia (164th Annual Meeting of the American Psychiatric Association, 14–18 May 2011, Honolulu, Hawaii) 7

ABILIFY MAINTENA P-3 Study Design

8

1)PANSS：Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 2)CGI-S： General assessment method. Assessment of general improvement level

Double-blind maintenance（52w）

Phase-4

ABILIFY MAINTENA 400mg or 300mg

N=269

Placebo N=134

Screening N1,025

(-42～-2Days)

Phase-0

Conversion N=843

(4～6w)

Phase-1

Oral stabilization

N=710 (4～12w)

Phase-2

ABILIFY MAINTENA stabilization

N=576 (12～36w)

Phase-3

R

Subject： Patients diagnosed with schizophrenia for at least 3 years (excluding newly diagnosed patients)

Assessments - Primary endpoint

• Time-to-impending relapse - Secondary endpoints

1) Proportion of subjects meeting impending-relapse 2) Mean changes in PANSS1) from baseline 3) Mean change in CGI-S2) from baseline

ABILIFY MAINTENA P-3 Study Results

9

20%

40%

60%

80%

100%

0 28 56 84 112 140 168 196 224 252 280 308 336 364

Hazard ratio 5.03 Long-rank test: p<0.0001

Placebo

Days from randomization

Pro

porti

on o

f sub

ject

s fre

e of

im

pend

ing

rela

pse

Aripiprazole IM depot

Time from randomization to impending relapse during double-

blind treatment

3.0%

5.6%

5.9%

5.9%

5.9%

9.7%

10.0%

3.7%

6.0%

1.5%

5.2%

7.5%

9.7%

9.0%

0% 2% 4% 6% 8% 10% 12%

注射部位痛

アカシジア

振戦

頭痛

不安

体重増加

不眠

プラセボ

アリピプラゾールIMデポ Aripiprazole IM depot

Adverse Events: >5% 1)

1) Depot formulation has less adverse events by temporal elevation of plasma concentration when administered oral tablet.

Primary endpoint: Time-to-impending relapse - ABILIFY MAINTENA significantly delayed time to

impending relapse - Relapse rate at 80 events of relapse (termination

criteria) Placebo: ABILIFY MAINTENA = 10.0%: 39.6%

Insomnia

Weight gain

Anxiety

Headache

Tremor

Akathisia

Injection-site pain

Placebo

Source: W. Wolfgang Fleischhacker et al., 165th Annual Meeting of the American Psychiatric Association, May 5–9, 2012, Philadelphia, PA

Comparison with competitive products Brand Name ABILIFY

MAINTENA® RISPERDAL CONSTA®

ZYPREXA RELPREVV®

INVEGA SUSTENNA®

Generic Name Aripiprazole Risperidone Olanzapine Paliperidone

Sales （2012）

• US：$484M • EU-5：€352M • JP：¥ 12B

• US：$11M • EU-5：€11M

• US：$557M • EU-5：$137M

Indications

Maintenance therapy for schizophrenia in adults

Schizophrenia, monotherapy or adjunctive therapy for maintenance of bipolar disorder

Acute and maintenance therapy for schizophrenia in adults

Acute and maintenance therapy for schizophrenia in adults

Concurrent use of oral tablet

Aripiprazole or other antipsychotic for 2 weeks

Risperdal or other antipsychotic for 3 weeks

Oranzapine for 2 – 4 weeks

Paliperidone or risperidone

Admn. interval 4 weeks 2 weeks 2 or 4 weeks 4 weeks

Injection site Gluteus Deltoid, gluteus Gluteus Deltoid, gluteus

Preparation Reconstitute before use （2ml）

Reconstitute before use（2ml）

Reconstitute before use （1～2.7ml）

Pre-filled syringe (0.5～1.5ml）

Storage Room temperature （< 30c）

Cold dark place (2～8 c）

Room temperature （< 30c）

Room temperature （15-30c）

Needle • 21G • 21G （deltoid） • 20G （gluteus）

• 19G（gluteus） • 22G(deltoid, gluteus) • 23G(deltoid)

10 Source: FDA

Three therapeutic options for patients with severe CNS disorders

Dis

ease

insi

ght

(Lev

el o

f und

erst

andi

ng o

f adh

eren

ce)

Relapse risk when not taking medicine (number of past hospitalizations)

+ _

Tablet

Understands the importance of adherence

Little experience of relapse

Smart Tablet

Understands the importance of adherence, but relapse occurs

frequently due to poor adherence

Abilify Maintena

Does NOT understand the importance of adherence and poor adherence

+

_

11

Brexpiprazole

Abilify

Partial Agonist

Second generation antipsychotics Dopamine-Serotonin Antagonist

First generation antipsychotics Dopamine Antagonist

Evolution of Otsuka’s CNS Research (partial agonist)

13

Product Concept • World first D2 dopamine partial agonist

• Distinct efficacy and safety profile

Patients Concept

• Long-term administration for social reintegration

Brexpiprazole Product Concept

• Better safety profile • Creation of new

market category with its wider affinity

Patients Concept

•Usefulness in quite different diseases

Schizophrenia

Bipolar disorder

MDD

Pediatrics

New indications

Brexpiprazole – New Partial Agonist Binding affinity to each receptor

Increased binding activity at 5-HT2A

receptor

Reduced intrinsic activity at D2

receptor

Decreased Irritation, nausea, vomiting

Therapeutic efficacy in negative

symptoms of schizophrenia

D2 D3 5-HT2A 5-HT1A α1A 5-HT2A/D2 α1A/D2

Brexpiprazole 0.29 1 0.47 0.12 3.8 1.6 13

Aripiprazole 0.87 1.1 4.7 1.3 52 5.4 60

Risperidone 1.9 - 0.22 - 0.60 0.043 0.31

Olanzapine 11 - 0.49 - 9.4 0.11 0.82

14

Partial agonist activity to D2 receptor

Source：Kikuchi T et al., Society of Biological Psychiatry 66th Annual Meeting (2011)

Brexpiprazole P-2 Study Result for Major Depressive Disorder

8 weeks Prospective treatment

6 weeks randomized

Screening (7-28 days)

N=850 NCT00797966

Placebo＋ADT (N=126）

Primary endpoint

•MADRS2)

Secondary endpoint

•CGI-S3) •IDS4) •SDS5)

Placebo +

ADT1)

Single-blind • Select patients with

an inadequate response to ADT

P=0.006 P=0.016

15

0.15mg Brexpiprazole ＋ ADT (N=62）

0.5mg±0.25mg Brexpiprazole＋ ADT (N=119）

1.5mg±0.5mg Brexpiprazole ＋ ADT (N=119）

Weeks after Randomization

Mea

n ch

ange

in M

AD

RS

Tot

al S

core

Placebo 0.15 mg 0.5±0.25 mg 1.5±0.5 mg

*

* * * * *

Secondary endpoints Mean change from baseline to CGI-S, IDS,

SDS

P=0.002

1) Antidepressant therapy; Desvenlafaxine, Escitalopram , Fluoxetine , Paroxetine CR , Sertraline , Venlafaxin, 2) MADRS：Montgomery-Asberg Depression Rating Scale, 3) CGI-S：Clinical Global Impression – Improvement scale, 4) IDS: Inventory of Depressive Symptoms, 5) SDS: Sheehan Disability Score

Primary endpoint Mean change from baseline to MADRS

Source： Michael E. Thase et al., ACNP 50th Annual Meeting

Source： Michael E. Thase et al., ACNP 50th Annual Meeting

Brexpiprazole P-2 Study Result for Schizophrenia

6 weeks treatment

Screening and washout

(14 days)

1 mg （N=88）Brexpiprazole

2.5 mg （N=90）Brexpiprazole

5 mg （N=92）Brexpiprazole

Primary endpoint: PANSS1)

Placebo （N=93）

15 mg±5mg （N=50）Aripiprazole

0.25 mg （N=41）Brexpiprazole

1)PANSS：Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 16

Enrollment N=454

NCT00905307

P-2 study for schizophrenia [dosage] - non-effective dose: 0.25 mg/day - effective dose range:1.0 – 5.0 mg/day [efficacy] -The placebo group exhibited higher than expected improvement making the results of this study difficult to interpret. -Improvements were similar to those observed with aripiprazole -Improvements in negative symptoms and cognition were greater than aripiprazole

-20

-15

-10

-5

0

0 1 2 3 4 5 6

Inpr

ovem

ents

from

bas

elin

e on

the

PAN

SS to

tal s

core

Week of treatment

Placebo

0.25mg OPC1mg OPC

2.5mg OPC

5mg OPC

Aripiprazole 15mg

Source：R. McQuade et al., 24th Annual US Psychiatric and Mental Health Congress

17

5.7%

6.1%

7.0%

8.3%

8.9%

10.8%

10.8%

2.0%

10.0%

6.0%

4.0%

10.0%

10.0%

8.0%

2.1%

4.2%

3.2%

4.2%

10.5%

10.5%

16.8%

0% 5% 10% 15% 20%

悪心

焦燥

体重増加

アカシジア

不安

頭痛

不眠

プラセボ

エビリファイ

Brexpiprazole

Incidence of adverse events in ≥5% of patients receiving brexpiprazole (schizophrenia)

Insomnia

Headache

Anxiety

Akathisia

Weight increased

Agitation

Nausea

Placebo

Placebo

Abilify

Brexpiprazole P-2 Study Result for Schizophrenia

Under Development：Brexpiprazole P-3 Study for Schizophrenia

6 weeks treatment

Enrollment N=660

NCT01393613

Lower dose (once daily)

Middle dose (once daily)

Higher dose (once daily)

Primary endpoint

• PANSS

Secondary endpoint

• CGI-S Placebo

Enrollment N=630

NCT01396421

1)PANSS：Positive and Negative Syndrome Scale. A medical scale used for measuring symptom severity of patients with schizophrenia. The scales consist of 7 positive scale items, 7 negative scale items and 16 general psychopathology scale items. 2) CGI-S: Clinical Global Impression – Improvement scale 18

Screening

Washout (14 days)

Enrollment N=1,000

NCT01397786

4 weeks treatment

1～2mg/ day

52 weeks treatment (open label) 1～4mg/ day

Long-term safety study

8～12 weeks treatment

52 weeks treatment (open label)

0.5～3mg Brexpiprazole + ADT

8 weeks treatment

Under Development：Brexpiprazole P-3 Study for MDD

6 weeks treatment

Enrollment N=826

NCT01360645 Placebo + ADT

2 mg Brexpiprazole + ADT

Placebo + ADT

3mg Brexpiprazole + ADT

1 mg Brexpiprazole + ADT

Primary endpoint

・MADRS

Secondary endpoint

・SDS

Enrollment N=1,650

NCT01360632 Placebo + ADT

19

Placebo + ADT

1～3mg Brexpiprazole + ADT Enrollment

N=1,340 NCT01727726

Placebo + ADT

Placebo + ADT

Seroquel XR + ADT

Enrollment N=3,000

NCT01360866

Further Development of Dopamine Partial Agonist

20

behavioral disorder

Mental disorder, Mood disorder

anxiety disorder Depression

Bipolar Schizophrenia

Abilify

Brexpiprazole

Brexpiprazole creates new category which Abilify doesn’t have.

E Keppra

Levetiracetam

Mechanism of Levetiracetam Levetiracetam

Shows antiepileptic action by regulating the release of excitatory and inhibitory neurotransmitters (glutamine, GABA, etc.) from the presynaptic region by binding to synaptic vesicle protein SV2A

The synaptic vesicle cycle Synaptic vesicles: Cycle of vesicles containing

neurotransmitters existing inside presynaptic nerve terminals

Role of synaptic vesicles (1) Load neurotransmitters into synaptic vesicles via

transporters

(2) Transport synaptic vesicles inside the cell via trafficking proteins

SV2: One of the synaptic vesicle proteins SV2: a glycoprotein that penetrate the synaptic

vesicle membrane 12 times; has three subtypes (2A, 2B, and 2C)

Its physiological role has not been elucidated in detail, but it is thought to be involved in the release of neurotransmitters.

Characteristics of Levetiracetam Characteristics: (1) binds to synaptic vesicle protein

2A (SV2A); (2) inhibits N-type calcium (Ca2+) channels; (3) inhibits intracellular release of Ca2+; (4) opposes allosteric inhibition of GABA- and glycine-gated currents; and (5) inhibits neuronal hyper-synchronization

High affinity for SV2A (not seen in any other existing antiepileptic drugs) 22

The synaptic vesicle cycle

priming (3) docking (4) calcium

sensing

(5) fusion (exocytosis)

(6) reuptake (endocytosis)

storage

(1) loading

(2) mobilization

translocation

(7) coat protein removal (8) recycling

Synaptic vesicle

Source: Richmond J et al., WormBook : the online review of C. elegans biology 2005

Epilepsy Epilepsy: a disease whose cardinal symptom is recurrent seizures with excessive excitement

(electrical discharge) in brain cell networks due to various causes and associated with diverse symptoms besides seizures such as a decline in consciousness and motor function.

- Seizures recur as a result of increased seizure readiness - May develop due to encephalitis, meningitis, or brain trauma due to traffic accident or other causes.

Characteristics: Recurrent seizures that occur repeatedly at regular intervals and that will continue to recur without appropriate treatment

- Opportunistic convulsions: convulsive seizures such as convulsions in an infant with a fever (febrile convulsions) or that occur from heavy drinking or during childbirth. Opportunistic convulsions are different from epilepsy, since seizures do not recur after recovery from the medical condition.

Idiopathic epilepsy: unknown etiology - Symptomatic epilepsy: caused by encephalitis, brain tumor, or brain trauma (with clear cause)

Site of onset: seizure symptoms can be extremely varied, and the method of treatment differs depending on the seizure symptoms

- Partial seizures: excessive excitement of the brain occurs and spreads out from one part of the brain - Generalized seizures: excessive excitement deep within the brain spreads throughout the entire brain

Four major classifications of epilepsy Type of seizure

Partial seizures Generalized seizures

Cause Unknown etiology • Idiopathic localization-

related epilepsy • Idiopathic generalized

epilepsy Caused by organic disorder of the brain resulting

from a tumor or traffic accident, etc. • Symptomatic localization-

related epilepsy • Symptomatic

generalized epilepsy 23

Diagnosis

Symptoms and Diagnosis of Epilepsy Pathogenic mechanisms of epilepsy

24

(1) Seizure at the cellular level due to increased electrical activity

(2) Synchronization with surrounding neurons

• Decline in GABA inhibition • Increase in extracellular

potassium concentration • Open NMDA channels

(3) Propagation to adjacent regions of the brain

Normal condition • Surround inhibition

caused by the refractory period of ion channels and GABAergic neurons

Primary symptoms - Convulsions: tonic, clonic, and other forms of

involuntary movement - Disturbance of consciousness: transient (several

minutes to more than 10 minutes) followed by recovery

Detailed history taking

Classification Localization-

related, generalized

EEG

Seizures and syndrome

Pathological diagnosis

Video-EEG Neuroimaging

Definitive diagnosis

Source: Societas Neurologica Japonica, Treatment Guidelines for Epilepsy 2010

Antiepileptic Drug Market

Antiepileptic market (Japan) - No new drug has been approved in the epilepsy

market after clobazam was launched in 2000. - Since 2006, new drugs, including gabapentin, have

been launched, indicated as add-on therapy to existing drugs for non-responders. Sales of such products are added onto those of existing products.

- ¥48 billion market in 2012, with add-on portion of new drugs pushing up the market

25

Patients diagnosed with epilepsy:

930,000 (0.7% of population)

Patients treated with drugs: 830,000

(89% of diagnosed patients)

Generalized seizures

(40% of patients treated with drugs)

Partial seizures (60% of patients

treated with drugs)

Refractory (22% of patients

treated with drugsto )

Source: Decision Resource 2013

127 127 131 135 138 137 140 136

32 32 33 33 33 31 31 29

90 87 86 88 88 87 87 88

1 6 13 18 22 19 166 14 19 23 25 7

24 49

94 2

32

87

249 246 256275

298323

381

476

0

50

100

150

200

250

300

350

400

450

500

2005 2006 2007 2008 2009 2010 2011 2012

LEVETIRACETAM

LAMOTRIGINE

TOPIRAMATE

GABAPENTIN

Others

ZONISAMIDE

VALPROIC ACID

LaunchedGABAPENTIN

LaunchedTOPIRAMATE

LaunchedLAMORTIGINE

LaunchedLEVETIRACETAM

Antiepileptic Drug Market (Japan)100 mil Yen

Source：IMS 2013

Epilepsy Therapeutic Algorithm (NHS) Epilepsy treatment

(first stage)

Reconsider diagnosis

Consider alternative monotherapy

Consider surgical treatment

Consider combined treatment

Seizures not controlled



Consider surgical treatment



Refer to a third-party epilepsy specialist

Seizures controlled (follow-up)

•Consider discontinuing treatment if no seizures for two years

Partial: 82% monotherapy Generalized: 85% monotherapy

Partial: 54.1% combined regimen Generalized: 44.3% combined regimen

Partial: 74% combined regimen Generalized: 65% combined regimen

26

Mechanism of Antiepileptic Drugs

27

Excitatory neurotransmission

(glutamic acid neurons)

Na+ channels Glutamate receptors

Inhibitory neurotransmission

(GABA neurons)

SV2A

L-type Ca2+ channels

GABA receptors

SV2A

Ca2+ channels

AMPA/KA receptors

Phenytoin

Carbamazepine

Benzodiazepine

Topiramate

Topiramate Levetiracetam

Benzodiazepine

T-type Ca2+ channels

Valproic acid

Phenobarbital

Topiramate

Levetiracetam Gabapentin

Phenobarbital

Topiramate

Valproic acid

Rufinamide

Lamotrigine

Comparison of Mechanism among Antiepileptic Drugs

Substance Na2+

channels K+

channels Ca2+ channels GABA

nervous system

Glutamic acid nervous system

SV2A N L P/Q T

Phenytoin (PHT) ++ (+) + - Carbamazepine (CBZ) ++ (+) -

Zonisamide (ZNS) ++ + - Lamotrigine (LTG) ++ + + Valproic acid (VPA) ++ (+) + - Gabapentin (GBP) + ++ + (+) -

Ethosuximide (ESM) - ++ Diazepam (DZP) (+) (+) ++ -

Phenobarbital (PB) + (+) ++ (+) - Topiramate (TPM) + + + + ++

Levetiracetam (LEV) - + - - - ++ 28

++: strong effects, +: moderate effects, (+): slight effects, -: no effect (Source: Quoted from Sasa., J. jpn. J. Psychopharmacol. 13, 1671-1683 (2010))

6.11

19.6

27.7

0

10

20

30

40

Pracebo (n=65) LEV1000mg(n=64)

LEV3000mg(n=63)

(%)

* patients failed 1-3 existing antiepilepitic drugs (half of them have been receiving 3 drugs) and were not well responded to those drug(s.)

Analysis of N165 Study in Japan

Precentage reduction in seizure frequency in partial epilepsy case

（Wilcoxon rank sum test）

p=0.007

p=0.005

Prec

enta

ge re

duct

ion

in s

eizu

re fr

eque

ncy

(Med

ian)

Observation period (12 weeks)

Partial Epilepsy P-2/3 Short-term Trials in Japan

29

Titration period (4 weeks)

Assessment period (12 weeks)

1,000mg/day 2,000mg/

day

3,000mg/day

500mg/day 1,000mg/day

1-3 existing antiepileptic drugs



Levetiracetam 3,000mg group

(n=71)

Levetiracetam 1,000mg group

(n=72)

Placebo group (n=70)

Number of Concomitant AEDs

Primary endpoints Partial seizure frequency

Secondary endpoints Percentage reduction in partial

seizure frequency 50% responder rate Percentage of seizure-free

subjects Percentage reduction in seizure

frequency by partial seizure type

Characteristics of Levetiracetam 1. Inhibits seizures by binding to SV2A

The higher the binding affinity for SV2A of levetiracetam derivatives, the stronger the anticonvulsant action

2. Opposes inhibition by allosteric inhibitors of GABA-gated currents Activation of GABAergic nerves

3. Inhibits intracellular release of Ca2+ Different action from other drugs

Shows no affinity for receptors such as GABAA/B benzodiazepine receptors or glutamate receptors nor for transporters or second messengers

Has no effect on the main action-targets (Na+ channels and T-type Ca2+ channels) of existing antiepileptic drugs

Does not affect hepatic metabolic enzymes No need for titration (effective dose can be used

right from the initial administration) AE incidence: comparable to placebo Partial seizure frequency: reduction seen vs.

placebo - Enhanced effects is be expected from

concomitant use with other drugs.

Correlation between affinity of similar compounds for human SV2A (hSV2A) and inhibitory effects on audiogenic seizures (pED50)

pKi o

f bin

ding

to h

SV2A

pED50 for inhibitory effects on audiogenic seizures

30

Kaminski R. M. et al., Neuropharmacology 2008

Rotigotine

for Parkinson’s Disease

Parkinson’s Disease Causes - Attributable to a decline in dopamine content in the striatum resulting from degeneration of dopamine-

secreting cells in the substantia nigra pars compacta of the midbrain - Abnormalities in dopaminergic neurotransmission in the basal ganglia cause malfunction of the loop

circuit running through the motor area in the cerebral cortex of the frontal lobe and the basal ganglia, leading to development of serious motor disorders such as akinesia, rigidity, and tremors

Signs and symptoms - Four cardinal characteristics: akinesia/hypokinesia, tremor at rest, muscular rigidity, and disturbance of

posture and gait - Other symptoms

• Non-motor symptoms: constipation, drooling, orthostatic hypotension (autonomic nervous symptom), postprandial hypotension, hyperhidrosis, and dysphagia resulting from muscle stiffening in the face and throat, etc.

• Psychiatric symptoms: apathy, anhedonia, anxiety, depression (complication in 60% of cases), visual hallucinations, and cognitive impairment

Diagnostic criteria (2011 Treatment Guidelines for Parkinson’s Disease)

32

Neurologic findings

1. Tremor at rest 2. Akinesia/hypokinesia: mask-like face; low, monotone

voice; slow movement; inability to change posture readily 3. Muscular rigidity with the cogwheel phenomenon 4. Disturbance of posture and gait: forward-flexed posture;

no hand shaking while walking; difficulty stopping once starts walking (pulsion); short-stepped gait; impaired righting reflex

Clinical laboratory findings

1. No abnormalities on general tests 2. No abnormalities on brain imaging tests (CT, MRI)

Differential diagnosis

1. not a drug-induced illness 2. Symptoms improve with L-DOPA administration 3. Neurodegenerative disease showing characteristic

findings and parkinsonism due to cerebrovascular disease ruled out

Stage Hoehn & Yahr Scale (medical subsidy for stage 3 and above)

1 • Unilateral parkinsonism

2 • Bilateral parkinsonism without impairment of balance

3 • Mild to moderate bilateral parkinsonism; impairment of balance; assistance not needed

4 • Severe parkinsonism; impairment of balance; still able to walk or stand unassisted

5 • Wheelchair bound or bedridden unless aided; difficulty walking even with assistance

Gowers: A manual of diseases of the nervous system, 1893

Basal ganglia Striatum (GABA)

Parkinson’s disease • Decline in dopamine content in the striatum resulting

from degeneration and loss of dopaminergic cells in the substantia nigra

• D1 receptors: GABAergic neurons have a weak inhibitory effect, since there is no excitatory effect, due to little binding of dopamine

• D2 receptors: GABAergic neurons have a strong inhibitory effect, since there is no inhibition due to little binding of dopamine

Direct pathway • Loss of excitatory input attenuation of cell activity

neural activity increases in globus pallidus internal segment

Indirect pathway • Loss of inhibitory input cellular activity increases

attenuation of neural activity in globus pallidus external segment subthalamic nuclei neural activity increases neural activity accelerates in globus pallidus internal segment

Depletion of dopamine in the striatum in Parkinson’s disease works to increase neural activity in the globus pallidus internal segment, as motor information passes through either direct or indirect pathway, ultimately inhibiting activity in the thalamus and motor area.

Basal Ganglia Loop (Parkinson’s disease)

33

Cerebral cortex (glutamate)

Thalamus (glutamate) Motor thalamic nuclei

D1 receptors

D2 receptors

Globus pallidus internal segment/ substantia nigra pars reticulata (GABA)

Globus pallidus external segment

(GABA)

Midbrain substantia nigra pars compacta

Subthalamic nucleus

(glutamate)

Direct pathway

Indirect pathway

Brain stem/ spinal cord

Parkinson’s Disease Normal

• Dopamine has inhibitory and Acetylcholine has excitatory effect for GABAergic neuron, both controlling GABAergic neuron.

Dopaminergic neuron

Cholinergic neuron

GABAergic neuron

• Dopamine has inhibitory effect for cholinergic and GABAergic neuron.

• Acetylcholine has excitatory effect for GABAergic neuron.

Dopaminergic neuron

Cholinergic neuron

GABAergic neuron

Parkinson’s Disease

• The lack of dopamine causes increase of acetylcholine effect by decrease inhibitory effect of dopamine. Inhibitory effect of dopamine for GABAergic neuron also decrease, resulting the increase of the excitatory effect.

Excitatory effect

Dopamine receptor

Acetylcholine receptor

corpus striatum

corpus striatum

34

Dyskinesia (-) Dyskinesia (+)

Dyskinesia (-)

Dyskinesia (+)

Parkinson’s Disease Therapy

35

Initial Parkinson’s disease therapy/diagnosis

No interference with daily life

Interference with daily life

Diagnosis every 3-6 months

Under age 70 with no dementia

Above age 70 or has dementia

Non-ergot-derived dopamine agonists

Inadequate improvement Ergot-derived

dopamine agonists

L-DOPA combination (L-DOPA + DCI)

Advanced stage Wearing-off phenomenon

Anticholinergic agent

Dopamine releasing agent

MAO-B inhibitor

Zonisamide


Dopamine agonist L-DOPA combination ＋

Dopamine agonist L-DOPA combination

＋


Dopamine releasing agent MAO-B inhibitor

Zonisamide


＋


＋

Advanced stage Wearing-off phenomenon

Dopamine agonist

DCI: decarboxylase inhibitor

Midbrain substantia

nigra

Pharmacological Effects of Antiparkinson Drugs

36

Norepinephrine

Dopamine

Norepinephrine precursor

L-DOPA

L-tyrosine

DOPA decarboxylase

inhibitor Levodopa

Dopamine 3-O-methyldopa (3-OMD)

Peripheral COMT inhibitor

Tyrosine hydroxylase

DOPA decarboxylase

Dopamine-β- hydroxylase

DOPA decarboxylase

＋

Catechol-O-methyltransferase

(COMT)

3,4-dihydroxyphenylacetic

acid (DOPAC)

Homovanillic acid (HVA)

GA

BA

ergi

c ne

uron

Monoamine oxidase (MAO)

3-MT

Acetylcholine nervous system

MAO-B inhibitor

Monoamine oxidase (MAO)



Dopamine agonist


(COMT)


(COMT)

MAO-B inhibitor

T-Type Ca channel blockade

Existing Products

Drug Generic name Brand name Dopamine precursor (L-DOPA formulation) Levodopa Menesit

Levodopa + DCI Levodopa/Benserazide (combination) Madopar Levodopa/Carbidopa (combination) Menesit

Dopamine releasing agent Amantadine Symmetrel

Norepinephrine precursor Droxidopa Dops

Dopamine receptor agonists (Dopamine agonists)

Ergot-derived agonists

Bromocriptine Parlodel Cabergoline Cabaser

Pergolide Permax

Non-ergot-derived agonists

Ropinirole Requip Talipexole Domin

Pramipexole BI Sifrol

Anticholinergic agents Trihexyphenidyl Artane

Biperiden Akineton Profenamine Parkin

COMT inhibitor Entacapone Comtan

MAO-B inhibitor Selegiline FP

37

Number of Potential Patients and Market

Size of antiparkinson drug market (2012): 60 billion yen

• Dopamine agonists are mainstream: 41% share of sales • L-DOPA + DCI (combination): 15% share of sales Market’s average annual growth rate (2007-

2012): +4.4% • COMT inhibitors: +56.5% (launched in 2007) • L-DOPA + DCI (combination): +2.6%

38

Potential patients: 250,000

(0.2% of population)

Diagnosed patients: 180,000

(72% of potential patients)

Drug treatment patients: 170,000


Population (Japan): 126.7 million

Number of potential Parkinson’s patients

• Main Parkinson’s patients: above age 40

• Population in 40s: will increase by 0.7% per year for the next 10 years

• 30% have cognitive impairment

Hoehn-Yahr Scale

• Stage-1: 21% • Stage-2: 44% • Stage-3: 16% • Stage-4: 15.7% • Stage-5: 3.3%

Source: Decision Resource

Source: IMS 2013

25,530 24,634 24,221 23,775 24,357 25,112

8,017 8,360 8,645 8,725 9,082 9,093

3,904 3,604 3,426 3,173 3,150 3,058

3,575 3,445 3,251 3,039 2,903 2,800735 2,767 4,320 5,453 6,172 6,906

6,398 6,777 7,088 7,210 7,351

7,440 505 2,345

4,382 5,868

48,877 50,224 52,049

54,251

57,907 60,750

-

10,000

20,000

30,000

40,000

50,000

60,000

70,000

2007 2008 2009 2010 2011 2012

Other

MAO-B inhibitor

COMT inhibitor

Anticholinergic agents

Norepinephrine precursor


Levodopa + DCI

Dopamine precursor

Dopamine agonist

（JPY mil） Antiparkinson drug market (Japan)

Rotigotine

Neupro Patch® (Rotigotine) - Non-ergot-derived dopamine receptor agonist

(D2/D3 receptor selectivity) - Formulation (transdermal patch, Terminal Heating formulation)

2.25mg, 4.5mg, 9mg, and 13.5mg formulations World’s first antiparkinson sustained-release transdermal patch Shows effects with little diurnal variation by maintaining a stable plasma concentration over

24 hours Reduction of burden on patients with dysphagia or many con-meds

- Formulation characteristics August 2007: Crystallization issue with the patch in the U.S. April 2008: recall from European and U.S. markets Phase III trials conducted by Otsuka with improved formulation (TH formulation) April 2012: FDA approval of new formulation (with room temperature storage)

as well as two additional indications of advanced Parkinson’s disease and restless leg syndrome July 16, 2012 : launch

- Patent exclusivity: December 2020 - Indications: Parkinson’s disease, restless leg syndrome

39

DA receptor selectivity

Lipid solubility

Dose titration / Maintenance period

Parkinson’s Disease Phase 3 Trial

40

Subjects: patients with advanced Parkinson’s disease on L-DOPA Study objectives: Superiority of rotigotine to placebo and non-inferiority to ropinirole Efficacy measurements Primary endpoints: Change in UPDRS Part III (ON state) score from the baseline Secondary endpoints:

• Changes in UPDRS II (average ON and OFF, ON, and OFF) score from the baseline • Changes in “time spent OFF” from the baseline and responder rate • Hoehn & Yahr scale

• UPDRS (Unified Parkinson's Disease Rating Scale): Consists of four parts—Part I: mentation, behavior, and mood; Part II: activities of daily life; Part III: test of motor ability; and Part IV: complications of treatment. Overall, 42 items are rate, generally in five levels, to quantify the severity of Parkinson’s disease.

Screening period

2 weeks N=546

16 weeks L-DOPA + rotigotine (N=168) 4.5 mg up to 36 mg/day

16 weeks L-DOPA + Ropinirole (N=167) 0.75 mg up to 15.0 mg/day

16 weeks L-DOPA + placebo (N=85)

Down- titration 4 weeks

Follow-up

1 week

Parkinson’s Disease Phase 3 Trial Results Primary endpoint

• Change in UPDRS Part III (motor ability, ON state) score from the baseline

Secondary endpoints (1) Change in UPDRS Part II (activities of daily life, ON)

score from the baseline

41

(2) Change in UPDRS Part II (activities of daily life, OFF) score from the baseline

Conclusions Efficacy • Superiority of rotigotine to placebo and non-

inferiority to ropinirole have been confirmed with statistical significance during a 16-week administration period.

Safety • Most common adverse event: application site

reaction (54.2%)

Y. Mizuno et al., 15th International Congress of Parkinson’s disease and Movement disorders

Rotigotine

for Restless Legs Syndrome

Restless Legs Syndrome (RLS) Epidemiology - Prevalence (Japan): 2.1 million (1.7% of population)

- No. of diagnosed patients: 43,000 (2% of potential patients)

- No. of treated patients: 43,000 (100% of diagnosed patients)

- Because of low recognition of the disease, it is often overlooked, misdiagnosed as insomnia or other disease, and not sufficiently treated.

Pathogenesis (exact cause unknown) - Metabolic abnormality resulting from decline in dopamine function

and insufficient iron in the central nervous system, abnormality of spinal cord and peripheral nerves, and genetic factors, etc.

Signs and symptoms - Subjective symptoms: Abnormal sensations such as creeping, an

urge to move, itching, or a feeling like bugs crawling, primarily in the legs, but potentially throughout the body, when in a still posture or lying down. Since it is difficult to suppress the symptoms, patients cannot stop moving legs and/or arms, trying to eliminate the sensations.

- From evening through the nighttime the symptoms exacerbate, causing sleep-onset insomnia, deep sleep disorder, or middle-of-the-night insomnia, which have a profound impact on everyday life.

- Secondary symptoms: Disturbed sleep causes fatigue during daytime. Worsening of symptoms may lead to depression and chronic pain.

43

Potential patients (2011)

2.1 million (1.7% of population)

Diagnosed patients 43,000

(2% of potential patients)

Drug treatment patients 43,000


Mild 46.1%

Moderate 33.8% Severe 16.2%

Very Severe 3.9%

20-29% of renal failure patients

20% of pregnant women

12% of Parkinson’s disease patients

Source： 1. Decision Resource 2013 2. Epidemiology and Clinical characteristics of restless legs syndrome, Dr. Kenji Kuroda, 15:

461-468, 2012, Japanese Journal of Clinical Psychopharmacology

Differential diagnosis • Tests: Blood tests, serum ferritin test • Ancillary tests - Overnight polysomnography (PSG) - Suggested Immobilization Test (SIT)2

• Diseases from which differentiation is needed - Polyneuritis, akathisia, peripheral circulatory

disorders of the lower extremities, Parkinson’s disease, etc.

Diagnostic Criteria

44

History taking • Family history, symptoms, time of symptom onset

Diagnostic criteria 1. Strong desire to move the legs due to abnormal

sensations in the legs. 2. The abnormal sensations exacerbate when at

rest or lying still. 3. The abnormal sensations improve with

movement. 4. The abnormal sensations increase in the evening

and at night.

Characteristics (diagnostic aids)

• Positive family history • Responds to dopamine agonists • Periodic limb movement disorder (PLMD1)

Severity rating International RLS Rating Scale

Severity Score Content of 10 questions

Mild Up to 10

• The system consists of 10 questions about the patient’s subjective symptoms that are answered by patients and scored in five levels from 0 to 4 based on the symptoms.

(1) leg discomfort, (2) tiredness or sleepiness, (3)

need to move, (4) frequency of symptoms, (5) relief of discomfort from moving, (6) affect on daily affairs, (7) sleep disturbance, (8) level of mood disturbance, (9) RLS as a whole, (10) severity of symptoms

Moderate 11-20

Severe 21-30

Very severe

31 and above

1) PLMD: Rapid leg movement caused by involuntary contraction of the tibialis anterior muscle in one or both legs. The rapid leg movement lasts for 0.5-5 seconds and occurs at intervals from 20-40 seconds apart. 2) SIT: An objective test, lasting 60 minutes and conducted 90 minutes before bedtime, that has been tried to evaluate periodic limb movement while waking (PLMW). The subject lies down in an easy chair at a 45-degree angle with the eyes open and the legs outstretched while EMG recording of activity in the tibialis anterior muscle is performed on the still state. A visual analog scale is filled out for leg discomfort every five minutes during the test. In a case of restless leg syndrome, PLMW increases in the second half of the SIT.

Refractory

RLS Therapy

45

Idiopathic RLS (60-80%) • Dopaminergic neuropathy • Iron disorder • Genetic factors

Ferritin level < 50 μg/L

Iron preparation

Benzodiazepine or add-on

Intermittent RLS

Continuous RLS

Clonazepam

Non-pharmacological therapy

• Abstain from caffeine, nicotine, and alcohol in the evening

• Taking a short walk, bath, cold shower, or messaging the limbs before bedtime

• Sleep hygiene instruction: regular bedtime, relax before bedtime

Suspension or dose reduction of drugs that could cause RLS (antihistamines, dopamine inhibitors, antidepressants)

Secondary RLS (20-40%) •Caused by other disease or drug

• Iron-deficiency anemia • Chronic renal failure • Congestive heart failure • Parkinson’s disease • Spinal cord disease • Folic acid deficiency, caffeine,

tricyclic antidepressants

GABA derivative Dopamine agonist

Low-strength opioid

Strong opioid

Pharmacotherapy

Switch to another drug

RLS Drugs

46 Otsuka Holdings September 13 2011

Mechanism Generic name Brand name Characteristics

Dopamine precursor L-DOPA Doparl • Tendency toward augmentation1 and rebound

Non-ergot-derived dopamine agonist

Pramipexole BI Sifrol • Contraindicated for renal failure • Indicated for RLS

Ropinirole Requip • Hepatic excretion

Rotigotine Neupro patch

• No drug interactions, transdermal patch • Indicated for RLS

Ergot-derived dopamine agonist Pergolide Permax • High risk of valvular heart disease and fibrosis

GABA derivative

Gabapentin Gabapen • Antiepileptic drug • Short plasma half-life, non-linear drug concentration

Gabapentin enacarbil Regnite

• A prodrug of gabapentin, little difference in blood levels • No tendency toward augmentation • Indicated for RLS

Opioid Oxycodone Oxycontin • Drug dependence, constipation

1) Augmentation: The increase in severity of RLS symptoms with the benefits of medication seen initially no longer being maintained. The time of symptom onset could become earlier than before medication began, symptoms could cause trouble both day and night, there may be pain, and symptoms could extend throughout the body. Diagnosed based on criteria released by the Max Planck Institute (MPI) in 2007.

Source: Interview survey of physicians, 2011, drug combination rate 8%

RLS Phase 3 Trial

Changes in IRLS sum score

47

Maintenance (8 weeks) Titration (5 weeks)

2 mg/24hr (N=95)

3 mg/24hr (N=94)

Placebo (N=95)

Screening (N=480) •IRLS score ≥ 15 •Responder to L-DOPA •Patients with sleep disorders, etc excluded

Initial dose 1 mg/24hr

Initial dose 1 mg/24hr

Phase 3 study design

Time course changes in IRLS sum score (FAS, LOCF)

Main adverse events

2 mg/ 24hr

3 mg/ 24hr Placebo

Application site reaction 42.1% 50.0% 7.4%

Nausea 33.7% 43.6% 9.5%

Somnolence 10.5% 14.9% 2.1％

Inoue Y et al., The 36th Annual Meeting of Japanese Society of Sleep Research

Taiho Oncology

Oncology Vision

“We contribute to cancer therapy worldwide through providing innovative drugs which lead to life extension, QOL improvement and potential cure, and trusted cancer care information.”

March 21,2013 Taiho Pharmaceutical Co., Ltd

Taiho Oncology pipeline

Copyright©Taiho Pharmaceutical Co., Ltd. 49

metastatic colorectal cancer JP ：NDA (Feb. 26, 2013)

JP/US/EU ：Phase 3

TAS-102 trifluorothymidine、pyrimidinedione hydrochloride compounding agent

“novel oral fluorothymidine antitumor drug”

Copyright©Taiho Pharmaceutical Co., Ltd. 50

We filed a J-NDA with the JMHLW for the approval of TAS-102 for the indication of colorectal cancer on Feb. 26, 2013.

51

TAS-102：NDA in Japan

Copyright©Taiho Pharmaceutical Co., Ltd.

News release

52

TAS-102：Mechanism of Action

FTD：trifluorothymidine TPI：thymidine phosphorylase inhibitor

molar ratio 1:0·5


•TAS-102 is a novel combination anti-tumor agent, consisting of FTD and TPI.

•FTD induces DNA dysfunction through efficient incorpora-tion into DNA, which leads to the inhibition of tumor growth.

•TPI prevents degradation of FTD.

TAS-102：Profile

53 Copyright©Taiho Pharmaceutical Co., Ltd.

• A novel oral fluorothymidine antitumor drug under development

• Extends overall survival in colorectal cancer patients with 3rd or later-line chemotherapy

• Significantly improve overall survival in KRAS mutation group

• Main Adverse Event: Myelosuppression Non-hematological AE was uncommon.

Japan US 5EU

Incidence※1 102,000 154,000 229,000

Mortality※1 43,000 51,000 95,000

≧3rd line Standard

Chemotherapy※2 KRAS Wild Type

CPT-11+C-mab Cape

FOLFIRI

P-mab FOLFOX+P-mab

FOLFIRI+ P-mab

Cape P-mab

CPT-11+C-mab

≧3rd line Standard

Chemotherapy ※2 KRAS Mutation

type

Cape FOLFIRI

Cape FOLFIRI +B-mab XELOX

Cape CPT-11 5FU+LV

C-mab：Cetuximab、P-mab： Panitumumab、B-mab：Bevacizumab、Cape：Capecitabine、FOLFIRI：5FU+leucovorin＋CPT-11、 FOLFOX：5FU+leucovorin＋oxaliplatin、XELOX：Capecitabine＋ oxaliplatin ※1 GLOBOCAN2008 ※2 Kantar Health CancerMpactⓇ

54

TAS-102：Standard Chemotherapy of CRC


TAS-102：clinical trial


N=112

N=57

Primary Endpoint：Overall Survival（OS） ※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO

TAS-102：Overall Survival（OS）


TAS-102 significantly improved overall survival compared with the placebo group.

TAS-102

Placebo

※ Yasutoshi Kuboki (The Cancer institute Hospital of JFCR, Tokyo, Japan) #6005 2011 ESMO

57

TAS-102：Subgroup analysis



KRAS KRAS

TAS-102 significantly improved overall survival in KRAS mutation group.

58

TAS-102：Safety

Myelosuppression was the main adverse events. Non-hematological adverse event was uncommon in TAS-102 treatment.



We are conducting global Phase 3 study of this Japan-origin compound, TAS-102 to meet patients’ needs worldwide.

59

TAS-102：Ongoing Study

Placebo + BSC

TAS-102 + BSC Radomized Primary Endpoint: Overall Survival(OS)

Secondary Endpoint: Progression Free Survival (PFS) N=800(TAS-102:Placebo = 2 : 1） Study period : Jun. 2012～ Dec. 2014

Main Clinical Sites： US：Dana-Farber Cancer Institute, Boston, MT EU：University Hospital Gasthuisberg, Leuven, Belgium JP：National Cancer Center Hospital East, Kashiwa, Chiba

Subjects: metastatic colorectal Cancer patients treated with Standard Chemotherapy

35 mg/㎡, b.i.d. d1-5, 8-12 q4wks until Progression

BSC：best supportive care

RECOURSE Study （Global Phase 3）


Gastric Cancer・Head & Neck Cancer Colorectal Cancer・Non-small cell lung cancer

Metastatic Breast Cancer Pancreatic Cancer・Bile Duct Cancer

TS-1 (S-1)


Japan ：Taiho Europe ：out-licensed to Nordic

60

61

TS-1：Proven efficacy


study name indication study design result

SPIRITS n=305

Gastric Cancer 1st line

TS-1 vs TS-1+cisplatin Lancet Oncol 2009

ACTS-GC n=1059

Gastric Cancer Adjuvant

Surgery alone vs TS-1 N Engl J Med 2007

FIRIS n=426

Colorectal Cancer 2nd line

FOLFIRI (5FU+LV+CPT-11) vs IRIS (TS-1+CPT-11)

Lancet Oncol 2010

ACTS-CC n=1504

Colorectal Cancer Adjuvant

UFT+LV vs TS-1 Ongoing

LETS n=564

NSCLC 1st line

Carboplatin+Paclitaxel vs Carboplatin+TS-1

J Clin Oncol 2010

CATS n=608

NSCLC 1st line

Cisplatin+Docetaxel vs Cisplatin+TS-1 ASCO 2012

SELECT BC n=618

Breast Cancer 1st line

Taxanes (Paclitaxel or Docetaxel) vs TS-1 Ongoing

GEST n=834

Pancreatic Cancer 1st line

Gemcitabine vs TS-1 vs Gemcitabine+TS-1 ASCO 2012

JASPAC-01 n=385

Pancreatic Cancer Adjuvant

Gemcitabine vs TS-1 ASCO-GI 2013

※ 2013 Gstrointestinal Cancer Symposium LBA#145 Presenter： Katsuhiko Uesaka (Shizuoka Cancer Center)

62

TS-1：Adjuvant therapy of Pancreatic Cancer


N=191 N=187

JASPAC-01 (Phase 3): Study Design




TS-1 demonstrated superiority in OS over GEM

News release

64



JASPAC-01 (Phase 3): Compliance

全生存期間

TS-1 was well tolerated as adjuvant therapy of pancreatic cancer

S-1群

GEM群


< Indication & Approval Date > Breast Cancer : Sep. 23, 2010 Non-Small Cell Lung Cancer : Feb. 21, 2013 Gastric Cancer : Feb. 21, 2013 Pancreatic Cancer : Ongoing (Phase 1/2)

Abraxane


in-licensed from Celgene（Area：Japan）

nab-paclitaxel

65

Abraxane：Profile


• nab-Paclitaxel (Abraxane), an albumin-bound form of paclitaxel, was developed to avoid toxicities associated with the Cremophor in solvent-based paclitaxel, with shorter infusion schedules (30 minutes) and no premedication.

• Approved in 41 countries (Sep. 2010） • NCCN guideline 【Breast Cancer, Non-Small Cell Lung Cancer】 recommends

abraxane as “Preferred Regimens”.

nab-paclitaxel

Particle of abraxane

Paclitaxel

albumin abraxane

erythrocyte

Abraxane：Clinical Trial Status


Trial Name/ CancerType Area Study Design P1 P2 P3 NDA

CA-012 Breast Cancer

US/EU q3w sb paclitaxel vs q3w Abraxane

Nov. 2005 Published

July. 2010 Approved

CA-024 Breast Cancer

US/EU q3w Docetaxel vs q3w/qw Abraxane

Aug. 2009 Published

J-0201 Breast Cancer

JP q3w Docetaxel vs qw Abraxane Ongoing

CA-031 NSCLC

JP/US/EU Carboplatin+Paclitaxel vs Carboplatin+Abraxane

June. 2012 Published

Feb. 2013 Approved

J-0200 Gastric Cacner

JP q3w Abraxane (2nd line) June. 2011 Presented

Feb. 2013 Approved

MPACT/CA046 Pancreatic Cacner

US/EU Gemcitabine vs Gemcitabine+Abraxane

Jan. 2013 Presented

J-0107 Pancreatic Cancer

JP Gemcitabine+Abraxane (feasibility) Ongoing

※ 2013 Gstrointestinal Cancer Symposium LBA#148 Presenter： Daniel D. Von Hoff (Virginia G. Piper Cancer Center, US )

68

Abraxane：1st L treatment of Pancreatic Cancer


MPACT/CA046（Phase 3）： Study Design

Primary endpoint：Overall Survival（OS）

GEM+Abraxane demonstrated superiority in OS over GEM alone.

69



MPACT/CA046（Phase 3）：Overall Survival



No increase in serious life threatening toxicity was observed. AEs associated with GEM+Abraxane treatment were acceptable and manageble.

Adverse Events （≧G3） GEM+Abraxane GEM

Neutropenia 38% 27% Feblire Neutropenia 3% 1% Thrombocytopenia 13% 9% Amenia 13% 12% Fatigue 17% 7% Sensory Neuropathy 17% <1% Diarrhea 6% 1%


MPACT/CA046（Phase 3）：Safety Profile


MPACT/CA046（Phase 3）： Summary

71

• GEM+Abraxane is superior to GEM alone (Median OS: 8.5 vs 6.7 months [HR 0.72, P=0.000015] , 1-yr: 35% vs 22%)

• No increase in serious life threatening toxicity • AEs associated with GEM+Abraxane were acceptable

and manageable.

Abraxane combination shows the benefit of 1st line treatment in patients with advanced pancreatic cancer. We are conducting a bridging study in Japan.



Positioning of TAIHO’s pipeline in pancreatic cancer treatment in Japan


1st line

2nd line

2013

GEM, S-1 GEM+S-1

GEM+Erlotinib

GEM, S-1 GEM+S-1

GEM+Erlotinib

GEM+ABI FOLFIRINOX GEM, S-1

S-1, GEM, GEM+S-1 S-1 GEM+S-1,GEM

Adjuvant S-1 GEM, S-1 GEM+S-1

72

73

Next Generation : Oncology Pipeline

At EORTC-NCI-AACR 2012, we presented exciting preclinical in vitro and in vivo data for 8 New Compounds, developed exclusively at Taiho Oncology. Copyright©Taiho Pharmaceutical Co., Ltd.

★Anti-Metabolites Drug discovery targeting “clear molecular target”

→ World first’s dUTPase inhibitor Drugs to “improve overall survival” and to “reduce

adverse events”

★Molecular-targeted drugs Targeting cancer driver gene Strongly inhibiting important cancer signaling pathways Overcoming drug-resistance

Discover unique molecules based on original chemistry

technology

Selective ATP competitive inhibitors Allosteric inhibitors Target molecule specific covalent binders


Strategy of Drug Discovery in Oncology

74

Direction of the Development of Novel Anti-Metabolites

Novel deoxy-uridine type antimetabolite

TAS-114 （dUTPase inhibitor） + S-1 or Cape

Launched in 1999

Launched in 1984

Launched in 1974

FT

UFT

TAS-102 FTD+TPI

Global PIII on going

PI on going

TS-1

“Maximizing TS inhibition by 5FU and reducing side effects”

“Maximizing TS inhibition by 5FU + additional antitumor effect of

5FU which incorporated into DNA due to the inhibition of dUTPase”

“Maximizing the antitumor effect of the compound which incorporated into DNA. ”

75

76

Target of antimetabolites and signaling transduction inhibitors

Copyright©Taiho Pharmaceutical Co., Ltd. DNA

PI3K

AKT

dUTPase

AuroraA

NR NR

TAS-115

TAS-116

TAS-114

TAS-2104

Nucleus

Blood vessel

Cell

Cell growth

TAS-2985

Tumor growth Metastasis

TAS-2913

AKT TAS-117

TAS-102


TAS-114 dUTPase inhibitor (First in class)

Mechanism of Action Key Data <Preclinical Study>

Concept： TAS-114 is a novel potent inhibitor of dUTPase with modest DPD inhibition. TAS-114 demonstrates the potential to improve the therapeutic efficacy of 5-FU-based chemotherapy. Clinical benefits : Potentiating anti-tumor activity of 5-FU based drug with dUTPase inhibition. DPD inhibition enables the dose reduction of Capecibatine and it would improve AE profiles caused by 5-FU higher dosing. (e.g. HFS). Status： Phase I Solid tumors JP/US/EU

TS inhibition

FBAL

DNA incorporation

of 5-FU

dUTPase DPD

Antitumor Activity

Survival

Adverse Events

Reduced

5-FU

Enhanced

TAS-114

0 10 20 30 40 50 60 70 80 90

100

0 50 100 150

Sur

viva

l rat

e (%

)

Time (days)

Capecitabine/TAS-114 (160/600)

Capecitabine(539) Control

78

TAS-115 VEGFR/MET dual inhibitor


Improved survival by TAS-115 in sunitinib*-resistant MET amplified

cancer dissemination models

Tumor vessels

Tumor

VEGFR signal * Sunitinib: approved VEGFR-targeted multi-kinase inhibitor

Concept : To aim at more potent curative effect via inhibiting both angiogenesis and tumor growth/metastasis with improved safety properties. Clinical benefits : A highly potent c-MET + VEGFRs dual inhibitor with preeminent safer profile. Potential therapeutic value in mono- or combination therapy. Status： Phase I Solid tumors JP

Mechanism of Action Key Data <Preclinical Study>

79

TAS-116


Highly potent, oral HSP90 inhibitor with unique tissue distribution properties

Mechanisms of Action Key Data <Preclinical>

Concept : Induction of multiple cancer-related HSP90 clients degradation provides an opportunity to treat several types of cancer. Compound profile : Novel structural class oral HSP90 inhibitor. Potential to maximize antitumor activity while minimizing adverse events such as ocular toxicity observed with other compounds of this class by unique tissue distribution. Clinical benefits : Effective in chemotherapy or molecular-targeted drug refractory/resistant tumors.

TAS-116 is highly distributed in sc tumor over retina in rat model

TAS-116 induces tumor regression in human AML xenograft model


Annals of Oncology(2010) 21; 683-691

p110 PTEN loss AKT

Protein synthesis Cell growth

Cell survival Proliferation Cell cycle

Metabolism

Control

Lapatinib 100 mg/kg Oral, BID, Day1-14

TAS-117 24 mg/kg Oral, QD, Day1-14

KPL4 xenograft mouse model Human breast cancer (Her2 gene amplification, PI3K mutation)

Mechanisms of Action Key Data <Preclinical Study>

TAS-117 Highly potent and selective AKT inhibitor

TAS-117

Concept : AKT regulates multiple cellular functions, including proliferation, survival and glucose metabolism. AKT activation involved in resistance to chemotherapies and targeted therapies by inhibiting apoptosis. Inhibition of AKT sensitizes tumor cells to above therapies Compound profile : Potent and highly selective oral allosteric AKT inhibitor. Good physicochemical and pharmacokinetic properties. Clinical benefits : Enhance antitumor effects of chemotherapies and targeted therapies


TAS-2104 Selective Aurora A inhibitor

Concept : Enhance anti-tumor efficacy of taxanes through activation of spindle assembly checkpoint, unique concept Compound Profile : Potent and selective Aurora A inhibitor. Unique prolife compared with competitor’s Aurora inhibitors (selective over Aurora B & C) Clinical benefits : Aurora A overexpression in various types of cancer with high frequency; breast, gastric, lung, prostate, ovarian, pancreatic etc. TAS-2104 has combination effect with paclitaxel, docetaxel, abraxane, cabazitaxel

Aurora A Inhibition causes activation of spindle checkpoint

Cells in mitotic phase

Paclitaxel Cell cycle arrest,

cell death Aurora A

overexpression Abnormal spindle

formation

Activation of spindle assembly checkpoint


TAS-2104 Key Data <Preclinical Study>

Enzyme IC50 (nM), human Aurora A 0.41

Aurora B 135 Aurora C 37

Paclitaxel

TAS（4days）

500

1000

1500

2000

0 5 10 15 20 Days

Tum

or V

olum

e (m

m3)

Control

Combo （2day）

Paclitaxel alone

Combo （4days）

TAS（2day）

500

1000

1500

2000

0 5 10 15 20 Days

Tum

or V

olum

e (m

m3)

Docetaxel alone

Control

Combo （2day）

Combo （4days）

Docetaxel

TAS（4days） TAS（2day）

Potent and selective Aurora A inhibition

Enhancement of anti-tumor efficacy in vivo

Paclitaxel Docetaxel

263 kinase panel

83

TAS-2913 Mutant Selective EGFR Inhibitor


6-12month

Molecular target drug≑Key

EGFR-TKIs potently inhibit muEGFR

Drug Resistant mutation

NSCLC 1st line

No response

Concept : The 1st generation EGFRi; Gefitinib and Erlotinib, have been found effective in treatment of a subset of NSCLC patients harboring activating mutations. Over time (median of 6-12 months), most tumors develop resistance to EGFR inhibitors by the development of drug-resistant mutations including gatekeeper T790M mutations. Compound profile : Potent and oral mutant EGFR (T790M) selective inhibitor. Clinical benefits: Effective in acquired resistance to EGFRi (Gefitinib and Erlotinib) in NSCLC.


TAS-2913 showed tumor growth inhibition on NCI-H1975 xenograft model and a significant prolongation of lifespan in treated mice.

0

2

4

6

8

10

12

0 5 10 15

Rel

ativ

e Tu

mor

Vol

ume

Day

Control

TAS-2913 25mg/kg/day




Tumor growth inhibition Prolongation of lifespan


TAS-2985 Potent and irreversible FGFR inhibitor

Concept ：FGFR is considered as a cancer driver gene as its gene abnormalities are reported in various types of cancers Compound Profile : First irreversible FGFR inhibitor which will be tested in clinic. Highly potent and selective. Selectively inhibits tumor growth of cancer cells with FGFR abnormalities. Clinical benefits : Tumors with FGFR gene abnormalities; gastric (undifferentiated, type IV), breast, lung (SCLC), bladder, endometrial, multiple myeloma

FGFR gene abnormalities in cancers Microenvironment

Translocation

Amplification Active

mutation



Enzyme IC50 (nM)

FGFR1 5.2

FGFR2 1.7

FGFR3 2.0

FGFR4 13.0

Potent and selective inhibition of FGFR FGFR2

TAS-06-02985

-40

-20

0

20

40

60

80

100

120

140

0 0.3 1 3 10 30 100 300 1000 3000 10000

AZ-521 MKN-45 Kato III NCI-N87 AGS MKN-74 SNU-1 OCUM-2M OCUM-2MD3 SNU-16

Selective growth inhibition in vitro

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 2 4 6 8 10 12 14 16Days

RTV

ControlTAS-06-02985 3mg/kg/day

Potent anti-tumor efficacy; tumor regression in gastric cancer model

87

Taiho Oncology http://www.taiho-oncology.com/


Tolvaptan

Development History of Tolvaptan

1991 Discovery

of non-peptidie

V1 receptor(2)

2009 US:Hyponatremia

EU:SIADH

2010 Japan: Cardiac

edema

2003 V2

antagonist inhibits PKD in vivo4)

2013 1980 1990 2000 2010

1979 Discovery of

V1/V2 receptor 1)

ADPKD

1983 Needs from clinicians

1984 Focus on vasopressin

1989 Lead compound

discovered

1991 synthesis of

tolvaptan 1992

Discovery of non-peptidid

V2 receptor3)

SALT （Hyponatremia）

1)Biochem.Soc.Trans. 7, 861 1979 2) Science 252 (5005) 572, 1991 3) Br.J Pharmacol 105; 787, 1992 4) Nature Medicine 9 (10), 2003

EVEREST (heart failure)

Quest (Cardiac edema )

TEMPO （PKD）

89

Mode of Action of Tolvaptan

90

2 actions of V2-Receptor

Tolvaptan（SAMSCA®） V2-Receptor Antagonist

1) Diuretic function that excretes water

only

Changes electrolyte concentration

• Hyponatremia • Hyponatremia by

SIADH

Decreases body fluid

• Cardiac edema • Hepatic edema

2) Inhibits kidney cyst formation by V2-

Receptor

ADPKD Autosomal Dominant

Polycystic Kidney Disease





only

Changes electrolyte concentration


SIADH

Decreases body fluid


2) Inhibits kidney cyst formulation by

V2-Receptor



91

Hyponatremia

92

Water Metabolism Control： urinary concentrating mechanism and drinking behavior

- Urinary concentrating mechanism （maintain body fluid): renal function and pituitary hormone AVP are involved.

- Renal function: Filtering blood approx. 150L/day at the glomerulus. 90% of filtered primitive urine is passively reabsorbed at Proximal convoluted tubule and 10% are actively reabsorbed at collecting duct by AVP. Urine volume is controlled 1-2L/day.

- AVP secretion: Controlled through hypothalamic osmoreceptor and baroceptor in carotid sinus, aortic arch and left atrium.

- Osmoreceptor: Promotes AVP secretion by plasma osmolarity increases. - Baroceptor: Promotes AVP secretion by low body fluid, low

blood pressure and low left atrial pressure.

- Secreted AVP binds to AVP2 receptor at collecting duct cells, increases inner-cell cAMP and promotes water reabsorption by activating aquaporin-2. This results in water reabsorption promotion, increase of body fluid, decrease of plasma osmolarity, inhibits AVP secreting activity.

carotid sinus・ aortic arch ・left

atrium

Hypothalamus osmoreceptor（perceives changes in

plasma osmolality)

AVP synthesis and secretion

collecting duct cells

AVP V2 receptor

Increase cAMP

aquaporin-2 expression

water reabsorption

plasma osmolality/

circulatory blood volume

baroceptor （reacts to decrease in

body fluid volume, blood pressure and left artial

pressure)

Hyponatremia - Condition that sodium level in the blood is under136mEq and excess of total body water for total sodium volume in the body.

- Symptoms：Functional disorder in CNS such as altered personality, lethargy and confusion. Stupor state, enhancement of neuromuscular excitability, twitch, lethargy and sometimes death occur due to the decrease in blood sodium level to under 115mEq. Sequela: Hypothalamic infarction, posterior pituitary infarction，brain-stem hernia.

Activates PKA

Characteristic of Tolvaptan

93

Most of the existing diuretics also work at other sites than distal tubule, excreting both sodium and water

Category Mode of Action Major drugs

Thiazide diuretics

• Act on Na+/Cl-cotransporter of distal convoluted tubule

• Excretion of Na+, K+, Cl-

• Trichlormethiazid • hydrochlorothiazide • Indapamide • Chlorthalidone, etc

Loop diuretics

• Act on Henle's loop Na+/K+/2Cl-cotransporter

• Excretion of Na+, K+, Ca2+, Cl-

• Furosemide • Torasemide • Azosemide • Bumetanide, etc

Aldosterone antagonist (K-sparing diuretic)

• Act on distal convoluted tubule and aldosterone receptor at collecting duct

• Promote Na+ excretion

• Spironolactone • Eplerenone

• Tubule Na+ channel inhibitor • Triamterene • Amiloride

Tolvaptan (V2-receptor antagonist) Tolvaptan shows water diuretic action without directly affecting the excretion of electrolytes by inhibiting of water re-absorption at renal collecting tubule.

The more use, the more imbalance of blood electrolytes

hemofiltration 150L/day

Thiazide diuretics

Aldosterone antagonist

Loop diuretics Aquaretics

(V2-receptor antagonist)

K-sparing diuretic

dist

al c

onvo

lute

d tu

bule

Glomus

Henle’s loop

Collecting duct

10% reabsorption 90%

reabsorption

Prox

imal

co

nvol

uted

tubu

le

Types of Hyponatremia

94

Na+ Na+ Na+Na+

Normal Condition A Condition B Condition C

Decrease of Na Decrease of body

fluid volume

•disease：vomiting, diarrhea, salt losing nephropathy, primary hypoadrenalism

Decrease of Na Body fluid

volume±10% •disease：SIADH, MRHE, Hypothyroidism, Glucocorticoid deficiency, hypopituitarism

Decrease of Na Increase of body

fluid volume

•disease: Renal failure, Heart failure, Cirrhosis, Nephrosis syndrome

extr

acel

lula

r flu

id v

olum

e

Na reabsorption disorder

Decrease of extracellular fluid

AVP supersecretion

AVP supersecretion

Increase of Na and water reabsorption

Collecting duct Blood

Tolvaptan Mode and Site of Action

95

H2O

GS ↑cAMP PKA

DNA

AQP2 H2O

V 2

AVP

AQP2

AQP-3&4 Na+

K+ H2O

Collecting duct Blood

H2O

Na+

K+

GS

DNA H2O

V 2

SAM

SCA

Vasopressin binds to

V2-receptor

Tolvaptan inhibits

binding to V2-receptor

Enhance water permeability and

reabsorption

Inhibits expression of aquaporin 2

Enhance water excretion

Nor

mal

Tr

eatm

ent b

y To

lvap

tan

AVP:arginine vasopressin、PKA:protein kinase A、AQP:aquaporin

Number of Patients

96

Hyponatremia（%HN<125）0.33 mil3)

Insufficient with existing drug

0.23 mil2)

Japan：Indication (cardiac edema) • Indication: Treatment of volume overload in

heart failure when adequate response is not obtained with other diuretics (e.g., loop diuretics).

• Dosage and administration：orally-administered 15mg/day, once daily

Hyponatremia（US）

chronic cardiac failure 1.04 mil1)

CHF Cirrhosis SIADH other

Data source: Otsuka Fact Book

SIADH (no. of patients in Europe)

Germany4) Spain5) UK5) Italy5) Nordic5)

3,591 2,472 974 682 528

Source 1)Decision Resource Patients Base, 2)OECD data 2008, 3)Verispan Database, 4)Netigate Research, Germany, May 2012, 4) Market Survey data, 5)Sales Provision

Sales of SAMSCA ¥100 mil

EU Launch

US Launch

Japan launch

5)


97




only

Change electrolyte concentration


SIADH

Decrease body fluid


2) Inhibits kidney cyst formation by V2-

Receptor



PKD (Polycystic Kidney Disease)

98

PKD ：Polycystic Kidney Disease - Prevalence （There are 2 kinds of genetic conditions in PKD）

• ADPKD- Autosomal Dominant Polycystic Kidney Disease: Frequency of genetic mutation in one in 400 to 1000 people. 85% caused by genetic mutation of PKD1, 15% by PKD2 which is less severe.

- Estimated diagnosed patients: Japan: 31,0001), US: 116,0002), EU (G5): 143,0003) • ARPKD- Autosomal Recessive Polycystic Kidney Disease: This is a rare disease observed in infants

and pediatrics, causing death within 1 year from birth in most cases.

1) source: abstracted from application document approved as orphan drug in 2006 (reference: article by Prof. Higashihara) 2) source: Applied for orphan drug based on prevalence report by Prof. Willy of University of Rhode Island and approved on April 6. 3) EU G5 population 319 mil (source: World Bank 2011), number of patients are worked out 4.5 per 10,000. 4) source: research team of progressive renal impairment, Ministry of Health, Labour and Welfare

Characteristic of ADPKD - Genetic disorder - No symptoms until 30s to 40s in most of cases - Subjective symptoms: hematuria, abdominal pains, lumbar

backache, abdominal bloating, high blood pressure. - Formation and growths of a number of cysts in both kidneys.

Cysts growth causes decline in kidney function with aging. Half of the patients develop ESRD, an end-stage renal disease, and receive dialysis.

- Faster progression of disease is shown in patients with PKD1 genetic mutation than PKD2.

- Average age requiring dialysis: PKD1: 54.3, PKD2: 74.0 - Approx. 5-10 % of ESRD patients have ADPKD4) - Treatment: No available therapeutic drugs

father mother

Inheritance probability: 50%

ADPKD genetic form

Chromosome No.4 or No. 16.

Genetic mutation A a A a

a A A a a a A A

Genetic test ・ Genetic test is not conducted in Japan as a reliable method has not been established

Diagnosis of ADPKD

99 Source: Japanese Society of Nephrology Magazine (2011) Medical treatment policy of PKD, August 2010

Initial symptoms hematuria, abdominal pains, lumbar backache,

abdominal bloating, high blood pressure.

Family history No family history

Ultrasonography CT, MRI

More than 3 cysts in both

kidney

Under 15 Over 16


kidney


kidney


kidney

imaging test

Diagnosed as ADPKD

exclusive diagnosis

Criteria of severity severity serum creatinine

1 Less than 2mg/dl

2 Less than 2～5mg/dl

3 Less than 5～8mg/dl

4 Over 8mg/dl without dialysis

5 Initiation of dialysis or renal transplant

• Judgment of severity is based on renal function and the volume of intracranial aneurysm, intracranial bleeding and abdominal bloating

Judgment of severity is based on renal function using serum creatinine level as a substitute, and adds the volume of intracranial aneurysm, intracranial bleeding and abdominal bloating.

Gene Responsible for ADPKD

100 Source: Naohiko Yokoyama, Cell Technology 2009, Nature Cell Biology (2010)

Primary cilium of kidney sensory organelle projected from ureter

Ca2+

PC1 Urine cilium

Ca2+

Gene Coding protein notes

PKD1 Polycystin-1 (PC1) 85 % abnormity in ADPKD patients

PKD2 Polycystin-2 (PC2) 15 % abnormity in ADPKD patients

＜responsibility＞ 1) Ciliary action by urinary flow in renal tubule 2) Proteins in PC1 and PC2 respond and

controls inner-cell calcium 3) Controls the size of renal tubular cell

PC2

Inside of a cell

ureter renal papilla

renal medulla

renal cortex

kidney

glomus Bowman's capsule

Proximal convoluted

tubule

distal convoluted

tubule

Henle’s loop

Collecting duct

cut

To renal papilla scanning electron microscopical

image in urine cytology

Function of Renal Tubular Epithelial Cells

101

cilium

Urine

endoplasmic

reticulum

Normal

Urine PC1

PC2

↑cAMP PKA

Ca2+

Ca2+ 5’AMP

Ca2+ ERK

V2

AVP

adenylate cyclase

ATP

※ ERK：Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is expressed broadly in whole body cells. Called as MAP kinase.

enhance inhibit

nuclear transcription

factor DNA


102

cilium Urine

endoplasmic

reticulum

PKD

Urine PC1

PC2

↑cAMP PKA

Ca2+

5’AMP

Ca2+ ERK

V2

AVP

adenylate cyclase

ATP

transcription factor

DNA

Growth of abnormal cells

Wallace DP et al., Biochim Biophys Acta (2011)

initiation development

※ ERK：Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is expressed broadly in whole body cells. Called as MAP kinase.

enhance inhibit


103

cilium Urine

endoplasmic

reticulum

PKD

Urine PC1

PC2

↓cAMP PKA

Ca2+

5’AMP

Ca2+ ERK

adenylate cyclase

ATP

transcription factor

DNA

Inhibits growth of abnormal cells

V2

Tolvaptan

Source: Torres VE et al., N Engl J Med. 2012 ※ ERK：Mitogen-activated Protein Kinase、MAPK. One of the Ser/Thr kinase and activates by stimulation. ERK is

expressed broadly in whole body cells. Called as MAP kinase.

enhance inhibit

Source：Torres VE et al., N Engl J Med. 2012

Tolvaptan P-3 Study Result (TEMPO3:4)

Secondary Endpoint Annual rate of kidney-function decline

Primary Endpoint Annual rate change in the total kidney volume

Methods - Patients：Total kidney volume>750 mL, creatinine clearance>60 mL/min - Duration：36 months - Tolvaptan(N=961) ( Oral administration, daily morning and afternoon doses of 45 mg/15 mg, 60 mg/30

mg, 90 mg/30 mg）, Placebo（N=484）

Slowed the increase in total kidney volume by approx. 50% Slowed decline in kidney function

104

Tolvaptan P-3 Study Result (TEMPO3:4)

105

Tolvaptan decreases the risks of multiple events with progression of disease

36% Decrease of Risk of Kidney Pain

61% Decrease of Risk of Worsening Kidney Function

Event Tolvaptan （N=961)

Placebo （N=483)

Thirst 55.3% 20.5% Polyuria 38.3% 17.2% Nocturia 29.1% 13.0%

Headache 25.0% 24.8% Pollakiuria 23.2% 5.4% Dry Mouth 16.0% 12.2%

Hypertension 32.2% 36.0% Renal Pain 27.0% 35.0%

Nasopharyngitis 21.9% 23.0% Back Pain 13.7% 18.2%

Increased creatinine level 14.0% 14.7% Hematuria 7.8% 14.1%

Urinary tract infection 8.3% 12.6% ALT elevation 0.9% 0.4% AST elevation 0.9% 0.4%

• white：over 15% AE in Tolvaptan group • yellow：over 10% AE in placebo group • gray：Serious AE more common in Tolvaptan group

Ophthalmology Business

Dry Eye

•Improves subjective symptoms such as foreign body sensation and pain in the eyes •Makes Innovation of dry eye treatment

Mucosta ophthalmic suspension

Glaucoma

•Prevents blindness of glaucoma patients with new mode of action

Dry AMD

•Provides a new drug for disease for which there is no treatment available

No. of patients; Dry eye (Japan 8 Mil, US 20 Mil), Dry AMD (US 10.5 Mil), Glaucoma (Japan 4.14 Mil, US 7.6 Mil)

Strategy of Ophthalmology Business In collaboration with Acucela (ophthalmology specialized R&D company),

Otsuka provides valuable novel products to clinical setting. Focus on total eye care

Anterior eye Posterior eye

Optic nerve

Macula

Retina

Sclera Conjunctiva

Iris

Pupil

Cornea

Lens

AC

PCIOL

OPA-6566 ACU-4429

107

Mucosta ophthalmic suspension (Generic name: rebamipide)

Active site

Pharmacol-ogical action

(1) Increases mucus (2) Repairs mucosa (3) Anti-inflammatory 1) Increases amount of gastric mucus 2) Repairs damaged gastric mucosa 3) Suppresses increase of inflammatory cytokines in gastric mucosal epithelial cells

1) Promotes production of corneal and conjunctival mucin 2) Ameliorates corneal and conjunctival epithelium injury 3) Suppresses production of IL-6 and IL-8 through TNF-α stimulation in corneal epithelial cells

Target diseases Gastric ulcer and gastritis Dry eye

Marketing status

• Best selling antiulcer drug in Japan (Rx no.)

• Marketed in 10 countries1

• Japan: Introduced in January 2012

• U.S.: Started P-3

Expanded Indications for Mucosta’s Action of Normalizing Mucosa

Gastric mucosa Ocular surface mucosa

1) 10 countries: Japan, South Korea, China, Indonesia, Malaysia, the Philippines, Thailand, Vietnam, Cambodia, and Egypt 109

Function and Structure of Tears Tears

• Secreted in a certain amount from the lacrimal glands at every blinking of the eyes (about 20-30 times per minute)

90% drains from the lacrimal canaliculi through nasolacrimal duct to the pharynx; 10% evaporates

Amount of tears covering the cornea and conjunctiva is 5-10 μl; protects the eyes by constantly coating the surface of the eyes through blinking

• Primary functions Prevents eye dryness; disinfects the eyes; cleans the eyes (dust, antigens,

allergens, etc.) - Supplies cornea and other tissues with oxygen and nutrition

22

Structure of tears • Tear film consists of three layers: lipid, aqueous, and mucin 1) Lipid layer: prevents evaporation of water; content is lipid film secreted from meibomian glands 2) Aqueous layer: primary component of tears; 95% water; moisturizes the

eyes; immune proteins such as IgA in this layer protect the eyes from bacteria

3) Mucin layer: stabilizes lacrimal fluid; allows even distribution of the tear as the cornea sheds water with a sticky substance; primary component is mucin secreted from conjunctival goblet cells

0.6μm

0.3μm

6μm

Main lacrimal glands Tear film layers

Mucin layer Aqueous layer Lipid layer

Meibomian glands

Structure of tears

Mucin Epithelial cells Microvilli

Flow of lacrimal fluid Lacrimal

gland Eyelid

Drains from lacrimal canaliculi

Lacrimal punctum

Lacrimal sac

Nasolacrymal canal

Evaporation 10%

110

Dry Eye

Definition of dry eye (corneal xerosis, keratoconjunctivitis sicca): A chronic disease of lacrimal fluid and corneal and conjunctival epithelium resulting from various causes and associated with eye discomfort and abnormal visual function 1.Dry spots appear when the amount of tears decreases. 2.Volume and quality of tears decrease 3.Dry spots remain and the cornea becomes exposed 4.The eyes stay dry

111

Dry eye

Destabilization of tear film

Damage of cornea and conjunctiva (decrease

in mucin)

Suppression of mucin secretion

Worsening of subjective symptoms

Chronic inflammation

Stress on cells by high osmolality, eyelids, and

external stimuli

Inflammation damages lacrimal glands, reducing tears

Mucin: high molecular weight glycoproteins - Secretory mucin: produced by epithelial cells, etc. - Membrane mucin: has a hydrophobic

transmembrane part and binds to cellular membrane

Conceptual diagram of lacrimal fluid layers Lipid layer

Aqueous/mucin layer

Secretory mucin and membrane mucin detached

from membrane surface

Membrane mucin

Epithelial cells

Conceptual diagram of dry eye

Membrane mucin

Epithelial cells

Aqueous layer caused by surface tension

Dry spot

Diagnostic Criteria of Dry Eye Diagnosis of dry eye Defini

tive Suspected

Suspected

Suspected

1) Subjective symptoms ✔ ✔ ✔

2) Lacrimal fluid abnormality1 ✔ ✔ ✔

a) Schirmer's test I (≤ 5 mm)

b) Tear film breakup time (B.U.T.) ( ≤ 5 seconds)

3) Corneal and conjunctival epithelium disorder2 ✔ ✔ ✔

a) Fluorescein staining score (≥ 3 < 9)

b) Rose bengal staining score (≥ 3 < 9)

c) Lissamine green staining score (≥ 3 < 9)

(2) Lacrimal fluid abnormality A) Schirmer's test I (tear quantity) Normal: ≥ 10 mm

Abnormal: ≤ 5 mm

B) Tear film breakup time (B.U.T.) (tear quality) - Determines the ability of tears to stay

together by measuring the time until the breakup of tear film on the corneal surface

Normal: ≥ 10 seconds

Abnormal: ≤ 5 seconds

112

Source: Shimazaki, Jun (Dry Eye Society). Journal of the Eye 24(2) 18) 2007

0-3 points

0-3 points

0-3 points

(1) Ocular subjective symptom severity - Determined using a subjective symptom

assessment scale - Eye pain, sensitivity to bright light, blurring of

eyes, foreign body sensation, feeling of dryness, photophobia, itching, eye discharge, feeling of dull pressure, eyestrain, eye discomfort, watery eye

1) Positive if either a) or b) fulfilled 2) Positive if any of a) to c) fulfilled

(3) Corneal and conjunctival epithelium disorder

- Cornea: mainly fluorescein - Conjuntiva: rose bengal, lissamine

green

Temporal conjunctiva

Nasal conjunctiva

Cornea

Mild dry eye

Severe dry eye

http://www.kajikawa-ganka.jp/img/dryeye/photo/img3-1.jpg�

Major Causes of Dry Eye

Dry Eye Tear evaporation

Meibomian gland dysfunction

Decreased tear production

Sjögren syndrome

LASEK, PRK1)

Aging, other

Others

Lack of blinks

Allergic conjunctivitis

Contact Lenses

Abnormality of tear drainage process

Population

Prevalence(201)～302) mil) 16.7～25.0%

Diagnosed （1.33)～2 4) mil） 6.5%～10%

Treated （1.13)～1.44) mil） 86%～56%

1) Japan Ophthalmologists Association “IT eye syndrome and environmental factor” Research Group (leader: Shigeru Kinoshita, Professor, Ophthalmology, Kyoto Prefectural University of Medicine

2） Miki Uchino, Debra A, Schaymberg et al, Ophthalmology 2008; 115, 1982-1988

3) EPOCA Marketing survey 4） IMS 2009

Causes of Dry Eye Dry Eye Prevalence

Sales of Dry Eye Drugs (Japan)

DIQUAS Launch

1)PRK：Photorefractive keratectomy is one of a laser eye surgeries. PRK does not formulate flap, different from LASEK, it changes the shape of the anterior central cornea using an excimer laser.

MUCOSTA Launch

Source：IMS 2013 Dataview

100 mil yen

113

Well improved

7%

Improved50%

Neither34%

Not improved8%

Not improved at all1%

Source: Total Planning Center OSAKA corp “Survey of Dry Eye Patients” Feb, 2010 N: 500 (dry eye patients aged 20-60)

Improvement rate by eye drop treatment

No subjective feeling of

improvement 43.4%

Issues of Existing Therapy and Efficacy of Mucosta Ophthalmic Suspension No improvement in symptoms confirmed by eye drops which

works on tears

114

Efficacy of Mucosta Ophthalmic Suspension

115

Efficacy of Mucosta Ophthalmic Suspension

Decrease in mucin secretion causes imbalance of tears

• Improves hydration by tear stabilization • repairs scars on conjunctiva and cornea

by its anti-inflammatory effect • Improves ocular symptom severity

Conjunctiva

•Increases mucin on conjunctiva •Increases goblet cells

Cornea

•Increases mucin on cornea • Promotes corneal epithelial cells growth

Epithelium disorder

• Protection • Repair

Mucosta Ophthalmic Suspension

fluid fluid

mucin

corneal and conjunctival epithelial cell

fluid

mucin

Rebamipide P-3 Study (Japan)

116

4-week treatment (data collected after 2 weeks)

Screening 2 weeks (use of

artificial tears)

Hyalein Mini Ophthalmic solution 0.1% (6 times/day)

(N=95)

Primary endpoints •Corneal Damage: Fluorescein corneal staining score ( non-inferiority) •Conjunctival damage: Lisamingreen conjunctive staining score (superiority)

Secondary endpoints • Tear film break-up time • Schirmer's test dry eye related symptoms • Major symptoms：foreign body

sensation, dryness sensation, photophobia, eye pain, blurred vision

• Secondary symptoms: eye itching, eye discharge, dullness of the eye, asthenopia, eye discomfort, lachrymation

• Patients’ impression

Rebamipide Ophthalmic suspension 2.0% (4 times/day)

(N=93)

Follow- up

2 weeks

Mucosta Ophthalmic Suspension (rebamipide) P-3 Study

117

4 weeks treatment

Japan

Enrollment N=200

NCT01660256

Placebo Primary endpoint

(2, 4weeks) ・change in fluorescein

Rebamipide (4 times/day) 2% ophthalmic solution

Rebamipide (4 times/day) 2% ophthalmic suspension

4 weeks treatment US

Enrollment N=560

NCT01632137

Placebo

Primary endpoints (4weeks)

・change in fluorescein ・ocular symptom severity

Secondary endpoint (2weeks)

・change in fluorescein ・ocular symptom severity

Rebamipide (4 times/day) 2% ophthalmic suspension

ACU-4429

119

Age-related Macular Degeneration: AMD Age-related Macular Degeneration: AMD - AMD is a disease that macular in retina degenerates with aging. - Dry AMD： results from atrophy of the retinal pigment epithelial layer below the retina, which causes vision loss

through loss of photoreceptors in the central part of the eye. Progression is slow. - Wet AMD: causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the

choriocapillaris, through Bruch's membrane, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated. Progression is fast.

- Symptoms 1) Metamorphopsia: a type of distorted vision in which a grid of straight lines

appears wavy and parts of the grid may appear by distortion of retina caused by swelling of retina or gathering of liquid under retina. Surrounding parts are clearly seen since other parts except macular is not damaged.

2) Decreased vision, central scotoma: Damaged retina of macula causes central scotoma and decreased vision. Wet AMD progression is fast and in most cases, leads to severe ingravescence of visual acuity

Healthy macular region

macular region

Corpus Vitreum

Retina Optic nerves

Macular Degeneration

Drusen

Neovascular

Blue light

Bruch’s membrane

Retinal pigmented epithelium (RPE)

Neovascular Rods and cones

http://www.astro.virginia.edu/class/oconnell/astr1230/im/human-eye-crossec.jpg�

120

all-trans-retinol dehydrogenase

11-cis-retinal dehydrogenase （alcohol dehydrogenase） Isomerase

Function of Retinol

11-cis-retinal

11-cis-retinol all-trans-retinal

all-trans-retinol （Vitamin A）

phosphatidylethanolamine

A2-PE

VISUAL CYCLE

Biological function

Opsin Protein

Rhodopsin

Protein

• Cone cell： A fundamental cell of color vision, that develops visual pigment with different wavelength characteristic. Cone cell has a low luminous sensitivity and needs abundant light volume.

• Rod cell: Develops only single visual pigment and no color vision. Rod cell functions in the darkness as it has a high luminous sensitivity,

while cone cell doesn’t. This results that the shape of object can be clearly identified but not the color in the darkness, • Rhodopsin：Pigment in rod cell responsible for formulation of light receptor cell in retina and early stage of light recognition. The object

can be seen red-purple color in the light and black-white in the darkness, as rhodopsin mostly absorb aeruginous light. Rhodopsin fades immediately by sudden exposure to the light and recovery takes approximately 30 minutes.

β carotene

Conformational change of isomerization from cis-retinol in protein to all-trans-retinol is transmitted into cells by light stimulation, which transmitted to visual cell as signal of “light”.

• There are abundant alcohol dehydrogenase in retina that oxidizes retinol to retinal.

• Production of formaldehyde in retina, when consumed methanol, results in death of visual cell and blindness by its toxicity.

• Rhodopsin consists of vitamin A. Lack of vitamin A causes shortage of rhodopsin necessary for rod cell. The rod cell cannot receive a small light stimulation, resulting in the vision loss at night.

• Lack of rod cell causes night blindness as cone cell cannot receive light stimulation under low-intensity light.

42)(CHNHRCH −=

422 )(CHNH −

121


11-cis-retinal dehydrogenase Isomerase (RPE65）

Mechanism of AMD

11-cis-retinal


all-trans-retinol


A2E biosynthesis

A2-PE

VISUAL CYCLE

A2E

lipofuscin

Nucleus

RPE

Nucleus

Phagosome contains

A2E

Drusen

atrophy, vestigium

blood vessel

formation

reactive oxygen species

Drusen

Neovascular

Ischemia chronic inflammation

WET type

DRY type

A2E accumulation

122


11-cis-retinal dehydrogenase Isomerase

MOA of ACU-4429

11-cis-retinal


all-trans-retinol


A2E biosynthesis

A2-PE

VISUAL CYCLE

A2E

lipofuscin

Nucleus

RPE

Nucleus

Phagosome contains

A2E

Drusen

atrophy, vestigium

blood vessel

formation

reactive oxygen species

Drusen

Neovascular

Ischemia chronic inflammation

WET type

DRY type

A2E accumulation

ACU-4429

ACU-4429 » Decrease of the all-trans-retinal

reduces the biosynthesis and accumulation of A2E.

» Retinal isomerase is a rate-limiting, retina-specific visual cycle enzyme.

» Inhibition of isomerization slows the rate of the visual cycle turnover and reduces the level of all-trans-retinal available for A2E biosynthesis.

AMD Prevalence

123

Prevalence rate over 40yrs 10.4 mil (10.7%)

Early Dry AMD over 40yrs 8.8 mil（7.2%）

Late AMD over 50yrs 2.6 mil（2.6%）

Dry AMD over 50yrs 1.16 mil（1.2%）

Wet AMD over 50yrs 1.44 mil (1.5%）

Prevalence rate over 50yrs 15.3 mil (13.1%)

Early Dry AMD over 55yrs 12 mil（8.6%）



Wet AMD over 50yrs 2.2 mil(1.8%）

USA

Europe

Prevalence rate over 40yrs 3 mil (4.2%)

Early Dry AMD over 40yrs 2.6 mil（3.6%）



Wet AMD over 55yrs 0.37 mil(0.8%）

Japan

Source：Epi-database

It is important to provide drugs for both types of AMD as primary care.

Early AMD • No visual parafunction nor

subjective symptom • 視機能異常なし、自覚症状なし

視機能異常なし自覚症状なし

Geographic atrophy

Intermediate AMD • Visual parafunction and subjective

symptom for some patients

Advanced Dry AMD • Loss of macula visual cells

Wet AMD •Bleeding from undeveloped new blood vessel under the retina and retinal detachment

choroidal neovascular

Prevalence rate

Development Status

Electroretinogram - Contact lenses-type electrodes are placed on the cornea and retina is exposed to standardized stimuli.

The resulting signal is displayed showing the changes of electrical potentials between retina and cornea, investigating if the retina is normal.

- Damages to rod photoreceptors lead to impaired adaptation to darkness. Adaptation to darkness is defined as a recovery of photoreceptors in retina in the darkness after exposure to brightness. Adaptation to darkness may be a bio-assay of conditions in RPE, Bruch's membrane and choroid layer. Impaired adaptation to darkness could be a clinical marker for the diagnosis of those diseases states.

124

Inhibits isomerase by drug

Rate-limiting of visual cycle

Inhibits A2E generation

Inhibits geographic atrophy

development

Electroretinogram(ERG）

• Confirmed POC as

a biomarker

Phase Population Objective Dose/duration Status

P1a Healthy volunteers：N=46 （ACU-4429: N=38、Placebo:N= 8）

Safety, tolerability, PK/PD (ERG)

• formulation and duration：tablet , once/day • dose：2, 7, 10, 20, 40, 60, and 75 mg (or

placebo)

completed （2008）

P1b Healthy volunteers：N=40 （ACU-4429:N= 30、Placebo: N=10）

Safety, tolerability, PK

• Route and duration：tablet, once/day for 14 days

• dose：5 , 10, or 20 mg (or placebo)


P2a Patients with Dry AMD：N=56 （ACU-4429:N= 42、Placebo: N=14）

Safety, tolerability, PK/PD (ERG)

• Route and duration：tablet, once/day for 3 months

• dose：5 , 10, or 20 mg (or placebo)


Standardized stimuli

ACU-4429 Study

125

24 month treatment

P2/3

Enrollment N=440

NCT01802886

Placebo

Primary Endpoint ・Geographic atrophy scale

Secondary Endpoint ・BCVA 1) score

ACU-4429 (2.5 mg/day)

ACU-4429 (5 mg/day)

ACU-4429 (10 mg/day)

1)BCVA: best corrected visual acuity

90 days treatment

P-2a

Enrollment N=72

NCT01002950

Placebo

Primary Endpoint ・Safety Secondary Endpoint ・PK

Safety assessed until 1-2 weeks after treatment ACU-4429

(titration)

2 mg 5 mg 7 mg 10mg

OPA-6566

126

Glaucoma Glaucoma

- Caused by elevation of intraocular pressure to abnormal level by imbalance of aqueous humor production and outflow.

- Aqueous humor is generated at ciliary body, flows to anterior chamber then outflows from angle. Intraocular pressure is stabilized by flows of aqueous humor .

- Visual loss from optic nerve compression is caused by elevation of intraocular pressure by slow outflow of aqueous humor in anterior chamber.

127

Classification - Open angle glaucoma: The drainage system gradually become clogged over several months to

years. Impediment to drainage of aqueous humor causes gradual elevation of intraocular pressure while it is produced normally.

- Closed angle glaucoma: Onset of this kind of glaucoma is less frequent. The drainage system suddenly becomes clogged and causes acute elevation of intraocular pressure. Angle：angle at joint of iris and cornea around anterior chamber. Over 96% of aqueous humor outflows

from angle through trabecular pathway, canal of Schlemm or surface of ciliary body and choroidal vessels.

Symptoms - Open angle glaucoma: At the initial stage there is no pain or apparent symptoms but expansion of

visual field defect gradually develops over the years. Many patients are unaware of the disease until the last stage as it develops slowly. Vision will be lost peripherally, causing concentric contraction of visual field. The disease results in blindness if not treated early.

- Closed angle glaucoma: Causes severe pain, headache, vomiting, red eye, blurred vision and sudden decrease of vision with acute elevation of intraocular pressure. Vision may be seriously damaged if prompt treatment was not given when the symptoms occur.

- In both open angle and closed angle glaucoma, once the disease develops in one eye, it tends to occur on the other eye.

pressure and damage on the optic nerve

Normal flow of aqueous humor Closed angle glaucoma

Angle

Iris Ciliary body

Lens

Aqueous humor

Narrow angle

Lens

Retina

Cornea

Macula

Optical nerve

pressure

Closed angle glaucoma Open angle glaucoma

Aqueous Humor

drainage

Aqueous Humor

drainage

Angle

lens lens

Aqueous humor

Iris Iris

Aqueous humor

Ciliary body

Aqueous humor

Ciliary body

Early phase Mid phase Late phase

MOA of Anti-glaucoma Agents

128

Collecting duct

Canal of Shlemm

Extraocular Vessels

Uvea sclera

trabecula

pupil

posterior chamber

anterior chamber

iris

ciliary body

aqueous vein

episcleral vein

aqueous humor flow

production • Sympathetic stimulant • Sympatholytic drug • Carbonic anhydrase

inhibitor

• Parasympathetic stimulant • Sympathetic stimulant

• PG related drug • α1 blocker • Parasympathetic stimulant • Sympathetic stimulant

Aqueous humor outflow through canal of Schlemm Uveoscleral outflow

inhibit

increase

Outflow(10%)

Outflow (90%)

canal of Schlemm

trabecular pathway

iris

the vitreous

lens

aqueous humor flow

uveoscleral outflow

ciliary body

increase

Issues of existing treatment • Prostaglandin, which is widely used, has side effects

such as decrease intraocular pressure. There is no drug with high safety profile for long-term use.

Problems of glaucoma patients • Hyperemia, ocular itchy sensation • Poor compliance Expectations of doctors · New drug that acts on trabecular pathway · Drugs that increase aqueous outflow, not decrease

aqueous humor formation (normal function)

OPA-6566

129

New MOA：adenosine A2a receptor agonist · Acting on adenosine A2a receptor as agonist,

OPA-6566 decreases intraocular pressure by increasing aqueous outflow from trabecular pathway.

inhibition of aqueous humor formation at ciliary body

• Beta blocker/ anticholinergic agen

increase uveoscleral outflow

• Prostaglandin/Alpha- agonist canal of

Schlemm

trabecular pathway

iris

the vitreous

lens

aqueous humor flow

increase trabecular flow

OPA-6566

Prevalence and Market

130

Prevalence rate over 50 yrs 3 mil (3.1%)

Secondary glaucoma 0.3 mil（0.3%）

Primary glaucoma 2.75 mil（2.8%）

Open angle glaucoma 2 mil（2.0%）

Closed angle glaucoma 0.75 mil(0.8%）

Prevalence rate over 50 yrs 4 mil (3.4%)


Primary glaucoma 3.7 mil（3.1%）

Open angle glaucoma 2.8 mil（2.4%）


USA

Europe

Prevalence rate over 50 yrs 3.1 mil (5.6%)


Primary glaucoma 3 mil（5.4%）

Open angle glaucoma 2.5 mil（4.5%）


Japan

source：Epi-database

視機能異常なし自覚症状なし

地図状萎縮脈絡膜新生血管

Prevalence Rate

Market Growth in 7 Major Countries Market size：$5,200 Mil（2010）

$ Mil

Documents

R&D Meeting...2013/03/25 · Source：Byerly.M.: the 41 st annual meeting of the American College of Neuropsychopharmacology, Dec. 10, 2002 Adherence Issue with Antipsychotics 3 61.9%