Eisai’s R&D Network
and Activities
R&D Information Meeting
September 1, 2004

Kentaro Yoshimatsu, Ph.D.
Vice President
Discovery & Development Research Headquarters

1

Safe Harbor Statementu Materials and information provided during this presentation may contain “forward-looking
statements” as defined in the Private Securities Litigation Reform Act of 1995. Thesestatements are based on current expectations, forecasts and assumptions that are
subject to risks and uncertainties which could cause actual outcomes and results to differ
materially from these statements.
u Risks and uncertainties include general industry and market conditions, and generaldomestic and international economic conditions such as interest rate and currency
exchange fluctuations. Risks and uncertainties particularly apply with respect to productrelated forward-looking statements. Product risks and uncertainties include, but are notlimited to, technological advances and patents attained by competitors, challenges
inherent in new product development, including completion of clinical trials; claims andconcerns about product safety and efficacy; obtaining regulatory approvals; domestic
and foreign healthcare reforms; trends toward managed care and healthcare cost
containment, and governmental laws and regulations affecting domestic and foreign
operations.
u Also, for products that are approved, there are manufacturing and marketing risks anduncertainties, which include, but are not limited to, inability to build production capacity tomeet demand, unavailability of raw materials, and failure to gain market acceptance.
u The Company disclaims any intention or obligation to update or revise any forwardlooking statements whether as a result of new information, future events or otherwise.

2

Eisai’ Global R&D Network

LondonBostonNew Jersey
North Carolina(RTP)

Kashima
TsukubaTokyo
Honjo
Kawashima
Kyoto

Discovery & Non-clinical
Non
ClinicalGlobal R&D Functions

Discovery Research Non-clinical Development*

Tsukuba
Kyoto

LondonBostonTsukuba
Kashima
Kawashima
Honjo

Clinical ResearchTokyo

LondonBostonNew Jersey
North Carolina (RTP)*Process chemistry, Analytical research, Formulation, Safety, Clinical Supply etc.
4

Japan/US/EU
Discovery Research Network
BostonTsukubaLondon

Kyoto

Neurology
Therapeutic
ApproachGI
Oncology
Frontier

Technological
Platform

New Targets

New Targets

Medicinal Genetics
Gene Hunting
CombiChem, SBDD,HTS, Compound Library

Gene Function Analysis
Gene Hunting

Natural Organic
Compound Synthesis

Medicinal Chemistry5Eisai Global Clinical Development (EGC)
Establishment in May, 2004
Integrated clinical development functions in US/EU
Unified accountability in US/EU
Prompt and efficient decision-making
Close cooperation in US/EU
Director of Clinical Development Europe
reports to EGC President
u Appointment of Global Therapeutic Area HeadØ CNS, GI, Oncology, Infection
u Appointment of Global Functional Head
Ø Clinical Pharmacology, DataManagement, Biometrics,
Project Management
6Eisai Research Institute of
Boston Expansion
uExpand capacity and center a rental laboratory on one campus
uGroundbreaking Ceremony - August 23, 2004
uCompletion of project – Planned for October 2006
uTotal floor space: 200,000 ft2 (18,580 m2)
uStaff Capacity for 250 (40% increase)7

Outline of PF Plant· API manufacturing Plant which combined Pilot Plant and Factory· Total Floor Space : 9,905m2· Total Cost : 9 billion yen· Floors : Five stories
32.7m

35m

55m

Concept1)Supply high quality API for clinical use by having a cutting edge
Pilot Plant which complies with GMP
2)Increase production capacity of Aricept and Aciphex/Pariet and reduce
cost of API substantially.
3)Prevent 'health hazard' and 'environmental pollution' by installation ofcontainment equipment.
4)Achieve seamless collaboration between R&D and Production

8

Current Status ofDrug Discovery

9Eisai R&D Product Pipeline
ClinicalCategory
Phase I

Immunology/
AllergyAnti-cancer

CV
Metabolic

Submission
Phase III

E2051
(Acute ischemic stroke)
E2070(Analgesics)

E2007(MS, PD, EP)
E2020 (US)
(Migraine)
E2020(Severe AD)
E2020(Vascular dementia)
TVP1012(AD)
E2014(Cervical dystonia)

E2020(Severe AD)
E2020(Dementia associated PD)

E3309(Hp eradication)

E3810 (US)(Intermittent therapy)
E3620(Prokinetics)

E3810(Hp eradication)
E3810(sGERD)

E6040(Autoimmune disease)

E5564(Sepsis, CABG)
D2E7(Rheumatoid arthritis)

E7389(Cancer)
E7820(Cancer)
E7070(Cancer)

E7070(Cancer)
E0167(Cancer)

Neuro

GI

Phase II

E5555
E0735
(Acute Coronary syndrome) (paf/PAF)
E3030, E3030(Diabetes)

E2020 (US)(Vascular dementia)
E2020 (US, EU)(Liquid formulation)
E2020 (US, EU)(Rapid disintegratingtablet)T614(Rheumatoid arthritis)

KES524(Anti-obesity)

E6010(Pulmonary
embolism)

E7210(Contrast agent for ultra sound)Contrast Media

Red: Development in Japan
Underline: under preparation
10

Neurology

Neuro-protective Effect of Aricept

Donepezil has a protective effect against oxygen-glucose
deprivation-induced injury to rat primary cultured cortical neurons.
A

B

20

20

∗

∗∗
∗∗∗
10

∗∗∗
∗∗∗

10

0
Cont

Vehi

0.1

1

10

<Donepezi l >OGD( - )OGD(+)

1

10

100

1

( µM)

0
Cont

<Gal antami ne> <MK801>

Vehi

0. 1

1

10

<Tacr i ne>
OGD( - )

1

10

100

1

(µM)

<Ri vasti gmi ne> <MK801>

OGD(+)

Primary culture of rat cerebral cortical neurons OGD: oxygen-glucose deprivation(Eur. J. Pharmacol., 2003; 472: 57-63)

11

Drug Discovery Approach for
Alzheimer’s Disease
Amyloid Precursor Protein

β site γ site

β-secretase

Inhibition ofcell deathγ-secretase

Inhibition ofβ amyloid
productionΑβEndopeptidase

Neuronal death

Neurology

Protofibril

Amyloid deposition

Digested peptide

Accelerationof amyloid
degradation

Immunotherapy
12Neurology

Strategy Toward Regenerating CNS
Using Neural Stem Cells
1. Activation of endogenous NSCs
Insult-induced, growth factor infusion
Identification of endogenous NSC-activating factors
Development of small chemical compounds

2. Cell Therapy (Transplantation)

13

Neurology

Collaboration with Neurogenetics, Inc.
uLOAD program– Discovery of genes responsible for Late Onset Alzheimer's
Disease (LOAD) to establish valid targets and to facilitate
the development of new therapeutic products

uDate of contract– October 1, 2002

uNeurogenetics, Inc.
– San Diego, founded in April 2000

14

Exploratory Research for GI Area

GI

-Target diseases and Therapeutic targetsAcid Relates Disease

Gastrointestinal Discomfort(due to GI Motility Dysfunction)

Gastro-Esophageal Reflux
Disease(GERD)

Upper GI Discomfort
Irritable Bowel Syndrome(IBS)

Peptic Ulcer Disease
Therapy for GI Disorders
related to Gastric Acid Secretion

Therapy for Gastric Dyspepsia
and Abdominal Discomfort
due to GI Motility Dysfunction

Inflammatory Bowel
Disease (IBD)
Crohn’s Disease
Therapy for Intractable
Bowel Inflammation

Ulcerative Colitis
15

Exploratory Research for GI Area

GI

-Therapeutic Approach & TargetsAcid Related Disease

Gastrointestinal Discomfort(due to GI Motility Dysfunction)

GERD/
Peptic Ulcer Disease

Upper GI Discomfort
GI Motility Approach

Acid Suppression Approach

E3620
Acid Suppression Research

Irritable Bowel Syndrome(IBS)
Inflammatory Bowel
Disease (IBD)

GI Motility Approach

Crohn’s Disease
Ulcerative Colitis
E3620;
Prokinetics

Novel Inflammatory
Drug

Inflammatory Suppression
Approach16Oncology Projects

Oncology

Meet Needs for Cancer Treatment
by Various Approaches
Tumor regression

Tumor
suppression

Life-span
Prolongation

Novelmechanism

Novelanti-mitotic

Antiangiogenesis

Preventionofrecurrence

E7070

E7389

E7820

E0167

Cell cycle G1 phasetargeting agent
US, EU and JP
Phase II

Tubulin polymerization
inhibitor
US
Phase I

Integrin α-2expression inhibitor
US
Phase I

E7107

E7974

E7080

Novel antitumor agent
derived fromfermentation
Pre-clinicalTubulin polymerization
inhibitor
Pre-clinical

VEGF receptor
tyrosine kinase inhibitor
Phase I
under preparation

Prevention of recurrenceof hepatocellular carcinoma
by vitamin K2

JP, Phase II

17

Oncology

E7070(indisulam)· Tumor regression of colon,
NSCLC, breast and gastriccancer xenografts· Additive effect with platinum
and 5-FU- Down regulation of Glutathione
synthetase- Down regulation of Thymidylate
synthase

Gastric

Breast Pancreatic· Synergistic effect with irinotecan- Down regulation of Topo II

NSCLC

Colorectal

G1 Phase Targeting Agent: Ph. II
HCT 116
HCT-15
SW480
SW620
COLO 320DM
COLO 205
DLD-1
WiDr
HT-29
PC-1
PC-9
PC-10
PC-14
A-427
NCI-H460
NCI-H520
NCI-H596
Lu99
MIA PaCa-2
PANC-1
AsPC-1KP-1
KP-4
SUIT-2
MDA-MB-231
MDA-MB-435
MDA-MB-453
MDA-MB-468
BSY-1
HBC-5
MKN1
MKN7
MKN28
MKN45
MKN74
KATOIII
-2

-1.5

-1

-0.5

Low sensitive

0

0.5

1

1.5

2

High sensitive18

Unique Profile of E7070 Oncology

Study to reveal mechanism is ongoing

Proteome
Technology

Gene Expression Bio-pharmacological
Analysis
Approach

E7070 binding proteins E7070 biological Marker E7070 Mode of ActionMore than 10 proteins
For example: cMDH
(Cytosolic malate dehydrogenase)

E7070 binds cMDH
competitively with NADH

A set of response
marker genes
Reduction of Topo II α etc.
In response toE7070 treatment

G1 cell cycle arrestby Induction of
CDK inhibitor p21
P21 inhibits G1/S
Cell cycle transition
19E7389Oncology

Tubulin Polymerization Inhibitor: Ph. I
u NCI demonstrated excellent
anti-tumor activity of marine
natural halichondrin B in several
human tumor xenograft models.
u Limited compound supply
prevented development ofhalichondrin B.
u Eisai Research Instituteidentified pharmacophore
u E7389 is totally synthetic
material.

MeO
HO
H2N

1
31

35

O

O

34

O

H
7

O

H

• HOMs

O 27

O
Me

23

10

O
O

14
13

O

H

19

E7389
Me

Me
H

H
H

O

H

O

O

HO

H
O

O
HO

H
O
O

H

H

H

O

O

O

Me
Me
HO

O

H
O

H

O

H

O
O

O

Halichondrin B

20

E7389Oncology

Tubulin Polymerization Inhibitor: Ph. I– MDA-MB-435 breast– COLO 205 colon– LOX melanoma– OVCAR-3 ovary– H522 lung• Significantly more potent thantaxol
• Active against taxol-resistantcancer cells

Average tumor volumes (µl)• Highly effective in several
human tumor xenograft models

MDA-MB-435 human breast
cancer xenograft model
800
600

Taxol 25 mg/kg

Control

400
200
E7389 1 mg/kg
0
0

14

28

Control

42

56
Day

70

84

98

E7389

• Unique mechanism of action
among anti-tubulins, taxanes
and vinca alkaroilds
21E7820Oncology

Oral Angiogenesis Inhibitor: Ph. I· Inhibition of capillary tube formation and proliferation ofendothelial cells· Inhibition of integrin α2 expression· Inhibition of VEGF and FGF-induced angiogenesis
In vitro anti-angiogenic activity in tube
formation assay
Compounds Angiogenic
factor
E7820
TNP-470
Marimastat
SU5416

bFGF
VEGF
bFGF
VEGF
bFGF
VEGF
bFGF
VEGF

IC50 (range)(mg/mL)0.20 (0.18 - 0.22)
0.24 (0.21-0.38)
>5
>5
>5
>5
>5
0.19 (0.18-0.19)

Growth factor

Stress, inflammation

Receptor
Antibody

Integrin α2/β1

Receptorkinase inhibitor
Endothelial
cellIntegrin α2

NuclearAngiogenic related genes

Integrin gene

mRNA
22

E7820Oncology

Oral Angiogenesis Inhibitor: Ph. I• Effective in human pancreatic, breast, colonand renal cancer xenograft models• Prolongs survival in human breast cancer xenograft model
Human Pancreatic Cancer(KP-1)
Vehicle3000

812.5 mg/kg

2500

25 mg/kg

7

50 mg/kg

6

vehicleTaxol 25 mg/kg
E7820 100 mg/kg

100 mg/kg

2000

Survival

Tumor Volume (mm3)3500

Survival curve in MDA-MB-435 humanbreast cancer xenograft models

200 mg/kg
1500? ? ? ? (1? 2? ? ? ? ? )
1000

5
4
3
2

500

1
0

0

0

10

20

30

40

50

0

10 20 30 40 50 60 70 80 90 100 110 120 130

Days

Days
23

E7080Oncology

Oral Angiogenesis Inhibitor: Ph. I (under preparation)· Highly potent VEGFR tyrosine kinase inhibitor
VEGF; Vascular endothelial cell growth factor receptor· Anti-VEGF (Avastin) showed clinical efficacy
Inhibition of cell free tyrosine kinase activity

SU11248 PTK787 ZD6474 CP-547,632

VEGFR

64

124

FGFR1
EGFR
PDGFRb1,500>10,000
120>10,000>10,000
410

191

178

1,400
220
6,750

160
>10,000
2,000

IC50 (nM)

E7080

3.6
25
>10,000
50
24

E7107

Oncology

Novel Anti-tumor Compound, Derivative of Pladienolide,
Derived from Fermentation: Pre-clinicalcell lines pRB loss Cyclin E T/C%

· Highly potent tumor regression
activity; tumor remission wasobserved in several xenografts· ‘pRB loss and high cyclin E’
is common feature among tumor
cells highly sensitive to E7107;
possible predictive factor*Discovered together with Mercian Corporation

BSY-1
BSY
Yes
+++
MDA-MB468
Yes+++
LC-6-JCKYes+++
OVCAR3Yes+++
NCI-H146
Yes(mt) +++NCI -H69
Yes(mt) ±NCI-H526
Yes
+
PC-3
++
FaDu
±
WiDr
±
HBC4
+ +
Lu99
±
Yes
NCI-H510+
NCI-H596
Yes
+++
KPL-4
+
SK-OV-3++
DU145
Yes(mt) +++MDA-MB435
++
HT-29
+
SW620
+
NCI-H460+
KM12+
NCI-H522
+++
DLD-1
+
Calu-1
++

0
0
0
0
1
1
1
2
3
4
5
8
10
18
23
27
28
28
28
28
33
34
42
47
55
25

Oncology

Alliance with Link Genomics

Genome-wide analysis of genetic aberrations in cancer
Genome-wide HR DNA chip
LGI

1. “DNA analysis of tumor tissues"
2. “Clinical samples"
3. "Relation of stage, responsibility andprognosis"

Genomic aberration–Cancer stage Data baseSpecificities of Tumors and Tissues, Drug response

Novel target genes

Anti-cancer
drug in Eisai
26

E5555

Frontier

Orally Active PAR-1 Antagonist: Ph I
Indication: Acute coronary syndrome(ACS)PAR-1: protease-activated receptor-1

Bleeding

Atherosclerosis

E5555

Thrombosis

Platelet Aggregation
Fibrin formation

ACS(UA, MI)

Thrombin

MonocyteLympho
cyte

Endothelium

Adhesion

Migration

SMC
Proliferation
27

E5555

Frontier

Orally Active PAR-1 Antagonist: Ph I
Indication: Acute coronary syndrome(ACS)
Summary of pharmacological studies
Test

MonkeyGuinea pig

Rat

N.T.

N.T.

N.T.

PRP aggregation (IC50) 64 nM

12 nM

N.T.

N.T.

SMC proliferation (IC50)28 nM

N.T.

N.T.

160 nM

In vitro
PAR-1 Binding (IC50)

Human

19 nM

In vivo
Thrombosis model (30mg/kg)

Intimal Hyperplasia model (30mg/kg)
Bleeding Time (1000mg/kg)

Effective
plasma conc.: 56 nM
Effective
No prolongation
plasma conc.: 281 nM
N.T.: Not Tested

28Discovery Research Projects Frontier
In Frontier Area
Target: MEKK1, MEK1 and IKK β
EGF, KGF, …. IL-1, TNF, LPS,…

Inflammation pathways
Proliferation pathways

C-RAF

MEKK1

MEK1

MEK4/7

IKK β

ERK2

JNK

IkBa

ELK-1
Cell
Growth?

C-Fos C-Jun

AP-1
Cell Growth

NF-kB
Cytokine
Chemokine
Adhesion Molc.
29

FrontierCollaboration with LocomoGene
Inc.
Research program for Rheumatoid Arthritis Treatment

SynoviolinTargetSynovial Cell Growth

Crisis of Rheumatoid Arthritis
LocomoGene Inc.
Established as a research and development venture company to find new genes andproteins related to aging diseases. All shares are held by the investment fund, The
1st Biotech Healthcare Investment Business Limited Liability Association" supported
by Development Bank of Japan.
30

Global Clinical Research
Jiro Hasegawa, Ph.D.
Vice President, Head of Global Clinical Research,
Eisai Co., Ltd.
September 1, 2004

31

Clinical Development Priorities
in FY2004 (1)1. Increasing the Probability of Success Future
Global Products- Achievement of Proof of Concept(POC) for the four Global
Priority Projects E2007
E5564

E7070
E7389

Phase IIb Study in Parkinson’s disease (EU)Phase II Study in Sepsis (US)Phase II Study in CABG (US)Phase IIb Study in CABG (EU)Phase IIb Monotherapy in Breast Cancer (US)Phase II Combination Study with irinotecan in CRC (EU)Phase II Study in Breast Cancer (US)32

Clinical Development Priorities
in FY2004 (2)2. Lifecycle Management Reinforcement for Aricept andAciphex/Pariet
Aricept
Completion of Patient Enrollment in FY2004 of Phase III Studies for:Vascular Dementia (US/EU)
Severe Alzheimer`s Disease (US/EU/JP)
Filing: FY 2005
Dementia associated with Parkinson’s Disease (EU)Approval of Rapid Disintegrating Tablet and Liquid Formulation (US/EU)

Aciphex/Pariet
Progress of Phase II Study for Intermittent Therapy (US)Progress of Phase III Study for s-GERD and H. pylori eradication (JP)33

E7070 (indisulam)
Cell Cycle G1 Phase Targeting Agent
Anti-cancer drug

34

E7070 Clinical Studies
Single agent Phase IIa studies
Completion: Colorectal (EU), Non-small cell lung (EU), Head & Neck (US),Breast (EU), Melanoma (EU), Renal (US/EU)
Under preparation: Stomach (JP)

Effective

BreastColorectal

Non-Small
Cell Lung

SinglePhase IIb

Combination
withcapecitabine

Combination
withirinotecan

Combination
withcarboplatin(US)(Ph I/II : EU)(Ph I : US)(Ph I/II : EU)35

Results of 204 Study (Breast, EU) and theComparison with capecitabine
E7070

capecitabine

capecitabine

II

II

II

NumbersofPatients

20

162

71

PR rate

15%

20%

17%

SD rate

40%

40%

38%

ClinicalPhase

PR: Partial Response
SD: Stable Disease36

Current Status of E7070
Clinical Studies
uSingle agent study
nInitiated Ph IIb for Breast cancer in January, 2004 in the US
nTarget NDA/MAA in 2006

uCombination study
lCombination with irinotecan
nConfirmed the recommended dose in the Ph I (US)nPartial Responses were observed in colorectal cancer patientsnInitiated the Ph II for colorectal cancer in July, 2004 (EU)nTarget NDA/MAA in FY2006

lCombination with capecitabinenConfirmed the recommended dose in the Ph I study (EU)nUnder preparation for Ph II study for colorectal cancer (EU)nUnder preparation for Ph II study for breast cancer (EU)lCombination with carboplatinnConfirmed the recommended dose in the Ph I study (EU)nInitiated the Ph II study for Non-small cell lung cancer (EU)37

E7389Tubulin Polymerase Inhibitor
Anti-cancer drug

38

E7389 - Phase I
u US NCI study– NC5730 (Day-1, -8, -15 q28 days, IV bolus)–Achieved MTD (Maximum Tolerated Dose)–Responses in NSCLC (refractory to taxane)u Eisai study– 101 study (Day-1, -8, -15 q28 days, 1 hour infusion)–Status: On going– 102 study (Day-1 q21 days, I hour infusion)–Status: On going

39

NSCLC Patient
04/2/24

ApicalMidpoint

04/4/15

E7389 - Phase I, II
Phase Iu US NCI study– NC5730 (Day-1, -8, -15 q28 days, IV bolus)– Achieved MTD– Responses in NSCLC (refractory to taxane)u Eisai study– 101 study (Day-1, -8, -15 q28 days, 1 hour infusion)– Status: On going– 102 study (Day-1 q21 days, I hour infusion)– Status: On going
Phase IIu Single agent therapy– 201 study (Breast cancer)– 202 study (NSCLC)

41

E2007
AMPA Receptor Antagonist
n Parkinson’s diseasen Epilepsyn Multiple sclerosis42

E2007 Clinical Studies

FY2003 Achievementn Completion of Phase IIa study for Parkinson’s

disease, Epilepsy and Multiple sclerosis in EU
Current statusn Initiated Phase IIb for Parkinson’s disease in EU
n Phase IIb for Epilepsy is in preparation in the US

43

Anti-Wearing Off Effect of E2007
in Parkinsonian Rats
Advanced Parkinson’s
diseasewith E2007
Plasma L-DOPA concentration

50

Dyskinesia

Therapeutic Window

L-DOPA (25mg/kg, i.p.)
Day 1

on-timeParkinsonism

0
0

Time

40

E2007 (mg/kg, p.o.)
L-DOPA (25mg/kg, i.p.)
44

E5564 (eritoran)
Endotoxin Antagonist
n Sepsisn CABG
Prevention of endotoxin-related
complications after coronary artery
bypass graft surgery

45E5564 (Endotoxin Antagonist)uIndication:– Sepsis– Coronary artery bypass graft (CABG)– Prophylactic use for endotoxemia after
Coronary artery bypass graft surgery

uStage:– Sepsis Ph II : Stage 3 on-going in US– CABG Ph IIa: Stage 3 completed in US– CABG Ph IIb: On going in EU and CanadauNDA / MAA:
– FY2007 (CABG), FY2008 (Sepsis)

46

E5564 Blocks LPS-induced
Symptoms in Phase I Study80
70

moderate

60
50

mild

40

moderate

30
20
10
0

E5564,
250 mcg

Placebo E5564, 50
mcg

Dose Group

Percent of group

Tachycardia

Percent of group

Percent of group

mild

Placebo E5564, 50 E5564,
mcg
100 mcg

100
90
80
70
60
50
40
30
20
10
0

Myalgia

mild
moderate

Placebo E5564, 50 E5564,
mcg
100 mcg
Dose Group

E5564,
250 mcg

100
90
80
70
60
50
40
30
20
10
0

E5564,
100 mcg

100
90
80
70
60
50
40
30
20
10
0

E5564,
250 mcg

mildmoderate

Placebo E5564, 50 E5564,
mcg
100 mcg

Dose Group

Dose Group

NauseaHeadache

Percent of group

100
90
80
70
60
50
40
30
20
10
0

Fever

Percent of group

Percent of group

Chillsmildmoderate

Placebo E5564, 50 E5564,
mcg
100 mcg
Dose Group

E5564,
250 mcg

100
90
80
70
60
50
40
30
20
10
0

E5564,
250 mcg

mildmoderate

Placebo E5564, 50 E5564,
mcg
100 mcg

E5564,
250 mcg

Dose Group

E5564 is the only drug which has achieved complete suppression of LPS
induced symptoms in human endotoxemia

47

Basis for Efficacy in CABG
-Incidence of Major Complications as a Function of AntiEndotoxin IgM Antibody Titers-

Patients (N=301) were evaluated for EndoCAb IgM value and CABG surgical outcome.
Major complications were defined by hospital length of stay > 10 days and plotted vs. quartile rankof pre-surgical plasma EndoCAb IgM value. For details see Bennet-Guerrero et al. (1997).

48

UpdateAciphex/Pariet
Aricept49

Recent Regulatory Achievements
uApproval of On Demand Therapy of Pariet (EU)– April 2004 in EU
uApproval of Zollinger-Ellison Syndrome Indication of Pariet(EU)– June 2004 in EU
uApproval of Rapid Disintegration Tablet of Aricept– March 2004 in JapanuFiling of Rapid Disintegration Tablet of Aricept– December 2003 in EU and US
uFiling of Liquid Formulation of Aricept– December 2003 in US– May 2004 in EU
50

Aciphex/Pariet

51

Aciphex/Pariet Lifecycle Management
Compound/Indication

Phase I

Phase II

Phase III

Submission

LaunchAciphex/Pariet (H. pylori eradication)
US, EU
Aciphex/Pariet (Symptomatic GERD/GORD)
US, EU
Pariet (Maintenance Therapy of GERD)
JP
Pariet (On-demand Therapy of GORD)
EU
Pariet (Zollinger Ellison Syndrome)EU
Pariet (H. pylori eradication)
JP
Pariet (Symptomatic GERD)
JP
Aciphex (Intermittent Therapy of Symptomatic
GERD) JP52

Aricept

53

Aricept Lifecycle Management
Compound/Indication

Phase I

Phase II

Phase III

Submission

LaunchAricept (Vascular Dementia)
US
Aricept (Severe Alzheimer’s)
US, EU, JP
Aricept (Dementia Associated with PD)
EU
Aricept (Migraine Prophylaxis)
US, EU
Aricept (Rapid Disintegration Tablet)
JP
Aricept (Rapid Disintegration Tablet)
US, EU
Aricept (Liquid Formulation)
US, EU

54

Vascular Dementia
Severe Alzheimer Dementia(New Indication)uVascular Dementia– US– NDA submission:
Sep 02– Non approvable letter : Jul 03– EU– MAA submission:
Oct 02– Withdrawal:
Apr 04– Future Strategy– Complete 3rd pivotal study (E2020-A001-319)– US: continue negotiation and submit the 3rd study results to reinforce
data set (FY05: expected)– EU: Re-submit MAA including the 3rd study results (FY05: expected)

uSevere Alzheimer Disease Dementia– DON-NY-324 (preliminary study)– Moderate to moderately severe AD patient– E2020-A001-315 (pivotal study)– Severe AD patient55

DON-NY-324 (MSAD Study)
Objectives
n Evaluate the safety and efficacy of donepezil in patients withmoderate to moderately severe AD(sMMSE = 5 –17)

Designu A multicenter, multinational, randomized, double-blind, placebocontrolled 24-week study
u 291 patients with moderate to moderately severe ADu Randomization was 1:1 (donepezil:placebo)– Aricept 5 mg daily for 28 days increased to 10 mg daily for the remainder ofthe study based on the clinicians judgment– 82% of total patients was administered 10mg daily
Feldman, H et al. Neurology., 57: 613-620 (2001)

56

Change from Baseline Scores
SIB(Severe Impairment Battery)
LS mean squares change
from baseline ± SE

8.0
6.0

p<0.0001
p=0.0051
p=0.0078

4.0

Aricept
p=0.0009

p<0.0001p<0.0001

Improvement

2.0
0.0
-2.0
-4.0

mean±S.E.

DeclinePlacebo-6.0

Aricept
Placebo

0

4

8

1
1
2
8
Study Week

2
4

Wee24
LOCF

139
145

130
139

115
119

123
128

120
126

(139)
(145)

119
128

Feldman, H et al. Neurology., 57: 613-620 (2001)

57

Severe AD NDA/MAA
uE2020-A001-315 study:– On-going (study completion: mid FY05)
uNDA/MAA: FY05 (expected)

58

Dementia Associated with
Parkinson’s Disease(New Indication)
E2020-E044-316 (PD study)
Objectives
n Evaluate the efficacy, tolerability and safety of donepezil in
Parkinson’s Disease (PD) patients with dementia

Study Design
uE2020-E044-316– Clinical phase on going–Completion: mid FY05 (expected)
uEU MAA: FY05

59

Mild Cognitive Impairment-MCI
Working Criteria for MCI
u Subjective memory complaint and objective memory deficit (i.e,delayed recall >1.5 SD below age and education norms)
u Preserved general cognitive ability (Mini-Mental State Examination[MMSE] =24)
u Intact activities of daily living (ADL)u Not demented (Clinical Dementia Rating [CDR] 0.5)
u MCI may be regarded as incipient or prodromal Alzheimer’s
disease (AD)u Patients with MCI progress to AD at a higher annual rate
(10% to 15%) than normal elderly patients (1% to 2%)

Petersen RC et al. The Neurologist. 1995;1:326-344. Petersen RC et al. Arch Neurol. 2001;58:19851992.
Grundman M, Petersen R. Neurology. 1996;46:A403. Flicker C et al. Neurology. 1991;41:1006-1009.
Petersen RC et al. JAMA. 1995;273:1274-1278.
60

MCI Trial with Vitamin E
and donepeziluRecruit people with MCI
u3 treatments•Vitamin E – 2,000 IU/day•Donepezil – 10 mg/day•Placebo•Open-label donepezil after conversion to AD

uStudy objectives•Prevent development of Alzheimer’s disease•Slow decline on measures of cognitionu3-year duration
u790 participants
u69 centers
61

Mean Time to Conversion to AD
Time to Conversion(mean days ± SD)

Aricept(n=63)661±270*

Vitamin E (n=76)

540±257

Placebo (n=73)484±272

177days*P=0.0003
62

Aricept

Efficacy in Long-term Studies

63

A 52-Week, Multicenter, Randomized,
Double-Blind, Placebo-Controlled
Study (The Nordic Study)
nObjective
Evaluate the Long-term Clinical Efficacy and Safety of
Aricept in patients with mild to moderate AD
nStudy Design
A 52-Week, Randomized, Double-Blind,
Placebo-Controlled Study :· Patients (n = 286, MMSE = 10-26)
Aricept 10mg (n=142, 5 mg daily for 28 days increased to 10 mg
daily based on the clinicians’ judgment) Placebo (n=144)

Winblad, B., et al. : Neurology., 57, 489 (2001)

64

Time Course of MMSE
( Points)

LS mean change fromBaseline (mean ± S.E)

2.0

mean±S.E.
*: p<0.05**: p<0.01***: p<0.001

Aricept

1.0( n=142)

Improvement

***
*

0

**
***

Decline-1.0
Placebo( n=144)

-2.0
-3.0
0

12

24

36

52 End Point (wks)(LOCF)

Study week
Aricept
Placebo

135
137

127
128

121
120

104
105

91
98

135
137

(n)
65

Winblad, B., et al. : Neurology., 57, 489 (2001)

A 1-year, Placebo-controlled
Preservation of Function Survival
Study of donepezil in AD Patients(Attrition Study)n Objective
Examine the effects of donepezil compared with placebo on
the preservation of function in patients with ADn Study Designu A 1-year double-blind, placebo-controlled studyu Probable AD Patients (n = 431, MMSE=12-20) were randomized
u donepezil (n = 214, 5 mg/day for 28 days, 10 mg/day
thereafter)u placebo(n = 217)
u ADL was measured based on instrumental and basic ADL scales
widely used in clinical researchu The primary efficacy analysis was the time in days to reach clinicallyevident functional decline.
Mohs, R.C. et al : Neurology 57, 481 (2001)

66

Inhibition of ADL Function Decline
ratio of patients keeping ADL function

1.0*: p = 0.0019
log- rank test

0.9
Aricept

0.8( n= 214)0.7
0.6

Placebo*( n= 217)

0.5
0.4

51%
35%

0.3
0.2

The median time to clinically evident functional decline
Aricept 357 days
donepezil-treated patients maintained their function

0.1
0.0

72% Prolongation

Placebo 208 days

0

6

12

18

24

30

36

42

48

54(wks)Administration Period
Mohs, R.C. et al : Neurology 57, 481 (2001)

67

Nursing Home Study
Objectives
n Assess the relationship between donepezil treatment and time tonursing home placement (NHP) for patients with Alzheimer`s Disease
Designu Patients previously enrolled in one of three placebo controlled studies andparticipated in subsequent open label extension studies were followed byinterviewing caregivers
u Information on the date and reason for each NHP and treatment compliance wereobtained
u 671 patients provided complete data for analysis
u Continued treatment of up to 240 weeks in the open label studies were available

D.S.Geldmacher, et.al., J.Am.Ger.Assoc., 51(7)937,2003

68

Time to First Dementia-related
NHP with Increasing Donepezil
Exposure
66.1

Maximal (n=310)

58.0

Delayed (n=194)

44.7

Early (n=54)

Limited (n=113)
0

44.7

21.4 month
delay

20
40
60
80
Median time to first dementia-related NHP (mo)Error bars represent 95% CIs of median values.

D. S. Geldmacher, et al., J. Am. Ger. Assoc., 51(7), 937, 2003 69

AD2000 StudyuObjective– Assess the effects of donepezil from the viewpoint such as
patient institutionalization

uStudy Design– Double blind, placebo controlled long-term study– Patients: selected by DSM-? diagnosis of dementia of Alzheimer
type based on uncertainty (mild to moderate patients living in
the community)– 565 patients enrolled– 12 weeks: placebo vs. donepezil (5 mg/day) à 48weeks:rerandomised to placebo vs. donepezil (5 or 10 mg/day) à
6weeks washout ? 48weeks: placebo vs. donepezil à 4weeks
washout à (48weeks: placebo vs. donepezil à 4weeks washout)à (repeated)

uPrimary endpoint– Entry to institutional care and progression of disability (BADLS)70

AD 2000: Eisai's Statement(1)uMethods for patient selection– Non Eligible: a definite indication for or against donepezil
treatment– Eligible: "substantially uncertain whether or not a particularpatient would derive worthwhile benefit from donepezil"– the investigators introduced bias to their results.

uSample size
– 3,000 patients(original) à only 566 patients– Underpowered studyuAttrition rate
– Within one year, 48% of patients had discontinued– Less than 20% (n=111) remained by the end of year 2.
– Statistically, this small sample is not sufficient to refute thefindings of other published studies
71

AD 2000: Eisai's Statement(2)uRandomization procedures– Limited geographic location on subject selection
and physician practice patterns– Further decrease the conclusion generalizationuMultiple washout periods– Data had been published indicating that such
washouts were associated with loss of donepezil
treatment benefit– This design would be expected to lead to a decreased
benefit on cognition, and may impact factors
important for institutionalization.

72

Clinical Researchin JapanHisashi Tanaka, Ph.D
Vice President, Head of the Clinical Research Center
Eisai Co., Ltd.
September 1, 2004

73

Eisai R&D Product Pipeline
Projects
ClinicalCategory

Submission
Phase I

Phase II

Phase III

E2051
(Acute ischemic stroke)
E2070(Analgesics)

E2007(MS, PD, EP)
E2020 (US)
(Migraine)
E2020(Severe AD)
E2020(Vascular dementia)
TVP1012(AD)
E2014(Cervical dystonia)

E2020(Severe AD)
E2020(Dementia associated PD)

E3309(Hp eradication)

E3810 (US)(Intermittent therapy)
E3620(Prokinetics)

E3810(Hp eradication)
E3810(sGERD)

E6040(Autoimmune disease)

E5564(Sepsis, CABG)
D2E7(Rheumatoid arthritis)

Anti-cancer

E7389(Cancer)
E7820(Cancer)
E7070(Cancer)

E7070(Cancer)
E0167(Cancer)CV
MetabolicE5555(Acute Coronary
syndrome)
E3030, E3030(Diabetes)

E0735(paf/PAF)

Neuro

GI

Immunology/
AllergyContrast MediaE2020 (US)(Vascular dementia)
E2020 (US, EU)(Liquid formulation)
E2020 (US, EU)(Rapid disintegrating tablet)

T614(Rheumatoid arthritis)

KES524(Anti-obesity)

E6010(Pulmonary embolism)

E7210(Contrast agent for ultra
sound)

Red: Development in Japan
Underline: under preparation74

Outline of D2E7
Human Anti-TNF-α Monoclonal Antibody
Themeadalimumab (D2E7)

NoteCo-development with
Abbott Japan Co., Ltd.
(Launched in US/EU)

Indication

Rheumatoid Arthritis(moderate to severe)

SupplyPre-filled Syringe

Phase

II

NDA
target

FY2005

Merits1) More rapid and sound efficacy than that of DMARDs.
2) Every other week mono-therapy revealed efficacy with/without MTX.
3) Ready-to-use liquid formulation suitable for subcutaneous injection.

75

Comparison with Competitors
INN
Company
Structure

infliximab
Centocore/ Tanabe

etanercept
Immunex / Wyethadalimumab
Abbott/ Eisai

Black-areaindicates
mouse-gene
derived parts

Type
Phase
Indication

Mouse/human chimera
Soluble TNF receptor
Fully humanAnti-TNF-alpha Mab
Ig-Fc fusion protein
Anti-TNF-alpha Mab
Launched
Registered
Phase II
Rheumatoid Arthritis ( inadequate response to at least one DMARD)

76

Outline of KES524
Obesity Management /Central Acting Serotonin &Noradrenaline Reuptake Inhibitor
Themesibutramine (KES524)

Note

Exclusive development
in Japan(Launched in US/EU)

Indication

Obesity

SupplyCapsule

Phase

III

NDA
Target

FY2007

Merits1) Enhance energy consumption and a feeling of fullness to reduce ingestion
and body weight.
2) Expected to reduce body weight and to maintain the reduced weight
for a long period.
3) Expected to improve complications related to obesity.

77

%Change of body weight in Phase II study
0.00%Change of Body Weight

-1.00

-2.00

-3.00

Placebo? ? ? ? ?
5 mg
5mg?
10
mg
10mg?
15
mg
15mg?

-4.00

-5.00

-6.00

-7.00
0

2

4

6

8

10

12

Weeks ?after
dosing? ? ? (? )

14

LOCF
16

18

78

Outline of T-614
Anti-rheumatic Agent
Theme

iguratimod(T-614)Note

Co-development with
Toyama Chemical Co., Ltd.

Indication

Rheumatoid Arthritis

SupplyTabletPhase

Submitted

NDA

FY2003

Merits1) Suppress antibody production from B cell without inhibiting
lymphocyte proliferation.
2) Suppress cytokine production.

79

Improvement Rate
based on the ACR Diagnosis Criteria

Improvement rate(%)

ACR20 & ACR50 (Non-inferiority analysis set)
80
60
40

62.5

58.1

32.7

34.3

20
0

T-614

ACR20
ACR50

SASP

EULAR June-2004

80

Eisai’s R&D Goals
Kentaro Yoshimatsu, Ph.D.
Vice President,
Discovery & Development Research Headquarter
Eisai Co., Ltd.
September 1, 2004

81

Eisai’s R&D Goals
uGlobal leader in franchise areas– Creation of neurodegenerative diseases
treatment through cutting-edge research– Strengthen oncology pipelineuFurther improve the competitive advantagesof Aricept, Aciphex/Pariet– Aricept: “Gold standard” of AD treatments– Aciphex/Pariet: Strong branding based onevidence

uFile one NME a year82Enhanced NME Pipeline
Pre-clinical

Neuro

Neurodegenerative diseases
ｷ Aβ accumulation
suppressor
ｷ Neuro cell death inhibitor

Phase I
E2051
(Acute ischemic stroke)
E2070(Analgesics)

E2007(MS, PD, EP)
TVP1012(AD)
E2014(Cervical dystonia)

E3309(H. pylori eradication)

E3620(Gastroprokinetic)

E7389(Tubulin polymerase
inhibitor)
E7820(Angiogenesis inhibitor)

E7070(Cell growth cycle GI phaseinhibitor)

ｷ Neuro-stem cell activator
Acid-related disorders

GI

Irritable bowel syndrome

Phase II

Phase III

IBD

Anti-cancer

E7080(Angiogenesis inhibitor)
E7107(pladienolide derivative)
E7974(Tubulin polymerase inhibitor)

Frontier

Immunology/Allergy

OthersDiabetes

Alimentary tract

E5555
E5564
(Acute Coronary syndrome) (Sepsis, CABG)
E6040
D2E7
(Rheumatoid arthritis)(Autoimmune disorders)

E3030(Diabetes)

E7210(Contrast agent)

KES524(Obesity)83

File One New Molecular Entity(NME) A Year
FY2008E5564 (Sepsis, US/EU)
E7070(Cancer, JP)
E5564 (Prevention of endotoxinrelated complications after
coronary artery bypass graft
surgery, US and EU)
KES524 (Obesity Management, JP)
E2007 (Parkinson’s disease, US and EU)
E7070 (Cancer, US and EU)
E7389 (Cancer, US and EU)

FY2007

FY2006

FY2005 D2E7 (Rheumatoid Arthritis, JP)
E2014 (Cervical Dystonia, JP)
E7210 (Contrast Medium, JP)

FY2004rufinamide (Epilepsy, US and EU)

Submitted

Zonegran (Epilepsy, EU)
T-614 (Rheumatoid Arthritis, JP)84