2016 Eisai Scientific Day
Transcript of 2016 Eisai Scientific Day
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Eisai Scientific Day
Opening Remarks
Haruo Naito, KBE
CEO
2
3
Plan ‘EWAY2025’
Eisai in 2025
Base Camp
2025
Camp I
Camp II
Camp III
Attack Camp
2016
Hideo Tachi
Focus on Neurology Area
and Oncology Area
to Provide
Prevention-Cure-Care
Realize Community-
based Healthcare that
Delivers Safe and Peace
to Patients
4
Converting Knowledge into Business
We Make Medicines, We Make Solutions through Eisai’s WAY
Main Concept of Plan ‘EWAY 2025’
Socialization
Spending time together and sharing experiences with patients
True Needs
Understanding real needs of the patients
Motivation for Innovation*1
Fulfilling hhc needs with our innovation
Finding Out “Ricchi”*2
In order to fulfill such needs, we will find “Ricchi”, a place where
no one has achieved success, an untapped space or an
opportunity where Eisai can be a frontrunner.
Establishment of House at “Ricchi”
Major presence in “Ricchi” with our innovation (House)
*1: Innovation refers to “attempts which potentially generate outputs such as science, technologies and business models”
*2: Source: “Strategy in Action 1: The High Road to Business Profitability” Kazuhiro Mishina, Toyo Keizai Inc. 2015
0
500
1,000
1,500
2,000
2,500
3,000
3,500
Aricept
-The First Global Anti-AD Drug-
At the Tsukuba Research Laboratories, Dr. Hachiro Sugimoto discovered the
compound which showed excellent penetration through Blood-Brain-Barrier and
inhibited the acetylcholinesterase selectively, and then developed the first global
anti-AD drug with the well-proven efficacy profile.
Approved in 97 countries and launched in more than 85 countries
(million USD) 3,447 million USD*1
in FY2009
*1: Global Aricept revenue *2: Dementia with Lewy Bodies approved in Japan and Philippines 5
Launch Meeting
in US in 1997
Donepezil Hydrochloride
Mild to Moderate Severe DLB*2
molecular weight: 416
and enantiomer
Marine sponge
Halichondria okadai
: Chiral
carbon
Chiral Carbon: 19
Halaven
-Winning of Modern Chemistry Development-
At the Andover Innovative Medicines Institute, Halaven was synthesized from a natural
product isolated from the marine sponge Halichondria okadai in Miura Peninsula,
Japan. Halaven has 19 chiral carbons, which means the theoretical number of
stereoisomers is 219
(524,288) making stereocontrol potentially extremely difficult.
Halaven is the first and only single-agent therapy to demonstrate a significant overall
survival (OS) benefit both in patients with late-stage metastatic breast cancer (MBC)
and in patients with advanced or recurrent and metastatic soft tissue sarcoma (STS*1).
Approved in 60 countries and launched
in more than 45 countries
0
50
100
150
200
250
300
350
FY2010 FY2011 FY2012 FY2013 FY2014 FY2015
(million USD) 334 million USD*2
in FY2015
6 *1: Approved indication in U.S. and EU: advanced liposarcoma. Approved indication in Japan: soft tissue sarcoma *2: Global Halaven revenue
Eribulin Mesylate
MBC STS
molecular weight: 826
Common Factors for Success
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Talent
Strong sense of ownership
Day and night efforts to overcome hurdles
Risk mitigating
Science/Technology
Chemistry
Human biology
ICT*
* Information communication technology
“ ” and Innovation in
Alzheimer’s Disease and
Dementia Field
Eisai Scientific Day
Ivan Cheung President, Neurology Business Group
In Japanese, “Ricchi” is a place where the landscape is clear and a
place far away from the crowds, where one would build a home.
At Eisai, our “Ricchi” challenges the innovation boundaries of new
medicines toward preventive and curative therapies.
Ricchi
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Understanding Patients’ True Needs:
Our Human Health Care (hhc) Mission
• It’s hardly possible that I have dementia. I deny it.
• I want to take care of myself, at least my personal care,
dressing, bathing, eating. But I am missing such
capabilities day by day.
• Now I am talking, but it is quite tough to me and then I
feel severe fatigue of my brain. It is different from my
body as I feel my brain becomes puffed up.
• I was shocked when I receive diagnosis of AD. I thought
it was much better to die but then I tried to set objective
to live.
• My wife doesn’t want me to go out because I look like a
normal person so she is afraid that people may consider
I pretend to be a dementia patient.
• I decided to go see a doctor by myself because I can’t
bear to carry this anxiety. I need an answer.
• Doctor, please tell me the name of this disease together
with hope.
• Though I took action for early detection, it took six years
to receive a diagnosis of dementia with lewy bodies.
Before then, wrong diagnosis made me worse.
• I was so shocked when my grandmother couldn’t
recognize me, and she has been complaining that she
was scared because an unknown man has been talking
to her.
• People don't want to show their weakness. It's the same
for a dementia person.
From Alzheimer’s Disease & Dementia Patients:
Aspiring to be the most respected company that revolutionizes AD/Dementia “Total Care” across the patient’s journey
Improve human health care (hhc) in the field of neurodegeneration by making medicines that fulfill the explicit/implicit needs of patients and follow the
evolution of human biology toward the “root causes” of human illness
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Platforms in 6 “Ricchi” to Realize Total
Care for Alzheimer’s Disease/Dementia
Pre
em
ptive
C
urative
Early and Minimally-Invasive Diagnostics
Super-high-resolution Fluorescence Microscopy, Blood-based Biomarker
Novel Neuro-Transmission Pathways
AMPA Platform, Orexin Platform, PDE Platform Comprehensive analysis methods by integrating behavior, electrophysiology, neurochemistry
and PET tracer imaging in various animal models
Neuro-Inflammation
& Immuno-Genetics
Immuno-Dementia Platform,
Functional Genomics & Genome Editing Platform,
Fractalkine Platform Analysis of large genome sequence data followed by
functional genomics to identify drug targets supported by
strong human biology
Neuronal
Regeneration
Genetically Engineered Glia Implantation Platform Technology to handle stem cell and iPS aiming at next
generation therapy including glia cells (astrocyte)
implantation
Ricchi 1:
Ricchi 2:
Ricchi 4:
Ricchi 6:
Proteinopathy
Dual-track Platform (Combining production/aggregation
inhibition + Toxic species clearance),
Dementia Know-how (Integrating target species selection
+ stratification & PD markers + sensitive clinical scale)
Human translation technologies through correlation between
function and pathophysiology in genome-editing cell/animal
models
Synapse
Micro-Environment
Neurotrophic Factor Platform,
Protein-protein-interaction Modulation Platform Platform to discover small molecules or functional biologics
to modulate protein-protein interaction in synapse micro
environment
Ricchi 3:
Ricchi 5:
Su
pp
ortive
Today’s Focus 10 *Platform refers to the drug-discovery technology infrastructure based on innovation, aiming for bearing sequential projects
Partnership with Sysmex Corporation
Other partnership projects targeting blood-based diagnostics
E2027: PDE9 Inhibitor aiming for cognitive and neuropsychiatric benefits in dementia patients
(Ph 1)
Lemborexant: Insomnia in populations including
elderly patients (Ph 3)
Sleep-Wake Fragmentation in Dementia (Ph 2 prep.)
E2609: BACE Inhibitor (Ph 2, under Ph 3 prep.)
BAN2401: Anti-Aβ protofibrils antibody (Ph 2)
Aducanumab: Anti-Aβ antibody (Ph 3)
(Eisai has option to jointly develop & commercialize with Biogen)
Tau targeting projects (antibody &
aggregation inhibitor projects) Immuno-dementia projects Synapse micro- environment projects Combination therapy with different MOAs
An Industry-leading Portfolio for
Alzheimer’s Disease/Dementia “Total Care”
AD, DLB PDD, FTLD,
etc.
Potential for Modifying
Underlining Disease Biology
Cognitive Enhancement
Supportive Care Early
& Minimally -invasive
Diagnosis
E2609: in partnership with Biogen, BAN2401: in partnership with BioArtic and Biogen, Lemborexant: in partnership with Purdue Pharma All compounds mentioned above are investigational AD=Alzheimer’s Disease, DLB=Dementia with Lewy Bodies, PDD=Parkinson’s Disease Dementia, FTLD=Frontotemporal Lobar Degeneration
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Projects targeting other novel neuro-transmission pathways
Neuronal Regeneration
Tsukuba Research Laboratories (Ibaraki, Japan) Platform Technology
• Integration of bio-pharmacology and medicinal chemistry with sound knowledge on CNS
drug discovery
• Competitive discovery platforms established through in-house discovery projects
• Super-high-resolution fluorescence microscopy (partner), blood-based biomarker
• Human translation technologies (EEG, fMRI, amyloid/tau PET, CSF measurement) in
genome-editing cell/animal
• Analysis method by integrating behavior, electrophysiology, neurochemistry and PET
tracer imaging in various animal models
Hatfield Research Laboratories (Hatfield, UK) Platform Technology
• Open innovation by strong network to UK/EU academia
• Easy access to patient’s samples
• Biomarker research collaboration with Leonard Wolfson Experimental Centre
KAN Research Institute (Kobe, Japan) Platform Technology • Integrated cell biology: synapse, developmental and inflammation biology
• New perspective in pathophysiology by sharing knowledge/technology among neural,
immune and tumor cell biology
• Identification of novel cells and molecules causing disease
• Modulation of protein-protein interaction by functional biologics
• Handling stem cell and iPS aiming at next generation therapy including glia cells
(astrocyte) implantation
Andover Innovative Medicines Institute (Andover, US) Platform Technology
• Immunogenetic and immunoepigenetic driven target discovery
• Analysis of large genome sequence data followed by functional genomics focusing on
neuroinflammation to identify drug targets strongly supported by human biology
Proteinopathy
Synapse Micro-Environment
Four Discovery Engines in Eisai
Neurology Business Group
Neuro-inflammation and Immuno-genetics
Novel Neuro-Transmission Pathways
Proteinopathy
Synapse Micro-Environment
Neuro-inflammation and Immuno-genetics
Neuro-inflammation and Immuno-genetics
Early and Minimally-Invasive Diagnostics
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Have the courage to innovate without borders and make evidence-based decisions
to deliver solutions that address real patient needs
AiM Institute hhc mission statement
Delivering precision medicines for dementia
A new paradigm of human genetic driven drug discovery
Eisai Scientific Day
Nadeem Sarwar
President, Eisai AiM Institute Andover innovative Medicines
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Maturation of human genetics enables a
disruptive new paradigm for drug discovery
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Human genetics & drug discovery: Improving the odds of success
A new paradigm for drug discovery:
Breaking down ownership & innovation borders
Genetics
Unit
Biomarkers
Unit
Statistics
Unit
Screening
Unit …
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
“Support” “Guide” “Assist” “Impact” “Enable”
Disruptive potential of human genetics shackled by conventional pharma models and cultures
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Genetics
Unit
Biomarkers
Unit
Statistics
Unit
Screening
Unit …
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
Drug Discovery
Unit
A new paradigm for drug discovery:
Breaking down ownership & innovation borders
Disruptive potential of human genetics shackled by conventional pharma models and cultures
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute: Industry unique commitment to realize new
paradigm for human genetics driven drug discovery
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
90-scientist institute at dedicated drug
discovery facility in greater Boston
Multi-disciplinary scientists under one roof
prosecuting validated genetic targets
Sharply focused precision medicine
discovery pipeline and portfolio
“Biotech-like” culture but with decades of
experience and track record
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Data to drugs
Identify and validate therapeutic targets and
biomarkers from causal human biology insights
Eisai AiM Institute: Industry unique commitment to realize new
paradigm for human genetics driven drug discovery
Big data
analytics
Integrative
neurogenetics
Clinical data
sciences
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Human biology insight to impact
Focused prosecution of validated targets &
precision medicine biomarkers
Functional genomic target
validation
Systematic gene editing
NextGen Sequencing
In vitro cell biology
iPSC based methods
Immune phenotyping
Model organisms
Proteomics
Dense phenotyping
In-vitro & in-vivo
biopharmacology
Functional
genomics
Translational
biomedicine
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Drugging the “undruggable”
Establish innovative screening systems to
identify potent and selective compounds
Assay
development
Structural &
chemical biology
Compound
screening
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Compounds to medicines
Exploit Eisai’s recognized small molecule
chemistry firepower to make medicines
Medicinal
chemistry
Complex drug
synthesis
Novel
libraries
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Illuminate right drug for right patient
Quantitative assessment of target engagement,
dose, mechanism and response
PET
Tracers
Functional
imaging
Imaging
genetics
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Eisai AiM Institute: Leveraging external environment through unique
and flexible entrepreneurial collaborative models
Eisai AiM
Institute
Human Biology &
Data Sciences Engine
Integrated Biology Engine
Imaging Center of
Excellence
Target Modulation
Engine
Integrated Chemistry
Engine
Open innovation
Research consortia
Pre-competitive
collaborations
Scientific partnerships
Scientific training
programs
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Human genetics and immunodementia:
Moving beyond amyloid & tau for NextGen therapeutics
Large-scale human genetic data highlight immune dysfunction as causal in dementia
Most enriched causal pathway in unbiased
genetic analyses of AD risk genes
Several common and rare variants in immune
related genes associated with AD risk
Functional systems available to enable
understanding of molecular mechanisms
Potentially viable translational biomarkers to
identify patient subsets most likely to benefit
Gene editing, functional genomics
and “disease in dish” models
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Working example:
Immuno-phagocytosis hypothesis
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Microglia
Cytotoxic activity
Cytotoxic T cell
Tumor cell
PD-L1
PD1
MHC
TCR
Immuno-oncology checkpoint
Cell debris AbTau
XXXX
XXXX
Phagocytosis
Immuno-dementia checkpoint?
Working example:
Immuno-phagocytosis hypothesis
Bioparticle Phagocytosis
Aggregated fluor-labeled Ab peptidepHrodo-labeled bioparticles
Ab Phagocytosis
Eisai AIM Institute neuro-immunology lab
Eisai AiM Institute has launched human genetics validated discovery programs to
deliver precision medicine clinical candidates within 3-5yrs
Eisai AiM Institute: Andover Innovative Medicines (I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
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Discovering novel dementia medicines is – on average – expensive, risky
and takes a long time
Maturation of human genetics provides a new paradigm for dementia
drug discovery by:
(i) Identifying novel therapeutic targets increase the probability of
success
(ii) Matching them to patients most likely to benefit
The Eisai AiM Institute is an industry unique commitment to fully harness
disruptive drug discovery opportunities provided by human genetics
We are at the forefront of delivering precision medicines from human
genetics for the targeted subset of patients with immuno-dementia
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KAN Research Institute Strategy
Integrative cell biology to find hidden drug targets
Fractalkine platform and EphA4 platform
Eisai Scientific Day
Toshio Imai, PhD President, CEO & CSO, KAN Research Institute
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KAN Research Institute
Focus our multi-disciplinary approach to cell biology and world class
translational research on “Ricchi”
Mine hidden targets and reveal their pathophysiological functions
by integrative cell biology
Prioritize developing mAbs and nucleic acid drugs, then cell therapy
Implementation:
| 30
Information
Effectors
Functional Unit
Pathways
Leveraging the multi-disciplinary study of neurobiology, immunology
and tumor biology to discover novel targets and innovative therapies
KAN Research The Medicine of “Integrative” Cell Biology
Neuronal
regeneration
Neuro-inflammation
and immuno-genetics
Synapse
micro-environment
Novel targets
and therapies
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Integrative cell biology focusing on
brain microenvironment
Cell death
Infiltrated immune cells
Abnormal astrocyte
Genomic
mutation
Environmental
Factors
Abnormal synapse
Abnormal microglia
phosphoTau
Amyloid b
Blood vessel
phosphoTau
Amyloid b
Discovery of ‘non-reported’ cells and
molecules causing disease (amyloid,
phosphoTau).
Target cells: Synapse, astrocytes,
microglia and peripheral immune
cells
Abnormal regulation
of synapse microenvironment
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A novel theory of neuronal loss: A role for E6011*? Fractalkine-mediated immune cells infiltration of the brain
Infiltrated
& activated
immune
cells
Neuron death
E6011: Anti-FKN mAb
Synapse loss
Aβ
Fractalkine (FKN) is a chemokine present in the blood
vessels.
Its receptor mediates specific immune cells migration
Chemotaxis Capture Firm adhesion
Enhancement
Accessory Function
Crawling
Survival
*Investigational
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E6011 removes immune cells from blood vessels, suppressing infiltration of immune cells
Note that movie
has to be short
in order to allow
time for all other
slides to be
presented
Hoechst
Detachment of crawling/adhered macrophages on blood vessels
in colon of Oxazolone-induced colitis by anti-FKN mAb
Before anti-FKN mAb i.v.
30 min after anti-FKN mAb i.v.
E6011*: Mechanism of Action
*Investigational
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Phase 1b E6011* study:
Efficacy signals in Rheumatoid arthritis
ACR* Core Data Set response rate at Wk 12
ACR 70 at week 12 was 20 % in the cohort of 200 mg
Now an additional dose (400 mg) is being evaluated
*Investigational
ACR 20 ACR 50 ACR 70 0
100
50
(%)
100mg (n=12)
200mg (n=15)
* ACR: Standard for assessing the clinical improvement of rheumatoid arthritis symptoms
defined by the American College of Rheumatology
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Phase 1b E6011* study:
Efficacy signals in Crohn’s disease
Clinical Response & Remission at week 12
High remission rate at 10 mg/kg in Crohn’s disease
An additional dose (15 mg/kg) is being evaluated
*Investigational
CR-70
CR-100
Remission
2 mg/kg
(Cohort 1)
(1/5 1/5 0/5)
5 mg/kg
(Cohort 2)
(2/7 1/7 0/7)
10 mg/kg
(Cohort 3)
(4/6 4/6 3/6)
0
20
Pro
po
rtio
n o
f p
atie
nts
(%
)
40
60
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E6011*: Challenge in new science for
Alzheimer’s disease (AD)
Monocytes
Blood-Brain Barrier
Central Nervous System
Ab plaque Microglia
Neuron
Macrophage
Microglia
Peripheral blood vessels
*Investigational
Hypothesis
• Well known that microglia
expresses risk genes of AD
• But NO clear evidence the microglia
is mono-population
• Infiltrated monocyte may
express as well
Next step
• Proof that the function of monocyte,
becoming E6011 is a drug
candidate for AD
• Conditional KO is critical study for
proof of biology
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Story of EphA4 targeting synapse modulator:
g-Secretase inhibition as classical concept for AD therapy
• Inhibition of g-secretase became the strategy for AD treatment
• However, PS1/PS2 double KO mice exhibit AD-like neurodegenerative
phenotypes
• And clinical trial results indicated that AD patients treated with a g-secretase
inhibitor can have worse cognition and function
Synapse
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Finding hidden substrate of g-secretase:
The path to EphA4
Inoue (KAN) et al., J. Cell Biol., 2009
Inhibition of g-secretase causes
synapse dysfunction, and a key
substrate of g-secretase is EphA4.
Moreover, EphA4 cleavage mediates
healthy dendritic spine function, but
EphA4 cleavage is reduced in AD.
Could EphA4 cleavage enhancers
help in AD?
Hypothesis:
Axon
Dendrite
Synapse
g-secretase
Maintenance of synapse
and
brain homeostasis
Axon
Dendrite
Neuron
Synapse
EphA4
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EphA4 cleavage enhancer: A novel therapy for AD
R&D objective:
Induce synapse stabilization via increased EphA4 cleavage
EphA4/Ephrin
Interaction EphA4
Cleavage
(Undesirable) (Desirable)
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Preclinical data suggests that cleaved EphA4
increments synapse density
In-vitro data (Rat primary neuron)
Cleaved EphA4 Control
Bar: 5mm
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Summary
KAN is committing on the novel molecule hunting with integrative
cell biology concept.
FKN concept (E6011*), with mechanism validated in Rheumatoid
arthritis and Crohn’s disease patients, may challenge new
science for Alzheimer’s disease.
EphA4 cleavage enhancer encourages creation of new
therapeutic field next to Ab concept.
KAN makes patients’ hopes by the innovative medicines.
*Investigational
Tsukuba Research Laboratories: Strengths in
neurotrophic factor, proteinopathy and novel
neurotransmission platforms to realize total care for
Alzheimer's Disease and dementia patients
Teiji Kimura, Ph.D.
Chief Discovery Officer
Neurology Business Group
Eisai Scientific Day
42
Next Approach Beyond Amyloid and Tau
Age
Co
gn
itiv
e F
un
cti
on
Anti-proteinopathy
Agent E2609*1, BAN2401*2
Aducanumab(Biogen)*3
Tau program
Typical AD progression
Early AD
Mild AD
Moderate AD
Severe AD
Synapse Restoration
Agent
Symptomatic
Treatment Aricept
Synapse restoration agent may not only revitalize synaptic
function, but also slows down disease progression. AD=Alzheimer's Disease All projects are investigational except for Aricept.
*1: In partnership with Biogen *2: In partnership with Biogen and BioArctic *3: Eisai has an option to jointly develop and commercialize 43
Concept of Neurotrophic Factor Enhancement
NGF (nerve growth factor) gene therapies improve MMSE
and ADAS-Cog score in all Phase 1 studies for AD patients.
AD11 animal (chronic depletion of NGF) show AD-like
pathology. 1. Loss of cholinergic neurons.
2. Accumulation of Aβ and NFT(neurofibrillary tangle).
icv injection of NGF rescues these phenotypes.
• M. H. Tuszynski, et. al., Nature Medicine, 2005, 11, 551.
• H. Malkki, Nature Reviews Neurology, 2015, 11, 548.
• D. Ferreira, et. al., J Alzheimers Dis. 2015, 43, 1059.
• A. Karami, et. al., Alzheimer’s & Dementia, 2015, 11
44
How Neurotrophic Factor Enhancers Work?
Neurotrophic factor enhancer showed rescue of
neuronal cell death and recovery of synaptic function.
* All projects are investigational
Tau Transgenic animals (P301S) exhibits
• Loss of cholinergic neurons
• Decrease of cholinergic presynapse
A neurotrophic factor enhancer increased
• the number of ChAT (choline acetyltransferase) positive cells in septum
• the optical density of VAChT (vesicular acetylcholine transporter) in
hippocampus
Revitalize Presynapse Rescue Cell Body Damage
Neurotrophic Factor Enhancer
45
Summary
Synapse restoration agent not only revitalizes synaptic
function, but also slows down disease progression.
A small molecule rescued neuronal death and
recovered synaptic function in tau transgenic animal.
Neurotrophic factor modulator could open a new
treatment paradigm as a disease modifier for AD.
Ricchi 5: Synapse Micro-Environment
Neurotrophic factor and protein-protein-interaction modulation platform
Neurotrophic factor activators, EphA4 processing enhancers and other projects
46
APP
Aβ
Aβ protofibrils
Dementia
Microglia activation
Synaptic
dysfunction
Cell death
Neuronal dysfunction
Mitochondria
P
P
P
P
tau
Neurogenesis
Tau
phosphorylation
aggregation
Neuroinflammation Aβ accumulation
Circuits/networks
dysfunction
Proteastasis
Cellular Metabolism
Tau
Amyloid
Synapse
Challenge to Disease-Modifying Therapy
47
Amyloid-based Approach: E2609*1and BAN2401*2
Protofibril
*1: In partnership with Biogen *2: In partnership with Biogen and BioArctic. All projects are investigational. 48
E2609*: Human genetic validation of BACE1
cleavage of APP as therapeutic target of AD
Rare functional variant in APP gene discovered in Iceland:
Reduces BACE1 cleavage of APP
by approx. 40%*1
Reduces risk of developing AD
by approx. 75%*1
Pharmacological inhibition of BACE (in right patient at right time) should:
reduce amyloid, with the aim to protect against Alzheimer’s & delay
cognitive decline
Genetic inhibition of BACE should: reduce amyloid, with the aim to protect
against Alzheimer’s & delay cognitive decline
*1: T. Jonsson, et. al., Nature. 2012 Aug 2;488(7409):96-9.
* In partnership with Biogen. Investigational. 49
E2609*: Translation from Animal to Human
Dose response of Aβ-reduction by E2609 in animal
Clinical study confirmed change in
Aβ Isoforms in CSF compared to
the baseline after 14 days of E2609
dosing
Brain Ab reduction is correlated with
CSF reduction.
Dose response of the CSF Aβs changes by E2609 in the Ph1 MAD study
Internal data
* In partnership with Biogen. Investigational. 50
BAN2401*: Characters
Amyloid Protofibril Definition:
• 80-500 KDa
• 18-114 mers
• Height 1.8-3.0 nm
• Diameter: 25-40 nm
Affinity to amyloids
• For protofibril: IC50 1.1 nM
• For monomer: IC50 40000 nM
Toxic species
• Protofibril induces cell toxicity in vitro study
• Protofibril shows significantly high level in AD compared to age-
matched control
Comparison among anti-amyloid antibodies
PLoS ONE, 2012, 7, e32014
Adapted from Biogen Presentation in AD/PD 2015
BAN2401 Aducanumab Solanezumab Bapineuzumab Crenezumab Gantenerumab
Epitope structural N-terminus mid-domain N-terminus mid-domain N-terminus
Origin Humanized Human Humanized Humanized Humanized Human
Isotype IgG1 IgG1 IgG1 IgG1 IgG4 IgG1
Target Protofibrils Fibrillar
Oligomer Soluble Ab
Fibrillar
Oligomer
Monomeric
Fibrillar
Oligomer
Monomeric
Fibrillar
Oligomeric
MOA
Microglia-
mediated
clearance
Microglia-
mediated
clearance
Sink effect
Microglia-
mediated
clearance
Microglia-
mediated
clearance
Microglia-
mediated
clearance
* In partnership with Biogen and BioArctic . All projects are investigational. 51
BAN2401*: Mechanism of Action
Increased microglia level and engagement following treatment
suggest that amyloid clearance may be mediated by microglia
SPECT imaging analyses indicated measurable improvements in
markers of neuronal health in response to mAb158 at 12 weeks for
some brain regions, particularly in the hippocampus and cortex
* In partnership with Biogen and BioArctic. Investigational.
June Kaplow et al, Bradford Navia et al
Presented at Alzheimer's Association International Conference (AAIC) 2013
Internal Data
52
Tau Hypothesis-based Approach
Transmission
Aβ
Aging
Hyper- phosphorylation Aggregation Neuronal
death Microtubule dynamics
Hyper-
phosphorylation Aggregation Neuronal death
Microtubule dynamics
Aggregation
inhibitor
Kinase
inhibitor
Aβ production inhibitor Aβ – tau
Pathway inhibitor
Transmission
inhibitor
Neuro-
protectant
Clearance
enhancer
Known
target
Unknown
Target
Microtubule
stabilizer
Synaptic impairments
Enhancer of
synaptic function
Eisai is developing tau-targeting discovery
projects internally and also through the
partnership with externals.
53
Concept of Anti-Tau antibody
Cell-to-cell transmission of misfolded Tau causes spread of
the pathology.
A therapeutic antibody targeting Tau could stop seeding and
spreading of pathological Tau in a number of Tauopathies i.e. AD,
FTD, PSP etc.
Antibody to prevent
Tau seeding and
spreading
= Tau
Monomer
Misfolded ‘seed’
54
Concept Validation in Preclinical Model
Tau seeds injecting
Tau seeds spread
to whole brain and
induce tau
aggregation
Tau seeds induced insoluble tau aggregation.
Antibody captured tau seeds and prevented cell-to-cell
transmission of tau seeds.
Antibody reduced insoluble tau aggregation in neurons.
Inhibition of primary seeding: Brain injection of the mixture of an antibody with P301S tau seeds to P301S tg animal reduced level of hippocampal insoluble tau.
Inhibition of secondary seeding: An antibody ip dosing before and after brain injection of the P301S tau seeds reduced level of cerebrum cortical insoluble tau.
55
Summary
Genetic study strongly supports the concept of BACE for AD
treatment.
MOA of E2609*1 was translated from preclinical model to clinical
study.
MOA and functional effect of BAN2401*2 were demonstrated in
preclinical study.
Anti-Tau antibody validated tau cell-to-cell propagation hypothesis.
Ricchi 3: Proteinopathy
Translational studies linking function (behavior, EEG, fMRI) to pathobiology (amyloid/tau PET)
in genome-editing cell/animal models
E2609, BAN2401, tau projects, alpha-synuclein and TDP-43 projects
*1: In partnership with Biogen *2: In partnership with Biogen and BioArctic. All projects are investigational 56
Lemborexant*: Sleep disturbance in AD is part of
more broadly dysregulated circadian rhythms
AD patients show sleep-wake fragmentation (SWF).
Sleep efficiency is positively correlated with cognitive function.
Sleep efficiency is negatively correlated with orexin level in CSF.
Lemborexant has potential for improvement of SWF in AD
Liguori et al, JAMA Neurol. 2014;71(12):1498-1505.
Sle
ep
Eff
icie
nc
y %
MMSE Score
CSF Orexin Level pg/ml
Sle
ep
Eff
icie
nc
y %
* In partnership with Purdue Pharma. Investigational.
A. Satlin et al., Neurobiol. Aging, 1995, 16, 765.
57
E2027*: PDE9 inhibitor
GC
GTP
cGMP
PKG
NMDA R
AMPA R
Ca2+
Na+
Glu
Glu
Glu
NOS
GC
GTP
cGMP
NO
5’-GMP
5’-GMP
Pre-synaptic site Post-synaptic site
PDE9
PDE9
PKG
cGMP: cyclic guanosine monophosphate
GC: guanylyl cyclase
NO: nitric oxide
PKG: protein kinase G
Synaptic region
Glutamatergic
neuron
Glutamatergic neural network
Glutamatergic
neuron
hippocampus
PDE9 regulates cGMP signaling downstream of multiple neurotransmitter systems.
E2027 would provide therapeutic benefits in cognitive impairment and
neuropsychiatric symptoms.
* Investigational 58
E2027*1: Pharmacological Character
*: p<0.05 compared
#: p<0.05 compared
Hippocampal cGMP was decreased in Tg2576 animal.
E2027 improved the hippocampal cGMP decrease.
E2027 improved contextual fear memory deficit in Tg2576 animal.
Cognitive improvement is correlated to cGMP level in CSF.
3 10 vehicle vehicle
Tg2576 animal Wild-type animal
3 10 vehicle vehicle
Tg2576 animal Wild-type animal
E2027 (mg/kg, p.o.)
Highly potent & selective PDE9 inhibitor
PDE9 IC50: 0.0035 μM; >1000-fold selective over other PDEs
Freezing %
in contextual fear conditioning test
E2027 (mg/kg, p.o.)
*1: Investigational 59
Summary
Orexin is the key pathway on regulation of sleep-wake cycle.
Lemborexant has potential for treatment of sleep-wake
fragmentation in dementia patients.
PDE9 inhibitor E2027 may help improve both cognitive function
and neuropsychiatric symptoms through regulation on multiple
neurotransmitters.
Ricchi 2: Novel Neuro-Transmission Pathways
AMPA platform, Orexin platform and PDE platform
All projects are investigational 60
]
]
Cell Based HTS Fragment Based Drug Design
Structure Based Drug Design Computer-Aided Drug Design
Combination
of unique
GPCR library
and panel
assay
Chemistry capability with various approaches enable delivery of
small molecules for various targets which are previously thought
undruggable (protein-protein interaction etc).
Capability of Small Molecule Discovery
in Tsukuba Research Laboratories
61
Strong Progress in Clinical-stage Pipeline
in Alzheimer's Disease and Dementia Field
Eisai Scientific Day
Lynn D. Kramer, MD FAAN
Chief Clinical Officer & Chief Medical Officer,
Neurology Business Group
62
Robust Pipeline for Alzheimer’s Disease
and Dementia “Total Care”
63
Phase I POC/Ph II Pivotal/Ph III Launched
Aricept AD/DLB
AChE inhibitor
Pre-clinical
BAN2401
Early AD Anti Aβ protofibril mAb
E2609
Early AD BACE inhibitor
E2027 Dementia
PDE9 inhibitor
Aducanumab Early AD
Anti Aβ mAb
Lemborexant
SWF* in AD/Dementia Orexin receptor antagonist
SWF Pre-IND meeting with FDA in July 2016
Phase II initiation anticipated in 3Q FY2016 * Sleep-Wake Fragmentation
End of Ph II meeting with FDA in July 2016
Ph III start-up activities underway
Ricchi 2: Novel Neuro -Transmission
LPI (800 patients) by 3Q FY16
(Biogen): Eisai has an option
to jointly develop and commercialize
PDE Platform Orexin Platform AMPA Platform
Ricchi 3: Proteinopathy
Ricchi 4: Neuro-Inflammation & Immuno-Genetics
Ricchi 5: Synapse Micro-Environment
Ricchi 6: Neuronal Regeneration
EphA4 Cleavage Enhancer Platform
Fractalkine Platform
TDP-43 Platform
Genetically Engineered Glia Implantation Platform
Functional Genomics & Genome Editing
Platform
alpha-synuclein Platform
Neurotrophic Factor Enhancer Platform
Immuno- Dementia Platform
Tau Platform
E6011 RA / CD
Anti-Fractalkine mAb
Potential indication expansion
to AD/Dementia
E2609: in partnership with Biogen, BAN2401: in partnership with BioArtic and Biogen, Lemborexant: in partnership with Purdue Pharma All compounds mentioned above are investigational except for Aricept AD=Alzheimer’s Disease, DLB=Dementia with Lewy Bodies
How to identify “Early AD” patients in need of targeted disease modifier therapy?
Stage 1: At-home screening procedures to identify patients at earlier stage disease, i.e. “GENERAL TRIGGER”
Stage 2: Specialized screening procedures by primary care physicians, i.e. “SIMPLE SCREENING”
Stage 3: Specific diagnostic procedures that meet guidelines by physicians treating AD, i.e. “CONFIRMING EXAMINATION”
Potential Population
Early AD
In-office computerized tests or simple questionnaires
Web-based test, wearable devices, smartphone measures etc.
Amyloid PET imaging, gradually supplemented/replaced with CSF IVD*s, but remaining need to evolve to easy-to-use and minimally-invasive diagnostics
Progressive Adaptation of Diagnostic
Repertoire for Early AD Therapeutics
64
Therapy by “Disease Modifier”
* in vitro diagnostics
E2609* Concept for Mode of Action
Hypothesis on the Amyloid Cascade
65
BACE
Gamma secretase
-
AP
P
Oligomeric Aβ
Amyloid plaque
Neurofibrillary tangle
Extracellular
Intracellular
The Amyloid Cascade Hypothesis synaptic dysfunction & loss
Aβ
P
P P
P P
P
P P P
P P P
P P
Tau
Paired Helical Filaments
E2609
* In partnership with Biogen, investigational
E2609* Phase II Progress
Study 202 (Outpatient Study) Multi-center, outpatient study Based on the PK/PD model, doses of 5, 15, and 50 mg were selected for
Phase II to achieve 25, 50 and 75% BACE inhibition
Outcomes of Study 202 Preliminary safety confirmed at all doses PK/PD data for CSF and plasma confirmed models developed from earlier
Phase I and Phase II – doses achieve expected levels of Aβ inhibition in CSF and plasma
Have identified a relevant dose based upon results from safety and aggregate PK/PD modeling from all Phase I and Phase II data
66 * In partnership with Biogen, investigational
E2609* Phase III Start-up Activities Underway
Regarding Study Design Will discuss study design at end-of-phase II meetings with regulatory
agencies FDA (US): July 2016 EMA (EU): 3Q FY2016 PMDA (Japan): 3Q FY2016
Potential Design Concept Global, multi-center, outpatient studies Placebo-controlled 24 months of treatment Primary endpoint: Clinical Dementia Rating Sum of Boxes (CDR-SB) Seeking streamlined development scenarios in consultation with Health
Authorities
67 * In partnership with Biogen, investigational
BAN2401* Concept for Mode of Action
Anti-Amyloid Beta Protofibril Antibody
Antibody against Aβ protofibril
made for novel AD immunotherapy
Aβ monomers (4 kDa)
LMW-Aβ (8-20 kDa)
Protofibrilar Pores Protofibrils
(> 100 kDa)
Aβ fibrils
Aβ plaques
SOLUBLE INSOLUBLE
ADDLs Aβ*56
Oligomers Globulomers
Spheroids (20-100 kDa)
Prof. Lars Lannfelt
BAN2401
Plaque Related-Toxicities:
Neurotoxicity on neuron (in vitro) LTP impairment (in vitro/in vivo) Memory deficits (in vivo)
in
68 * In partnership with Biogen and BioArctic, investigational
BAN2401*1
Novel Phase II Design and Current Status
Phase II (Study 201): Efficacy and Dose/Schedule Finding Study Fixed Burn-in Period: Fixed enrollment for first 196
patients Response Adaptive Randomization
Begins at 196 subjects enrolled [1st Interim Analysis (IA)] Successive IA at 250 and every 50 subjects enrolled until
full enrollment
Full Enrollment Successive IA every 3 months from full enrollment until all
subjects complete 12 months treatment
Futility assessed at every IA Early success assessed at IA starting at 350 subjects
Current Status 11th IA at 700 patients occurred in June 2016 LPI (800 patients) by 3Q FY2016
Bayesian adaptive design A novel approach to address challenges in AD
Response adaptive randomization assigns patients to more favorable doses based on IA results, leading to more efficient trial with greater acceptability to investigators, IRBs, and patients Andrew Satlin et al, Alzheimer's & Dementia: Translational
Research & Clinical Interventions, Volume 2, Issue 1, January 2016, Pages 1–12
Trial completion with robust results improves regulatory utility of the trial
69
Minimal % Reduction to Call Success at various IA
N at Interim Analysis
Bayesian Approach 95% Threshold
Estimate
Traditional Approach*2
Analysis of covariance
650 63 %
700 62 %
750 61 %
800 59 %
800 + 3 months 57 %
800 + 6 months 54 %
800 + 9 months 52 %
800 + 12 months 38 % 54 %
Continuing to explore with Health Authorities on how to leverage the ongoing Phase II study in future pivotal program should the Phase II study achieve positive outcome
* 1: In partnership with Biogen and BioArctic, investigational *2: Phase III sample size to detect differences of 25-30%
Combination Therapy in AD/Dementia May
Unlock Therapeutic Possibilities
70
Inhibition of Aβ generation (BACE inhibitor)
Clearance of toxic oligomeric Aβ (Anti-Aβ mAb)
Combination Use
Amyloid Precursor
Protein (APP) Oligomeric Aβ Aβ Plaques
Inhibition Elimination
Combination provides the possibility for improved therapy • Increased efficacy vs. monotherapy or Increased safety with equal efficacy (dose sparing reducing AEs)
More permutations for combination treatment provides a broader choice to tailor multi-drug regimens to individual patient needs
Combination may accelerate development and reduced costs in development programs • 2X2 (1 trial)-factorial designs can potentially support each agent in monotherapy and the combination • Combination can provide label extension opportunity • Monotherapy followed by combination (efficacy or dose sparing lifecycle strategy depending on experiences in monotherapy program)
Ultimate goal is to create potentially preventive and curative therapies for this complex disease
An Example of Combination Therapy of the Future
Other Examples of Combination Therapy of the Future • BACE Inhibitor + Anti-Tau mAb, BACE Inhibitor + Tau Aggregation Inhibitor, Anti-Aβ mAb + Anti-Tau mAb • Proteinopathy Targeting Agent Combining with Disease Modifier Targeting Neuro-inflammation/Immuno-
genetics or Synapse Microenvironment • Disease Modifier + Symptomatic Treatment
Lemborexant*
Parallel Programs in Sleep-Wake Fragmentation in Dementia & General Insomnia
General Insomnia Aiming toward a clinically
differentiated and best-in-class insomnia product that can be
uniquely positioned as the insomnia treatment of choice for elderly patients
Sleep-Wake Fragmentation (SWF) in
Dementia
Aiming toward the first product indicated for treatment of sleep-wake fragmentation in dementia
Sleep-wake fragmentation is not insomnia and is diagnostically
distinct from insomnia
Potential Pillars of Differentiation • Superior safety profile compared to zolpidem in head-to-head studies • Superior sleep efficacy compared to zolpidem in head-to-head studies
(sleep maintenance and potentially sleep onset) • No impairment of next-morning driving performance
Pivotal Study Initiation May 2016
Expected Approval Before FY2020
Unmet need: Available medications are not appropriate • Potential to be a novel treatment for sleep-wake fragmentation in
dementia • Sleep-Wake Fragmentation is associated with behavioral disturbances
that often lead to institutionalization • Lack of approved therapies puts dementia patients at risk due to off-
label use of other therapies, including antipsychotics • Allow for speed to market by leveraging the general insomnia clinical
development program • Phase II potential design: double-blind, placebo-controlled, multi-center
study with primary endpoints of sleep efficiency and wake efficiency
SWF Pre-IND Meeting with FDA July 2016
IND Submission 2Q FY2016
Phase II Study Initiation 3Q FY2016
Expected Phase III Study Initiation FY2017
Expected Approval Before FY2020
71 * In partnership with Purdue Pharma. Investigational
E2027* Inhibits PDE9 and Increases Brain
cGMP
cGMP is a secondary messenger with critical role in learning & memory
The enzyme phosphodiesterase 9 (PDE9) specifically degrades cGMP; thereby regulating cGMP signaling within brain
PDE9 is abundantly expressed in brain cognition pathways
cGMP is decreased in brains/CSF of patients with cognitive deficits
The PDE9 inhibitor strengthens signaling in cognition pathways
E2027*
PDE9 inhibitor
Preliminary proof-of-mechanism observed in Phase I study
Planning designs for additional clinical development studies targeting improvement in cognitive function and behavioral psychological symptoms of dementia (BPSD) in dementia patients
Launch target: Beyond FY2020
72 * Investigational
Study 202 (Phase II) confirms preliminary safety at all doses and expected levels of a-beta inhibition in CSF and plasma – have identified a relevant dose based upon results from safety and aggregate PK/PD modeling from all Phase I and Phase II data
Phase III design to be discussed at End of Phase II meeting with FDA in July 2016 Phase III start-up activities underway
BAN2401
Anti-A-beta protofibrils antibody
Aducanumab
(BIIB037, Biogen)
Anti-A-beta antibody
Lemborexant
Orexin receptor antagonist
E2027
PDE9 inhibitor
E2609
BACE inhibitor (Beta-secretase)
11th Interim analysis at 700 patients in Study 201 occurred in June 2016 Last-patient-in (800 patients) anticipated in 3Q FY2016 Continuing to explore with Health Authorities on how to leverage the ongoing Phase II
study in future pivotal program should the Phase II study achieve positive outcome
Two Phase III studies (18-month primary endpoint) in patients with early AD ongoing Eisai has an option to jointly develop and commercialize
Phase III insomnia program initiated in May 2016 including elderly patients Sleep disturbances are prevalent in over half of dementia patients and bidirectional
relationship between sleep and dementia is being implicated*
Pre-IND meeting with FDA for Sleep-Wake Fragmentation in July 2016, with Phase II initiation anticipated in 3Q FY2016
Preliminary proof-of-mechanism observed in Phase I study Planning for additional clinical development studies targeting improvement in
cognitive function and behavioral psychological symptoms of dementia (BPSD) in dementia patients
Launch target: Shortly after FY2020
Summary of Five Clinical-stage Assets in
Alzheimer’s Disease and Dementia
Launch target: Before FY2020
Launch target: Beyond FY2020
Po
ten
tial fo
r M
od
ifyin
g U
nd
erl
inin
g D
isease
Bio
log
y
Su
pp
ort
ive
Care
an
d
Co
gn
itiv
e E
nh
an
cem
en
t
73 E2609: in partnership with Biogen, BAN2401: in partnership with BioArtic and Biogen, Lemborexant: in partnership with Purdue Pharma All compounds mentioned above are investigational * Liguori C et al. JAMA Neurol. 2014 Dec;71(12):1498-505
“Ricchi” and Innovation
in Oncology Field
Eisai Scientific Day
Teru Iike
President, Oncology Business Group
74
Eisai Oncology Business Group
Side Effects
• Side effects of chemo was like a hell. If I have a
recurrence of cancer, I would never take a
chemo, rather go to hospice.
• I asked a doctor what if I have a numbness as
side effects but I got answer “There is no coping
technique to the side effects”.
Maintaining a normal/social life
• Survival is important. What I can do after survival is also important.
• As long as I can live my life and continue to work full-time, that is my
goal. My goal is to stay away from systemic chemos.
Maintaining a normal/social life • I was afraid that I would be unable to
continue working due to side effects of
chemo and social stigma.
• Who is going to support my family if I am
too sick to work, or not here?
Financial concerns ・ My husband and I had to declare bankruptcy
because of the outrageous costs of my
leukemia medicine ($7000 per month) and tests.
The unreasonable costs of the medicine I
needed to stay alive has taken everything we
have.
・ They are taking the pills every other day or
missing a month—and the reasons are
completely financial.
Mental/Spiritual pain • Please don’t compare patients. Every single patient
is different.
• Mental pain was tougher than pain from surgery or
chemo therapy.
• Physicians may say that “Your cancer has a good
prognosis in general”. However, cancer is cancer.
The way how to see the disease is different between
physicians and patients.
• I’m very much worried about potential recurrence of
the cancer.
Make Cancer
curable or
manageable
Find a Cure
• “My ultimate hope is to find a cure. But that’s not realistic. What I’m after is as much time as
possible. Your drug, Halaven, has given me extra time and I am so very thankful for that. It has
allowed me these precious months with my family. But I know it will not last forever.
Affordable
pricing
Total Disease
Management:
Mental/Spiritual
care, Tailor-
made treatment,
Advance Care
Planning
Solution to
maintain
patient’s
normal life
"Patient Profile" chart is prepared by Eisai, modifying from "Customer Profile" chart in the following source:
Value Proposition Design: How to Create Products and Services Customers Want (Strategyzer)
Pain
From Pain to Gain - hhc Needs We Fulfill -
75
Platform technology
• Eribulin platform
• Morphotek’s antibody platform
• Cancer stemness platform
Projects
• Eribulin + Pembrolizumab*, Eribulin + PEGPH20*,
Halichondrin research* and other new projects
Ricchi 1: Cancer Microenvironment
1-1. Mesenchymal Cancer and Stromal Cells
(Cell Differentiation, Cancer Stemness, etc.)
Platform technology
• Cancer genomics platform
• Splicing platform
Projects
• FGFR4 inhibitor*, SF3B1 modulator* and other
new projects
Ricchi 2: Cancer Gene Dependence
and Aberrant Splicing
Platform technology
• Lenvatinib/kinase inhibitor platform
Projects
• Lenvatinib + Pembrolizumab*, Lenvatinib +
Everolimus*, and other new projects
1-3: Endothelial Cells
(Abnormal Tumor Vessels)
Platform technology
• Prostaglandin/Toll-like receptor platform
(cancer immunity platform targeting myeloid
cells)
Projects
• E7046 (EP4 inhibitor)* and other new projects
These platforms refer to the drug-discovery technology infrastructure based on innovation, aiming for bearing sequential projects.
* Investigational single agents or combination treatments
Oncology “Ricchi” and Innovation “Center-Line” Platforms to Provide Cure for Cancer Patients
1-2: Myeloid Cells
(Immunosuppressive Myeloid Lineage)
76
Our Focus in Cancer Microenvironment
Epithelial cancer cells
Mesenchymal cancer cells
Myeloid cells
Lymphoid cells
Cancer stem cells
Endothelial cells
EMT*1 MET*2
Mesenchymal stromal cells
(Fibroblasts, etc.)
• Cytotoxics
• 1st generation RTKIs*3
77
Immune checkpoint
inhibitors
Angiogenesis
inhibitors *1 Epithelial-Mesenchymal Transition *2 Mesenchymal-Epithelial Transition,
*3 Receptor tyrosine kinase inhibitors
Tsukuba Research Laboratory (Tsukuba, Japan) Lenvatinib/Kinase Inhibitor Platform • Diverse small molecule libraries to inhibit target kinases • Clinical samples and translational research tools via Lenvima development to identify new cellular
targets in cancer
Cancer Stemness Platform • Functional cell based phenotypic assay systems to evaluate cell differentiation, epigenetic control
and tumor metabolism • Single cell-based analysis to address tumor heterogeneity
Eribulin Platform • Natural product chemistry to synthesize highly complex small to mid-size molecules with
halichondrin-based compound library. Translational research tools via Halaven development
• Immunosuppressive
Myeloid Lineage
• Cell Differentiation
• Cancer Stemness
• Abnormal Tumor
Vessels
Oncology Discovery Engine Four Sites
• Immunosuppressive
Myeloid Lineage
Eisai Andover Innovative Medicines Institute (Andover, US)
Prostaglandin/TLR Platform (Cancer immunity Platform targeting
Myeloid cells) • Unique compound libraries consisting of EP2, EP4 and toll-like receptor (TLR) antagonists • Cell free and cell-based assay systems to evaluate myeloid-derived cancer immunity
Morphotek (Exton, US) Morphotek’s Antibody Platform • Anti-folate receptor alpha antibody, anti-mesothelin antibody, anti-TEM1 antibody and others • Morphotek original site specific conjugation technologies
• Cell Differentiation
• Cancer Stemness
• Cancer Gene
Dependence
• Aberrant Splicing
H3 Biomedicine (Cambridge, US) Cancer Genomics Platform • State-of-the-art genomics, genetics and bioinformatics tools to identify and validate cancer gene
dependence, such as driver gene mutations and abnormal gene expression
Splicing Platform • Compound libraries to identify novel, splice variant-specific splicing modulators • A unique set of high throughput screening systems
78
Markus Warmuth, MD President and CEO, H3 Biomedicine
Eisai Scientific Day
H3 Biomedicine
H3 - At the interface of Big Molecular Data and Precision Chemistry
H3 Biomedicine
Translate cancer patient data into powerful precision
therapeutics
Precision
Chemistry
Novel
Therapies
Big Data
Science
80
The H3 Knowledge Base
Generation Processing Management Integration Analysis Mining
TiP Wart
Therapeutic Hypothesis
H3 Biomedicine 81
H3’s portfolio projects impact several important hallmarks of cancer
Modified from Cell, Volume 144, Issue 5, Douglas Hanahan and Robert A. Weinberg, Hallmarks of Cancer: The Next Generation, p646–674, Copyright 2011, with permission from Elsevier.
H3 Biomedicine 82
Fragment- based
Approaches
Structure- based Design
H3’s Chemistry Approach
H3 INTEGRATES SEVERAL DIFFERENT APPROACHES WITH A GOAL TO TACKLE HARD TO DRUG CANCER GENES
Diversity- oriented Synthesis
Natural Products
Covalent Inhibitors
H3 Biomedicine 83
H3 Pipeline*
TARGET INDICATION(S) TARGET
VALIDATION HIT TO LEAD LEAD
OPTIMIZATION PRECLINICAL
DEVELOPMENT IND / PHASE I
CLINICAL
SF3B1 (H3B-8800) Advanced Myeloid Malignancies
FGFR4 (H3B-6527) FGF19-High HCC, CCA, CRC
ESR1 ER+ BrCa
SF3B1 / MCL1 MCL1-Amplified Cancers
Target A MYD88-mutant DLBCL
SF3B1 (Mutant Selective)
Advanced Myeloid Malignancies
SRSF2 (Mutant Selective)
Advanced Myeloid Malignancies
Target E Bladder Cancer
Multiple Exploratory Programs
Various genetically defined cancers
2017
*all projects are investigational
H3 Biomedicine 84
FGFR4: an attractive target in Hepatocellular Carcinoma (HCC)
• Member of a family of highly conserved tyrosine kinase receptors
• Involved in the regulation of bile acid synthesis as well as other metabolic processes
• Signaling critically depends on Klotho-b (KLB) as a co-receptor
• Ligand (FGF19) binding induces downstream signaling pathways, including MAPK, AKT and STAT-3
H3 Biomedicine 85
H3B6527 Cancer Cell
Proliferation and Survival
FGF19 FGF19 FGF19
Au
tocr
ine/
Par
acri
ne
Hyper activation
H3B-6527 selectively inhibits FGFR4 leading to growth inhibition and cell death in FGF19 dependent cells and animal models
1
H3B-6527* shows efficacy in HCC with activated FGF19/FGFR4 signaling
D a y o f T re a tm e n t
HE
P3
B T
um
or
vo
lum
e (
mm
3)
Me
an
+/-
SE
M
0 5 1 0 1 5
0
5 0 0
1 0 0 0
1 5 0 0 V e h ic le , P O , B ID
H 3 B -6 5 2 7 3 0 0 m g /k g , P O , B ID
H 3 B -6 5 2 7 1 0 0 m g /k g , P O , B ID
H 3 B -6 5 2 7 3 0 m g /k g , P O , B ID
FGFR
4
(internal data) *investigational
H3 Biomedicine 86
0 1 0 2 0 3 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
D a y p o s t a d m in is tra tio n
LIX
00
6 T
um
or v
olu
me
(m
m3
)
H3B-6527* demonstrates efficacy superior to Sorafenib in HCC models
0 5 1 0 1 5
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
V e h ic le , P O , B ID
S o ra fin ib 4 0 m g /k g , P O , Q D
H 3 B -6 5 2 7 5 0 0 m g /k g , P O , B ID
D a y s p o s t a d m in is tra tio n
LIX
01
2 T
um
or v
olu
me
(m
m3
)
0 5 1 0 1 5 2 0 2 5
0
5 0 0
1 0 0 0
1 5 0 0
D a y s p o s t a d m in is tra t io n
LIX
10
8 T
um
or v
olu
me
(m
m3
)
0 1 0 2 0 3 0 4 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
D a y s p o s t a d m in is tra t io n
LIX
06
6 T
um
or
vo
lum
e (
mm
3)
Model 1 Model 2
Model 3 Model 4
-1
0
1
2
3
4
5
6
7
-3 -2 -1 0 1 2 3 4 5 6 7 8
FG
F1
9 E
xp
res
sio
n (
Lo
g2 R
ati
o)
FGF19 Copy Number (Log2 Ratio)
HCC Tumor Expression and Copy Number of FGF19 Patient Tumor Samples
Model 1
Model 2
Model 3
Model 4
(internal data) *investigational
H3 Biomedicine 87
H3B-6527*: profile summary
• Potent and highly selective small molecule inhibitor of FGFR4
• Covalent mechanism of action results in irreversible inhibition of FGFR4
• Selective growth inhibition seen in FGF19 expressing cell lines in vitro
• Inhibition of FGFR4 signaling observed in cell line and xenograft models
• Tumor regressions in FGF19 expressing in-vivo xenograft models
• Acceptable non-clinical DMPK profile for oral dosing
• Acceptable non-clinical safety profile with all identified toxicities manageable and reversible
*investigational
H3 Biomedicine 88
• IND approved April 2016, FPFV Phase 1 in July 2016
• Phase I in advanced, unresectable HCC (with and without cirrhosis) and IHCC
• Global Clinical Trial (US, Europe, Asia)
• Clinical proof of concept in patients with high FGF19 expression
• Aim for accelerated approval in 2nd line HCC
• Additional opportunities:
• HCC 1st line as monotherapy or in combination
H3B-6527*: clinical development
*investigational
H3 Biomedicine 89
U2AF1 (S34 or Q157)
MDS (6%), AML (5%), CMML (8%), lung (3%),
uterine and pancreatic cancer (~1%)
SRSF2 (P95 or P95-R102 indel)
CMML (47%), MDS (15%), PMF (17%),
AML/sAML (19%)
SF3B1 (several across HEAT domain 4-8)
MDS (25%), CLL (10%), CMML (5%), AML
(5%), Breast (2%), Uveal melanoma (20%)
ZRSR2
CMML (8%), MDS (6%), AML (1%)
• Somatic mutations in the mRNA splicing machinery lead to aberrant splicing
• Aberrant splicing induce key hallmarks of cancer, including blockage of differentiation and
evasion of the immune system
Spliceosomal mutations: A new class of Cancer genes
H3 Biomedicine 90
SF3B1/SRSF2/U2AF1
Hematopoietic Failure and Cell Death
Mild effects
Selective Cell Death
Exploiting spliceosomal sickness as a therapeutic approach
Normal
Malignancies
SF3B Modulator H3B-8800
WT/WT
MUT/WT
-/WT
-/-
MUT/Inhibitor
H3 Biomedicine 91
0 5 1 0 1 5 2 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
K 5 6 2 S F 3 B 1K 7 0 0 K
T u m o r V o lu m e
T im e (D a y )
Tu
mo
r V
olu
me
, m
m3
(Me
an
S
EM
)
V e h ic le
8 m g /k g P O , Q D
0 5 1 0 1 5 2 0
0
5 0 0
1 0 0 0
1 5 0 0
2 0 0 0
K 5 6 2 S F 3 B 1K 7 0 0 E
T u m o r V o lu m e
T im e (D a y )T
um
or
Vo
lum
e,
mm
3
(Me
an
S
EM
)
V e h ic le
8 m g /k g P O , Q D
• Inhibition of tumor growth observed only in SF3B1 mutant model
• Activity seen in several additional xenograft models
H3B-8800* shows differential activity in models of malignancies with spliceosomal mutations
(internal data) *investigational
H3 Biomedicine 92
H3B-8800*: profile summary
• A potent and selective SF3B modulator
• Dose-dependent pharmacodynamic modulation of RNA splicing and selective induction of apoptosis and anti-tumor activity in SF3B1MUT cells and xenografts
• Active in xenograft and PDX models of SRSF2 mutant leukemia
• Pharmacodynamic activity observed at tolerated doses
• GLP toxicology studies predict favorable therapeutic index
• Projected human half-life predicts compound suitable for QD dosing
*investigational
H3 Biomedicine 93
• IND approved April 2016, FPFV Phase I in July 2016
• Ph1 in advanced myeloid malignancies, with multiple expansion arms to probe activity in selected patients with MDS, CMML and AML
• Global clinical trial (North America, Europe)
• Potential Ph2 registrational trials in splice factor mutant-positive patients (assumes strong signal/good safety) with MDS – use hematological improvement as readout.
• CMML might offer additional opportunity for accelerated approval
• Other development opportunities exist sAML, CLL, NSCLC, Uveal Melanoma
H3B-8800*: clinical development
*investigational
H3 Biomedicine 94
H3 Biomedicine Splicing Platform
BIOINFORMATICS
• Novel RNAseq pipelines • Aberrant splicing
SPLICING CHEMISTRY
• Small molecule splice modulators • DOS and Natural product chemistry
SPLICING BIOLOGY
• High through-put In vitro minigene and splicing assays • U2-snRNP complex component crystallography
H3 Biomedicine 95
Scaffold A
Scaffold B
Scaffold C
Indication Indication Indication
“Omics” Characterization and Driver Splice Events
Splice Modulators
Combinatorial approach to Splice Modulation in Cancer
H3 Biomedicine 96
Splice modulation can induce tumor specific immunity
High Affinity
Antigens
Splice Modulator
Neo- Antigen
Tumor Cell
Cell Death
H3 Biomedicine 97
• Within 4.5 years of commencing scientific operations H3 has build an industry leading R&D engine at the interface of big molecular data and precision medicine
• Focus on connecting cancer genomics and aberrant splicing to key hallmarks of cancer
• 2 INDs (H3B-6527*, H3B-8800*) filed and approved, FPI expected in July
• Additional projects are being advanced towards preclinical development and IND stage
• First approval targeted for 2020
Summary
*investigational
H3 Biomedicine 98
Have the courage to innovate without borders and make evidence-based decisions
to deliver solutions that address real patient needs
AiM Institute hhc mission statement
Delivering NextGen Targeted Immunotherapies
Myeloid lineage targeting therapeutics to address
unmet needs in immuno-oncology
Eisai Scientific Day
Nadeem Sarwar
President, Eisai AiM Institute Andover innovative Medicines
99
Our generation of drug discoverers
have the tools needed to cure cancers
100
Unprecedented hope for cancer patients:
but only small subset of patients currently benefit
Immunotherapies & precision medicines provide most powerful arsenal
ever available in fight against cancer
Considerable and unmet residual needs remains
Game changing scientific discoveries have driven unprecedented
translational investments
101
*1: Genomics England: A genome analysis project in the UK involving more than 100,000 people
*2: Cancer MoonShot: A $ 1 billion national project in the US led by the Vice president Joe Biden aiming to make more cancer therapies available to more patients
*3: Parker Institute for Cancer Immunotherapy in US: A collaboration between the country's leading immunologists and cancer centers, established by Sean Parker aiming for cancer cure
*4: Bloomberg-Kimmel Institute: A new institute for cancer immunotherapy research established in John’s Hopkins University with support from Michael R. Bloomberg, Sydney Kimmel and others.
Genomics England*1
Cancer MoonShot Initiative*2
Parker Institute*3
Bloomberg-Kimmel Institute*4
……….
NextGen precision immunotherapeutics:
Targeting the tumor microenvironment
The tumor and its cellular environment are interdependent, with both defining the extent of:
immune tolerance, growth, evolution
Tumor
Microenvironment
102
Novel immune-microenvironment clues from an old source:
Aspirin, prostalandins and myeloid cells
Aspirin may reduce risk of several cancers –
MoA likely prostaglandin and myeloid cell driven
11,000 participant RCT
of cancer prevention
Potent and specific modulation of EP receptors may provide
novel therapeutic opportunity for targeting tumor immune microenvironment
Reduction in cancer incidence associated
with aspirin in large-scale meta-analyses:
Esophageal: 30%
Stomach: 30%
Colorectal: 35%
Adapted from Rothwell et al. Several
103
Prostaglandin E2 (PGE2) signaling disrupts anti-tumor activity of
immune cells
Macrophage
Dendritic cell
T-cell
EP4 receptor
EP2
Investigational E7046: First in Class EP4 Specific Antagonist
Reverses of PGE2-mediated tumor promotion and immune suppression
E7046 PGE2
104
E7046 clinical plan and status
RP2D
Submission
Phase I:
Open-labeled multi-center study
Selected cancers with high myeloid cell infiltration
Collection of multiomic data, samples and FDG-PET
Phase 1b/2 with CRT:
Open labeled multi-center combination study
PET tracer development currently ongoing
Combination with pre-operative radiotherapy in locally advanced rectal cancer
Regulatory Activities
/Full Development
101 Study:
Monotherapy,
RP2D (Recommended
Phase 2 Dose)
RT/CRT
comb. (Radiotherapy/
Chemo-
radiotherapy)
FY2015 FY2016 FY2017 FY2018 FY2019 FY2020
Ph-1
Ph-1b comb.
Ph-2 comb. CRT
105
Available immunotherapies provide unprecedented hope for subsets of
oncology patients in whom such therapies work
Immunosuppresive myeloid cell lineage in tumor microenvironment
provide novel and complementary path to address unmet patient needs
Our first in class EP4 receptor antagonist – E7046 – currently in clinical
development provides a unique opportunity to test this hypothesis
Integration of large-scale multi-omic and imaging data being employed to
identify right target, right tumor, right patient & right dose for E7046
106
Eisai Scientific Day
Takashi Owa, Ph.D.
Chief Medicine Creation Officer
Oncology Business Group
“Ricchi” and Innovation in Small Molecule
Science to Target Cancer Microenvironment
at Tsukuba Research Laboratories (TRL)
107
Eribulin New Mechanisms of Action
1. Tubulin-based Antimitotic Effects
2. Complex Non-Mitotic Effects on Cancer Biology
1) Tumor Vasculature Remodeling
2) Reversal of Epithelial-Mesenchymal Transition (EMT)
3) Inhibition of Cancer Metastasis
4) Inhibition of Cancer Stem Cells
Linked with Phenotypic Changes in Cancer Cells and Cancer Microenvironment
Agoulnik et al., Dezso et al., Matsui et al., and McCracken et al., 2013 AACR Meeting;
Yoshida et al., 2013 AACR-NCI-EORTC; Funahashi et al., 2014; Yoshida et al., Br J Cancer, 2014
108
After a Single Dose of Eribulin, Perfusion
Becomes Uniform Across Tumor Core and Rim
with MX-1 human breast cancer xenografts (day 6)
Vehicle
Well perfused
Poorly perfused,
hypoxic area
Uniform perfusion,
tumor shrinkage
Eribulin, 0.3 mg/kg
Funahashi et al., 2014
DCE-MRI of representative tumors in vehicle- or eribulin-treated nude rats
109
Eribulin Reverses EMT in Tumors In Vivo
MX-1 human breast cancer cells xenografts in vivo
(single dose, 8 days, nude mice)
Yoshida et al., 2014
Epithelial marker
Mesenchymal markers
110
Eribulin Prevents Experimental Metastasis
and Increases Survival in Mice
Number of lung nodules
Yoshida et al., 2014
Survival of mice
Inject eribulin-treated or 5FU-
treated surviving breast cancer
cells into tail vein
111
Anti-Cancer Stem Cell Activity with Eribulin in the In Vivo
Serial Transplantation Model of HSAEC RD Cells
112
Control
PTX QD5 20 mg/kg
ERI Q4D3 1 mg/kg
Day
Tum
or
volu
me
(mm
3)
HSAEC RD lung cancer xenograft
Serial transplantation
Control
PTX Eribulin
( N = 10 )
HSAEC RD: Human small airway epithelial cell infected with retroviral vectors expressing KRASV12 (R) and CYCLIN-D1 (D)
Cell number
112
Presentation at AACR 2016 Shows Human Biology Evidence
on Eribulin New MOAs
• 52 patients with locally advanced or metastatic breast cancer treated with eribulin
• Before/after biopsies from 10 patients • Correlated response rate (RR) with immunohistochemical evaluation:
o TILS: PD-1, CD8, FOXP3 o Cancer cells: PD-L1, PD-L2 o EMT markers: E-cadherin, N-cadherin, vimentin, CA9
Conclusions • Statistically significant correlations
between clinical RR and change in marker status for PD-L1 (p = 0.024) FOXP3 (p = 0.004) E-cadherin (p = 0.004) CA9 (p = 0.024)
• Immune suppression markers (PD-L1, FOXP3) going negative correlated with Clinical RR Reversal of EMT (E-cadherin going
up)
• Loss of hypoxia (CA9 going down) correlated with clinical RR
113
Halichondrin Family
Cytotoxicity against B-16 melanoma cells
IC50 (nM)
Halichondrin B 12.5 mg C 7.2 mg
Norhalichondrin A 35.0 mg B 4.2 mg C 2.4 mg
Homohalichondrin A 17.2 mg B 3.1 mg C 2.1 mg
0.083 0.31 4.6 - - 0.23 0.089 -
Halichondria okadai Kadota 600 kg
• Isolation, structure determination and biological activity:
Hirata, Uemura et al J. Am. Chem. Soc. 1985, 107, 4796; Pure Appl. Chem. 1986, 58, 701.
• For isolation from different species of sponges, see:
Pettit et al J. Med. Chem. 1991, 34, 3339; J. Org. Chem. 1993, 58, 2538.
Blunt, Munro et al Tetrahedron Lett. 1994, 35, 9435; J. Org. Chem. 1997, 62. 1868; Bioorg. Med. Chem. 2009, 17, 2199. 114
Halichondrin B In Vitro Antiproliferative Profile
115
Eribulin
(NSC 707389)
Halichondrin B
(NSC 609395)
GI50 values from NCI-60 cell panel analysis
https://dtp.cancer.gov/timeline/posters/Halichondrin.pdf
Halichondrin B In Vivo Antitumor Profile
116
LOX melanoma s.c. xenograft model
in nude mice
LOX melanoma bone marrow metastasis model
in nude rats
Halichondrin B
Vinblastine
Halichondrin B
Vinblastine
Vehicle
Days Su
rviv
al (
%)
The i.v. treatment schedules and doses were 20 mg/kg Q2D5 for halichondrin B (-□-) and homohalichondrin B (-◆-) given i.v. and 4 mg/kg Q7D2 i.v. for vinblastine (-◇-). Control animals (-■-) were treated with saline at Q2D5 schedule.
Animals were injected intracardially with 1 x 106 LOX cells day 0 , and the i.p. treatments of halichondrin B (9 mg/kg, Q2D5) , vinblastine (1.8 mg/kg, Q7D2) and saline (Q2D5) were started on day 7.
J Exp Ther Oncol. 1996;1(2):119-25
Lenvatinib Combination with Anti-PD-1 Therapy
Scientific Rationale
Lenvatinib reduces immune suppressive myeloid derived cells (TAM) and induce activated cytotoxic T cells (CD8 T-cell) , promoting antitumor activity of anti-PD-1 therapy.
Kato et al., EORTC-NCI-AACR 2015
117
Lenvatinib Combination with Anti-PD-1 Therapy
Lenvatinib reduces immune suppressive myeloid derived cells and induce activated
cytotoxic T cells, promoting antitumor activity of anti-PD-1 therapy
TAM
VEGF CSF
Treg
TCR
MHC Antigen
CTL
Cancer
Monocyte
TGF-b
TAM
TCR
MHC Antigen
Cancer
Monocyte
Attack
PD-1
CTL
PD-L1
TAM
Decrease
Immune Inhibitory Cytokine (TGF-b)
Down
Immune Inhibitory Receptor
(PD-1, Lag3) Down
Immune Stimulatory cytokine(IL12)
Up
PD-1 Ab
Lenvatinib (VEGF blockade)
IFNg
Immune suppressive tumor microenvironment
Lenvatinib causes Immune stimulating tumor microenvironment
Improved antitumor activity of anti-PD-1 therapy
Rayman et al. also reported the similar MOA for sunitinib with
PD-1 blockade in the mouse RCC model (SITC 2015)
TAM secretes TGF-b, which activates immune suppressive Treg and inhibits cytotoxic T cells.
PD-L1 expressed on tumor cells activate PD-1 and suppressed CTL
118
Kato et al., EORTC-NCI-AACR 2015
Cancer Stemness Platform in TRL (1)
AXL inhibitor Targeting Mesenchymal Cancer Cells &
Tumor Vessel Formation
AXL is a key regulator for mesenchymal cancer (stem-like) cells & tumor vessel formation.
Activation of AXL and concomitant epithelial-mesenchymal transition (EMT) were reported in EGFR-mutant NSCLC with acquired resistance to erlotinib. Nat Genet., 44, 852 (2012) AXL was identified as a mesenchymal marker gene associated with innate anti-PD-1 resistance in melanoma patients. Cell, 165, 35 (2016) A clinical sample of triple negative breast cancer after weekly paclitaxel treatment showed upregulation of AXL expression.
AXL/Gas6 signaling was shown to accelerate the formation of pericyte covered tumor vessels resistant to anti-VEGF therapies. Cancer Res., 65, 9294 (2005)
119
Endothelial cell (EC)
Smooth muscle cell (SMC)
Cancer cell
Autocrine/paracrine AXL/Gas6 signaling
EC migration, proliferation.
and survival
SMC migration,
proliferation and survival
Cancer cell EMT
AXL IHC staining
Cancer Stemness Platform in TRL (2)
ALDH (Aldehyde Dehydrogenase) Inhibitor Targeting Cancer Stemness
ALDH consists of 19 isoforms • ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH1L2
• ALDH2
• ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2
• ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1,
ALDH9A1, ALDH16A1, ALDH18A1
1. High ALDH expression in variety of cancers 2. Upregulation of ALDH expression after chemotherapy 3. Positive correlation between ALDH expression and tumor grade relevant to poor prognosis
• Kaplan–Meier curves among ALDH1(-) and ALDH1(+) patients with all breast cancer subtypes showed a statistically significant correlation between ALDH(+) status and shorter disease-free survival (DFS)/overall survival (OS): Breast Cancer Res Treat., 156, 261 (2016).
4. ALDH knock-down led to suppression of cancer stem-like properties in vitro and tumor growth in vivo.
120
Stemness markers
In vitro In vivo H358 s.c. model
Oncology “Ricchi” and Innovation to
Provide Cure with Particular Focus on
Cancer Genomics and Cancer Microenvironment
Epithelial cancer cells
Mesenchymal cancer cells
Myeloid cells
Lymphoid cells
Cancer stem cells
Endothelial cells
EMT*1 MET*2
Mesenchymal stromal cells
(Fibroblasts, etc.)
Cytotoxics
1st generation RTKIs*3
Immune checkpoint
inhibitors
Angiogenesis
inhibitors
TRL Platform
Lenvatinib/Eribulin
H3B Platform
Cancer genomics
Splicing
AIM Institute Platform Prostaglandin receptors
TRL Platform
Eribulin/Cancer Stemness
TRL Platform
Lenvatinib
MOR Platform
Anti-TEM-1 Ab
*1 Epithelial-Mesenchymal Transition *2 Mesenchymal-Epithelial Transition
*3 Receptor tyrosine kinase inhibitors 121
Alton B. Kremer MD, PhD
Chief Clinical Officer
Chief Medical Officer
Key Global Assets
Eribulin and Lenvatinib:
Toward Establishing
New Treatment Paradigms
Eisai Scientific Day
122
Mechanism of Action of Lenvatinib
RAS
RAF
T202/Y204
MEK
PI3K
AKT
mTOR
Lenvatinib
S6K
S6
P P
P
ERK1/2 P
S235/S236
T389
T421/S424
Angiogenesis
FGFR VEGFR
Adapted from Stjepanovic N, Capdevila J. Biologics: Targets and Therapy. 2014:8;129-139; Eisai data on file.
123
Proposed Mechanism of Interaction
Between Lenvatinib and Everolimus
Everolimus
RAS
RAF
T202/Y204
MEK
PI3K
AKT
mTOR
Lenvatinib
S6K
S6
P P
P
ERK1/2 P
S235/S236
T389
T421/S424
Angiogenesis
FGFR VEGFR
Adapted from Stjepanovic N, Capdevila J. Biologics: Targets and Therapy. 2014:8;129-139; Eisai data on file. 124
Laboratory Rationale for the Combination of
Lenvatinib with Everolimus
Complementary activities of lenvatinib plus everolimus
Enhancement of the inhibitory activity against VEGF-induced angiogenesis by the combination of lenvatinib with everolimus
Synergistic enhancement of the inhibitory activity against FGF-induced angiogenesis by the combination
Combination of potent antiangiogenic activity as well as direct antitumor activity by the combination
Dual targeting of the mTOR-S6K-S6 pathway by the combination
Source: Module 2.6.2, Discussion and Conclusion 125
Phase II Study in Renal Cell Carcinoma (RCC)
(Study 205, NCT01136733)
Global, randomized, open-label, phase II trial
Key eligibility criteria
• Advanced or
metastatic RCC
• Measurable disease
• Progression on or
within
9 months from prior
treatment
• Progression on/after
1 prior VEGF-targeted
therapy
• Eastern Cooperative
Oncology Group
Performance Status
(ECOGPS) ≤ 1
Lenvatinib, 18 mg
+ Everolimus, 5 mg
Both PO once daily
n = 51
•
Lenvatinib 24 mg PO qd
n = 52
•
Everolimus 10 mg PO qd
n = 50
Primary endpoints
• Progression-free
Survival*
LEN/EVE vs EVE
LEN vs EVE
Selected secondary
endpoints
• Progression-free
Survival
LEN/EVE vs LEN
• Objective
Response Rate
• Overall Survival
• Safety and
tolerability
1:1:1
R
A
N
D
O
M
I
Z
E
Treatment until
disease progression or unacceptable toxicity
*Based on investigator review and RECIST v1.1 126
Kaplan-Meier Plot of Progression-Free Survival
(Investigator Assessment – Study 205)
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24
Pro
gre
ss
ion
-Fre
e S
urv
iva
l
Time (months) Number at risk:
Lenvatinib/Everolimus 51 41 27 23 16 10 5 1 0
Everolimus 50 29 15 11 7 3 1 0 0
+ +
LEN+EVE
(n = 51) EVE
(n = 50)
PFS, months, median
(95% CI) 14.6 (5.9-20.1) 5.5 (3.5-7.1)
HR vs everolimus
95% CI 0.40
(0.24-0.68)
+ +
United States Package Insert. *Internal data
After post-hoc multiplicity adjustment with the Bonferroni method, the adjusted P value for lenvatinib/everolimus compared with single agent everolimus was P = 0.0011*
127
Lenvatinib 18 mg +
Everolimus 5 mg
(n=51)
Everolimus 10 mg
(n=50)
Progression-Free Survival (PFS)a
Median PFS in months (95% CI) 14.6 (5.9, 20.1) 5.5 (3.5, 7.1)
Hazard Ratio (95% CI)b
Lenvatinib + Everolimus vs Everolimus
0.37 (0.22, 0.62) −
Overall Survivalc
Median OS in months (95% CI) 25.5 (16.4, 32.1) 15.4 (11.8, 20.6)
Hazard Ratio (95% CI)b
Lenvatinib + Everolimus vs Everolimus
0.67 (0.42, 1.08) −
Objective Response Rate (Confirmed)
Objective response rate, n (%) 19 (37) 3 (6)
(95% CI) (24, 52) (1, 17)
Tumor assessments were based on RECIST v1.1 criteria for progression but only confirmed responses are included for ORR.
Data cutoff date = 13 Jun 2014
CI = confidence interval
a. Point estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation.
b. Hazard ratio is based on a stratified Cox regression model including treatment as a
covariate factor and hemoglobin and corrected serum calcium as strata.
c. Data cutoff date = 31 Jul 2015
Efficacy Results in Renal Cell Carcinoma
(Investigator Assessment – Study 205)
128
FDA Approval
On May 13, the U.S. Food and Drug Administration (FDA) approved lenvatinib capsules (18 mg) in combination with everolimus (5 mg) for the treatment of patients with advanced renal cell carcinoma (aRCC) who were previously treated with an anti-angiogenic therapy, which is a standard of care for this disease.
This was a Priority Review following Breakthrough Therapy Designation
The first and only FDA-approved combination of a multiple receptor tyrosine kinase inhibitor (lenvatinib) and an mTOR inhibitor (everolimus) for the treatment of advanced RCC
129
Phase III Study in Renal Cell Carcinoma (RCC)
Study 307, to open Sept 2016
Global, randomized, open-label, phase III trial
Key eligibility criteria
• Age ≥18 years
• Advanced RCC with a
clear-cell component and
histologic / cytologic
confirmation
• No prior systemic
anticancer therapy for
RCC
• Karnofsky Performance
Score ≥70
Lenvatinib 18 mg orally once daily
+ Everolimus 5 mg orally once daily
•
Lenvatinib 20 mg orally once daily
+ Pembrolizumab 200 mg IV every 3 weeks
•
Sunitinib 50 mg orally once daily
4 weeks on / 2 weeks off
Primary endpoints
• PFS (independent
imaging review
using RECIST 1.1)
Secondary endpoints
• ORR
• OS
• Safety and
tolerability
Selected exploratory
endpoints
• HRQoL
• DOR
• PK/PD
• Biomarkers
1:1:1
n = ~735
R
A
N
D
O
M
I
Z
E
Treatment until
disease progression
or unacceptable toxicity
Stratification factors:
• Geography
(Western Europe and North
America, Rest of World)
• MSCKK prognostic group
(Low, Intermediate, High)
130
First Line RCC Study 307:
Key Target Dates
Study Open
September 2016
Database lock
December 2019
Topline results
4Q FY2019
131
Phase III Study in Investigational
Hepatocellular Carcinoma (HCC)
(Study 304, NCT01761266)
Key eligibility
criteria
(N = 940)
• Confirmed
unresectable HCC
• Measurable
disease by
mRECIST
• Barcelona Clinic
Liver Cancer Stage
B or C
• Child-Pugh score A
• ECOG PS:0 or 1
• No prior anticancer
agents
R
A
N
D
O
M
I
Z
E
1 : 1
Lenvatinib
12 or 8 mg daily PO
(based on body
weight)
Sorafenib
400 mg daily PO
BID
Primary endpoint
• Overall Survival
Selected secondary
endpoints
• Progression-free
Survival
• Time to Progression
• Objective Response
Rate
• Safety and
tolerability
• PK parameters
• Quality of life
Treatment until
disease
progression (mRECIST)
Stratification • Geographic
Region
• Macroscopic
portal vein
invasion or
extrahepatic
spread or both
(No/Yes)
• ECOG (0/1)
• Body weight
(< 60 kg/ ≥ 60 kg)
132
Phase Ib/II Study of Lenvatinib +
Pembrolizumab in Selected Solid Tumors
(Study 111, NCT02501096)
Phase Ib Phase II (opened 31 Jan 2016)
Lenvatinib 20 mg QD (RP2D)
+ Pembrolizumab 200 mg Q3W
(21-day cycle)
n = 60-120
Renal Cell (20)*
Melanoma (7)
Urothelial (6)
NSCLC (1)
Endometrial (20)
SCCHN (5)
* Number Of Subjects Enrolled As Of 23 June 2016
Cohort Lenvatinib Pembrolizumab
1A 24 mg 200 mg
2A 20 mg 200 mg 3A 14 mg 200 mg
Same tumor types as Phase 2
n = 10 – 30 subjects (13 subjects actual)
133
Study in planning: Phase Ib Study of Lenvatinib
+ Pembrolizumab in Hepatocellular Carcinoma
(Study 116)
DLT evaluation part
• N=6-10
• Starting dose of
lenvatinib:
12mg QD (BW ≥ 60 kg)
/8 mg QD (BW < 60 kg)
• Dose of pembrolizumab:
200mg /Q3W
• BCLC: Stage B or C
• Child-Pugh A
• ECOG PS: 0-1
Expansion part
• No prior
systemic
therapy
• N=20
(10 in Japan
/10 in US)
Primary endpoints
• MTD & RP2D for combination
of lenvatinib + pembrolizumab
Selected secondary endpoints
• Safety and tolerability
• Efficacy: ORR/ PFS/ OS/
Duration of response
(Tumor assessments to be
performed using irRECIST)
• Pharmacokinetics
• Blood / tumor biomarkers
134
Phase Ib/II Study of Eribulin + Pembrolizumab in
Metastatic Triple-Negative Breast Cancer
(Study 218, NCT02513472)
Key eligibility criteria
• Aged 18 years or greater
• 0-2 prior lines of
chemotherapy for
metastatic disease
• Measurable disease
• ECOG PS:0 or 1
• Adequate bone marrow,
renal, and hepatic
function
Primary endpoints
• Dose-limiting
Toxicities
• Objective
Response Rate
Selected secondary
endpoints
• Progression-free
Survival
• Overall Survival
• Duration of
Response
• Outcomes in the
PD-L1–positive
subgroup
• Safety and
Tolerability
Eribulin 1.4 mg/m2 on Days 1, 8
+ Pembrolizumab 200 mg on Day 1
(21-day cycle)
n = approximately 95
Current enrollment: 85 patients*
* Number Of Subjects Enrolled As Of 23 June 2016 135
Current Status of Combinations with PD-1
• Lenvatinib (Study 111)
– Preliminary data to be presented at major conference
– Further studies based on cohort data as they accumulate
– Phase 3 RCC study already planned (Study 307)
• Eribulin (Study 218)
– Preliminary data to be presented at major conference
– Cohorts for patients with urological malignancies to be added
• Total 52 patients
• Cohorts: a) ineligible for cis-platinum; b)following cis-platinum
• Will open October 2016
136
Summary
Lenvatinib has obtained a second line RCC indication in combination with everolimus in the U.S.
We will initiate a phase 3 study in first line RCC in September studying lenvatinib in combination with everolimus and in combination with pembrolizumab
We expect the results of the phase 3 study of lenvatinib in HCC by the end of 2016
Combination studies with pembrolizumab are ongoing with both lenvatinib and eribulin across 8 different tumors
137
Flagship Programs in Oncology
All the compounds shown in this slide are investigational. *1: Collaboration with Merck for the Ph 1b/2 combination study with Pembrolizumab. *2: Collaboration with Halozyme Therapeutics, Inc for the combination with PEGPH20. 138
Combination therapy with pembrolizumab: Ph 1b/2 study is ongoing for Triple-negative breast cancer.
Combination therapy with PEGPH20: Phase Ib/II study site initiation in 1Q FY16. Investigating the potential to treat HER2-negative breast cancer.
Lenvatinib*1
E7046
EP4 Inhibitor
H3B-6527
FGFR4 Inhibitor
H3B-8800
Splice Modulator
Eribulin*1,2
Global, randomized, open-label, Ph 3 study for RCC 1st line is planned to start in September 2016 in combination with pembrolizumab or everolimus.
Global submission for HCC 1st line is planned within FY16. Combination therapy with pembrolizumab: Ph 1b/2 study is ongoing for Lung,
melanoma, head and neck, bladder, renal and endometrial cancer.
Multi-center Ph 1study is ongoing to determine recommended Ph 2 dose. Open-label multi-center Ph 1b/2 study is planned to start in the 2nd half of FY16, a
combination study with pre-operative radiotherapy in locally advanced rectal cancer.
IND approved April 2016, FPFV for Ph 1 study in July 2016 Phase I in advanced, unresectable HCC (with and without cirrhosis) and IHCC (Intra
Hepatic Cholangiocarcinoma)
Clinical proof of concept is planned in patients with high FGF19 expression
IND approved April 2016, FPFV for Ph 1 study in July 2016 Ph1 in advanced myeloid malignancies, with multiple expansion arms to probe
activity in selected patients with MDS, CMML and AML. Potential Ph2 registrational trials in splice factor mutant-positive patients with MDS.
Can
cer
Gen
e
Dep
en
den
ce a
nd
Ab
err
an
t S
plicin
g
En
do
thelial
cells
Launch target: FY2020
Launch target: Beyond FY2020
Launch target: FY2017 for HCC
Can
cer
Mic
roen
vir
on
men
t
Eisai Scientific Day
Closing Remarks
Haruo Naito, KBE
CEO
139
TO THE LARGEST UNMET MEDICAL NEEDS
OF THE GLOBE “AD/DEMENTIA”,
WE WILL PROVIDE
A VARIETY OF PREEMPTIVE OPPORTUNITIES
BY USING DIFFERENT MOA AGENTS
140
UTILIZING OUR WORLD-CLASS
SMALL MOLECULE SCIENCE,
AND FOCUSING ON
“CANCER MICROENVIRONMENT”
AND “ONCOGENOMICS”,
WE WILL AIM CURE OF CANCERS