Transcript Document

Pre-competitive projects can work to deliver
science and change culture
The SGC: A model for sharing in experimental science
• Established 2003
• 200 scientists; labs in Toronto, Oxford and Stockholm
• Funded by
- Private:
- Govt:
- Charities:
GSK, Merck, Novartis, Lilly, Pfizer, Life Tech
Canada, Ontario, Sweden
Wellcome Trust, Wallenberg Foundation
SGC: open access works
• 1000 human protein structures – all available without
restriction
– ~30% of novel human proteins in PDB per annum
– Structures used to be “competitive”
• >100 structures of proteins from parasitic protozoa
– Chemical validation for drug targets in toxoplasmosis (Nature,
2010) and sleeping sickness (Nature, 2010)
• 500 cDNA clones distributed freely every year (academia,
biotech, pharma)
• 75 visiting scientists per annum
Why does the SGC model work?
• SGC model allows opportunity to work with the very best
– 200+ collaborations
• SGC model drives fast data dissemination
– On average, each SGC structure enters public domain 18-24
months in advance of academic norms
• SGC model promotes collaboration
– Average of >3 non-SGC authors for each paper
• SGC model focuses on milestones
– 1000 structure target (2004-2011); 1,100 achieved to date
• No IP
In biomedicine, the system is the greatest
hurdle to the discovery of innovative medicines
The funding system does not support “innovation”
How have we responded to the genome?
Citations as a function of time
CITATIONS (normalized)
1950-2002
2003-2008
2009
HUMAN PROTEIN KINASES
(ordered by most citations 1950-2002)
Another way of looking at it
• 65% of 2009 kinase publications on the 10%
of the kinome that was “hot” in early 1990’s
• 5% of 2009 kinase publications on the 300
kinases that were the least studied in 2002
Others also feel trapped by the system
What should the scientific community do?
1. Pay less attention to the literature
2. Be more daring when funding research
3. Support young scientists to dream bigger
Another path emerges from examining the history of
nuclear hormone receptor research (1950-2010)
35000
30000
CITATIONS
25000
20000
15000
10000
5000
0
NUCLEAR HORMONE RECEPTOR
ERa
AR
PPARa
PPARg
PR
GR
RARa
VDR
MR
PXR
LXRa
LXRb
PPARd
FXR
TRb
CAR
RORg
NGFIBa
ERb
NGFIBb
HNF4a
RORa
SHP
ERRa
SF1
DAX
Rev-erba
RARb
COUP2
RARg
TRa
ERRg
LRH1
COUP1
NGFIBg
Rev-erbb
RXRa
RXRb
RXRg
PNR
ERRb
RORb
GCNF
TLX
TR2
TR4
COUP3
HNF4g
CITATIONS
In 2009, the research is even more biased
3000
2500
2000
1500
1000
500
0
NUCLEAR HORMONE RECEPTOR
3000
1000
ERa
AR
PR
GR
RARa
MR
VDR
RARb
TRa
TRb
RARg
RXRa
PPARa
COUP2
NGFIBa
COUP1
RXRb
HNF4a
SF1
RXRg
Rev-erba
NGFIBb
RORa
Rev-erbb
FXR
COUP3
PPARg
RORb
TR2
TR4
DAX
LXRb
PXR
RORg
ERb
CAR
GCNF
LRH1
LXRa
NGFIBg
PPARd
TLX
ERRa
ERRb
ERRg
HNF4g
PNR
SHP
Pre- and post-genome NR citations
7000
1950-1995
6000
2009
5000
4000
*
*
2000
*
** *
**
0
3000
ERa
AR
PPARa
PPARg
PR
GR
RARa
VDR
MR
PXR
LXRa
LXRb
PPARd
FXR
TRb
CAR
RORg
NGFIBa
ERb
NGFIBb
HNF4a
RORa
SHP
ERRa
SF1
DAX
Rev-erba
RARb
COUP2
RARg
TRa
ERRg
LRH1
COUP1
NGFIBg
Rev-erbb
RXRa
RXRb
RXRg
PNR
ERRb
RORb
GCNF
TLX
TR2
TR4
COUP3
HNF4g
CITATIONS
The power of open access reagents
Chemical probe
available
No chemical probes
available
2500
2000
1500
1000
500
0
NUCLEAR HORMONE RECEPTOR
Family member
Can we be proactive?
Epigenetics – a pioneer area of science and medicine
Number of Citations
The SGC: Delivered(ing) on its core mandate
Wellcome
Trust
Canada
Ontario
GSK
Novartis
Merck
Sweden
Construct
Design
Cloning
Expression
&
Purification
• >2000 purified human proteins
• >1000 human crystal structures
Crystallography
Pushing the pre-competitive boundary
Wellcome
Trust
Canada
Ontario
GSK
Novartis
Merck
Sweden
Construct
Design
Cloning
Expression
&
Purification
• >2000 purified human proteins
• >1000 human crystal structures
Crystallography
• Epigenetics Chemical Probes
Consortium
• Pre-competitive tools for new
drug target validation
Medicinal
Chemistry
GSK
Pfizer
Lilly
Novartis
Oxford:
SGC
Chemistry
Biochemistry
Toronto SGC
UNC CICBDD
OICR
More than 50
universitiies
Our Model for Pre-Competitive Chemistry
Public/Private
Partnership
Public
Domain
Chemical
Probes
Target
Validation
Drug
Discovery
Screening
Chemistry
Structure
Bioavailability
No IP
No restrictions
Publication
(re)Screening
Chemistry
Lead optimization
Pharmacology
DMPK
Toxicology
Chemical development
Clinical development
Creative commons
Industry
Proprietary
Epigenetics Chemical Probes Consortium
Accessing expertise, assays and resource quickly
July 11
June 09
April 09
Jan 09
Lilly,
Pfizer
(8FTEs)
OICR
(2FTEs)
Well. Trust (£4.1M)
NCGC (20HTSs)
GSK (8FTEs)
UNC Novartis
(3FTEs) (8FTEs)
Ontario ($5.0M)
15 acad. labs
Sweden ($3.0M)
….more than $50M of resource
It’s working. The BET probe
Ki67 Positive ( %)
100
80
250+ labs
across
the globe
60
40
20
0
Vehicle
JQ1
Vehicle
797
Identified
Jan 10
Published
Sep 10
JQ1
403
Distributed
Jan 11
Take home message:
SGC and its pharma partners have moved the
pre-competitive boundary to medicinal
chemistry
How is this linked to the development of new
medicines?
Structural Genomics Consortium
SGC Toronto
SGC Oxford
SGC Stockholm
The Challenge of Pioneer Drug Discovery
Yearly FDA Approvals
120
100
New Drug Approvals
New Chemical Entities
Priority Reviewed NCEs
80
60
1312 18
10
91619
40
9
7 7
17
9
13
20
6 7
7
Public Data from Center of Drug Evaluation and
Research: www.fda.gov/cder/
0
• Number of pioneer drugs
(Priority Reviewed NCEs) has
not increased from 1993-2008
• Investment in pharmaceutical
R&D has risen dramatically
over this period
• >90% failure rate in clinical
trials for pioneer drugs due to
lack of efficacy
Impact on pharma and biotech in 2009
• $100B in R&D
• 21 drugs approved (7 truly novel)
• 70,000 pharma employees let go
• Investment houses writing that pharma
should “get out of R&D”
• Industry relying on academia for “innovation”
How industry acceses “innovation”
What’s the “innovative” drug discovery process?
Hypothesis generated
Target
ID/
Discovery
HTS
50%
Hit/
Probe/
Lead
ID
LO
Clinical
candidate
ID
10%
Toxicology/
Pharmacy
Phase
I
30%
30%
Phase
IIa/ b
90+%
Failure rates
And tested
And here is how industry currently works
Target
ID/
Discovery
Target
ID/
Discovery
Target
ID/
Target
Discovery
ID/
Discovery
Target
ID/
Discovery
Target
ID/
Discovery
Target
ID/
Discovery
HTS
50%
Hit/
Probe/
Lead
Hit/
ID
Probe/
Lead
Hit/
ID
Probe/
Hit/
Lead
Probe/
ID
Lead
Hit/
ID
Probe/
Lead
Hit/
ID
Probe/
Lead
Hit/
ID
Probe/
Lead
ID
LO
10%
Clinical
candidate
ID
Clinical
candidate
ID
Clinical
candidate
Clinical
ID
candidate
ID
Clinical
candidate
ID
Clinical
candidate
ID
Clinical
candidate
ID
Toxicology/
Pharmacy
Phase
I
Phase
IIa/ b
Toxicology/
Pharmacy
Phase
I
Phase
IIa/ b
Toxicology/
Pharmacy
Toxicology/
30%
Pharmacy
Phase
I
Phase
30%
I
Phase
IIa/ b
Phase
90+%
IIa/ b
Toxicology/
30%
Pharmacy
Phase
30%
I
Phase
90+%
IIa/ b
30%
30%
30%
30%
90+%
90+%
Toxicology/
Pharmacy
Phase
I
Phase
IIa/ b
Toxicology/
Pharmacy
Phase
I
Phase
IIa/ b
30%
30%
90+%
30%
30%
90+%
30%
30%
90+%
One example of the real world
Total number of patents on TRPV1
Source: Derwent World Patent Index
Aurora Kinase Inhibitors
>60
11
Preclinical
•
Antimitotic kinase – potential treatment for numerous
cancer types
•
Will also affect healthy proliferating cells – risk of low TI
•
>60 separate organizations have pre-clinical programs with
patents
•
11 compounds in Phase I
•
Further 4 compounds in Phase II
•
Estimated total expenditure >£200M
•
No data available on outcomes of clinical studies, apart
from rumours
AT9283
PF03814735
AS703569
AMG-900
KW-2449
CYC116
AZD-1152
MLN-8054
VX-667
SU-6668
SNS-314
MLN-8237
PHA-739358
VX-680
ENMD-981693
Phase I
Phase II
4
What can we do?
Structural Genomics Consortium
SGC Toronto
SGC Oxford
SGC Stockholm
Why not change the system?
Let’s imagine….
• A steady stream of pioneer targets whose links to disease
have been validated in humans
• Engagement of top scientists and clinicians
• A process in which regulators can fully collaborate to solve
key scientific problems
• An engaged citizenry that promotes science and
acknowledges risk
• Mechanisms to avoid bureaucratic and administrative
barriers
• Sharing of knowledge to more rapidly achieve
understanding of human biology
Imagine…
• Pooled public and private sector funding into independent
organization
• Public sector provides stability and new ideas
• Private sector brings focus and experience
• Funding can focus explicitly on high-risk targets
• A pre-competitive model to test hypotheses
•
•
•
•
•
•
Disassociates science from financial gain
Will attract top scientists and clinicians
Will allow regulators to participate as scientists
Will reduce perceived conflicts of interests – engages citizens/patients
Will reduce bureaucratic and administrative overhead
Will allow rapid dissemination of information without restriction informs public and private sectors and reduces duplication
Progress
• arch2POCM concept
• University of Toronto, University of Oxford, University of
California, San Francisco committed
• CIHR and Genome Canada helping drive
• Six large pharma engaged (none committed yet!)
• Regulators (FDA) keen to be involved as participants
• Patient groups fully engaged
• Therapeutic foci selected
• Oncology, neuroscience and inflammation
• Business plan being written
What is needed
• A set of public funders keen to take the “risk” and drive the
concept (Canada???)
• Leadership identified
• A core set of pharmaceutical funders
And when we succeed?
•
•
•
•
Less duplication
Broader scientific assessment
Faster dissemination of data
Pool academic and multiple pharma strengths and
funding – shared risk
• Increasing knowledge of human biology (which will
in turn reduce attrition?)
More clinical POCs on novel targets….more clinically
validated targets …..more novel drugs
How it might play out
Invalid
mechanism
Publish
quickly
1 or more
partners
develop
probe *
80%
POC
Developable
probe
20%
Auction IND
& all clinical
data
to partners
Proceeds to
independent
research
fund
30%
Other
partners
develop
proprietary
molecules
Valid
mechanism
70%
Non
developable
probe
*Based on existing market exclusivity laws
All partners
develop
proprietary
molecules
Commercial opportunities for Canada in the new
“open access” drug discovery ecosystem
Market size: ~$20B up for grabs
Potential opportunities for research and business
1.
2.
3.
4.
Academic partnerships that deliver new targets
High value clinical trials
Contract research organizations with leading edge science
Biotech companies with compounds and technologies
Potential impact
1.
2.
3.
4.
More industry funding for University and Hospital-based research
A business community built on high value service
A clinical trial network that works on innovative targets
Better business climate for biotech due to enhanced links with industry