Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman, SVP, GM Pharmaceutical Research Division, Takeda

1. Reprogramming Mindsets:
Innovation from Everyone, Everywhere
Discovery Summit, Cannes
22nd March, 2012
Paul Chapman

2. Overview
• The scale of the problem (really brief)
• Some basic ideas for addressing the problem
• Focus on central nervous system
– Schizophrenia
– Alzheimer’s disease
1

3. Why Put A Man on The Moon?
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
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

4. How Is This Relevant to Discovery?
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
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.

5. Many Projects Must Be Started
130
120
Number of projects required to produce 5
110 IND per year at industry standard PoS
100
90
80
70
60
50
40
30
20
…but how to
10 Modest increase in PoS across late stages dramatically
reduces number of early projects required increase PoS?
0 Target
Hit to Lead Safety and Toxicology IND
identification and
lead optimization
screening
4

6. Our Humble Home: Takeda’s Shonan Research Center
5

7. Vision for Innovative Culture
Allow for decision-making VALUE ON
Offer performance feedback
AGILE PROCESSES
discretion at all levels of the quickly,PEOPLE
continuously and
organization DEVELOPMENT
directly
OPEN-MINDED
Hire for and promote civility
SUPPORTIVE
Actively promote effective
among CULTUREand teams to
individuals THAT
information-sharing and
ENVIRONMENT prevent ENABLES
negative feedback
stripping of silos
FOR INNOVATION loops
DIFFERENTIATION

8. Allow for decision-
Drug Discovery Units making discretion at
all levels of the
organization
Five DDUs
Four are therapeutically aligned MD DDU Oncology DDU
Fifth is dedicated to creating extra XV
value through repositioning DDU Immunology
Full alignment of resource & CNS DDU
accountability
DDU
Budgets 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

9. Takeda Exploratory Challenge: Helping to Test New Ideas
Preparation Period 6/1 Application Period 6/30
Basic concept
34
Single
Applications
Target Value
Anything OK Date
Poster Presentation
Award = JPY 5 MM + 365 days
IT with Project Team (Form, Website & Announce)
8/21

10. Support for the Awardees
7/1 Check-in Period
Basic concept
Entrepreneurship
Mentor
Planning (Gantt Chart with Criteria)
Actual expense Management
virtual Shonan Incubation Lab.
Contract
Performance evaluation
9/21

11. Ideas Came from All Grades and Disciplines
Application
Approval
How many votes
by Reviewer?
Job title ≧ Associate Director Principal Scientist Scientist
Affiliation BRL DRL MCRL ONC CNS MD Staff
10/21

12. Takeda Research Idea Pageant
Actively promote
Design features of the Idea Pageant effective
information-sharing
▪ Researchers (~1000 people including all PRD) will be involved in this project and stripping of silos
▪ 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
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

13. Plan for Takeda Innovation Center
Takeda Innovation Center
Shonan Incubation lab Multiple type lab
(Shonan Research Center) (On-site or off-site of SRC)
Takeda
“Open” collaborations
with academics
Global
Sites
Internal
entrepreneurs
• 1 Oncology project (committed)
• 2 Inflammation/Immunology projects
(planned)
• 1 Neuroscience project (planned) Outside of Shonan Center
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14. 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
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
13

15. SCHIZOPHRENIA
Looking for new targets with Envoy Therapeutics
14

16. Schizophrenia Treatments and Pipeline
• Marketed products
– Typical antipsychotics
•
•
haloperidol
chorpromazine
• Clinical pipeline
• trifluoperazine
– Atypical antipsychotics
• clozapine
– 3 atypical
•
•
•
risperidone
aripiperazole
Iloperidone
antipsychotics
• Ziprazidone
•
•
paliperidone
lurasidone – 3 DA or DA+5HT
• asenapine
• quetiapine
•
•
olanzapine
melperone
– 1 GlyT
• sertindole
•
•
amisulpride
blonanserine – 1 mGluR
– Others
• None
– 2 PDE10
…although new aspects of schizophrenia are also being addressed….
15

17. Cognitive Impairment Associated with
Schizophrenia: Potential MOAs
…but still with limited MOAs.
How to break into entirely new
targets?
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18. 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
Whole Cortex
Promoter of selected disease associated gene and
ribosome tag-eGFP segment is inserted into BAC DNA
Some cell specific
genes Some genes are ubiquitous
not seen at all in
bulk tissue Oligodendrocyte Lineage Cells in the Cortex
Isolated mRNA that was
expressed only by cells Biochemic
Add test al function
expressing the target protein molecules of target
and cell
Cells with target type is
are highlighted in characteri
Profile cultured tissue zed
sections
transcriptome
Comparisons between:
Mixture of mRNA/ribosome complexes Reference. Cell, 135, 738, 2008 naïve vs. drug treated, normal vs. diseased
wild-type vs, KO animals….
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19. ALZHEIMER’S DISEASE
Looking for prevention with Zinfandel Pharmaceuticals
18

20. Why Prevention Is Better than Treatment
By the time
cognitive
symptoms are
detected, brain
changes may be
insurmountable
Even “mild”
symptoms are
distressing and
should be avoided
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21. 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-
years
– 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
20

22. APOE e4 - a Susceptibility Gene Variant Associated with
Alzheimer’s Disease - 1993
Mean age of onset
genotype unaffected
1.0
’
of Alzheimer’s
Proportion of each
0.8 2/3
disease as a
0.6 3/3
2/4 function of the
0.4
inheritance of the
3/4 five common APOE
0.2 4/4 genotypes
0
60 65 70 75 80 85
Age at onset
Case Study: Takeda-Zinfandel collaboration

23. SNP and structural variants are prevalent in regions of the TOMM40 gene
E1
E6 E7 E8 E9
0
rs8106922 SNP
95% “A” allele in clade A
”
Coun
40
97% “G” allele in clade B
” 20
t
10 15 20 25 30 35
Length
rs10524523 poly-T polymorphism
poly-T
SNP

25. People with One Form of The Gene Develop AD at a
Younger Age
Age of AD onset (years)
82
80 APOE3/4 AD patients
AD Age of Onset (Years)
78
78
76
74
72
70
70
68
66
64
Very Long/Long p<0.03
P < 0.03 Short/Long
Longer Form Shorter Form
523 genotype

26. Is The Genetic Difference Associated with Alzheimer’s Disease?
• Yes
• Age of onset
• Endo-phenotypes, including biomarkers
– 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

27. We Can Use the Gene to Design a Better Clinical Prevention Trial
PGx-assisted AD prevention Trial Design
Validate PGx Test Clinical Trial Treatment
High
Risk Randomize
Placebo
523 PGx
Predictive
Placebo
Test
Separate clinical Low Randomize
trial of early cognitive Risk
dysfunction Placebo

28. 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 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
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29. Overall Summary
• Drug discovery was never easy, but it seems to be getting harder
• 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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