July 17, 2007

Eisai
R&D Meeting
July 17, 2007
3:00-6:00 PM
Tokyo International Forum
1
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 and
uncertainties which could cause actual outcomes and results to differ materially
from these statements.
•
Risks and uncertainties include general industry and market conditions, and
general domestic and international economic conditions such as interest rate
and currency exchange fluctuations. Risks and uncertainties particularly apply
with respect to product-related forward-looking statements. Product risks and
uncertainties 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; and
governmental laws and regulations affecting domestic and foreign operations.
•
Also, for products that are approved, there are manufacturing and marketing
risks 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 events
or otherwise.
2
Agenda
I.
Eisai R&D: Overview
II. Global Clinical Development
III. Clinical Research in Japan
IV. Oncology Research Strategy
V. Introduction to Morphotek
3
Eisai R&D: Overview
Kentaro Yoshimatsu
Senior Vice President, Research & Development, Eisai Co., Ltd.
President, Eisai R&D Management Co., Ltd.
4
Eisai’s R&D Strategy
„ Optimizing Multi-Regional and Multi-Functional R&D Activities under
Eisai R&D management Co., Ltd.(ERDC) management system
Exploratory
Research
Key Strategies
Preclinical
Research
Clinical
Development
Marketing
Franchise Areas – Integrative Neuroscience & Integrative Oncology
Frontier Area
Chemical/Biologic
Drug Discovery
Technologies
HTS, SBDD
Natural compound library
LibradomaTM
Morphodoma ®
New targets
Translational
Research
Multi-Regional
Clinical Development
Omics
LibradomaTM
Project
Management
International Project Team
Annual Project Performance Objectives
Drug Development Plan
5
Eisai Discovery Research Network
- Implementation of Chemical/Biologic Drug Discovery
at World’s Knowledge Clusters Eisai London
Research
Laboratories, Ltd.
London
Tsukuba Research
Laboratories
Tsukuba
Kobe
Eisai Research
Institute of Boston,
Inc.
Andover, MA
Exton, PA
Morphotek, Inc.
KAN Research
Institute, Inc.
Chemical
entities
New
target
Unmet Medical
Needs
Biologic
entities
6
Application of the New
Technologies for Efficient Drug
Discovery
Genomic
Transcript
-omic
Proteomic
Compound
Library,
HTS
Cellomic
Natural
Compound
Library
Omics
Technology
Drug
Target
Academia
CADD,
SBDD
Lead
Generation
LibradomaTM
Lead
Optimization
Tumor
Bank
Translational
Research
Morphodoma®
7
Eisai Global Clinical Development
Eisai Ltd.
London
Eisai Medical
Research, Inc.
Clinical Research
Center
Tokyo
India
Eisai Clinical
Research Singapore
Pte., Ltd.
New Jersey
Eisai Global
Clinical
Development
Singapore
„ Reinforcing clinical research staff
•
700 employees (Japan: 270, US: 320, Europe: 110)
„ Strengthening asian clinical management to promote global studies
•
Establishment of Eisai Clinical Research Singapore Pte. Ltd,
„ To improve the quality, speed and costs for data management and
statistical analysis
•
Optimization of the operation regarding data management / statistical
analysis including transformation to the India.
8
Eisai R&D Management Company
Board of Directors
Chairman
VP: Vice President
IPT: International Project Team
President
Project Management
Intellectual Property
VP: Global Clinical
VP: Global Clinical
VP: Global Clinical - Japan
VP: Japan Research
VP: US Research
VP: US Research - Biologics
VP: EU Research
VP: Global Safety Officer
VP: Global Marketing
VP: Strategy/Planning
VP: Global Regulatory
IPT
IPT
IPT
IPT
IPT
IPT
IPT
Total 30 IPTs
9
Enhance Project Management
Capability
•
Project management by Eisai R&D Management Company
– Direct management of 50 projects
– Sharing of goals, single management vision
– Decision-making by all officers responsible for R&D functions with
participation from marketing, regulatory and safety management
– Setting Drug Development Plan (DDP) and Annual Project
Performance Objectives (APPOs) for each IPT and checking on the
progress
– R&D resource allocation to maximize overall productivity
10
Drug Development Plan (DDP)
•
•
Concept
– One DDP per New Molecular Entity
– Established before starting clinical development
Benefit
– Early input into strategy by all functions
Drug Development Plan
Strategy
Tactic
Regulatory
Safety
Clinical
Global
Regulatory
Strategy
Document
Safety
&
1)
PV Plan
CDP2)
Other Plans
- CMC
- Preclinical
Marketing
Marketing Plan
LCM3)
1) Pharmacovigilance
2) Clinical Development Plan
3) Life Cycle Management
11
Annual Project Performance
Objectives (APPO)
• APPO as a single common IPT performance objectives
shared by all parties within Eisai R&D Concept
Annual Objectives
– Clinical
– Chemistry, Manufacturing & Control
• Drug Substance
• Drug Product
ERDC Officer
– Preclinical
• Pharmacology
• ADME
ERDC Officer
• Safety/Toxicology
– Regulatory
– Marketing
ERDC
ERDC Officer
APPO
ERDC Officer
IPT
ERDC Officer
ERDC Officer
ERDC Officer
12
Major Achievements
since April 2006
Phase I
start
E2012
- Alzheimer’s
disease
E7389
- Non-small cell
lung cancer
(comb.)
E7107
- Cancer
Phase II
start
Proof
of
Concept
E7389
E2007
E2007
- Epilepsy
(US and EU)
- Sarcoma (EU)
- Neuropathic pain
(US and EU)
E5555
- Acute Coronary
Syndrome
(US and EU)
Phase III
start
E7389
- Breast cancer, 3rd
line, (EU)
- Breast cancer,
2nd line
(US and EU)
E5564
- Severe sepsis
(US and EU)
E3210
D2E7
E3710
E0302
- Irritable bowel
syndrome
- Acid related
disease
E2110
- Overactive
bladder
E6201
- Crohn's disease
(JP)
- Amyotrophic
lateral sclerosis
(JP)
ARICEPT ®
- Sustained release
formulation (US)
Submission
E2014
- Cervical dystonia
(JP)
PARIET ®
- Secondary
treatment for H.
pylori eradication
(JP)
VASOLAN®
- Atrial fibrillation
and paroxysmal
supraventricular
tachycardia (JP)
IOMERON®
- Additional dosage
& formulation in
CT angiography
(JP)
Approval
INOVELON®
- Lennox-Gastaut
Syndrome (EU)
ARICEPT®
- Severe
Alzheimer's
disease (US)
PARIET®
- H. pylori
eradication (JP)
TAMBOCOR®
- Paroxysmal atrial
fibrillation/flutter
(JP)
NITOROL®
- Pre-filled syringe
formulation (JP)
- Psoriasis
ARICEPT
- Jelly formulation
(JP)
13
Pipeline: New Molecular Entities
Phase I
Neurology
Phase II
E2012
E2007
- Alzheimer’s disease
- Epilepsy
- Migraine prophylaxis
- Multiple sclerosis
- Neuropathic pain
E2508*
- Depression
Phase III
Submission
E2007
Rufinamide
AS-3201
E2014
- Parkinson’s disease
- Diabetic neuropathy
E0302
- Epilepsy (US)
- Cervical dystonia
- Amyotrophic lateral
sclerosis
E7389
- Non-small cell lung cancer
Oncology
(combination)
E7070, E7820, E7080,
E7974, MORAb-009
E7107, E6201*
E1224/ Antifungal
E3210/ Irritable bowel
syndrome
Frontier
E3710/ Acid related disease
E2110/ Overactive bladder
E6201/ Psoriasis
E6007*/ Inflammatory bowel
disease
* in preparation
E7389
- Breast cancer (3rd line,
US)
- Prostate cancer
- Sarcoma
E7389
- Breast cancer (3rd line,
EU)
- Breast cancer (2nd line)
MORAb-003
E5555
- Acute Coronary
Syndrome
- Atherothrombotic
Disease
E5564
T-614
D2E7
D2E7
- Psoriasis, Crohn’s
disease
Gasmotine
- Rheumatoid arthritis
- Severe sepsis
KES524
- Gastroprokinetic
Clevudine*
- Obesity
SA-001
- Rheumatoid arthritis
- Hepatitis B
- Pancreatic exocrine
insufficiency
Green: Japan/Asia projects14
Pipeline
New Indications and Formulations
(Aricept®, AcipHex®/Pariet®, Zonegran®)
Phase I
- Jelly formulation (JP)
- Patch formulation*
Aricept®
Pariet®/Aciphex®
Zonegran®
* in preparation
**under discussion with FDA
Phase II
- Pediatric usage**
-Down syndrome
-cognitive impairment
due to cancer
treatment
- Pediatric gastro
esophageal reflux
disease
Phase III
Submission
- Dementia with
Parkinson’s disease
- Mild cognitive
impairment
- Sustained Release
formulation
- Severe Alzheimer’s
disease (JP)
- Liquid formulation
- Extended Release
formulation*
- Over-the-counter
- Non-erosive reflux
disease (JP)
- Secondary
eradication
of H. pylori (JP)
- Monotherapy
- Generalized seizure*
- Pediatric usage*
Green: Japan/Asia project
15
Global Clinical
Development
Masanori Tsuno
Vice President, Global Clinical Research, Eisai Co., Ltd.
President, Eisai Medical Research,
President, Eisai Global Clinical Development
16
E2007 (perampanel)
AMPA Receptor Antagonist
17
E2007
AMPA Receptor Antagonist
•
•
•
Highly selective AMPA (a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid) -type glutamate receptor antagonist
Potential for therapeutic utility in various neurological diseases
Development Status
– Parkinson’s disease
• 3 Phase III studies ongoing
• NDA/MAA in FY2007
– Epilepsy
• POC achieved
• Phase III study in preparation
– Migraine prophylaxis
• Phase II study with 2 mg completed
• Higher doses to be evaluated
– Neuropathic pain
N
N
O
CN
• POC study initiated
– Multiple sclerosis
• POC study in preparation
18
E2007
Mechanism of Action
Excessive activation of AMPA Receptor
Imbalance of CNS circuit
Excitotoxicity
Multiple sclerosis
Parkinson’s disease
Epilepsy
Pain
GABA
Glutamate
（AMPA)
E2007
E2007 redress the imbalance between
excitatory and inhibitory transmitter
GABA
Glutamate
（AMPA)
L. Steinman, Nature Medicine • Vol 6 (2000)
19
E2007
Parkinson’s Disease
• Placebo control Phase III studies (Study 301 and 302)
– Target: Add-on therapy in idiopathic PD patients with levodopa
therapy with motor fluctuations of a “wearing off” type
– Purpose: To compare the efficacy of 2mg and 4mg of E2007 and
placebo on motor function
– Treatment groups: 2mg, 4 mg or Placebo
– Endpoints: OFF time change
– Target number of patients: 702 patients
• Placebo and Entacapone control Phase III study (309
study)
– Treatment groups: 4 mg E2007, placebo or 200mg Entacapone
– Target number of patients: Total 702 patients
• Target submission
– 4Q FY2007 in U.S. and Europe
20
Epilepsy
E2007
• Phase II POC study (Study 206)
– Target: Adjunctive therapy in patients with refractory partial seizure
– Dosing period: 4 weeks of baseline phase, 8 weeks of dose titration, 4 weeks of
maintenance phase
– Treatment groups: E2007 (increase from 1mg to 4mg) or placebo
• Results
– 153 patients enrolled (E2007 group: 102 patients; placebo group: 51 patients)
– Responder rate (percentage of patients who reduced the frequency of seizure by 50% or
more) and percent reduction in frequency of seizure were better than placebo group, and
effect size was about same level as low doses of existing epilepsy drugs.
Results supported the activity of E2007 in epileptic seizure (below)
– E2007 4mg was very well tolerated
• Finalize Phase III study design based on the result of ongoing high-dose
Epilepsy study
Median Percent Reduction by Treatment Group
Responder Rate By Treatment Group
35
P=0.43
Placebo
E2007
P=0.19
31
30
Responder Rate (%)
30
P=0.16
25
21
21
22
20
15
14
10
5
Median Percent Reduction (%)
30
26
Placebo
Active
25
21
19
20
15
11
10
7
8
5
0
Titration
Maintenance Phase
Maintenance LOCF
0
Titration
Maintenance
Maintenance LOCF
21
E2007
Neuropathic Pain
• Outline of Phase II study (Study 227)
– Purpose
• To evaluate the efficacy and safety of E2007 for treating the pain of
diabetic peripheral neuropathy
– Dosing Period
• 21 weeks
• 2-week screening + 15-week double-blind treatment phase + 4week single blind follow-up phase
– Treatment groups
• 2, 4, 6, 8 mg or placebo
– Target number of patients
• 350 patients
– Primary endpoint
• Pain intensity score, captured on an 11-point Likert-type numeric
rating scale
22
E2007
Clinical Studies on E2007
• Parkinson’s disease
– 3 Phase III studies ongoing
– NDA/MAA in FY2007
• Epilepsy
– POC achieved
– Phase III study in preparation
• Migraine prophylaxis
– Phase II study with 2 mg completed
– Higher doses to be evaluated
• Neuropathic pain
– POC study initiated
• Multiple sclerosis
– POC study in preparation
23
E7389 (eribulin mesylate)
Microtubule Growth Suppressor
24
E7389
Microtubule Growth
Suppressor
H2N
H3CO
OH
H
H
H
H
O
H
O
H
H
H2C
Marine sponge Halichondria okadai
H
O
CH2
H
CH3
H
H
O
H
O
O
H
H
O
O
H
H
O
H3C S OH
O
O
H
H
E7389
• Synthetic analog of halichondrin 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.
25
E7389
Breast Cancer Study 201
Presentation at ASCO 2007
• Study 201: Advanced/metastatic breast cancer heavily pre-treated
(median prior regimens = 4) with chemotherapy including
anthracycline and taxane
– Dose: 1.4 mg/m2 by 2-5 min IV administration
– Schedule: Days 1, 8, and 15 of a 28-Day cycle (Group 1) or on Days 1 and 8
of a 21-Day cycle (Group 2)
¾ Efficacy
•
•
•
•
ORR: 11.5% (all PR)
Clinical benefit rate: 17.2%
Median response duration: 162 days
Median survival: 253 days
ORR: Objective Response Rate
PR: Partial Response
AE: Adverse Events
¾ Safety
• Group 2 showed an acceptable tolerability profile
– Most common drug-related AE: neutropenia (61% grade 3/4;
4% febrile neutropenia)
– Incidence of neuropathy: grade 3 (5% ) and No grade 4
26
E7389
Breast cancer
Study 201 (Phase II): Proof-of-Concept
¾ORR (n = 103)
¾Completed
3rd line (Phase II): Subpart H in US
¾ After anthracycline, taxane, capecitabine
¾ ORR (n = 299)
¾ Pre-NDA meeting: August 2007
¾ Subpart H submission: 3Q FY2007
3rd line (Phase III): Full Approval in EU
¾
¾
¾
¾
¾
After anthracycline, taxane
E7389 vs TPC
OS (Target: n = 630)
Enrollment: Ongoing
Target submission: FY2009
2nd line (Phase III): Full Approval in US/EU
¾ After anthracycline, taxane
¾ E7389 vs capecitabine
¾ OS/PFS (Target: n = 1,100)
¾ Enrollment: Ongoing
¾ Target submission: FY2010
ORR: Objective Response Rate, OS: Overall Survival, PFS: Progression Free Survival
TPC: Treatment of Physician's Choice
27
E7389
Non-Small Cell Lung Cancer : Study 202
Presentation at ASCO 2007
• Study 202: Advanced NSCLC progressed during or after platinum-based
doublet chemotherapy (median prior regimens = 2)
– Dose: 1.4 mg/m2 by 2-5 min IV administration
– Schedule: Days 1, 8, and 15 of a 28-Day cycle (Group 1) or on Days 1 and 8 of a 21Day cycle (Group 2)
¾ Efficacy
• Objective response rate: 9.7%
– Eribulin mesylate appears to show activity in patients who have previously received
taxane therapy (ORR 10.8%)
• Median response duration: 176 days
• Median overall survival: 287 days (as of April 26, 2007)
– 6-month survival rate 60.7%, 1-year survival rate 39.0%
• Median progression free survival: 102 days
¾ Safety
• Adverse events: generally manageable, with neutropenia being the most
common hematological AE
– 21-day cycle showed fewer dose interruptions, delays, reductions or omissions due to
neutropenia
– Incidence of neuropathy: 34.0% of patients (mostly mild or moderate), grade 1/2
(31.1%) and grade 3 (2.9%)
28
E7389
Other Studies
• Prostate cancer (Phase II POC study)
– Target number of patients: 110
– Endpoints: Objective prostate specific antigen (PSA) response rate, duration
of PSA response, tumor-related symptom assessment, Progression Free
Survival, overall tumor response rates, duration of tumor response
– Enrollment completed (June 2007)
– Accomplish POC: FY2007
• Sarcoma (Phase II POC study)
– Target number of patients: 150
– Endpoint: Progression free survival in 12 weeks
– Enrollment ongoing in EU
• NSCLC (Phase Ib study in combination with carboplatin)
– Enrollment ongoing in US
• Cancer (Phase I study in Japan)
– Recommended dose for Japanese population determined
• 1.4mg/m2 (same as the global recommended dose)
– Phase II study under preparation
29
E7389
Current Status of E7389
• Proof of Concept (POC) achieved
– Breast cancer
– Non-small cell lung cancer (NSCLC)
• Submission studies ongoing
– Breast 3rd line; Subpart H Phase II, Phase III
– Breast 2nd line; Phase III
• Phase II POC studies ongoing
– Prostate cancer
– Sarcoma
• US National Cancer Institute (NCI) studies
– Ovarian cancer, Head & Neck cancer, etc.
• Phase Ib study ongoing
– NSCLC (combination with carboplatin)
• Japan
– Phase I study completing
– Phase II study under preparation
30
E5564 (eritoran tetrasodium)
Endotoxin Antagonist
31
E5564
The First TLR4 Antagonist
for Treatment of Severe Sepsis
•
•
•
A structural analogue of the Lipid A portion of endotoxin which is
widely considered to be a major factor in the pathogenesis of severe
sepsis
The proposed mechanism of this activity is the binding of MD2 by
eritoran, then competitively inhibiting the binding of endotoxin to MD2
and subsequent activation of TLR4
Resulting in statistically significant improvements on the 28-day
mortality in patients with sepsis
H 3 CO
O
(NaO )2OPO
O
O
NH
HO
NH
O
O
OPO( ONa) 2
O
O
O
H 3CO
n
Repeating unit
Outer core
O-Specific side chain
Innner core
Lipid A
Core
Polysaccharide
Lipid
Monosaccharide
Long-chain (hydroxyl) fatty acid
Chemical
Structure of Endotoxin
(LPS)
Phosphate
Ethanolamine
E5564
32
E5564
Strong inhibition of TLR4 Pathway
TLR4 agonist,
Endotoxin, etc.
E5564
H 3C O
E5564
O
(N a O ) 2 O P O
O
O
HO
NH
O
O
O P O (O N a ) 2
NH
O
O
O
Cell Membrane
TLR4
Signal
Transduction
H 3C O
MD2
Transcription
Factor NFkB
Nucleus
DNA
Gene
Transcription
Inflammatory
cytokines,
TNF, IL-1 etc
Severe
Sepsis
33
E5564
TLR4 Antagonist for Severe Sepsis
•
Phase III (ACCESS study)
– To demonstrate reduction of 28-day all cause mortality for sever sepsis
patient
– Randomized, double-blind, placebo-controlled study
– Administration: intravenous infusion total dose 105mg, administered as one
28mg loading dose followed by a 14mg loading dose at 12 hours, and nine
7mg maintenance doses every 12 hours
– 2000 patients (interim analysis for 1500 patients)
– Bring Japanese sites into Phase III study (international development)
•
Status and Plan
– Enrollment ongoing well
• 144 sites (target 250 sites) across 16 countries (Americas: 5, Europe: 8, Asia and
others: 3)
• 274 patients enrolled, as of July 11, 2007
– Confirmed similarity in pharmacokinetic/pharmacodynamic profiles between
Japanese and others
– Goal is to simultaneously submit in Japan, U.S. and Europe in FY2009
•
FDA fast track designation
34
E5555
Thrombin Receptor (PAR-1)
Antagonist
35
E5555
PAR-1 Antagonist for
Cardiovascular Disease
Platelet
Aggregation
Path
IIb/IIIa inhibitors
Abciximab
ADP receptor
Eptifibatide
antagonist
Clopidogrel
Thromboxane Ticlopidine
inhibitor
Aspirin
Aggregation
PAR-1 antagonist
E5555
Dual effect
SMC
Proliferation
Path
SMC: Smooth muscle cell
Proliferation
36
E5555
Phase I
• Suppressed platelet aggregation with once-a-day administration
• Maximum platelet inhibition approaching 100% on ≥ 100 mg dose
• No trends of bleeding time prolongation
• Well tolerated for 14 days at daily doses up to 200 mg
• No severe adverse events
• No dose-related ECG trends for repeat dose study
37
E5555
Phase II
Two studies, parallel development, for different targeting populations
• Acute coronary syndrome (ACS)
• Atherothrombotic Disease
- Within 24 hours of the onset
- Administration
• Loading dose, 400mg on Day 1,
Once a day
• Placebo, 50mg, 100mg, 200mg/day,
600 patients
• Treatment 12 weeks, Follow up 4
weeks
- Efficacy endpoints
• Major Adverse Cardiovascular
Events (MACE) at Day 7 and
Weeks 4, 12, and 16
• ST-segment shifts during the first
48 hours following randomization
• Plasma levels of possible
biomarkers: hsCRP, MPO, soluble
CD40 ligand, PlGF, IL-6, IL-18 and
LpPLA2
– Symptomatic CAD, with high risk of
cardiovascular events
– Administration
• No loading dose, Once a day
• Placebo, 50mg, 100mg,
200mg/day, 600 patients
• Treatment 24 weeks, Follow up 4
weeks
– Efficacy endpoints
• Major Adverse Cardiovascular
Events (MACE)
• Plasma levels of possible
biomarkers: hsCRP, MPO,
soluble CD40 ligand, PlGF, IL-6,
IL-18 and LpPLA2
hsCRP: high sensitivity C-reactive protein
PlGF: Placental growth factor
IL-18: Interleukin-18
MPO: Myeloperoxidase
IL-6: Interleukin-6
LpPLA2: Lipoprotein-associated phospholipase A2
38
E5555
Phase III
• Acute coronary syndrome (ACS)
• Atherothrombotic Disease
– Multicenter, randomized, double-blind,
placebo-controlled
– Multicenter, randomized, double-blind,
placebo-controlled
– Targeting population: Unstable
Angina (UA) or Non-ST Elevation
Myocardial Infarction (NSTEMI) ACS
– Targeting population: Stable
symptomatic CAD, stroke or
peripheral arterial disease (PAD)
– Endpoints:
– Endpoints:
• Major Adverse Cardiovascular
Events (MACE: death, myocardial
infarction, stroke, and recurrent
ischemia)
• Major Adverse Cardiovascular
Events (MACE: death, myocardial
infarction, stroke, and recurrent
ischemia)
• Safety (including bleeding)
• Safety (including bleeding)
• 12-month imaging in sub-studies
• 12-month imaging in sub-studies
– Treatment duration: Minimum 12
months
– Target submission: FY2012
39
Approaches to
Alzheimer’s Disease Treatment
Takehiko Miyagawa
Neuro Internal Medicine Group
Discovery Research Laboratories
Eisai Co., Ltd.
40
Alzheimer’s Disease (AD)
Therapies
• Present therapeutic agents improve the symptoms of AD
– Such as the declining cognitive function, activities of daily living and
behavior
– Disease modification is not sufficient with current doses
• Recent findings implicate beta amyloid (Aβ) 42
as a potential causative agent in AD
– Suggesting that reducing Aβ levels in the brain, in particular Aβ42
levels, is a viable therapeutic strategy for the treatment of AD
– A number of therapeutic strategies targeting various steps in the
production, deposition, or clearance of Aβ42 are presently being
evaluated in pre-clinical studies and in clinical trials
– New therapies designed to modify its progression could reduce the
overall number of people suffering from AD
41
Therapeutic strategies
targeting Aβ
Amyloid Precursor Protein (APP)
β α
γ
β-secretase
C-99 (CTFβ)
Production inhibitor
γ-secretase
Aβ
Aggregation inhibitor
Plaque
fibril
Protofibril / Oligomer
(β-sheet Aβ)
Clearance enhancer
(Immunotherapy)
synaptic dysfunction and cell loss
42
Multidisciplinary Approach to
Alzheimer’s Disease
Small Molecule
Improving Cognitive
Function
Immunotherapy
Disease Modifier
Reduction of Aβ deposition
Collaboration with
BioArctic
Neuroscience Inc.
Aricept ®
E2012
Ab antibody therapy
(γSecretase
Modulator)
Gene related therapy
Possible
Disease Cure
Collaboration
with
TorreyPines
Therapeutics
Inc.
Collaboration with
DNAVEC Corp.
vaccine therapy
Sustained
release
Transdermal
patch
Aricept ®
New formulations
43
E2012
γ- Secretase Modulator
44
E2012
Mode of Action
APP
γ-secretase
inhibitor
E2012
β-secretase
C-99
Notch signal
γ-secretase
Aβ42(40)
Plaque
Fibril
Protofibril /
Oligomer
neuronal dysfunction and cell loss
45
E2012
Potential Benefits
– E2012 is a novel and potent γ-secretase modulator that
has been shown to inhibit the production of both Aβ42
and Aβ40 in rat primary neuron culture
– E2012 decreased Aβ42 and Aβ40 levels in rat brain,
cerebrospinal fluid (CSF) and plasma
– Chronic treatment of E2012 reduced Aβ plaque formation
in the brain of human-APP transgenic mice
– E2012, unlike γ-secretase inhibitors, did not inhibit the
cleavage of Notch, a molecule implicated in cell
differentiation, at effective concentrations for Aβ reduction
– E2012 will lead to a new way of managing the cognitive
and functional decline in patients with AD while also
modifying the course of the disease
46
E2012
γ-Secretase Inhibitor/Modulator
in Clinical Study
Potent
Inhibitor
Modulator
Latest
Developments
LY4501391)
tarenflurbil2)
(Phase II)
(Phase III)
E2012
(Phase I)
Target Aβ
All Aβs
Aβ42 selective
Aβ42 and 40
<100 nM
(Aβ42 )
Class
Potent
Modulator
Cell IC50 for
Aβ production
15 nM
>100μM2),3)
(Aβ42 )
Substrate specificity
(Notch signal)
Notch signal is
inhibited
Notch signal is
not affected
Notch signal is
not affected
Aβ reduction in
clinical study
Reduction in
plasma
Not reported
To be measured
Other compounds
in same class
Many compounds
NSAIDs
Eisai compounds
Series A, B, C
1)
; Neurology 66, 602-604 (2006),
1)
2)
; J. Clin. Invest. 112, 440-493 (2003),
3)
; J. Neurochem. 83, 1009-1012 (2002)
47
E2012
Treatment of AD
⇐ Cognitive Function
Early diagnosis by bio-marker and/or brain imaging
E2012 + Aricept
Mild Cognitive
Impairment
E2012 + Aricept
Mild AD
Moderate AD
Aricept
Severe AD
Natural history of AD
Time ⇒
48
E2012
Suspension of Phase I
• Lenticular change in rats
– In the 13-week oral toxicity study, lenticular opacity
was observed in rats treated at high doses
– In the rat (4-week) and monkey (4-week, 13-week)
toxicological studies, lenticular change have not been
observed
• Suspension of Phase I study
– Eisai voluntarily suspended a single Phase I study
and notified this finding to FDA on February 2007
– FDA then imposed a Clinical Hold on April 2007
49
E2012
Development Plan
• Plan for resuming Single-Dose Phase I Study (Study 001)
– To complete the lenticular safety assessments after 1 month and 6
month follow up visits
– To establish no effect levels and assess recovery on lenticular
opacity in rat additional 13W Tox study
– To investigate the mechanism of lenticular opacity
• Results to be reported to US FDA within FY2007 and hope to restart
Phase I study
• Development Strategy
– Seeking fast-track development
– Conclude bio-marker analysis in Phase I study to determine
effective dose
– Utilize adaptive design to expedite Phase II and III
– Target submission: FY2011
50
AS-3201
Aldose Reductase Inhibitor
51
AS-3201
Diabetic Neuropathy
• Japan Phase IIa study and good safety profile warrant
subsequent clinical development
• Japan Phase IIa study by Dainippon Sumitomo
– AS-3201 20mg/day showed significant improvement in summed
SNCV in comparison with placebo
– mTCNS sensory score showed the trend in the whole population and
improved in mild to severe population
• 253 study (Phase II/III in US) by Dainippon Sumitomo
– Statically significant effect for SNCV was not achieved, while some
effect on MNCV was shown
– Well tolerated, with more than 100 patients treated at doses of 20mg
and 40mg for at least 1 year
– Unexpected high placebo effect
SNCV: Sensory Nerve Conduction Velocities
MNCV: Motor Nerve Conduction Velocities
mTCNS: Modified Toronto Clinical Neuropathy Score
52
AS-3201
Diabetic Neuropathy
• Strategy
– Study duration
• Due to slow progression of disease, long-term treatment would
be necessary
– Patient population
• Based on the MOA, AS-3201 is expected to prevent worsening
rather than to show quick improvement
• Prevention of disease progression is beneficial for the patients
– Endpoint
• Clinical meaningful scores reflecting electrophysiogical
measures
53
Aricept®, AcipHex®/Pariet®
New Formulations
54
Aricept®
Sustained Release Formulation
Maximization of Efficacy (High dose approach):
Higher Dose
Higher Efficacy
Unsaturated pharmacodynamic effect in
the brain with current 10mg dose tablet
Concept: Maximum Increase of AUC (efficacy)
with Minimum Effect on Cmax
AChE Inhibition
40
10mg
current
tablet
77.3
19-391, 2, 3)
23mg
Sustained
Release
Plasma Conc. (ng/ml)
10mg Current Tablet
Central (cortical)%
Peripheral (RBC) %
determined by PET
10mg Current Tablet X 2
30
23mg Sustaind Release Tablet
20
AUC
10
Sustained Release
0
1) Bohnen, NI, et al. J Neurol Neurosurg Psychiatry. 2005; 76: 315-319
2) Kaasinen, V, et al. Psychopharmacol. 2002; 22: 615-620
3) Shintoh H, et al. Neurology 2001; 56: 408-410
0
12
24
36
Time (hour)
55
Aricept® Sustained Release
Formulation: Phase III study
• Outline of Phase III (Study 326)
– A double-blind, double-dummy, parallel-group comparison of
23 mg donepezil SR to the currently marketed formulation,
10 mg donepezil current tablet
• Target Population
– Moderate to severe Alzheimer's disease patients
• Number of Sites & Patients
– 200 sites
– 1600 patients (23mg SR:10mg current tablet = 2:1)
• Dosage & Period
– Once daily, oral, 24 weeks
• Primary endpoints
– SIB (cognitive function of patient)
– CIBIC plus (global rating of patient functioning) or
ADCS-ADL (activities of daily living), depend on regions
• Status/Plan
– First Patient In: June 2007
– Patient recruitment ongoing
– Target submission: FY2009
56
Aricept® Patch Formulation
Equivalent Efficacy
Higher Compliance / Convenience
Pill burden and/or difficulty swallowing in Alzheimer’s disease patients
Reduction of caregivers and patients’ burden to administer
(no titration, easy to apply)
Target: Once a 3-days, or once a week patch
Improvement of compliance
Current status:
Pre-IND meeting with FDA (June 07)
Preparation of IND submission
Target submission: FY2009
57
Pariet® / AcipHex® Extended
Release Formulation
Longer pH holding time increases healing rate
Relationship between gastric acid suppression (% of 24 hrs with pH>4) and erosive
oesophagitis healing after 4 weeks treatment
100
Healing Rate (%)
80
60
y = 4.8847x + 4.8641
2
R = 0.9864
40
20
0
0
4
8
12
16
20
24
Holding Time (hr)
Summarized by Eisai referring published data
58
Pariet® / AcipHex® Extended
Release Formulation
ER Formulation significantly extended pH holding time
Percent of time Intragastric pH > 4 on day 5
100%
% of time pH>4 on Day 5
***
80%
***
60%
esomeprazole
40%
Extended
Formulation
20%
0%
day-time (8 am to 8 pm)
night-time (8 pm to 8 am)
***: P < 0.05 compared to esomeprazole
All day
59
Pariet® / AcipHex® Extended
Release Formulation
• End-of-Phase II meeting with FDA has been requested
• Phase III Plan
– Erosive Gastroesophageal Reflux Disease (GERD), vs.
esomeprazole
– Symptomatic GERD, vs. placebo
– GERD maintenance, vs. placebo
• Target submission: FY2009
60
Clinical Research
in Japan
Toshio Obayashi
Director,
New Product Development Department
Clinical Research Center
Eisai Co., Ltd.
61
KES524 (sibutramine)
• Noradrenalin and serotonin reuptake inhibitor
Sibutramine
Reuptake
Monoamine
Monoamine
• Reducing energy intake through enhancing satiety
• Mild thermogenic effect
(Accelerate energy consumption)
62
KES524
Obesity Management
• Phase III pivotal study (Study 161)
– Objective: To investigate the efficacy and safety of KES524 in
patients with obesity (visceral fat obesity with type 2 diabetes and
dyslipidemia)
– Study design: A Multi-center, randomized, double-blind, placebocontrolled, parallel group study
– Main inclusion criteria: BMI≧25 kg/m2, VFA≧100 cm2 ,
Diagnosed type 2 diabetes (6.1%≦HbA1c≦9.0%), Dyslipidemia
(TG≧150 mg/dL and/or HDL-C＜40 mg/dL)
– Dosage: KES524 10 mg/day (increased to 15 mg if inadequate
weight loss at week 4) or Placebo
– Study period: Screening period 4 weeks, Treatment period 52
weeks, Follow-up 12 weeks
– Primary endpoints: Change and percent change in bodyweight
– Secondary endpoints: BMI, waist circumference, VFA, HbA1c, TG,
HDL-C etc.
– Number of patients completed: 342
• Target submission for J-NDA
– November 2007
HbA1c:
TG:
HDL-C:
BMI:
VFA:
Hemoglobin A1c
Triglyceride
High-density lipoprotein cholesterol
Body Mass Index
Viceral fat area
63
D2E7 (adalimumab)
64
D2E7
Generations of TNF-α Antibodies
Fully Human
3rd Humanized
2nd Chimeric
Human
(No Mouse Protein)
1st Murine
adalimumab
Adalimumab (D2E7)
5–10% Mouse Protein
(D2E7)
CDP571
25% Mouse Protein
100% Mouse Protein
CDP870
infliximab
afelimomab
65
D2E7
Comparison with Competitors
INN
Adalimumab
Brand Name
Humira/Raheara
Infliximab
Etanercept
Structure
Fully Human
Human/Mouse
Mouse
Chimera
Dosing
40～80 mg sc
every other week
Formulation
Pre- filled syringe
3～5 mg/kg iv
infusion
at Week 0, 2, 6
and thereafter
every 8 weeks
Vial
Half-life
14 days
9 days
Soluble TNFα
Receptor-Fc
Fusion Protein
10～ 25 mg sc
twice a week
Vial
4 days
66
D2E7
Rheumatoid Arthritis
• Phase II / III study (Study M02-575)
– Objective: To evaluate the efficacy, safety and pharmacokinetics of sc doses
of 20 mg adalimumab eow, 40 mg adalimumab eow, and 80 mg adalimumab
eow and placebo eow in adult Japanese subjects with Rheumatoid Arthritis.
– Study design: A Multi-center, randomized, double-blind, placebo-controlled,
parallel group study
– Main inclusion criteria: Meet ACR criteria for diagnosis of active rheumatoid
arthritis, TJC: ≧12, SJC: ≧10, CRP: ≧2 mg/dL
– Dosage: Adalimumab 20 mg, 40 mg, 80 mg and Placebo, subcutaneous
injection, eow
– Study period: 24 weeks
– Primary endpoint: ACR20 response rate at Week 24
– Secondary endpoints: ACR 50/70 response rate, ACR Core Set, Morning
Stiffness etc.
– Number of patients completed: 352
• Submission for J-NDA
– December 2005
eow:
ACR:
TJC:
SJC:
CRP:
every other week
American College of Rheumatology
Tender joint count
Swollen joint count
C-reactive protein
67
D2E7
M02-575 / DE011: ACR Response
ACR20
60
50.6
53.4
*
ACR Response (%)
50
44.0
46.0
*
40
35.8
32.2
28.7
30
*
24.2
10.3
10
*
12.1
14.9
*
0
22.1
*
*
*
18.4
*
12.4
8.5
5.7
Pl
ac
eb
o
* : p<0.05
35.0
18.9
8.2
1.1
ACR70
*
*
*
16.1
13.8
ACR50
χ2 –Test
(vs. placebo)
*
19.1
20
*
*
*
*
1.8
20
m
g
40
m
g
Study M02-575 (24W)
80
m
g
Pl
ac
eb
o
20
m
g
40
m
g
40
m
g/
wk
Study DE011 (26W)
Source: Partially modified materials for the 51th Annual General Assembly and Scientific Meeting of Japan Colleague of Rheumatology
68
D2E7
Psoriasis
• Phase II / III study (Study M04-688)
– Objective: To assess the efficacy and safety of repeated administration of
adalimumab in adult Japanese subjects with moderate to severe chronic
plaque psoriasis
– Study design: A Multi-center, randomized, double-blind, placebo-controlled,
parallel group study
– Main inclusion criteria: Plaque Psoriasis, BSA ≧10%, PASI ≧12
– Dosage: Adalimumab 40 mg, 40 mg with 80 mg Loading Dose, 80 mg and
Placebo, sub-cutaneous injection, every other week
– Study period: 24 weeks
– Primary endpoint: PASI 75 at Week 16
– Secondary endpoints: PASI 50/75/90, PASI Score, PGA, DLQI, SF-36 etc.
– Number of patients completed: 169
• Target submission for J-NDA
– September 2007
BSA:
PASI:
PGA:
DLQI:
SF-36:
Body Surface Area
Psoriasis Area and Severity Index
Physician’s Global Assessment
Dermatology Life Quality Index
MOS Short-Form 36-Item Health Survey
69
D2E7
Crohn’s Disease
• Phase II / III study (Study M04-729)
– Objective: To demonstrate the efficacy and safety of adalimumab for the
induction of clinical remission in Japanese subjects with Crohn’s disease
– Study design: A Multi-center, randomized, double-blind, placebocontrolled, parallel group study
– Main inclusion criteria: Crohn’s Disease, 450 ≧ CDAI ≧220, Previous
infliximab failure included
– Dosage: Adalimumab 80 mg + 40 mg, 160 mg+80 mg and placebo; subcutaneous injection, every other week
– Study period: 4 weeks
– Primary endpoint: Remission Rate (CDAI<150) at Week 4
– Secondary endpoints: Responder Rate (ΔCDAI<-70, -100), IOIBD,
IBDQ, SF-36 etc.
– Target number of patients: 80
• Target submission for J-NDA
– September 2009
CDAI:
IOIBD:
IBDQ:
SF-36:
Crohn’s Disease Activity Index
International Organization of Inflammatory Bowel Disease
Inflammatory Bowel Disease Questionnaire
MOS Short-Form 36-Item Health Survey
70
®
Aricept
(donepezil HCl)
71
Aricept
Severe Alzheimer’s Disease
• Phase II study (Study 231)
– Objective: To determine donepezil’s efficacy and tolerability in
severe Alzheimer’s disease (AD)
– Study design: A Multi-center, randomized, double-blind, placebo
controlled, parallel group study
– Main inclusion criteria: Severe AD, FAST ≧6, MMSE 1-12
– Dosage: 5 mg, 10 mg, Placebo
– Study Period: Treatment period : 24 weeks
– Primary endpoint: CIBIC-plus, SIB
– Secondary endpoints: Behave-AD, ADCS-ADL-sev
– Number of patients completed: 325
• Submission for J-NDA
– December 2005
72
Aricept
Primary Efficacy : SIB（Cognitive Function）
Change over Time
Change from baseline
10
8
6
Placebo
5mg
The dose–response of 3 groups was also observed.
10mg
10mg +6.4 + 8.9 + 9.2 + 9.0
p<0.001*
4
5mg +7.2 + 8.3 + 6.9 + 6.7
p<0.001*
2
Clinical Improvement
Baseline
0
Clinical Decline
-2
-4
* : p<0.025
-6
-4W
0
8
16
Study week
24
LOCF
73
Aricept
Primary Efficacy:
CIBIC plus（ Global Function ）
FAS-LOCF
The dose–response of 3 groups was also observed.
Marked Improvement
p=0.003*
Moderate Improvement
10mg
Minimal Improvement
p=0.151
No Change
5mg
Minimal Worsening
Moderate Worsening
Placebo
Marked Worsening
Not Assessed
0%
50%
100%
* : p<0.025 CMH Test
74
NME Pipeline in Japan
Area
Project
E2007
Neuroscience
Mode of Action
AMPA receptor antagonist
Target Indication
Parkinson’s
disease
Current Status
Target
Submission
FY2011
Phase I study ongoing
Neuropathic Pain
FY2012
E2014
Botulinum toxin type B
Cervical dystonia NDA submitted in December 2006
E7389
Microtubule growth
suppressor
Cancer
Phase I study ongoing
FY2009
E7080
VEGF receptor tyrosine
kinase inhibitor
Cancer
Phase I study ongoing
FY2012
T-614
Suppression of lymphocyte
proliferation, immunoglobulin
and inflammatory cytokines
production
Rheumatoid
arthritis
NDA submitted in September 2003
Submitted
Rheumatoid
arthritis
NDA submitted in December 2005
Submitted
Phase II/III study ongoing
Sep2007
Crohn’s disease Phase II/III study ongoing
FY2009
Submitted
Oncology
D2E7
Fully human anti-TNF-alpha
monoclonal antibody
Psoriasis
Critical
Care, RA,
etc.
E5564
Endotoxin antagonist
Severe sepsis
J-IND for ACCESS study (Phase III) for severe sepsis completed in June 07.
Phase I study completed using Japanese volunteers in the U.S., before
conducting Phase III
Plan to submit simultaneously in the U.S., Europe and Japan in FY2009
KES524
Central acting serotonin &
noradrenaline reuptake
inhibitor
Obesity
management
Phase III study ongoing
E5555
Phase I study ongoing,
Acute coronary
syndrome and J-IND for Phase II study is scheduled for July 07.
Thrombin receptor antagonist Atherothrombotic
Plan to submit simultaneously in the U.S., Europe and in Japan for ACS and
Disease
Atherothrombotic Disease indication
FY2009
(Japan, U.S.
EU)
Nov.2007
FY2012
75
Oncology Research
Strategy
Kentaro Yoshimatsu
Senior Vice President, Research & Development, Eisai Co., Ltd.
President, Eisai R&D Management Co., Ltd.
76
Oncology projects
under development
Meet Needs for Cancer Treatment
by Various Approaches
Tumor
suppression
Tumor regression
Novel
mechanism
E7070
Novel
anti-mitotic
E7389
Cell cycle G1 phase
targeting agent
U.S.
Phase Ib
Microtubule
growth
suppressor
U.S., EU, JP
Phase III
E7107
E7974
Novel anti-tumor agent
derived from
fermentation
U.S., EU
Phase I
Tubulin
polymerization
inhibitor
U.S.
Phase I
Growth
signal
inhibitor
Antiangiogenesis
E6201
E7820
Multikinase
inhibitor
Phase I
(in preparation)
Integrin α2
expression inhibitor
U.S.
Phase Ib/ II
E7080
VEGF receptor
tyrosine kinase
inhibitor
U.S., EU, JP
Phase I
Antibody
Therapy
MORAb-003
Humanized MAb
targets folate
receptor alpha
U.S.
Phase II
MORAb-009
Chimeric MAb
targets mesothelin
U.S.
Phase I
77
Multiple approaches for the
treatment of cancers
Develop the best cancer treatment by pursuing multiple
approaches that consider the diversity of the disease
Breakdown of
cancer cells
Cyto
X
toxi
c
Inhibition of cellular function
essential for cancer cell
proliferation
nucleus
Y
E7389
E7070
E7974
E7107
Immunocyte
dy
Antibo
MORAb-003
MORAb-009
Grow
th s
inhib ignal
itor
E6201
Blockade of proliferation signal
Cancer Cell
Blockade of nutrient supply to cancer cells
Inhibition of metastasis of cancer cells
X
Angio
genes
is
inhibit
or
blood vessel
E7820
E7080
Small Molecule
Biologics
78
Significance of Having both Small
Molecules and Biologics
in drug discovery
• Drug discovery
– Improve R&D profitability by combining
research basis of small molecules,
pharmacological evaluation and antibodies
– Drug discovery utilizing both small
molecules and biologics
– One molecule may yield both antibodies and
small molecules: develop antibodies first
and then develop small molecules
• Discover new antigens and generate
candidate antibodies by utilizing
Morphotek’s partnerships with leading
research institutions
• Generate human antibodies by utilizing
MORPHODOMA® technology at
Morphotek and new antigens discovered
by Tsukuba Laboratories, Eisai Research
Institute of Boston, and KAN Research
Institute
• Tsukuba Laboratories and Eisai Research
Institute of Boston discover small
molecules which target new antigens
(molecular target)
Improve R&D Productivity
Pharmacological
evaluation
Small
Molecule
Biologics
MAb
Target Molecules
79
Oncology Portfolio Overview
Project
Mode of Action
Target Indication
Breast cancer
E7389
Microtubule growth
suppressor
Prostate cancer
NSCLC
Sarcoma
Cancer
Development Status
Phase IIb Studies for 3rd line Subpart H ongoing
Phase III studies ongoing for 2nd and 3rd line treatment
Phase II POC study enrollment completed
Phase Ib study in combination with carboplatin
ongoing
Phase II POC study ongoing
Phase I study ongoing in Japan
Phase Ib/II study for 3rd line use in combination with
cetuximab ongoing in the U.S.
Target
Submission
FY2007
(Subpart H)
E7820
Alpha 2 integrin
expression inhibitor
E7070
Cell cycle G1 phase
targeting agent
E7080
VEGF receptor tyrosine
kinase inhibitor
Cancer
Phase I studies ongoing (U.S., EU, Japan)
FY2012
E7974
Hemiasterlin type
tubulin polymerization
inhibitor
Cancer
Phase I ongoing (U.S.)
FY2012
MORAb003
Monoclonal antibody
(anti-folate receptor
alpha)
Ovarian cancer
Phase II ongoing (U.S.)
MORAb009
Monoclonal antibody
(anti-mesothelin)
Pancreatic cancer
Phase I ongoing (U.S.)
E7107
Novel mechanism
Cancer
Initiated Phase I (U.S., EU)
E6201
Multi-kinase inhibitor
Cancer
Preparation for Phase I
Cancer
FY2011
Small cell lung cancer,
pancreatic cancer Phase Ib in combination with irinotecan (U.S.)
80
E7820
NC
O2
S
N
H HN
Me
CN
α2 integrin expression inhibitor
oral anti-angiogenesis
•
•
•
•
Inhibits tube formation and proliferation of endothelial cells
Tube formation inhibition is due to integrin alpha 2 expression inhibition
Inhibits angiogenesis due to either VEGF or FGF
Anti-proliferation activity in human pancreatic, breast, colorectal, and
renal cancer cell xenograft model
• Anti-metastatic activity in human breast cancer xenograft model
• Synergic effect with anti-VEGF antibody and EGFR Kinase inhibitor
• Current status:
–
Phase Ib/II for 3rd line therapy is ongoing in the U.S. in combination with
cetuximab
81
E7820
Phase I monotherapy study
• Open label, non- randomized, chronic daily dosing, single
center
• Study conclusion presented at ASCO 2006
– Dose-limiting toxicity (DLT) and Maximum Tolerated Dose (MTD)
• E7820 can be safely administered to patients with advanced cancer at
all doses up to 100 mg
• DLT at 200 mg were thrombocytopenia (2 patients) and neutropenia (1
patient)
• MTD determined to be 100 mg
– Suggested drug activity
• Disease stabilization beyond Cycle 4 observed in 6 patients
• Three patients have been on study for > 6 months
• Two patients were on study for 11 and 14 months
82
E7070
SO 2NH 2
(indisulam)
Cell cycle G1 phase targeting agent
Cl
NHSO2
NH
• Different antitumor spectrum from existing anticancer drugs,
due to new mechanism (cell cycle G1-targeting)
• Synergic antitumor effect in combination with irinotecan
– Mechanism assumed inhibition of topoisomerase II
expression which is increased by irinotecan
(topoisomerase I inhibitor)
• Current Status:
– Phase Ib for small cell lung cancer and pancreatic cancer
is ongoing in the U.S. (combination with irinotecan)
83
H3 C
E7080
O
N
O
O
H2N
Cl
N
H
O
N
H
Oral VEGF receptor tyrosine kinase
inhibitor
• Inhibition of all VEGF receptor family (VEGFR1:Flt-1, VEGFR3:Flt-4), not
only VEGFR2:KDR
• Inhibition of other angiogenesis-related molecules such as FGFR1 and
PDGFRb, in addition to VEGFR family
• Inhibition of c-Kit, inhibition of proliferation of SCF-dependent small cell
lung cancer
• Anti-proliferation activity against human colorectal, pancreatic, non-small
cell lung, breast, ovarian, prostate and small cell lung cancers xenograft
models; tumor regression in some models
• Current status:
–
Three Phase I studies are ongoing (U.S., EU and Japan)
• Once a day, continuous dosing
• Twice a day, continuous dosing
• Twice a day, 2 weeks ON & 1 week OFF
84
H3C
E7974
CH3
O
C(CH3)3 CH3
N
O
N
N
H
OH
O
Hemiasterlin-type
tubulin polymerization inhibitor
H3C
CH3
CH3
50
IC , nM
• Synthetic derivative of Hemiasterlin (marine natural product)
• Binds both alpha and beta subunits of tubulin – different from existing
tubulin polymerization inhibitors
• Effective against multi-drug resistant tumors
Potent growth inhibition in a wide range of human cancer cell types
P a c lita x e l
1000
V in b la s tin e
100
E7974
E7974
10
Dx5-Rx1
H460
LoVo
DU 145
A-498
HT-29
HEL
K-562
U-87 MG
LOX
COLO 205
DLD-1
HCC 2998
SF-295
HCT-15
SW-480
HCT 116
KATO III
KP-1
MES-SA
PANC-1
MCF-7
SW-620
LNCaP
A2780/1A9
HT-1080
HeLa
U937
1A9PTX10
1A9PTX22
HL-60
MDA-MB-435
NIH:OVCAR-3
1
85
E7974
•
Ongoing Phase I studies
Three Phase I studies for MTD determination ongoing with patients with
solid malignancies:
– 101 (Day 1, 8, 15 of a 28-day cycle)
– 102 (Day 1, 15 of a 28-day cycle)
– 103 (Day 1 of a 21-day cycle)
Results of 101 and 102 studies were presented at ASCO 2007
•
Conclusion of 102 study at ASCO 2007:
– The recommended Phase II dose of E7974 on Days 1 and 15 of a 28-day
schedule is 0.31 mg/m2
– Neutropenia was the dose-limiting toxicity, but all observed toxicities were
manageable and reversible
– One patient with esophageal cancer had a confirmed PR and remained on
study treatment for 6 cycles. Patients with esophageal cancer, prostate
cancer, liposarcoma, and bladder cancer had a best response of SD and all
remained on the study for >6 cycles
86
E7107
(Pladienolide derivative)
Novel anti-tumor agent
• Pladienolide was discovered
from the fermentation broth of
streptomyces platensis Mer11107
• Different antitumor spectrum
from existing anticancer drugs
• Most potent tumor regression
activity in nude mouse
xenograft models (human
cancer cells)
• Inhibition of expression of
multiple genes, causing
splicing abnormality for mRNA
of specific proteins
• Current Status:
– Phase I ongoing
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
Streptomyces platensis
Mer-11107
Reference: T. Sakai et al, J Antibiot., 57, 173-179, 2004
87
E7107
Summary
of retrospective
analysis
Summary
of expression
levels of ‘cell
cycle of antitumor activities in vivo and the
expression
of cell-cycle
proteins in vivo (presentation at AACR 2007)
regulatory
proteins’
in variousrelated
in vivo tumors
[ qdx5 for 1 cycle ]
cell lines
pRB
p16
BSY-1
MDA-MB468
LC-6-JCK
OVCAR3
NCI-H146
NCI-H69
NCI-H526
PC-3
FaDu
WiDr
HBC4
Lu99
NCI-H510
NCI-H596
KPL-4
SK-OV-3
DU145
MDA-MB435
HT-29
SW620
NCI-H460
KM12
NCI-H522
DLD-1
Calu-1
－
－
－
（＋）
（±）
（++）
（＋）
++
＋
＋
－*
+++
（＋）
－
＋
+++
－
+++
＋
+++
+++
++
＋
++
＋
+++
++
+++
+++
+++
+++
+++
－
－
－
－
－
+++
+++
－
－
－
++
－
－
－
－
－
－
－
cyclin E cyclin D1
+++
+++
+++
+++
+++
±
＋
++
±
+++
＋＋
±
＋
+++
＋
++
+++
++
＋
＋
＋
＋
+++
＋
++
+++
++
+
++
±
±
±
+++
+++
+++
++
±
±
＋
+++
+++
++
+++
±
++
±
++
+++
+++
++
T/C%
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
Tumors that express a functional loss of
pRb, an increased p16INK4a expression
and upregulated cyclin E are almost
invariably sensitive to E7107.
pRB function are thought to be lost
－*
pRB are thought to be functional from the data of in vitro analysis
p16 cyclin E cyclin D1 are highly expressed
88
Oncology projects
under development
Meet Needs for Cancer Treatment
by Various Approaches
Tumor
suppression
Tumor regression
Novel
mechanism
E7070
Novel
anti-mitotic
E7389
Cell cycle G1 phase
targeting agent
U.S.
Phase Ib
Microtubule
growth
suppressor
U.S., EU, JP
Phase III
E7107
E7974
Novel anti-tumor agent
derived from
fermentation
U.S., EU
Phase I
Tubulin
polymerization
inhibitor
U.S.
Phase I
Growth
signal
inhibitor
Antiangiogenesis
E6201
E7820
Multikinase
inhibitor
Phase I
(in preparation)
Integrin α2
expression inhibitor
U.S.
Phase Ib/ II
E7080
VEGF receptor
tyrosine kinase
inhibitor
U.S., EU, JP
Phase I
Antibody
Therapy
MORAb-003
Humanized MAb
targets folate
receptor alpha
U.S.
Phase II
MORAb-009
Chimeric MAb
targets mesothelin
U.S.
Phase I
89
Morphotek Inc.
Eisai’s biologics R&D center
developing monoclonal antibody products through use of a
proprietary human antibody technology
Nicholas Nicolaides
Morphotek Inc. CEO
90
Product Development Approach
leverage technology with collaborations for product development
lead clinical products
product pipeline
MORAb-003-ovarian cancer
•MORAb-004-neovascular disease
• other cancers: lung, breast, colon cancer
• Ph1-Memorial Sloan Kettering
• Ph2- multi-centered
•MORAb-022-inflammatory disease
•MORAb-028-metastatic melanoma
targets accessed from collaborations
technology for discovery/products
human antibody discovery technology
immunize with
disease antigen
highhigh-titer cell lines
30
25
Human
Hybridoma
pg/cell/day
• other cancers: lung, mesothelioma
• Johns Hopkins, Fox Chase, National Cancer Inst
•MORAb-047-infectious disease
•MORAb-048-infectious disease
20
15
10
5
morphogenics
0
parental
human B-cell
MORPHODOMA
MORPHODOMA
cell Line
highhigh-affinity MAbs
antibody/cell line
optimization
myeloma cell
10-10
affinity ( nM)
) )
Affinity
( nM
MORAb-009-pancreatic cancer
5X10 -8
10-7
parental
parental
MORPHODOMA
MORPHODOMA
antibody
MORPHODOMA
MORPHODOMA
91
®
MORPHODOMA Technology
optimizing human antibodies and production lines via whole
genome evolution (morphogenics)
DISCOVERY
OPTIMIZATION
antibody
producing cell
antibody/cell line
optimization
FINAL PRODUCT
-GMP manufacturinghigh-titer cell lines
30
25
20
15
10
morphogenics
5
0
parent
MORPH
MORPH
cell Line
derived from:
patient lymphocytes
immunized B-cells
& other mAb platforms
whole genome
evolution
gene
duplication
Natural
-therapeutic efficacyhigh-affinity antibodies
10-10
Mismatch repair
identical offspring
cell division
5X10-8
natural occurring
genetic mutations
Mismatch repair
Morphogenics
gene
duplication
diverse offspring
cell division
10-7
parental
parent
MORPH
MORPH
antibody
92
Antibody Technologies
rodent
chimeric
humanized
human
95
100
VH
CH1
VL CDRs
mAb structure
CL
CH2
antigen
binding region
human
rodent
CH3
% human
0
70
-immunogenic
-lack of immune
effector activity
-immunogenic
-low affinity
-immunogenic
-high affinity,
target specificity
benefits as
human
therapeutics
-target pecificity
-target specificity
low
immunogenicity
-mediate immune
rx
-target specificity
-low
immunogenicity
-mediate immune
rx
-target specificity
-low
immunogenicity
-mediate immune
rx
commercial
examples
OKT3, Zevalin,
Bexxar
Rituxan, Erbitux,
Remicade
Avastin, Synagis,
Herceptin
Humira, Vectibix
PDL
Medarex, CAT,
Morphosys,
Morphotek
limits as human
therapeutics
companies with
proprietary
technology
not proprietary
not proprietary
93
Morphotek Human Antibody Platforms
Human MORPHODOMA®
LIBRADOMATM
antigen approach to develop mAbs
library approach to develop mAbs
Normal
donor
Ag-exposed
donor
validated target Ag
B-cells
de novo target
discovery
immunization
+ fusion
Screen for
target-specific hybrids
Æ MORPHODOMA
expansion
+ fusion
Screen for
disease-specific hybrids
Æ MORPHODOMA
94
Competitive
Antibody Platform Technologies
Morphotek’s unique process offers many advantages for product development
MORPHODOMA
Company
Morphotek-Eisai
Humanization
Technology
Phage
Technology
Xenomouse
Technology
CAT-
Abgenix-
Protein Design
AstraZeneca
Amgen
Labs
Dyax,
Medarex
Morphosys
Antibody source
Human B cells
Mouse B cells
Antibody
engineering
evolution of Ig
grafted CDRs to
genes in
human Ig
hybridomas
backbone
Hybridomas or
Recombinant
cells (CHO/NSO)
Production system
recombinant cells
Human FAbs
Mouse B cells
recombinant
recombinant
human MAbs
human MAbs
Recombinant
cells
(CHO/NSO)
Recombinant
cells
(CHO/NSO)
3rd party licenses required
Recombinant expression
not necessary
yes
yes
yes
Cell line
not necessary
yes
yes
yes
Expression vector
not necessary
yes
yes
yes
95
Morphotek Pipeline
Antibody
1st Indication
Other
indications
Description
Collaborator
Stage
MORAb-003
Ovarian cancer
Breast, CRC,
NSCLC, Renal
antigen on >90%
ovarian tumors
Memorial Sloan
Kettering
Phase I/II
MORAb-009
Pancreatic &
lung cancer
CRC, Ovarian
antigen on 100%
pancreatic tumors
Johns
Hopkins/NCI
Phase I
MORAb-004
Neovascular
disease
Cancer, AMD,
DR
antigen on 100%
tumor endothelia
Johns Hopkins/
John Wayne
PC, IND
FY 2008
MORAb-022
Rheumatoid
arthritis
Asthma, MS,
Psoriasis
cytokine involved in
RA in mouse models
Ludwig
PC
MORAb-028
Metastatic
melanoma
Brain, SCLC
Human mAb with
clinical activity
melanoma
John Wayne
Cancer Institute
PC, IND
FY 2008
MORAb-047
Infectious
disease
Biodefense
Antigen produced by
pathogenic microbes
USAMRIID
PC
MORAb-048
Infectious
disease
Biodefense
Antigen produced by
pathogenic microbes
USAMRIID
PC
MORAbs
Oncology,
inflammation
Pan-cancer
many additional leads now being pursued as part of
Eisai acquisition – will update periodically at scientific
and clinical meetings
PC: Preclinical
96
MORAb-003
• Humanized IgG1 mAb to Folate Receptor Alpha
• FRA over-expressed in ovarian, breast, colon, NSCLC and renal tumors
• FRA biology associated with transformation
• Suppresses growth of ovarian cancers in vivo
• No toxicity observed in cynomolgus GLP studies
• Phase I clinical trials in ovarian cancer at Memorial Sloan Kettering
– No DLT or SAEs observed
– 15 of 19 showed stable disease
• Multi-institutional Phase II open for 1st line relapse ovarian cancer
patients
• Granted orphan status by FDA June 2006
• IP to antibody and antigen
97
MORAb-003
Radio-labeled Study
antibody accumulates at tumor site
Arrows demonstrate
tumor mass in lung
Blood pool
(Heart)
Arrows demonstrate
tumor mass on
abdominal wall
98
MORAb-003
Phase II Study
Treatment of platinum-sensitive patients after primary relapse
Natural course of disease
s
no
n
1st line therapy
Carbo + taxane
om
pt
ym
ic
at
s
om
pt
ym
No treatment
Carbo + taxane
Relapse
Elevated CA125
Remission
6 mos
12 mos
18 mos
ic
at
2nd Remission
A
B
2nd remission always shorter than 1st
Remission
< 6 mos
< 12 mos
< 18 mos
C
Results to date (16 clinical sites; 24 evalauable patients)
•CA125 responses in Arm A (MORAb-003 monotherapy)
•Secondary remissions in combination in Arm B (combo therapy)
•Objective remission length in Arm C (MORAb-003 maintenance therapy)
•Well tolerated as monotherapy and in combination with Carbo + taxane
99
MORAb-009
• mAb to mesothelin (MT)
• MT confirmed to be over-expressed in pancreatic, lung, mesothelioma,
ovarian, and colon cancers
• MT biology associated with invasion
• Suppresses growth of pancreatic cancers in vivo
• No toxicity observed in cynomolgus GLP studies
• Phase I clinical trials in mesothelin+ cancers ongoing at JHU, FCCC,
NCI
• Granted orphan status by FDA November 2006
• IP to antibody and antigen
100
MORAb-009
Phase I Study Update
• Mesothelin-expressing tumors at JHU, FCCC, NCI
– Single agent in pancreatic, mesothelioma, NSCLC, and ovarian cancers
– Standard dose escalation design
• Dose cohorts (12.5, 25, 50, 100, 200 & 400 mg/m2)
• 3 patients per cohort until DLT/MTD reached
– Target to initiate Phase II in 1st line therapy for pancreatic cancer FY3Q-07
• Status:
– Completing 6th cohort
– Three patients were recommended by their physician for extended therapy
• Pancreatic cancer gemcitabine failure, stabilized disease for 7 months
101