Document

The Only Way Is… Open Access Generating Affordable and Pioneer
Treatments for Chronic
and Rare Diseases
Wen Hwa Lee, PhD
Structural Genomics Consortium
University of Oxford
ELRIG Nottingham – 18 Mar 2015
www.thesgc.org
Open Innovation Flavour of the day
Open
Access
The Crisis in Drug Discovery
But don’t worry: we have an innovative academia!
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
Myth: Academia will save the day
The Harlow-Knapp Effect
The (un)targeted cancer kinome.
Fedorov O, Müller S, Knapp S.
Nat Chem Biol. 2010 Mar;6(3):166-169.
Too many roads not taken.
Edwards AM, Isserlin R, Bader GD, Frye SV, Willson
TM, Yu FH.
Nature. 2011 Feb 10;470(7333):163-5.
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
The dreaded pipeline…
100
63
39
25
14
8
3.5
2
<2
Target
Discov.
Compound
Discov.
Lead
Optimis.
Compound
Clinical
Trials
Phase
I
Phase
II
Phase
III
Regist.
Market
$500-700 M
hypothesis
generated
Patent
5-7 years
Does it
work?
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
Clinical
Phase
I
Discov.
Optimis.
Discov.
II
Trials
Compound
Compound
Lead
Target
Phase
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
Clinical
Phase I
STOP
STOP
STOP
STOP
STOP
STOP
STOP
STOP
STOP
Old Dutch Masters knew about Drug Discovery!
The blind leading the blind (1568)
Pieter Bruegel
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
In summary
• Despite massive investments we are not
delivering enough “novel” medicines
• We don’t understand Human Biology!
– Most (90+%) early activity is destined for failure
• No organisation has all capabilities
• Current model requires early IP
– Secrecy prevents critical mass being reached
– Useless duplication
– Sub-optimal use of public (and industrial) resources
What can we do?
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
Research tools drive exploration in academia
1950-1995
7000
2009
6000
5000
4000
3000
2000
*
1000
*
*
** *
**
0
48 Nuclear Hormone Receptors
Tim Willson, GSK
Why not change the system?
Nature Chemical Biology 5:436 (2009)
• Small molecules to explore biology
• PPP = sharing expertise!
• Open tools = exploration by all
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
A general model for open innovation in early
stage drug discovery
CREATIVE COMMONS
Public-Private
Partnership
Tools & Basic
Knowledge
NOVEL Proteins only!
•
•
•
•
•
Structure
Chemistry
Antibodies
Screening
Cell Assays
PROPRIETARY
Public Domain
Commercial
Discovery and
Exploration
Drug Discovery and Development
• No patent
• No restriction on use
• Open access to tools
and data.
• Target identification &
validation
Facilitated by access to increased amount of
information in the public domain
-
(re)Screening
Lead Optimisation
Pharmacology
Metabolism
Pharmacokinetics
Toxicology
Chemical development
Clinical development
Weigelt J. EMBO Reports 10:941-5 (2009)
www.thesgc.org
wenhwa.lee@sgc.ox.ac.uk
A public-private partnership
that supports the discovery
of new medicines through
open access research
www.thesgc.org
SGC at a glance
• Operations started in June 2004
• 3 government agencies, Wellcome Trust and
10 leading pharma companies
• Aggregate funding in excess of $300M (2014)
• +200*-strong team in Oxford, Toronto &
Campinas
• Open Access Policy:
- Promptly placing results, reagents and
know-how in the public domain
- SGC scientists never file patents
Major SGC programmes
and...
www.thesgc.org
The Epigenetic Chemical Probes
Programme
(+)-JQ1
Publicly Available (No Patent) . No restriction on use
• Potent: in vitro IC50 /KD< 100nM
• Selective: 30 fold over other sub-families
• Cell Permeable: activity IC50 <1 µM
UNC0638
www.thesgc.org
- Develop well characterised small molecules
- To link pharmacological inhibition of an
individual target (or small group of targets)
with cellular biology/pathways/phenotype
- Target Validation
- To complement target knockdown/
knockout
Bromodomains
 61 domains in Human
 ~120 residue Kac interaction module
 Linked to many diseases
 Clinical POC targeting Kac regulation
Soluble protein (50)
Alphascreen (21)
Cell assay (16)
SGC structure (36)
Structure from others (9)
www.thesgc.org Stefan Knapp ,Filippakopoulos et al. Cell 2012
wenhwa.lee@sgc.ox.ac.uk
Bromodomains
 61 domains in Human
 ~120 residue Kac interaction module
 Linked to many diseases
 Clinical POC targeting Kac regulation
Soluble protein (50)
Alphascreen (21)
Cell assay (16)
SGC structure (36)
Structure from others (9)
www.thesgc.org Stefan Knapp ,Filippakopoulos et al. Cell 2012
wenhwa.lee@sgc.ox.ac.uk
The quick evolution of JQ1
Filippakopoulos et al, Nature 2010 (Dec)
Stefan Knapp
SGC Oxford
Panagis Filippakopoulus
SGC Oxford
The quick evolution of JQ1
Filippakopoulos et al, Nature 2010 (Dec)
6 Months
July 2009
11 Months
Jan 2010
1 Month 2
Dec 2010
Years
and 8 months
6 Months
3 Months
Jan 2011
July 2011
Oct 2011
GSK informs
SGC about
Mitsubishi
compound Oxford and
Harvard start
collaboration
Booming
interest in
Academia and
Industry
Co -publication of
JQ1 probe (SGC;
cancer) and
I-BET probe (GSK;
inflammation) JQ1 distributed
to 100+ labs
Brd4 linked to
AML (Nature)
MM (Cell)
Pfizer BET
probe
announced
Mar 2012
GSK carries
out first in
man
(for open
access discovered
indication!)
The power of chemical probes &
disease agnostic exploration
•
•
•
•
•
•
•
NUT midline carcinoma
Septic Shock/ Inflammation
Myeloma
Leukemia
MYC regulation
Pathologic Cardiac hypertrophy
Male Contraception (!)
>25 different companies are
now working on BRD inhibition
Pioneer work on
epigenetics regulator
bromodomains
unveiled a completely
new therapeutic
target family
Open
Access
stimulates
Innovation, rapidly!
(http://www.nature.com/nrd/journal/v11/n5/fig_tab/nrd3735_T1.html)
Progressing towards patients!
Bromodomain inhibitors in clinical trials
GSK
GSK525762
[NCT01587703]
Oncoethix
OTX015
[NCT01713582]
Resverlogix
RVX-208/RVX000222
[6 trials]
Constellation
CPI-0610
• NUT midline carcinoma, Mult. Myeloma, small cell
lung cancer, colorectal cancer, neuroblastoma
and MYCN-amplified solid tumours
• Haematological malignancies: Acute Myeloid
Leukaemia (AML), Acute Lymphoblastic Leukaemia
(ALL), DLBCL and Mult. Myeloma
• Dyslipidemia; Atherosclerosis; Acute Coronary
Syndrome; Cardiovascular Disease
• Progressive Lymphoma
[NCT01949883]
Tensha
TEN-010
[NCT01987362]
• NUT midline carcinoma
Creating Innovation Ripples
Tensha Therapeutics
USA – 2011
Bromodomains
Pharmas pursuing
internal proprietary
Constellation refocusing
Resverlogix/ Zenith
EpiSynesis
UK –2013
Lysine Demethylases
Produce & commercialise SGC probes &
clones (eg. Addgene, ToCris, Sigma)
Services based on SGC protocols
(eg. Proteros)
Co-development of assays &
screening panels (eg. DiscoveRx)
Creating Innovation Ripples
Tensha Therapeutics
USA – 2011
Bromodomains
Pharmas pursuing
internal proprietary
Constellation refocusing
Resverlogix/ Zenith
EpiSynesis
UK –2013
Lysine Demethylases
Produce & commercialise SGC probes &
clones (eg. Addgene, ToCris, Sigma)
Services based on SGC protocols
(eg. Proteros)
Co-development of assays &
screening panels (eg. DiscoveRx)
And more probes are coming!
Opportunities beyond BRDs
http://www.thesgc.org/chemical-probes/
Jan.2014
Probe/ Tool
Compound
BET
BET 2nd
CREBBP
CREBBP 2nd
SMARCA4
BAZ2B/A
Bromosporine
G9a/GLP
G9a/GLP 2nd
G9a/GLP 3rd
DOT1L
SETD7
PHD2
Pan 2-OG
EZH2
EZH2 2nd
SMYD2
JMJD3
LSD1
L3MBTL3
Screening / Chemistry
Potent &
Selective
Potent
Weak
None
In vitro assay
2OG Oxygenase
BRD
HAT
Cell
Cell
assay
assay
Cell
Cellactivity
activity
Me Lys Binders
(H)MT
WD Domain
KDM
TUD
Open Access enabling
Patient Driven Research
Ultra-rare
disease
No treatment
SGC co-dev.
compounds
“Stone-Man Syndrome”
+
Adult Polyglucosan Body Disease
+
Leukemia & Lymphoma
+
Rare disease
Neurodegeneration
SGC working on GBE1
Structural & functional
[Sep.2012]
LLS raised $7.5M & partnered
Constellation to dev. clinical
candidate, based on
bromodomain OA data [Sep.2013]
Clinical Trial Filed in the US
Patent-free pacts
Huntington’s Disease
+
To rapidly discover & develop drugs that
delay or slow Huntington's disease
To jointly explore the role of epigenetic
regulation in HD
Jointly with SGC under Open Access
Nature Medicine
5 June 2014
A template for Global Innovation
Centro de Biologia Química
de Proteínas Quinases
We are hiring!
http://www.thesgc.org/careers
Increasing the likelihood of
success in challenging
neurodegenerative areas
“Increase the likelihood that success in
preclinical development will translate to
success in clinical development (i.e., derisk clinical development) by conducting
translational research in a precompetitive
commons through public-private
partnerships (modelled on, e.g., the
Structural Genomics Consortium and
Arch2POCM,…”
Breadth and depth in the absence of Patents
gene
Cancer
Metabolic
Neuropsychiatry
proteins,
structures,
antibodies
biophysical/
biochemical
assays
initial
chemical
matter
ARUK DDI Oxford
Inflammation
IMI ULTRA-DD
24 TEPs for
novel proteins
validation
in cell
validation
in vivo
Wellcome
Trust
TEPs
Dementia
Unexplored
Kinases
probes
FAPESP SGC-Unicamp
3 targets for
lead optimisation
15 novel
chemical probes
13 novel kinase
chemical probes
The SGC Super-Network
Alzheimer’s Disease
& Neuro-degeneration
Patient Groups
Open
Clinical
POCs
Rare
Diseases
Structural
Parasitology
& SDDC/
Gates
Novel
Epigenetic
Inhibs
New
Biology
Soluble
Structures
New
Techs
Pioneer
Targets
Human
Tissue
Platforms
www.thesgc.org
SGC
UNICAMP
Kinase
inhibitors
Global
Academic
Network
Memb.
Protein
Structures
Target
Enabling
Packages
(TEPs)
Impact
Training
Hub
Public &
Private
Funders
Reducing
Duplication
Accelerating
Science
Catalysing Drug
Discovery
Start-Ups &
incubators
Ethics &
Economics
Governments
and policymakers
Creating New
commercial
activities &
Jobs
Integrating
model:
harnessing
strengths of all
stakeholders
ACKNOWLEDGEMENTS
Aled Edwards
Chas Bountra
Cheryl Arrowsmith
Stefan Knapp
Panagis Filippakopoulus
Susanne Muller
Peter Brown
Jay Bradner
Stephen Frye
Jian Jin
Chris Schofield
SGC Oxford
SGC Toronto
Our Friends &
Collaborators
around
the World
ABOUT THE SGC
The SGC is an international public-private partnership (UK charity number 1097737) that aims to
carry out basic science of relevance to drug discovery, placing all information, reagents and knowhow into the public domain without restriction.
www.thesgc.org
Contact
Wen Hwa Lee, PhD
Strategic Alliances
Programme Director
Disease Foundations Network
wenhwa.lee@sgc.ox.ac.uk
Mini-Agenda
(Mar.2015)
New Frontiers in Epigenetics
24th-26th June 2015, Oxford
www.thesgc.org/episymp2015
Current expertise and future directions in
drug discovery
Friday 31st July 2015, Oxford
www.chembiohub.ox.ac.uk/conversation
We are hiring
www.thesgc.org/careers
ABOUT THE SGC
The SGC is an international public-private partnership (UK charity number 1097737) that aims to
carry out basic science of relevance to drug discovery, placing all information, reagents and knowhow into the public domain without restriction.
www.thesgc.org
Open science enables faster target validation