discovery summit 2012: reprogramming mindsets: innovation from everyone, everywhere by paul chapman
DESCRIPTION
Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman, SVP, GM Pharmaceutical Research Division, TakedaTRANSCRIPT
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)
12
• 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
13
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
16
…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
18
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
19
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
20
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
28