Oncology Research& Development

September 16, 2008
Kentaro Yoshimatsu, Ph. D
Senior Vice President, R&D
Eisai Co., Ltd1

Safe Harbor Statement•

Materials and information provided during this presentation may contain socalled “forward-looking statements.” These statements are based on current
expectations, forecasts and assumptions that are subject to risks anduncertainties which could cause actual outcomes and results to differ materiallyfrom these statements.

•

Risks and uncertainties include general industry and market conditions, andgeneral domestic and international economic conditions such as interest rateand currency exchange fluctuations. Risks and uncertainties particularly apply
with respect to product-related forward-looking statements. Product risks anduncertainties include, but are not limited to, technological advances and patents
attained by competitors; challenges inherent in new product development,
including completion of clinical trials; claims and concerns about product safety
and efficacy; obtaining regulatory approvals; domestic and foreign healthcare
reforms; trends toward managed care and healthcare cost containment; andgovernmental laws and regulations affecting domestic and foreign operations.

•Also, for products that are approved, there are manufacturing and marketingrisks and uncertainties, which include, but are not limited to, inability to build
production capacity to meet demand, unavailability of raw materials, and failure
to gain market acceptance.

•

The Company disclaims any intention or obligation to update or revise any
forward-looking statements whether as a result of new information, future eventsor otherwise.
2

Agenda1. hhc company: Eisai
2. Oncology Research& Development
3. History of Oncology Researchin Eisai
4. Establishing Oncology Franchise3

1. hhc company: Eisai

4hhc company: Eisai
human health care is our goal. We give firstthought to patients and their families, and toincreasing the benefits health care provides.
 Providing meaningful contributions under any
healthcare system
 Observing the highest legal and ethicalstandards
 Providing integrated healthcare solutions

5

Thoughts of Cancer Patients

Desire of patients
Become healthy, become cured; Effective therapy
 Maintain the current condition; Live actively as long as
possible Live with normal life; Not suffering

Be Physician in Charge
Know cancer and understand my situation
 Understand the therapy and responsible for thedetermination

Effort to make evidence
Join the clinical trial
 Effort to evaluate objectively
 The cancer treatment stands close

the thoughts of patients and their families
62. Oncology Research& Development

7

Major differences in Oncology
Research & Development
 Many different kinds of Research

Approach Lower Probability of Success Pharmacological evaluation
 Manufacturing of Clinical Trial Material
 Clinical Studies/Clinical Development
Strategy
8Many Different Kinds ofResearch Approach－ Novel Cytotoxics－ Hormone Therapy－ Tyrosine Kinase Inhibitors－ Angiogenesis Inhibitors－ Signal Transduction Inhibitors－ Monoclonal Antibodies－ Cytokines－ Gene Therapy－ Cancer Vaccines－ Others
Research project is created based on the consideration of“research approach”, but clinical development & indication/labelingbased on tumor type9

Sales Forecast(Except for Hormone, Immunological and Supportive Therapy)

60000

New mechanism
Kinase inhibitors
Antibodies
New cytotoxics

Other Innovatives
Alkylating agents

50000

Anitbiotics

30000

Anti-metabolites$ Million

40000

Vinca alkaloids

20000

10000

0

2005

2006

2007

2008

2009

2010

2011

Year

From “Cancer Market Outlook” Business Insight 10

Lower Probability of Success
 POS from First-in-man to NDA/MAA

Submission－Oncology: 5%－Cardiovascular: 20%－Infectious Disease : 16%－Metabolic Disease: 11%－Urological Disease: 9%－CNS: 8%Nature Review Drug Discovery 3, 711, 200411

Pharmacological Evaluation
 Many kinds of Pharmacological models
 Difference of the effect size based on the mechanismof action, cytotoxic vs cytostatic
 Sensitivity difference between host (mouse) andtransplanted tumor (human) Narrow therapeutic window Difference of endpoint between animal model andclinical Correlation between pharmacological action and antitumor effect, immediate vs delayed
12

Clinical Studies/
Clinical Development Strategy
 Multi Dosing Schedules
 Optimum Dose selection for Mono andCombination Therapy
 Selection of Multiple Target Tumor Types
 Selection of Patient Population（1st line, 2ndline, 3rd line）
 Accelerated Approval vs Full Approval Labeling/Indication based on Tumor Typesand Treatment Line Pharmacogenomics and Biomarkers
133. History of Oncology
Research in Eisai

14

Aiming to enter into oncology area
Examination in a project (1986)¾ After a research group starts, the policy is
re-examined. (1987)⇒ Aim to create candidates at thefollowing three points.
- Novel mechanism of action- Novel chemical structure- Prominent in vivo anti-tumor effects¾

15

Our policy for oncology R&D
1. We do not research analogs of existing classes
for which competitors accumulate lots ofknowledge.
2. We aim what we can demonstrate uniqueadvantages of our own research.
3. We setup a goal of improving survival rate andsurvival time when we start research programs.
4. We setup endpoints and efficacy criteria inanimal models corresponding to the featureand the objectives of the theme.
5. Initiate Clinical studies in Japan quickly basedon our strategy and project status.
16

History of Oncology Research at
Tsukuba (TRL) and Boston (ERI)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

E7010 (ABT-751): Sulfonamide tubulin polymerization inhibitor(1987); TRL
Topoisomerase II inhibitor (1991); TRL
Farnesyl transferase inhibitor for ras, an oncogene product(1991); Full Collaboration
E7070: Sulfonamide G1 phase targeting agent (1992); TRL
E7820: Anti-angiogenesis (1992); TRL
E7389: microtubule growth suppressor, synthetic analog ofhalichondrin B (1992); ERI
E6020: TLR-4 agonist, Vaccine adjuvant (1997); ERI
E7974: Hemiasterlin-type microtubule polymerization inhibitor(1998); ERI
E7080: VEGFR kinase inhibitor, anti-angiogenesis (1999); TRL
E7107: RNA splicing modulator, pladienolide derivative (2000);
TRL
E6201: MEK-1 & MEKK-1 kinase inhibitor (2002); ERI
E7050: c-met & VEGFR kinase dual inhibitor (2003); TRL

17

4. EstablishingOncology Franchise18

Approach for establishingoncology franchise Steady progress of clinical development ofour pipeline; Prioritization
 Product acquisition of launched products;
Lymphoma Products Development of infrastructure of antibody
research; Acquisition of Morphotek
 Establishment of Oncology Franchise;
Acquisition of MGI Pharma

19Oncology Pipeline/Products
Novel
Cytotoxic
Anticancer

Preclinical

Early phaseclinical studies

Late phaseclinical studies

GPI21016

E7070

E7389

Cancer therapy,
Radiotherapy sensitizer

Cell Cycle G1 Phase
Targeting Agent

Microtubule Growth Suppressor

E7974

Irofulven Semi-synthetic

Hemiasterlin TypeTubulin Polymerization Inhibitor

Derivative of Toxin Illudin S

E7107

E7050

AntiAngiogenesisAntiproliferation

VaccineSupportivecare

DNA Methyltransferase
Inhibitor, MDS

Gliadel® Wafer
Implant Treatment
for Malignant Glioma

Ovarian Cancer

ONTAK®
CD25 Positive Cutaneous
T-cell Lymphoma

Targretin®
(Capsule & Gel)
Cutaneous T-cell Lymphoma

Panretin® gel
AIDS-related
Kaposi's Sarcoma

E7820
Alpha-2 Integrin
Expression Inhibitor

E7080
VEGF Receptor
Tyrosine Kinase Inhibitor

Eisai

Morphotek

MGI Pharma

LigandPharmaceuticals

E6201
Novel natural product-inspired
MEK-1/MEKK-1 Kinase Inhibitor

Monoclonal
Antibody

Dacogen®

Hexalen®

RNA Splicing Modulator

C-met & VEGFR
Tyrosine Kinase Inhibitor

Launched

MORAb-004
Antibody

MORAb-009
Anti Mesothelin mAb

MORAb-003
Anti folate receptor alpfa mAb

MORAb-028
Antibody

E6020

ZYC300 Cancer

Vaccine Adjuvant

Therapeutic DNA
VaccineGCPII Inhibitor

AKR-501

Chemo induced
neuropathy

Thrombocytopenia

amolimogene
HPV Therapeutic DNA Vaccine

fospropofol
Procedural Sedation
for Minor Surgery/Diagnostics

SaforisTM
Oral Mucositis： Biologics

Fragmin®
Anti-clotting Agent

Aloxi® Chemotherapy
induced nausea & vomiting(injection, oral)

Aloxi® postoperative
nausea and vomiting(injection)

Salagen®

Symptoms for Radiation-induced
Dry Mouth in Head and Neck
Cancer Patients20

Taxol and E7389
have opposing effects
on spindle microtubule dynamics
Taxol enhances spindlemicrotubule polymerization.

E7389 induces spindlemicrotubule shortening.

Green : microtubuleBlue : chromosome

21

E7389Microtubule Growth Suppressor
Me
H
H

O
O

O
H

O

H

MeO

Me

O
H

H

H

HO

O

O

HO
HO

H

H

O

O

O

Me
Me

HO

O

Halichondrin B

O

O

H
O

H2N

H
H

1
31

35
34

• HOMs

O

O

O

O

O
Me

23

E7389

O

H
27

O
O

H
7

O

10

O
O

14
13

H

19

• Synthetic analog ofhalichondrin B, marine sponge
natural product• Novel chemical structure• Unique effect on microtubule
dynamics*– blocks microtubule
polymerization– no effect on depolymerization– sequesters tubulin into
non-functional aggregates*Jordan et al. Mol Cancer Ther 2005;4:1086-1095. 22

E7389Microtubule Growth Suppressor
¾

¾

¾

¾

¾

Phase II studies in breast cancer and non-small cell lung cancer(NSCLC) demonstrated promising efficacy and safety profile– Observed antitumor effect in breast cancer patients who werepretreated with anthracycline, taxane and capecitabine (ORR by
Independent Review 9.3%, Investigator-assessed ORR 14.1%)– Potential advantage in safety profile in peripheral neuropathy– E7389 appears to show activity in NSCLC patients who havepreviously received taxane therapy (ORR 9.7%)
Breast cancer (pretreated with anthracycline, taxane and capecitabine)－ FDA agreed Eisai may submit NDA using breast cancer 305 study－ US NDA, EU MAA, J-NDA planned in FY 2009
Prostate cancer– Now in final stage of Phase II POC study
Sarcoma– Phase II POC study ongoing for four types of sarcoma, two-stage
design– Confirmed activity in 1st stage for leiomyosarcoma and decided toadvance into 2nd stage
Non-small cell lung cancer– Phase Ib/II combination study with carboplatin ongoing

23

MORAb-003<mAb targeting folate receptor alpha>

Current status

9

MORAb-003
Phase II ovarian cancer

Phase I resultszWell tolerated up to 400 mg/m2 (10mg/kg/wk)zRadiolabel demonstrated tumor localization

Platinumsensitive
recurrent ovariancancerElevated
Cancermarker(CA125)

ClinicalepisodeMORAb-003
monotherapy

9Phase II study for ovarian cancer ongoingzzzzInnovative clinical trial design to direct best use of mAb
Platinum-sensitive ovarian cancer after 1st relapse
Monotherapy and combination with carboplatin + taxane
To date, 6 out of 12 patients have 2nd remission longer than
1st remission in combination with carb. + taxane- Occurs in < 1% of patients on carbo + taxane

Diseaseprogression

Carboplatin+taxane+MORAb-003(Oral presentation “Exploratory Phase II efficacy study of MORAb-003, a monoclonal antibody against
folate receptor alpha, in platinum sensitive ovarian cancer in first relapse” in ASCO annual meeting,
Chicago, USA, May 30 – June 3, 208)

24

MORAb-003<mAb targeting folate receptor alpha>

Future Plan

¾ Phase III study; Platinum-sensitive relapsed ovarian cancer
9 Current Regulatory Status• FDA End of Phase II Meeting in Jan 2008
–Invited to submit SPA for full approval–CMC review meeting with FDA on April 17th 2008 (CMC plan agreed to)• SPA package submission July 2008
– Seeking EMEA scientific advice
9 Final protocol 3Q FY2008• Dependent on FDA review/feedback
9

Target BLA submission FY2012¾Phase II study; Platinum-resistant relapsed ovarian cancer
9 Weekly paclitaxel +/- MORAb-003
25

MORAb-009<Anti-mesothelin Monoclonal Antibody>– Phase I study completed– Phase II study for pancreatic cancer (1st line)• MORAb-009 + gemcitabine vs. placebo +gemcitabine• Target: 152 patients (76 patients/arm)• Primary endpoint: overall survival• FPI achieved in December 2007

– Preparing for Phase II study for mesothelioma

26

MORAb-028<Anti-GD2 Monoclonal Antibody>– Human IgM antibody to cell surface tumor antigen “GD2(ganglioside2)”– Targets melanoma, NSCLC, SCLC and brain tumors– Biology of target antigen ”GD2” associated withtransformation– Antibody suppresses growth of tumors in vivo
– MOA via complement dependent killing– L72 (human anti-GD2 IgM) antibody tested in 8 patient
clinical study and shown to have anti-tumor activity– MORAb-028 established from L72 producing hybridoma
line MORPHODOMA technology
27

E7080

H 3C
H2N

O

O
Best in Class
Oral VEGF receptor kinase inhibitor

N

O

Cl
N
H

O
N
H

¾

Inhibition of all VEGF receptor family (VEGFR1:Flt-1, VEGFR2:KDR,
VEGFR3:Flt-4) and other angiogenesis-related molecules such as FGFR1
and PDGFRb¾

Three Phase I studies are almost completed- Three Phase I studies in parallel in U.S., EU and Japan- Cmax and AUC appear to increase proportionally to dose
- PK-PD using biomarkers indicates Ctrough level exceeded
pharmacological active concentration- E7080 treatment decreased c-kit(+)CEP and c-kit(+)CEC- Many PR and long (> 6 months) SD were observed in renal,
sarcoma, melanoma, thyroid cancer, colorectal cancer(CEP; Circulating endothelial progenitors, CEC; Circulating endothelial cells)

28

E7080Study objectives
Primary objective- To determine the maximum tolerated dose(a)(MTD) in a continuous once daily dosing
schedule.
Secondary objectives- To determine the dose limiting toxicities (DLTs).
- To explore the safety and tolerability of E7080.
- To determine the pharmacokinetic profile.
- To explore the anti-tumor efficacy.
- To identify and validate pharmacodynamic
biomarkers and explore the biological effects. (a)Best response

Number ofpatients

PartialResponse

5

DiseaseStabilisation

25

Progressive
Disease

9

(b)

(b)

(c)

(d)

(Poster “A phase I dose escalation and pharmacokinetic study of E7080, a small molecule tyrosine kinase inhibitor, in patients with advanced malignancies”
in ASCO annual meeting, Chicago, USA. May30-Jun 3.)29

E7080Tumour type

Melanoma

Renal

SarcomaStarting dose
(mg)
0.8
12.5
16
20
25
32
32
32
25
3.2
20
25
3.2
6.4
12.5
12.5
16
16
25
32

Best
response
NA
NA
PD
PD
SD
SD
PR
PR
SD
SD
PR
PR
PD
NA
SD
PR
SD
SD
SD
SD

TTP
(weeks)
<8
NA
8
8
32
40
44+
49+
36+
76
68+
36+
8
7
44
24
56
24
36
12

Conclusion- E7080 displays linear
pharmacokinetics and is safe andwell tolerated at doses up to 25
mg daily.
- Very promising early indicationsof anti-cancer activity have been
observed, especially in patientswith melanoma, renal cell
carcinoma and sarcoma.

(Poster “A phase I dose escalation and pharmacokinetic study of E7080, a small molecule tyrosine kinase inhibitor, in patients with advanced malignancies”
in ASCO annual meeting, Chicago, USA. May30-Jun 3.)30

E7107(Pladienolide derivative)
RNA Splicing Modulator• New Molecular target; Splicing
factor SF3b
• Pladienolide was discoveredfrom the fermentation broth of
streptomyces platensis Mer11107• Different antitumor spectrum
from existing anticancer drugs• Most potent tumor regression
activity in nude mouse
xenograft models (humancancer cells)• Current Status:– Two Phase I studies in US& EU progressing rapidly– Biomarker studies basedon MOA

O
N

O H

N

HO H

H

H3C
H3C H

O
H HO CH3

H 3C
H
H
CH3

OH
CH3

O
O

H
OH

Nature Chemical Biology

31

Novel Anti Tumor Mechanism
Controlling Splicing

Exon
IntronPre-mRNA

Cell

Nuclear

E7107

snＲＮＡ
Splicing factor

SF3b sn ＲＮＡ

Splicing

spliceosome

Mature mRNA

Protein synthesis necessary forcancer cells
Anti-tumor effect32

Amolimogene:

Targeted DNA Vaccine for Treating HPVMediated Diseasez Human Papillomavirus (HPV) infection

can result in pre-cancerous diseasez Non-invasive disease treatment optionthat does not damage healthy tissue

Amolimogene:z A non-replicating, non-integratingDNA
z Expresses a HPV polyprotein (basedon E6 and E7 proteins) to activate an
immune responsez Encapsulated in PLG particles
z Lyophilized formulation

z If approved, amolimogene: would

represent the first DNA vaccine therapy
available for human use.
Normal

HPV Lesion

Immune cells

33

Amolimogene:

Treatment vs. Prophylaxis for Cervical Dysplasia

Prophylactic Vaccine• Goal: elicit antibody response• Antibody binds andneutralizes virus• Prevents infection
HPV

Medical Therapeutic
Vaccine• Goal: elicit immune response• Immune cells migrate to cervix;
recognize pre-cancer cells• Eliminate diseased cells Æcleared lesion

YY

Antibody

Y

Y

Y

Y
Y

Y
Y

Y

Immune cells

Prevent infection

Treat women with disease34

Amolimogene Clinical Development:
Cervical Dysplasia• Phase I trials– Demonstrated biologic activity– Clinical response in 100% of <25 year olds

• Phase II investigator study– Well tolerated; 67% clinical response overall and 100%
clinical response in patients <25 years old• Phase II company sponsored trial– 161 patients, randomized, controlled– Safe and well-tolerated– Resolution of CIN2/3 (all patients): 43% vs. 27%– Resolution of CIN2/3 (< 25 years old): 70% vs 23%;
(p =0.001)• Pivotal program underway– 2 pivotal trials– First trial (n=250) completed enrollment
CIN: cervical intraepithelial neoplasia

35Summary of Oncology Pipeline
E7389: FDA agreed Eisai will submit NDA using breast cancer 305 study;
simultaneous NDA/MAA submissions in Japan, U.S. and Europe; steadypatient enrollment; targeting NDA/MAA submissions in FY2009
MORAb-003: Presented Phase I and II data at ASCO; confirmed potential
anti-cancer effect against ovarian cancer; Phase III to be initiated; targeting
NDA submission in FY2012
MORAb-009: Phase II study for pancreatic cancer (1st line) ongoing.
Preparing for Phase II study for mesothelioma
MORAb-028: Phase I study in preparation.
E7080: Confirmed potential anti-cancer effect for multiple cancer types;
targeting best-in-class drug and NDA/MAA submissions in FY2012
E7107: Two Phase I studies in US & EU Progressing. Biomarker studies
based on MOA.
Amolimogene: Achieved LPO (Last Patient Out) of Phase II/III study fortreatment of CIN (Cervical Intraepithelial Neoplasia) in women under 25

36