2016 Eisai Scientific Day

Safe Harbor Statement

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

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

7

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


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

8

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

9

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 microenvironment 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

11

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



Early and Minimally-Invasive Diagnostics

12

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


Nadeem Sarwar

President, Eisai AiM Institute Andover innovative Medicines

13

Maturation of human genetics enables a

disruptive new paradigm for drug discovery

14

Human genetics & drug discovery: Improving the odds of success

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=GCU8V7_j-PliaM&tbnid=Mx4mZFH1yxeOmM:&ved=0CAcQjRw&url=http://www.siteselection.com/features/2007/mar/pharmaceutical/&ei=5BEjVLKLEon38AHwoYHACQ&bvm=bv.76180860,d.aWw&psig=AFQjCNEnMq-WT0W4VIvQpv7eP6BiWIci4w&ust=1411670852926964

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

15


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


16


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


17


Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


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


18


Eisai AiM Institute:

Industry unique commitment to realizing genetic drug discovery

Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


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


19




Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


Engine

Drugging the “undruggable”

Establish innovative screening systems to

identify potent and selective compounds

Assay

development

Structural &

chemical biology

Compound

screening


20




Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


Engine

Compounds to medicines

Exploit Eisai’s recognized small molecule

chemistry firepower to make medicines

Medicinal

chemistry

Complex drug

synthesis

Novel

libraries


21




Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


Engine

Illuminate right drug for right patient

Quantitative assessment of target engagement,

dose, mechanism and response

PET

Tracers

Functional

imaging

Imaging

genetics


22


Eisai AiM Institute: Leveraging external environment through unique

and flexible entrepreneurial collaborative models

Eisai AiM

Institute

Human Biology &



Imaging Center of

Excellence

Target Modulation

Engine


Engine

Open innovation

Research consortia

Pre-competitive

collaborations

Scientific partnerships

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

Gene editing, functional genomics

and “disease in dish” models


24


Working example:

Immuno-phagocytosis hypothesis


25

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


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

| 28

KAN Research Institute Strategy

Integrative cell biology to find hidden drug targets

Fractalkine platform and EphA4 platform


Toshio Imai, PhD President, CEO & CSO, KAN Research Institute

28

| 29

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

| 31

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

| 32

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

| 33

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

| 34

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

| 35

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

| 36

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

| 37

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

| 38

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

| 39

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)

| 40

Preclinical data suggests that cleaved EphA4

increments synapse density

In-vitro data (Rat primary neuron)

Cleaved EphA4 Control

Bar: 5mm

| 41

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



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


Lynn D. Kramer, MD FAAN

Chief Clinical Officer & Chief Medical Officer,


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


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


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


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


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


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


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


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


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


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


• 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


Selected secondary

endpoints


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)


• 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


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: FY2017 for HCC

Can

cer

Mic

roen

vir

on

men

t


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

Date post:	31-Dec-2016
Category:	Documents
Upload:	vodieu
View:	217 times
Download:	0 times

2016 Eisai Scientific Day

Documents