2016 Eisai Scientific Day

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 Materials and information provided during this presentation may contain so-called “forward-looking statements.” These
statements are based on current expectations, forecasts and assumptions that are subject to risks and uncertainties that
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; regulatory agency examination periods and 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.
 The Company cannot guarantee the actual outcomes and results for any forward-looking statements.
 Furthermore, 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.
1
Eisai Scientific Day
Opening Remarks
Haruo Naito, KBE
CEO
2
Plan ‘EWAY2025’
Eisai in 2025
Focus on Neurology Area
and Oncology Area
to Provide
Prevention-Cure-Care
2025
Realize Communitybased Healthcare that
Delivers Safe and Peace
to Patients
Attack Camp
Camp III
Camp II
Camp I
Base Camp
3
2016
Hideo Tachi
Main Concept of Plan ‘EWAY 2025’
Converting
Knowledge into Business
We Make Medicines, We Make Solutions through Eisai’s WAY
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)
4
*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
Aricept
-The First Global Anti-AD DrugAt 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
3,447 million USD*1
in FY2009
(million USD)
3,500
3,000
2,500
and enantiomer
Donepezil Hydrochloride
2,000
molecular weight: 416
1,500
1,000
500
Mild to Moderate
Severe
0
5
*1: Global Aricept revenue *2: Dementia with Lewy Bodies approved in Japan and Philippines
DLB*2
Halaven
-Winning of Modern Chemistry DevelopmentAt 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
334 million USD*2
in FY2015
(million USD)
350
Marine sponge
Halichondria okadai
300
250
200
150
:
Chiral
carbon
Chiral Carbon: 19
Eribulin Mesylate
molecular weight: 826
6
100
50
0
FY2010
MBC
FY2011
STS
FY2012
FY2013
FY2014
*1: Approved indication in U.S. and EU: advanced liposarcoma. Approved indication in Japan: soft tissue sarcoma *2: Global Halaven revenue
FY2015
Common Factors for Success
Talent
Strong sense of ownership
Day and night efforts to overcome hurdles
Risk mitigating
Science/Technology
Chemistry
Human biology
ICT
*
7
* Information communication technology
Ricchi
“
” 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.
8
Understanding Patients’ True Needs:
Our Human Health Care (hhc) Mission
From Alzheimer’s Disease & Dementia Patients:
• 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.
• 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.
• 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.
• 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 shocked when I receive diagnosis of AD. I thought
it was much better to die but then I tried to set objective
to live.
• 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.
• 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.
• People don't want to show their weakness. It's the same
for a dementia person.
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
Aspiring to be the most respected company that revolutionizes
AD/Dementia “Total Care” across the patient’s journey
9
Platforms in 6 “Ricchi” to Realize Total
Care for Alzheimer’s Disease/Dementia
Ricchi 1:
Super-high-resolution Fluorescence Microscopy, Blood-based Biomarker
Ricchi 2:
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
Ricchi 3:
Proteinopathy
+ stratification & PD markers + sensitive clinical scale)
Human translation technologies through correlation between
function and pathophysiology in genome-editing cell/animal
models
Ricchi 5:
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
10
Today’s Focus
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
Ricchi 6:
Neuronal
Regeneration
Genetically Engineered Glia Implantation Platform
Technology to handle stem cell and iPS aiming at next
generation therapy including glia cells (astrocyte)
implantation
Curative
Synapse
Micro-Environment
Neuro-Inflammation
& Immuno-Genetics
Preemptive
Dual-track Platform (Combining production/aggregation
inhibition + Toxic species clearance),
Dementia Know-how (Integrating target species selection
Ricchi 4:
Supportive
Early and Minimally-Invasive Diagnostics
*Platform refers to the drug-discovery technology infrastructure based on innovation, aiming for bearing sequential projects
An Industry-leading Portfolio for
Alzheimer’s Disease/Dementia “Total Care”



E2609: BACE Inhibitor (Ph 2, under Ph 3 prep.)
BAN2401: Anti-Aβ protofibrils antibody (Ph 2)
Aducanumab: Anti-Aβ antibody (Ph 3)

E2027: PDE9 Inhibitor aiming for cognitive and
neuropsychiatric benefits in dementia patients
(Ph 1)
(Eisai has option to jointly develop & commercialize with Biogen)

Projects targeting other
novel neuro-transmission
pathways
Cognitive

Tau targeting projects (antibody &
aggregation inhibitor projects)
Immuno-dementia
Potential for
projects
Modifying
 Synapse microUnderlining
environment projects
Disease
 Combination therapy
Biology
with different MOAs

AD, DLB
PDD, FTLD,
etc.
Early
& Minimally
-invasive
Diagnosis

Partnership with Sysmex
Corporation

Other partnership projects
targeting blood-based diagnostics
Enhancement
Supportive
Care

Insomnia in populations including
elderly patients (Ph 3)
Sleep-Wake Fragmentation in Dementia
(Ph 2 prep.)
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
11
Lemborexant:
Four Discovery Engines in Eisai
Neurology Business Group
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
Early and Minimally-Invasive
Diagnostics
Proteinopathy
Synapse Micro-Environment
Novel Neuro-Transmission
Pathways
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
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
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
12
Neuro-inflammation and
Immuno-genetics
Synapse Micro-Environment
Neuro-inflammation and
Immuno-genetics
Neuronal Regeneration
Proteinopathy
Neuro-inflammation and
Immuno-genetics
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
AiM Institute hhc mission statement
Have the courage to innovate without borders and make evidence-based decisions
to deliver solutions that address real patient needs
13
Maturation of human genetics enables a
disruptive new paradigm for drug discovery
Human genetics & drug discovery: Improving the odds of success
14
A new paradigm for drug discovery:
Breaking down ownership & innovation borders
Disruptive potential of human genetics shackled by conventional pharma models and cultures
Drug Discovery
Unit
Discovery
Biology
Discovery
Chemistry
Discovery
Pharmacology
“Support”
Genetics
Unit
“Guide”
Biomarkers
Unit
“Assist”
Statistics
Unit
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
“Impact”
“Enable”
Screening
Unit
…
15
A new paradigm for drug discovery:
Breaking down ownership & innovation borders
Disruptive potential of human genetics shackled by conventional pharma models and cultures
Drug Discovery
Unit
Drug Discovery
Unit
Drug Discovery
Unit
Drug Discovery
Unit
Discovery
Discovery
Discovery
Discovery
Biology Drug DiscoveryBiology Drug DiscoveryBiologyDrug Discovery Biology
Unit
Unit
Unit
Discovery
Discovery
Discovery
Discovery
Discovery
Chemistry Discovery Chemistry Discovery Chemistry
Chemistry
Biology
Biology
Biology
Discovery
Discovery
Discovery
Discovery
PharmacologyDiscoveryPharmacology
Pharmacology DiscoveryPharmacology Discovery
Chemistry
Chemistry
Chemistry
Discovery
Pharmacology
Genetics
Unit
Biomarkers
Unit
Discovery
Pharmacology
Statistics
Unit
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
Discovery
Pharmacology
Screening
Unit
…
16
Eisai AiM Institute: Industry unique commitment to realize new
paradigm for human genetics driven drug discovery
 90-scientist institute at dedicated drug
discovery facility in greater Boston
Human
Biology &
Data
Sciences
Engine
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Target
Modulation
Engine
 Multi-disciplinary scientists under one roof
prosecuting validated genetic targets
Integrated
Biology
Engine
 Sharply focused precision medicine
discovery pipeline and portfolio
 “Biotech-like” culture but with decades of
experience and track record
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
17
Eisai AiM Institute: Industry unique commitment to realize new
paradigm for human genetics driven drug discovery
Data to drugs
Identify and validate therapeutic targets and
biomarkers from causal human biology insights
Human
Biology &
Data
Sciences
Engine
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Target
Modulation
Engine
Big data
analytics
Clinical data
sciences
Integrative
neurogenetics
Integrated
Biology
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
18
Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Human biology insight to impact
Focused prosecution of validated targets &
precision medicine biomarkers
Human
Biology &
Data
Sciences
Engine
In-vitro & in-vivo
biopharmacology
Translational
biomedicine
Functional
genomics
In vitro cell biology
iPSC based methods
Systematic gene editing
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Integrated
Biology
Engine
Immune phenotyping
NextGen Sequencing
Functional
genomic target
validation
Dense phenotyping
Target
Modulation
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
Model organisms
Proteomics
19
Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Drugging the “undruggable”
Establish innovative screening systems to
identify potent and selective compounds
Human
Biology &
Data
Sciences
Engine
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Target
Modulation
Engine
Assay
development
Compound
screening
Structural &
chemical biology
Integrated
Biology
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
20
Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Compounds to medicines
Exploit Eisai’s recognized small molecule
chemistry firepower to make medicines
Human
Biology &
Data
Sciences
Engine
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Target
Modulation
Engine
Medicinal
chemistry
Novel
libraries
Complex drug
synthesis
Integrated
Biology
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
21
Eisai AiM Institute:
Industry unique commitment to realizing genetic drug discovery
Illuminate right drug for right patient
Quantitative assessment of target engagement,
dose, mechanism and response
Human
Biology &
Data
Sciences
Engine
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Target
Modulation
Engine
PET
Tracers
Imaging
genetics
Functional
imaging
Integrated
Biology
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
22
Eisai AiM Institute: Leveraging external environment through unique
and flexible entrepreneurial collaborative models
Human
Biology &
Data
Sciences
Engine
Open innovation
Research consortia
Integrated
Chemistry
Engine
Eisai
AiM
Institute
Integrated
Biology
Engine
Pre-competitive
collaborations
Scientific partnerships
Target
Modulation
Engine
Imaging
Center of
Excellence
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
Scientific training
programs
23
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
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
Gene editing, functional genomics
and “disease in dish” models
24
Working example:
Immuno-phagocytosis hypothesis
Immuno-oncology checkpoint
Immuno-dementia checkpoint?
Tau
Cell debris
Ab
Tumor cell
XXXX
PD-L1
MHC
PD1
TCR
XXXX
Cytotoxic activity
Cytotoxic T cell
Eisai AiM Institute: Andover Innovative Medicines
(I) Human Biology; (II) Chemistry Innovation; (III) Entrepreneurial Collaboration
Phagocytosis
Microglia
25
Working example:
Immuno-phagocytosis hypothesis
Bioparticle Phagocytosis
pHrodo-labeled bioparticles
Ab Phagocytosis
Aggregated fluor-labeled Ab peptide
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
26
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
27
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
28| 28
KAN Research Institute
Implementation:
 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
| 29
KAN Research
The Medicine of “Integrative” Cell Biology
Leveraging the multi-disciplinary study of neurobiology, immunology
and tumor biology to discover novel targets and innovative therapies
Novel targets
and therapies
Pathways
Synapse
micro-environment
Functional Unit
Neuro-inflammation
and immuno-genetics
Effectors
Neuronal
regeneration
Information
| 30
Integrative cell biology focusing on
brain microenvironment
Abnormal regulation
of synapse microenvironment
Genomic
mutation
Environmental
Factors
Blood vessel
Abnormal astrocyte
Infiltrated immune cells
Discovery of ‘non-reported’ cells and
molecules causing disease (amyloid,
phosphoTau).
Target cells: Synapse, astrocytes,
microglia and peripheral immune
cells
Amyloid b
Amyloid b
Abnormal synapse
phosphoTau
phosphoTau
Abnormal microglia
Cell death
| 31
A novel theory of neuronal loss: A role for E6011*?
Fractalkine-mediated immune cells infiltration of the brain
Fractalkine (FKN) is a chemokine present in the blood
vessels.
Its receptor mediates specific immune cells migration
Capture Firm adhesion
Crawling
E6011: Anti-FKN mAb
Chemotaxis
Infiltrated
& activated
immune
cells
Enhancement
Aβ
Synapse loss
Accessory Function
Survival
Neuron death
*Investigational
| 32
E6011*: Mechanism of Action
E6011 removes immune cells from blood vessels, suppressing infiltration of immune cells
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.
Hoechst
*Investigational
| 33
Phase 1b E6011* study:
Efficacy signals in Rheumatoid arthritis
ACR* Core Data Set response rate at Wk 12
(%)
100
100mg (n=12)
200mg (n=15)
50
0
ACR 20
ACR 50
ACR 70
ACR 70 at week 12 was 20 ％ in the cohort of 200 mg
Now an additional dose (400 mg) is being evaluated
* ACR: Standard for assessing the clinical improvement of rheumatoid arthritis symptoms
defined by the American College of Rheumatology
*Investigational
| 34
Phase 1b E6011* study:
Efficacy signals in Crohn’s disease
Proportion of patients (%)
Clinical Response & Remission at week 12
CR-70
CR-100
Remission
60
40
20
0
2 mg/kg
5 mg/kg
(Cohort 1) (Cohort 2)
(1/5 1/5 0/5) (2/7 1/7 0/7)
10 mg/kg
(Cohort 3)
(4/6 4/6 3/6)
High remission rate at 10 mg/kg in Crohn’s disease
An additional dose (15 mg/kg) is being evaluated
*Investigational
| 35
E6011*: Challenge in new science for
Alzheimer’s disease (AD)
Peripheral blood vessels
Monocytes
Blood-Brain Barrier
Microglia
Microglia
Ab plaque
Macrophage
Neuron
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
Central Nervous System
*Investigational
| 36
Story of EphA4 targeting synapse modulator:
g-Secretase inhibition as classical concept for AD therapy
Synapse
• 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
| 37
Finding hidden substrate of g-secretase:
The path to EphA4
Axon
Synapse
Hypothesis:
Dendrite
Neuron
Axon
Synapse
EphA4
g-secretase
Dendrite
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?
Maintenance of synapse
and
brain homeostasis
Inoue (KAN) et al., J. Cell Biol., 2009
| 38
EphA4 cleavage enhancer: A novel therapy for AD
EphA4/Ephrin
Interaction
EphA4
Cleavage
(Undesirable)
(Desirable)
R&D objective:
Induce synapse stabilization via increased EphA4 cleavage
| 39
Preclinical data suggests that cleaved EphA4
increments synapse density
Control
Cleaved EphA4
Bar: 5mm
In-vitro data (Rat primary neuron)
| 40
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
| 41
Tsukuba Research Laboratories: Strengths in
neurotrophic factor, proteinopathy and novel
neurotransmission platforms to realize total care for
Alzheimer's Disease and dementia patients
Eisai Scientific Day
Teiji Kimura, Ph.D.
Chief Discovery Officer
Neurology Business Group
42
Next Approach Beyond Amyloid and Tau
Synapse Restoration
Agent
Cognitive Function
Early AD
Anti-proteinopathy
Agent
Mild AD
E2609*1, BAN2401*2
Aducanumab(Biogen)*3
Tau program
Moderate AD
Severe AD
Symptomatic
Treatment
Aricept
Typical AD progression
Age
 Synapse restoration agent may not only revitalize synaptic
function, but also slows down disease progression.
43
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
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.
•
•
•
•
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
 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.
44
How Neurotrophic Factor Enhancers Work?
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
Neurotrophic Factor Enhancer
Rescue Cell Body Damage
Revitalize Presynapse
 Neurotrophic factor enhancer showed rescue of
neuronal cell death and recovery of synaptic function.
45
* All projects are investigational
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
Challenge to Disease-Modifying Therapy
APP
Neurogenesis
Microglia activation
Neuroinflammation
Amyloid
Aβ
Aβ accumulation
Aβ protofibrils
P P
Synaptic
dysfunction
tau
P P
Mitochondria
Tau
phosphorylation
aggregation
Proteastasis
Tau
Circuits/networks
dysfunction
Cell death
Neuronal dysfunction
Cellular Metabolism
47
Synapse
Dementia
Amyloid-based Approach: E2609*1and BAN2401
Protofibril
48
*1: In partnership with Biogen *2: In partnership with Biogen and BioArctic. All projects are investigational.
*2
E2609*: Human genetic validation of BACE1
cleavage of APP as therapeutic target of AD
Genetic inhibition of BACE should: reduce amyloid, with the aim to protect
against Alzheimer’s & delay cognitive decline
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
*1: T. Jonsson, et. al., Nature. 2012 Aug 2;488(7409):96-9.
49
* In partnership with Biogen. Investigational.
E2609*: Translation from Animal to Human
Dose response of Aβ-reduction
by E2609 in animal
Dose response of the CSF Aβs changes
by E2609 in the Ph1 MAD study
Internal data
 Brain Ab reduction is correlated with
CSF reduction.
50
* In partnership with Biogen. Investigational.
 Clinical study confirmed change in
Aβ Isoforms in CSF compared to
the baseline after 14 days of E2609
dosing
BAN2401*: Characters
Amyloid Protofibril Definition:
• 80-500 KDa
• 18-114 mers
• Height 1.8-3.0 nm
• Diameter: 25-40 nm PLoS ONE, 2012, 7, e32014
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 agematched control
Comparison among anti-amyloid antibodies
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
Microgliamediated
clearance
Microgliamediated
clearance
Sink effect
Microgliamediated
clearance
Microgliamediated
clearance
Microgliamediated
clearance
Adapted from Biogen Presentation in AD/PD 2015
51
* In partnership with Biogen and BioArctic . All projects are investigational.
BAN2401*: Mechanism of Action
 Increased microglia level and engagement following treatment
suggest that amyloid clearance may be mediated by microglia
Presented at Alzheimer's Association International Conference (AAIC) 2013
June Kaplow et al, Bradford Navia et al
Internal Data
 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.
52
Tau Hypothesis-based Approach
Aβ production
inhibitor
Eisai is developing tau-targeting discovery
projects internally and also through the
partnership with externals.
Aβ – tau
Pathway inhibitor
Kinase
inhibitor
Neuroprotectant
Aggregation
inhibitor
Aβ

Aging
Microtubule dynamics
Microtubule
stabilizer
Hyperphosphorylation
Neuronal
death
Aggregation
Synaptic
impairments
Clearance
enhancer
Transmission
Transmission
inhibitor
Enhancer of
synaptic function
Known
target
53
Unknown
Target
Microtubule dynamics
Hyperphosphorylation

Aggregation
Neuronal
death
Concept of Anti-Tau antibody
Misfolded ‘seed’
Monomer
Antibody to prevent
Tau seeding and
spreading
= Tau
 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.
54
Concept Validation in Preclinical Model
Tau seeds injecting
Tau seeds spread
to whole brain and
induce tau
aggregation
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.
 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.
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
56
*1: In partnership with Biogen *2: In partnership with Biogen and BioArctic. All projects are investigational
Sleep Efficiency %
Lemborexant*: Sleep disturbance in AD is part of
more broadly dysregulated circadian rhythms
Sleep Efficiency %
MMSE Score
CSF Orexin Level pg/ml
A. Satlin et al., Neurobiol. Aging, 1995, 16, 765.
Liguori et al, JAMA Neurol. 2014;71(12):1498-1505.
 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
57
* In partnership with Purdue Pharma. Investigational.
E2027*: PDE9 inhibitor
Glutamatergic neural network
Glutamatergic
neuron
hippocampus
Synaptic region
Glutamatergic
neuron
GTP
GC
cGMP: cyclic guanosine monophosphate
GC: guanylyl cyclase
NO: nitric oxide
PKG: protein kinase G
5’-GMP
cGMP
PDE9
NMDA R
Glu
Glu
5’-GMP
Ca2+
Glu AMPA R
Pre-synaptic site
NO
PDE9
cGMP
Na+
PKG
NOS
GC
GTP
PKG
Post-synaptic site
 PDE9 regulates cGMP signaling downstream of multiple neurotransmitter systems.
 E2027 would provide therapeutic benefits in cognitive impairment and
neuropsychiatric symptoms.
58
* Investigational
E2027*1: Pharmacological Character
Highly potent & selective PDE9 inhibitor
PDE9 IC50: 0.0035 μM; >1000-fold selective over other PDEs
Freezing %
in contextual fear conditioning test
vehicle
Wild-type animal
vehicle
3
10
E2027 (mg/kg, p.o.)
Tg2576 animal
vehicle
Wild-type animal
vehicle
3
10
E2027 (mg/kg, p.o.)
Tg2576 animal
*: 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.
59
*1: Investigational
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
60
All projects are investigational
Capability of Small Molecule Discovery
in Tsukuba Research Laboratories
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).
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”
Pre-clinical
Ricchi 2: Novel Neuro -Transmission
AMPA Platform
Orexin Platform
PDE Platform
Phase I
POC/Ph II
Pivotal/Ph III
Launched
E2027
BAN2401
Dementia
Early AD
AD/DLB
PDE9 inhibitor
Anti Aβ protofibril mAb
AChE inhibitor

Aricept
LPI (800 patients) by 3Q FY16
Ricchi 3: Proteinopathy
Tau
Platform
alpha-synuclein
Platform
E2609
TDP-43
Platform
Early AD
BACE inhibitor
Ricchi 4: Neuro-Inflammation & Immuno-Genetics
ImmunoDementia
Platform
Functional Genomics
& Genome Editing
Platform
Fractalkine
Platform
Ricchi 5: Synapse Micro-Environment


E6011
End of Ph II meeting with FDA in July 2016
Ph III start-up activities underway
RA / CD
Aducanumab
Anti-Fractalkine mAb

Early AD
Potential indication expansion
to AD/Dementia
Anti Aβ mAb

Neurotrophic Factor
Enhancer Platform
EphA4 Cleavage
Enhancer Platform
(Biogen): Eisai has an option
to jointly develop and commercialize
Lemborexant
Ricchi 6: Neuronal Regeneration
Genetically Engineered Glia Implantation Platform
63
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
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
Progressive Adaptation of Diagnostic
Repertoire for Early AD Therapeutics
How to identify “Early AD” patients in need of targeted disease modifier therapy?
Potential Population
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”
Early AD
Web-based test, wearable devices,
smartphone measures etc.
In-office computerized tests or simple
questionnaires
Amyloid PET imaging, gradually
supplemented/replaced with CSF IVD*s,
but remaining need to evolve to easy-touse and minimally-invasive diagnostics
Therapy by “Disease Modifier”
64
* in vitro diagnostics
E2609* Concept for Mode of Action
Hypothesis on the Amyloid Cascade
synaptic dysfunction & loss
The Amyloid Cascade Hypothesis
Oligomeric Aβ
APP
BACE
Aβ
Extracellular
E2609
Amyloid plaque
Intracellular
Neurofibrillary tangle
Gamma
secretase
-
P
Tau
P
P
P
P
P
Paired Helical
Filaments
65
* In partnership with Biogen, investigational
E2609* Phase II Progress

Study 202 (Outpatient Study)



Outcomes of Study 202



66
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
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
* 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





67
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
* 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
ADDLs
Aβ*56
Oligomers
Aβ fibrils
Globulomers
Spheroids
(20-100 kDa)
LMW-Aβ
(8-20 kDa)
in
Aβ monomers
(4 kDa)
Aβ plaques
BAN2401
SOLUBLE
Protofibrilar Pores
Protofibrils
(> 100 kDa)
INSOLUBLE
Plaque Related-Toxicities:
 Neurotoxicity on neuron (in vitro)
 LTP impairment (in vitro/in vivo)
 Memory deficits (in vivo)
Prof. Lars Lannfelt
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





Begins at 196 subjects enrolled [1st Interim Analysis (IA)]
Successive IA at 250 and every 50 subjects enrolled until
full enrollment
Full Enrollment


Bayesian adaptive design
 A novel approach to address challenges in AD
Fixed Burn-in Period: Fixed enrollment for first 196
patients
Response Adaptive Randomization



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
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
Minimal % Reduction to Call Success at various IA
N

69
Bayesian Approach
at Interim Analysis
95% Threshold
Estimate
650
63 %
700
62 %
750
61 %
800
59 %
800 + 3 months
57 %
800 + 6 months
54 %
800 + 9 months
52 %
Traditional
Approach*2
Analysis of covariance
Current Status
800 + 12 months
38 %
54 %
 11th IA at 700 patients occurred in June 2016
 LPI (800 patients) by 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
* 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
An Example of Combination Therapy of the Future
Inhibition of Aβ generation
(BACE inhibitor)
Inhibition
Amyloid
Precursor
Protein (APP)
Combination Use
Clearance of toxic oligomeric Aβ
(Anti-Aβ mAb)
Elimination
Oligomeric Aβ
Aβ Plaques
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/Immunogenetics or Synapse Microenvironment
Disease Modifier + Symptomatic Treatment
 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
70
Lemborexant*
Parallel Programs in Sleep-Wake Fragmentation in Dementia
& General Insomnia
Sleep-Wake
Fragmentation (SWF) in
Dementia
Aiming toward the first product
indicated for treatment of sleepwake fragmentation in dementia
Sleep-wake fragmentation is not
insomnia and is diagnostically
distinct from 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
71
* In partnership with Purdue Pharma. Investigational
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 offlabel 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
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
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
72
* Investigational

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
Potential for Modifying Underlining Disease
Biology
Summary of Five Clinical-stage Assets in
Alzheimer’s Disease and Dementia

E2609
BACE inhibitor
(Beta-secretase)
BAN2401
Anti-A-beta protofibrils
antibody





Aducanumab

(BIIB037, Biogen)

Anti-A-beta antibody
Supportive Care and
Cognitive Enhancement

73
Lemborexant

Orexin receptor antagonist

E2027
PDE9 inhibitor


Study 202 (Phase II) confirms preliminary safety at all doses and expected levels of abeta 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
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
Launch
target:
Shortly
after
FY2020
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
Launch
target:
Before
FY2020
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:
Beyond
FY2020
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
From Pain to Gain - hhc Needs We Fulfill 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.
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.
Affordable
pricing
Pain
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
• 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?
Mental/Spiritual pain
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.
75
Make Cancer
curable or
manageable
• 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.
Solution to
maintain
patient’s
normal life
Total Disease
Management:
Mental/Spiritual
care, Tailormade treatment,
Advance Care
Planning
"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)
Oncology “Ricchi” and Innovation
“Center-Line” Platforms to Provide Cure for Cancer Patients
Ricchi 1: Cancer Microenvironment
1-1. Mesenchymal Cancer and Stromal Cells
(Cell Differentiation, Cancer Stemness, etc.)
Platform technology
• Eribulin platform
• Morphotek’s antibody platform
• Cancer stemness platform
Projects
• Eribulin + Pembrolizumab*, Eribulin + PEGPH20*,
Halichondrin research* and other new projects
1-3: Endothelial Cells
(Abnormal Tumor Vessels)
1-2: Myeloid Cells
(Immunosuppressive Myeloid Lineage)
Platform technology
• Prostaglandin/Toll-like receptor platform
(cancer immunity platform targeting myeloid
cells)
Projects
• E7046 (EP4 inhibitor)* and other new projects
Ricchi 2: Cancer Gene Dependence
and Aberrant Splicing
Platform technology
• Lenvatinib/kinase inhibitor platform
Platform technology
• Cancer genomics platform
• Splicing platform
Projects
• Lenvatinib + Pembrolizumab*, Lenvatinib +
Everolimus*, and other new projects
Projects
• FGFR4 inhibitor*, SF3B1 modulator* and other
new projects
76
These platforms refer to the drug-discovery technology infrastructure based on innovation, aiming for bearing sequential projects.
* Investigational single agents or combination treatments
Our Focus in Cancer Microenvironment
Mesenchymal cancer cells
EMT*1
MET*2
Cancer stem cells
Myeloid cells
Epithelial cancer cells
• Cytotoxics
• 1st generation RTKIs*3
Lymphoid cells
Immune checkpoint
inhibitors
Endothelial cells
Mesenchymal stromal cells
(Fibroblasts, etc.)
Angiogenesis
inhibitors
77
*1 Epithelial-Mesenchymal Transition *2 Mesenchymal-Epithelial Transition,
*3 Receptor tyrosine kinase inhibitors
Oncology Discovery Engine Four Sites
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
• Cancer Gene
Dependence
• Aberrant Splicing
• Compound libraries to identify novel, splice variant-specific splicing modulators
• A unique set of high throughput screening systems
Tsukuba Research Laboratory (Tsukuba, Japan)
• Abnormal Tumor
Vessels
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
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
• Immunosuppressive
Myeloid Lineage
• Cell Differentiation
• Cancer Stemness
• Cell Differentiation
• Cancer Stemness
Eisai Andover Innovative Medicines Institute (Andover, US)
Prostaglandin/TLR Platform (Cancer immunity Platform targeting
Myeloid cells)
78
• 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
• Immunosuppressive
Myeloid Lineage
Eisai Scientific Day
Markus Warmuth, MD
President and CEO, H3 Biomedicine
H3 Biomedicine
H3 - At the interface of Big Molecular Data
and Precision Chemistry
Translate cancer patient data
into powerful precision
therapeutics
Big Data
Science
80
Precision
Chemistry
H3 Biomedicine
Novel
Therapies
The H3 Knowledge Base
Generation
Processing
Management
Integration
Wart
TiP
Analysis
Mining
Therapeutic Hypothesis
81
H3 Biomedicine
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.
82
H3 Biomedicine
H3’s Chemistry Approach
H3 INTEGRATES SEVERAL DIFFERENT APPROACHES WITH A GOAL TO TACKLE
HARD TO DRUG CANCER GENES
Diversityoriented
Synthesis
Structurebased
Design
Natural
Products
Fragmentbased
Approaches
83
Covalent
Inhibitors
H3 Biomedicine
H3 Pipeline*
TARGET
INDICATION(S)
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
TARGET
VALIDATION
LEAD
OPTIMIZATION
PRECLINICAL
DEVELOPMENT
IND / PHASE I
CLINICAL
2017
*all projects are investigational
84
HIT TO LEAD
H3 Biomedicine
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
85
H3 Biomedicine
H3B-6527* shows efficacy in HCC
with activated FGF19/FGFR4 signaling
Cancer
Cell
3
Proliferation and Survival
V e h ic le , P O , B ID
1500
H 3 B - 6 5 2 7 3 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
M e a n + /- S E M
H3B6527
FGFR4
Hyper activation
H E P 3 B T u m o r v o lu m e ( m m )
FGF19
FGF19
FGF19
Autocrine/Paracrine
H3B-6527 selectively inhibits FGFR4 leading to
growth inhibition and cell death in FGF19
dependent cells and animal models
H 3 B - 6 5 2 7 3 0 0 m g /k g , P O , B ID
1000
500
0
0
5
10
15
D a y o f T r e a tm e n t
1
(internal data)
*investigational
86
H3 Biomedicine
H3B-6527* demonstrates efficacy superior to
Sorafenib in HCC models
HCC Tumor Expression and Copy
Number of FGF19
Patient Tumor Samples
V e h ic le , P O , B ID
7
S o r a 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
Model 1
3
3
L IX 0 1 2 T u m o r v o lu m e (m m )
5
4
3
Model 3
Model 1
2000
1500
1000
500
0
0
5
10
1500
Model 2
1000
500
0
0
15
5
0
-1
Model 3
2000
1500
1000
500
0
0
-3 -2 -1 0 1 2 3 4 5 6 7
FGF19 Copy Number (Log2 Ratio)
8
3
3
1
L IX 0 0 6 T u m o r v o lu m e (m m )
2
10
20
30
D a y s p o s t a d m in is t r a t io n
10
15
20
25
D a y s p o s t a d m in is t r a t io n
D a y s p o s t a d m in is t r a tio n
Model 4
40
Model 4
2000
1500
1000
500
0
0
10
20
30
D a y p o s t a d m in is tr a tio n
(internal data)
*investigational
87
L IX 1 0 8 T u m o r v o lu m e ( m m )
Model 2
L IX 0 6 6 T u m o r v o lu m e (m m )
FGF19 Expression (Log2 Ratio)
6
H3 Biomedicine
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
88
H3 Biomedicine
H3B-6527*: clinical development
• 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
*investigational
89
H3 Biomedicine
Spliceosomal mutations:
A new class of Cancer genes
SF3B1 (several across HEAT domain 4-8)
U2AF1 (S34 or Q157)
MDS (25%), CLL (10%), CMML (5%), AML
(5%), Breast (2%), Uveal melanoma (20%)
MDS (6%), AML (5%), CMML (8%), lung (3%),
uterine and pancreatic cancer (~1%)
ZRSR2
CMML (8%), MDS (6%), AML (1%)
SRSF2 (P95 or P95-R102 indel)
CMML (47%), MDS (15%), PMF (17%),
AML/sAML (19%)
90
•
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
H3 Biomedicine
Exploiting spliceosomal sickness as a
therapeutic approach
SF3B1/SRSF2/U2AF1
91
WT/WT
Normal
MUT/WT
Malignancies
-/WT
Mild effects
-/-
Hematopoietic
Failure and
Cell Death
MUT/Inhibitor
Selective
Cell Death
H3 Biomedicine
SF3B Modulator
H3B-8800
H3B-8800* shows differential activity in models
of malignancies with spliceosomal mutations
K562 SF3B 1
2000
T u m o r V o lu m e
2000
1000
500
0
1500
1000
500
0
0
5
10
15
20
0
T im e ( D a y )
5
10
15
20
T im e ( D a y )
•
Inhibition of tumor growth observed only in SF3B1 mutant model
•
Activity seen in several additional xenograft models
(internal data)
*investigational
92
T u m o r V o lu m e
8 m g /k g P O , Q D
(M e a n  S E M )
1500
K700E
V e h ic le
3
T u m o r V o lu m e , m m
8 m g /k g P O , Q D
(M e a n  S E M )
K562 SF3B 1
V e h ic le
3
T u m o r V o lu m e , m m
K 700K
H3 Biomedicine
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
93
H3 Biomedicine
H3B-8800*: clinical development
•
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
*investigational
94
H3 Biomedicine
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
95
H3 Biomedicine
Combinatorial approach to Splice
Modulation in Cancer
“Omics”
Characterization
and
Driver Splice
Events
Scaffold
A
Splice
Modulators
Scaffold
B
Indication
96
Scaffold
C
Indication
H3 Biomedicine
Indication
Splice modulation can induce tumor specific
immunity
Splice
Modulator
Tumor Cell
High
Affinity
Antigens
NeoAntigen
97
Cell Death
H3 Biomedicine
Summary
•
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
*investigational
98
H3 Biomedicine
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
AiM Institute hhc mission statement
Have the courage to innovate without borders and make evidence-based decisions
to deliver solutions that address real patient needs
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
Game changing scientific discoveries have driven unprecedented
translational investments
 Genomics England*1
 Cancer MoonShot Initiative*2
 Parker Institute*3
 Bloomberg-Kimmel Institute*4
 ……….
Considerable and unmet residual needs remains
*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.
101
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
Microenvironment
Tumor
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
Reduction in cancer incidence associated
with aspirin in large-scale meta-analyses:
Adapted from Rothwell et al. Several
 Esophageal: 30%
 Stomach: 30%
 Colorectal: 35%
11,000 participant RCT
of cancer prevention
Potent and specific modulation of EP receptors may provide
novel therapeutic opportunity for targeting tumor immune microenvironment
103
Prostaglandin E2 (PGE2) signaling disrupts anti-tumor activity of
immune cells
Investigational E7046: First in Class EP4 Specific Antagonist
Reverses of PGE2-mediated tumor promotion and immune suppression
Macrophage
EP2
PGE2
E7046
EP4 receptor
T-cell
Dendritic cell
104
E7046 clinical plan and status
FY2015
101 Study:
Monotherapy,
RP2D
FY2016
FY2017
FY2018
FY2019
FY2020
Ph-1
RP2D
(Recommended
Phase 2 Dose)
RT/CRT
comb.
(Radiotherapy/
Chemoradiotherapy)
Ph-1b comb.
Ph-2 comb. CRT
Regulatory Activities
/Full Development
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
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
“Ricchi” and Innovation in Small Molecule
Science to Target Cancer Microenvironment
at Tsukuba Research Laboratories (TRL)
Eisai Scientific Day
Takashi Owa, Ph.D.
Chief Medicine Creation Officer
Oncology Business Group
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
DCE-MRI of representative tumors in vehicle- or eribulin-treated nude rats
with MX-1 human breast cancer xenografts (day 6)
Well perfused
Uniform perfusion,
tumor shrinkage
Poorly perfused,
hypoxic area
Vehicle
Eribulin, 0.3 mg/kg
Funahashi et al., 2014
109
Eribulin Reverses EMT in Tumors In Vivo
MX-1 human breast cancer cells xenografts in vivo
(single dose, 8 days, nude mice)
Epithelial marker
Mesenchymal markers
110
Yoshida et al., 2014
Eribulin Prevents Experimental Metastasis
and Increases Survival in Mice
Inject eribulin-treated or 5FUtreated surviving breast cancer
cells into tail vein
Number of lung nodules
111
Survival of mice
Yoshida et al., 2014
Anti-Cancer Stem Cell Activity with Eribulin in the In Vivo
Serial Transplantation Model of HSAEC RD Cells
HSAEC RD: Human small airway epithelial cell infected with retroviral vectors expressing KRAS V12 (R) and CYCLIN-D1 (D)
Control
Tumor volume (mm3)
HSAEC RD lung cancer xenograft
Cell number
Serial
transplantation
PTX
Eribulin
Day
Control
PTX QD5 20 mg/kg
ERI Q4D3 1 mg/kg
112
( N = 10 112
)
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
Halichondria okadai Kadota
600 kg
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
-
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.
114 Blunt, Munro et al Tetrahedron Lett. 1994, 35, 9435; J. Org. Chem. 1997, 62. 1868; Bioorg. Med. Chem. 2009, 17, 2199.
Halichondrin B In Vitro Antiproliferative Profile
Eribulin
(NSC 707389)
GI50 values from NCI-60 cell panel analysis
https://dtp.cancer.gov/timeline/posters/Halichondrin.pdf
115
Halichondrin B
(NSC 609395)
Halichondrin B In Vivo Antitumor Profile
LOX melanoma s.c. xenograft model
in nude mice
LOX melanoma bone marrow metastasis model
in nude rats
Halichondrin B
Vinblastine
Survival (%)
Halichondrin B
Vinblastine
Vehicle
Days
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.
116
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
Immune suppressive tumor
microenvironment
Lenvatinib
(VEGF blockade)
Improved antitumor activity
of anti-PD-1 therapy
Monocyte
Monocyte
PD-L1 expressed on
tumor cells activate PD-1
and suppressed CTL
VEGF
CSF
TAM
TGF-b
Cancer
Decrease
Cancer
MHC
Antigen
TCR
TAM
PD-L1
PD-1
CTL
Immune Inhibitory
Cytokine (TGF-b)
TAM
Down
Immune Inhibitory
Receptor
(PD-1, Lag3)
Down
Immune Stimulatory
cytokine(IL12)
Treg
TAM secretes TGF-b, which activates
immune suppressive Treg and inhibits
cytotoxic T cells.
118
Up
MHC
Antigen
TCR
Attack
PD-1 Ab
IFNg
CTL
Lenvatinib causes Immune
stimulating tumor
microenvironment
Kato et al., EORTC-NCI-AACR 2015
Rayman et al. also reported the similar MOA for sunitinib with
PD-1 blockade in the mouse RCC model (SITC 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.
Endothelial cell (EC)
Activation of AXL and concomitant epithelialmesenchymal transition (EMT) were reported in
EGFR-mutant NSCLC with acquired resistance to
erlotinib.
Smooth muscle cell (SMC)
Cancer cell
Nat Genet., 44, 852 (2012)
AXL was identified as a mesenchymal marker
gene associated with innate anti-PD-1 resistance
in melanoma patients.
Cancer cell EMT
Cell, 165, 35 (2016)
EC migration, proliferation.
and survival
SMC migration,
proliferation and survival
A clinical sample of triple negative breast cancer
after weekly paclitaxel treatment showed
upregulation of AXL expression.
Autocrine/paracrine AXL/Gas6 signaling
AXL/Gas6 signaling was shown to accelerate the
formation of pericyte covered tumor vessels
resistant to anti-VEGF therapies.
119
AXL IHC staining
Cancer Res., 65, 9294 (2005)
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
Stemness markers
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.
In vivo H358 s.c. model
In vitro
120
Oncology “Ricchi” and Innovation to
Provide Cure with Particular Focus on
Cancer Genomics and Cancer Microenvironment
TRL Platform
Eribulin/Cancer Stemness
Mesenchymal cancer cells
EMT*1
MET*2
Epithelial cancer cells
Cytotoxics
1st generation RTKIs*3
H3B Platform
Cancer genomics
Splicing
TRL Platform
Lenvatinib
Endothelial cells
Angiogenesis
inhibitors
121
Cancer stem cells
AIM Institute Platform
Prostaglandin receptors
Myeloid cells
TRL Platform
Lenvatinib/Eribulin
Lymphoid cells
Immune checkpoint
inhibitors
MOR Platform
Anti-TEM-1 Ab
Mesenchymal stromal cells
(Fibroblasts, etc.)
*1 Epithelial-Mesenchymal Transition *2 Mesenchymal-Epithelial Transition
*3 Receptor tyrosine kinase inhibitors
Key Global Assets
Eribulin and Lenvatinib:
Toward Establishing
New Treatment Paradigms
Eisai Scientific Day
Alton B. Kremer MD, PhD
Chief Clinical Officer
Chief Medical Officer
122
Mechanism of Action of Lenvatinib
VEGFR
FGFR
Lenvatinib
RAS
PI3K
RAF
AKT
MEK
mTOR
T202/Y204
P
ERK1/2
P
P T389
S6K
T421/S424
S235/S236
P
S6
Angiogenesis
123
Adapted from Stjepanovic N, Capdevila J. Biologics: Targets and Therapy. 2014:8;129-139; Eisai data on file.
Proposed Mechanism of Interaction
Between Lenvatinib and Everolimus
VEGFR
FGFR
Lenvatinib
RAS
PI3K
RAF
AKT
MEK
mTOR
T202/Y204
Everolimus
P
ERK1/2
P
P T389
S6K
T421/S424
S235/S236
P
S6
Angiogenesis
124
Adapted from Stjepanovic N, Capdevila J. Biologics: Targets and Therapy. 2014:8;129-139; Eisai data on file.
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
R
A
N
D
O
M
I
Z
E
*Based on investigator review and RECIST v1.1
•
Lenvatinib
24 mg PO qd
n = 52
 LEN/EVE vs EVE
 LEN vs EVE
Selected secondary
endpoints
• Progression-free
Survival
 LEN/EVE vs LEN
•
•
Everolimus
10 mg PO qd
n = 50
1:1:1
126
Both PO once daily
n = 51
Primary endpoints
• Progression-free
Survival*
Treatment until
disease progression or
unacceptable toxicity
•
•
Objective
Response Rate
Overall Survival
Safety and
tolerability
Kaplan-Meier Plot of Progression-Free Survival
(Investigator Assessment – Study 205)
1.0
+EVE
+LEN+EVE
Progression-Free Survival
(n = 51)
PFS, months, median
(95% CI)
0.8
14.6 (5.9-20.1)
HR vs everolimus
95% CI
0.6
+
(n = 50)
5.5 (3.5-7.1)
0.40
(0.24-0.68)
+
0.4
0.2
0.0
0
3
6
9
12
15
18
21
24
10
3
5
1
1
0
0
0
Time (months)
Number at risk:
Lenvatinib/Everolimus
Everolimus
51
50
41
29
27
15
23
11
16
7
 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*
United States Package Insert.
127 *Internal data
Efficacy Results in Renal Cell Carcinoma
(Investigator Assessment – Study 205)
Lenvatinib 18 mg +
Everolimus 5 mg
(n=51)
Everolimus 10 mg
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)
−
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, n (%)
19 (37)
3 (6)
(95% CI)
(24, 52)
(1, 17)
(n=50)
Progression-Free Survival (PFS)a
Overall Survivalc
Objective Response Rate (Confirmed)
128
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
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
Stratification factors:
•
Geography
(Western Europe and North
America, Rest of World)
•
MSCKK prognostic group
(Low, Intermediate, High)
130
Lenvatinib
18 mg orally once daily
R
A
N
D
O
M
I
Z
E
+ 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
1:1:1
n = ~735
Treatment until
disease progression
or unacceptable
toxicity
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
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
Stratification
• Geographic
Region
• Macroscopic
portal vein
invasion or
extrahepatic
spread or both
(No/Yes)
• ECOG (0/1)
• Body weight
(< 60 kg/
≥ 60 kg)
R
A
N
D
O
M
I
Z
E
Lenvatinib
12 or 8 mg daily PO
(based on body
weight)
Sorafenib
400 mg daily PO
BID
1:1
Treatment until
disease
progression
(mRECIST)
132
Primary endpoint
• Overall Survival
Selected secondary
endpoints
• Progression-free
Survival
• Time to Progression
• Objective Response
Rate
• Safety and
tolerability
•
PK parameters
•
Quality of life
Phase Ib/II Study of Lenvatinib +
Pembrolizumab in Selected Solid Tumors
(Study 111, NCT02501096)
Phase Ib
Phase II (opened 31 Jan 2016)
Renal Cell (20)*
Cohort Lenvatinib Pembrolizumab
1A
2A
3A
24 mg
20 mg
14 mg

200 mg
200 mg
200 mg
Same tumor types as Phase 2
n = 10 – 30 subjects
(13 subjects actual)
Lenvatinib
Melanoma (7)
20 mg QD (RP2D)
+ Pembrolizumab
Urothelial (6)
200 mg Q3W
(21-day cycle)
n = 60-120
NSCLC (1)
Endometrial (20)
SCCHN (5)
133
* Number Of Subjects Enrolled As Of 23 June 2016
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
134
Primary endpoints
• MTD & RP2D for combination
of lenvatinib + pembrolizumab
Expansion part
• No prior
systemic
therapy
• N=20
(10 in Japan
/10 in US)
Selected secondary endpoints
• Safety and tolerability
• Efficacy: ORR/ PFS/ OS/
Duration of response
(Tumor assessments to be
performed using irRECIST)
• Pharmacokinetics
• Blood / tumor biomarkers
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
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*
135
* Number Of Subjects Enrolled As Of 23 June 2016
Selected secondary
endpoints
• Progression-free
Survival
• Overall Survival
• Duration of
Response
• Outcomes in the
PD-L1–positive
subgroup
• Safety and
Tolerability
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
Cancer
Microenvironment
Cancer Gene
Dependence and
Aberrant Splicing
Endothelial
cells
Flagship Programs in Oncology
138

Lenvatinib*1
H3B-6527
FGFR4 Inhibitor
H3B-8800
Splice Modulator
E7046










EP4 Inhibitor

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.
Launch
target:
FY2017
for HCC
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.
Launch
target:
FY2020
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.
Combination therapy with pembrolizumab: Ph 1b/2 study is ongoing for Triplenegative breast cancer.
Combination therapy with PEGPH20: Phase Ib/II study site initiation in 1Q FY16.
Investigating the potential to treat HER2-negative breast cancer.
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.
Launch
target:
Beyond
FY2020
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
UTILIZING OUR WORLD-CLASS
SMALL MOLECULE SCIENCE,
AND FOCUSING ON
“CANCER MICROENVIRONMENT”
AND “ONCOGENOMICS”,
WE WILL AIM CURE OF CANCERS
140