Reprogramming Mindsets: Innovation from Everyone, Everywhere

22nd March, 2012

Paul Chapman

Discovery Summit, Cannes

Overview

• The scale of the problem (really brief)

• Some basic ideas for addressing the problem• Some basic ideas for addressing the problem

• Focus on central nervous system

– Schizophrenia

– Alzheimer’s disease

1

We choose to go to the moon. We choose to go to the moon… and do the other things, not

because they are easy, but because they are hard, because that goal will serve to organize

and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone….

But if I were to say… that we shall send to the moon… a giant rocket more than 300 feet tall…made of

Why Put A Man on The Moon?

new metal alloys…which have not yet been invented, capable of standing heat and stresses several times more than have ever been experienced, fitted together with a precision better than the finest watch… on an untried mission, to an unknown celestial body, and then return it safely to earth, re-entering the atmosphere at speeds of over 25,000 miles per hour, causing heat about half that of the temperature of the sun…and do all this, and do it right, and do it first before this decade is out--then we

must be bold.

John F. Kennedy, September 1962

Innovation is not a process you ensure with SOPs, it is what happens along the

way to solving big problems; when you take on major challenges that we are willing to accept; ones we are unwilling to postpone

But if I were to say that in spite of declining productivity across the

pharmaceutical industry, in spite of an increasingly challenging regulatory

How Is This Relevant to Discovery?

pharmaceutical industry, in spite of an increasingly challenging regulatory

environment, patent expirations and declining revenues that we intend to

create important new medicines with the potential to change the world – then we must be bold.

Many Projects Must Be Started

70

80

90

100

110

120

130

Number of projects required to produce 5

IND per year at industry standard PoS

4

0

10

20

30

40

50

60

70

Target

identification and

screening

Hit to

lead

Lead

optimization

Safety and Toxicology IND

Modest increase in PoS across late stages dramatically

reduces number of early projects required

…but how to

increase PoS?

Our Humble Home: Takeda’s Shonan Research Center

5

Vision for Innovative Culture

AGILE PROCESSES

VALUE ON PEOPLE

DEVELOPMENT

Allow for decision-making

discretion at all levels of the

organization

Offer performance feedback

quickly, continuously and

directly

SUPPORTIVE ENVIRONMENT

FOR INNOVATION

OPEN-MINDED CULTURE THAT

ENABLES DIFFERENTIATION

Hire for and promote civility

among individuals and teams to

prevent negative feedback

loops

Actively promote effective

information-sharing and

stripping of silos

Drug Discovery Units

MD DDU

CNS DDUImmunology

DDU

Oncology DDUFive DDUs

Four are therapeutically aligned

Fifth is dedicated to creating extra

value through repositioning

Full alignment of resource & accountability

XV DDU

Allow for decision-

making discretion at

all levels of the

organization

accountabilityBudgets and FTE given to DDU Heads

Authority to spend internal or external at

DDU Heads discretion

Resource allocation in future years to be dependent on performance against DDU goals

Takeda Exploratory Challenge: Helping to Test New Ideas

Preparation Period Application Period

Basic concept Single

Anything OKPoster

Target Value

Presentation

34

6/1 6/30

Date

Applic

ations

Award = JPY 5 MM + 365 days

Poster

IT with Project Team (Form, Website & Announce)

Presentation

8/21

Support for the Awardees

Basic concept

Entrepreneurship

Mentor

Planning (Gantt Chart with Criteria)

Actual expense Management

virtual Shonan Incubation Lab.

Contract

Performance evaluation

Check-in Period7/1

Performance evaluation

9/21

Application

Approval

Ideas Came from All Grades and Disciplines

How many votesby Reviewer?

Job title

Affiliation

≧ Associate Director Principal Scientist Scientist

BRL DRL MCRL ONC CNS MD Staff

10/21

▪ Researchers (~1000 people including all PRD) will be involved in this project

▪ Researchers to vote for the most promising and the least promising project in each

categorized stages to obtain clinical POC (Proof of Concept)

▪ All projects will be ranked by the number of votes and the top project by stage will be

announced to entire PRD

Design features of the Idea Pageant

Takeda Research Idea Pageant

What is the value of an Idea Pageant?

Actively promote

effective

information-sharing

and stripping of silos

What is the value of an Idea Pageant?

▪ Encourage the more information sharing across projects and enable researchers

to understand the whole pipeline projects in PRD

▪ Identify the jewels projects and projects that need further support

▪ Invite healthy competition and improve transparency among project teams

Key visions for

new PRD

Plan for Takeda Innovation Center

Takeda Innovation Center

Shonan Incubation lab(Shonan Research Center)

“Open” collaborationswith academics

TakedaGlobalSites

Multiple type lab(On-site or off-site of SRC)

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• 1 Oncology project (committed)• 2 Inflammation/Immunology projects

(planned)• 1 Neuroscience project (planned)

with academicsSites

Internalentrepreneurs

Outside of Shonan Center

Central Nervous System Diseases Must Benefit from New Discovery Paradigms

• Psychiatric Disease (e.g., schizophrenia, autism spectrum disorders)– Enormous unmet need

• Medicines are available to treat some symptoms, but they are not consistently efficacious

• Safety and tolerability concerns limit utility of even the best medicines

• Many key features (e.g., negative or cognitive symptoms in schizophrenia) are totally unmet

– Growing understanding of the diseases have not yet translated into – Growing understanding of the diseases have not yet translated into treatment strategies based on biology

• Neurodegenerative disease (e.g., Alzheimer’s, Parkinson’s)– Symptomatic treatments exist, but nothing slows progression– Leading hypotheses may be misleading– Clinical trials to test prevention or disease modification appear to be too

difficult and/or too costly

• As an industry we need solutions that address core issues

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SCHIZOPHRENIA

Looking for new targets with Envoy Therapeutics

14

Schizophrenia Treatments and Pipeline

• Marketed products– Typical antipsychotics

• haloperidol• chorpromazine• trifluoperazine

– Atypical antipsychotics• clozapine• risperidone• aripiperazole• Iloperidone• Ziprazidone

• Clinical pipeline

– 3 atypical

antipsychotics• Ziprazidone• paliperidone• lurasidone• asenapine• quetiapine• olanzapine• melperone• sertindole• amisulpride• blonanserine

– Others• None

– 3 DA or DA+5HT

– 1 GlyT

– 1 mGluR

– 2 PDE10

15

…although new aspects of schizophrenia are also being addressed….

Cognitive Impairment Associated with Schizophrenia: Potential MOAs

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…but still with limited MOAs. How to break into entirely new targets?

Takeda’s Strategic Alliance with Envoy Therapeutics to Generate Truly Novel Schizophrenia Targets

1. bacTRAP mice that express Engineered Ribosomal Proteins-eGFP

2. “Transcriptonomic profile” exclusively from cells of interest

3. Generate target hypotheses from genes modified in cell-type and model-specific manner

Promoter of selected disease associated gene and

ribosome tag-eGFP segment is inserted into BAC DNA

Oligodendrocyte Lineage Cells in the Cortex

Whole Cortex

Some cell specific

genes

not seen at all in

bulk tissue

Some genes are ubiquitous

17

Mixture of mRNA/ribosome complexes Reference. Cell, 135, 738, 2008

Isolated mRNA that was

expressed only by cells

expressing the target protein

Profile transcriptome

Comparisons between: naïve vs. drug treated, normal vs. diseasedwild-type vs, KO animals….

Add test

molecules

Cells with target

are highlighted in

cultured tissue

sections

Biochemic

al function

of target

and cell

type is

characteri

zed

ALZHEIMER’S DISEASE

Looking for prevention with Zinfandel Pharmaceuticals

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Why Prevention Is Better than Treatment

� By the time

cognitive

symptoms are

detected, brain

changes may be

insurmountable insurmountable

� Even “mild”

symptoms are

distressing and

should be avoided

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Why a Prevention Trial Is More Challenging than a Treatment Trial

• Age of onset in non-familial (i.e., Late Onset AD) ranges from early 60s to 90s

• Incidence of AD is relatively low in the general population– Approximately 6 per thousand person-years for people between the ages of 65 and 79

– Risk increases with age (about 70 per thousand person-years above the age of 90) but prevention trials with very old would still be challenging

– Without a biomarker to enrich, the trial would require tens of thousands of person-yearsyears

– Investigational drug must be “safe as water” in order to dose healthy elderly subjects

• Choice between relatively simple treatment trial that is very likely to fail and very challenging prevention trial that has a higher probability of success unless

• The trial makes use of a predictive biomarker to find people of any age who are at high risk

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1.0

0.8

0.6

Pro

po

rtio

n o

f e

ach

ge

no

typ

e u

na

ffe

cte

d

2/3

2/4

APOE e4 - a Susceptibility Gene Variant Associated with

Alzheimer’s Disease - 1993

Mean age of onset

of Alzheimer’’’’s disease as a function of the

60 65 70 75 80 85

0.6

0.4

0.2

0

Pro

po

rtio

n o

f e

ach

ge

no

typ

e u

na

ffe

cte

d

Age at onset

2/43/3

3/4

4/4

function of the inheritance of the five common APOE

genotypes

Case Study: Takeda-Zinfandel collaboration

E1

0E9E8E7E6

SNP and structural variants are prevalent in regions of the TOMM40 gene

rs8106922 SNP95% ““““A”””” allele in clade A97% ““““G”””” allele in clade B

rs10524523 poly-T polymorphism

20

40

10 15 20 25 30 35

Co

un

t

Length

poly-T

SNP

74

76

78

80

82

AD

Age

of O

nset

(Yea

rs)

78

APOE3/4 AD patients

People with One Form of The Gene Develop AD at a Younger Age

Ag

e o

f A

D o

nset

(years

)

64

66

68

70

72

74

AD

Age

of O

nset

(Yea

rs)

70

P < 0.03 Very Long/Long Short/Long

523 genotype

Ag

e o

f A

D o

nset

(years

)

p<0.03

Longer Form Shorter Form

Is The Genetic Difference Associated with Alzheimer’s Disease?

• Yes

• Age of onset

• Endo-phenotypes, including biomarkers– Data predicts neuropsychological changes before recognizable – Data predicts neuropsychological changes before recognizable

disease

– MRI gray matter density and thickness varies with 523 genotype before recognizable disease

– Data supports ethnic differences in age of onset distributions for different ethnic groups

We Can Use the Gene to Design a Better Clinical Prevention Trial

PGx-assisted AD prevention Trial Design

High

RiskRandomize

Treatment

Placebo

Validate PGx Test Clinical Trial

523 PGx

Predictive

Test

Placebo

Low

RiskRandomizeSeparate clinical

trial of early cognitive

dysfunction

Placebo

Placebo

Summary of Innovative CNS Collaborations

• New medicines for schizophrenia and related psychiatric disorders require a different way of finding and prioritizing targets

– Unbiased explorations based on known biology

– Bioinformatics to understand the relationships between presumed targets

– Partnerships that bring this biology together with medicinal chemistry and pharmacology expertise should be very productivepharmacology expertise should be very productive

• New medicines for Alzheimer’s and related neurodegenerative disorders require a different way of designing and executing clinical trials

– Many target ideas and opportunities (that look great in mice)

– Progressive diseases almost certainly require early intervention

– Partnerships that bring biomarkers or innovative trial designs should be very productive

27

Overall Summary

• Drug discovery was never easy, but it seems to be getting harder

• Partnerships are certainly required to solve the most difficult • Partnerships are certainly required to solve the most difficult problems

• No single way of partnering is best; solutions must be tailored to institutions and disease areas

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