History of Drug Discovery (a personal view)

Report
The Imperial Drug Discovery
Centre; enabling translation of
academic projects towards
clinical validation
Cathy Tralau-Stewart PhD
Head of Drug Discovery
Drug Discovery Centre
Imperial College
www.imperial.ac.uk/medicine/drugdiscove
rycentre
Drug Discovery Landscape
Pharma 2020: The Vision PWC 2010
2
Future of drug discovery
•‘Investors will not tolerate suboptimal returns on R&D’
•‘This will be the last generation of
high R&D spend unless return to
investors is greater’
•‘Ten year doomsday scenario- No
R&D only generics’
‘>50% of future pipeline
will come from outside
major pharma’
David Redfern
CSO, GSK,
Feb 2011
‘Research-led Pharma
needs new innovative
models’
John Lechleiter
President & CEO Eli Lilly
Feb 2011
‘in the next 10 years,
pharma spend will
continue to decrease
and most of preclinical candidate
drug discovery will be
done in academia’
Dr Dave Tapolczay
CEO MRC Technology 2009
3
What future for UK science base?
4
The Future of Healthcare Industries
• Fewer and more consolidated health care
companies
• Focused on developing low risk assets
• Competition to in-license the ever-decreasing
number of advanced assets
• Without focus, there will be a reduced supply
of innovative drugs to treat real un-met need
5
Between 1962 and 2000, no major classes
of antibiotics were introduced
M. A. Fischbach et al., Science 325, 1089 -1093 (2009)
Published by AAAS
and resistance is a major issue
~ 30 years
~ 3 years
AE Clatworthy et al (2007) Nature Chemical Biology p 541
7
Why Do Drug Discovery in Academia ?
Pull:
pipelines
Pharma require products for their
Push:
Translate publicly funded research to the
clinic
Ability:
Demonstrate research excellence
Moral case: Need for new approaches to disease
Reward:
Potential for commercial reward and
publications
8
Academic v Industrial skill base
Academic/ Clinical
Industrial
• In-depth disease knowledge
• Novel pathway knowledge
• Clinical expertise & access
• Innovative approaches
• Drug discovery Know-how
• Quantitative robust assays
• Data security
• Candidate definition
Complementary skills and
capabilities
9
Profile of a drug candidate
Active
• phenotypic activity reflecting clinical endpoint
• defined target (receptor, enzyme, ion channel)
Selective
• against targets associated with toxicity
Bioavailable
• available at site of action
• suitable elimination kinetics
Safe
• Significant adverse effects only occur at higher dose than the effective
dose
10
Licenseable assets
6-10
2. Pre- Clinical Candidate with required safety/
toxicology/ pharmacokinetics & efficacy profile (IP)
4-6
3. Candidate molecule with defined optimised target
profile
2-4
2-3
4. Lead series (+/- backup)
0
5. Novel target or effect
Time (years)
Value
1. Candidate with human PoC or Phase I safety (IP)
Drug Discovery takes 10 years +
Discovery
Development
Pre-Clinical:
years 4-6
Basic research:
years 0-3
1000’s
Disease
Target
Hypothesis
Protein, Assay,
Screen, Hit
Academic expertise
100’s
Clinical:
years 7-10
10’s
Lead, Med Chem,
Pharmacology, ADMET,
Candidate, Tox, FTIH
Lack of expertise
Drug to public:
years 11+
1’s
PoC (Phase 2), Phase 3,
File
DRUG
Industrial expertise
12
The Drug Discovery Centre (DDC)
Most academic institutions do not have capabilities or expertise to
achieve this alone
However, Imperial College had the foresight to invest in creating a
a Drug Discovery Centre of expertise
The DDC;
• Supports the translation of research into quality drug discovery
projects
•
Is a recognized leader in the developing ‘discipline’ of academic
drug discovery
•
Is a Cross-Faculty Centre hosted by The Faculty of Medicine,
(Experimental Medicine)
13
A flexible cost efficient academic
virtual biotech
• Projects sourced from Imperial’s 2000 +
researchers
• Multidisciplinary expertise in-house
• Limited expensive lab capabilities
• Compound library (x1800 biologically active)
• Chemoinformatics
• Screening lab
• Outsource specific expertise, skills and
capabilities from extensive world-wide array of
Contract Research Organisations (CROs)
• Project and outsourcing management essential
14
DDC team: respected, expert, multi-disciplinary
Expertise
Background
Pharmacology
Cathy Tralau-Stewart PhD
Medicinal Chemistry
Albert Jaxa-Chamiec PhD
Molecular Modeling &
Medicinal Chemistry
Cell Biology & Project
Management
Assay Development &
Screening
Caroline Low PhD
20 years Glaxo,
GlaxoWellcome, GSK
30 years Pfizer, Searle,
SK&F, Glaxo, GSK
20 years James Black
Foundation / J&J
Hayley Cordingley PhD
10 years GSK
Katie Chapman PhD
2 years GSK
Chemistry & Project
Management
Matt Fuchter PhD
Imperial, CSIRO Melbourne
& Royal School of
Pharmacy
Drug Metabolism and
Pharmacokinetics
Richard Starkey
Servier, Shire
Chemistry Post-doc
Katie Judd PhD
Bath
Biology Post-doc
Katherine Scott PhD
Manchester
15
DDC Outputs
The DDC has expertise to
• Create chemical tools for basic research
• Create small molecule starting points for drug discovery
• Develop target biology
• Develop robust bioassays to test drug candidates
• Create candidate molecules
We create “Composition of Matter” patents
• the starting point for Industrial Drug Development campaigns
We aim to develop new approaches to drug discovery
• To shorten the 10-15 year timeframe from the bench to the clinic
• Tackle the hard problems - no “low hanging fruit” left
• Create the next generation of drugs
Contract studiesengaging expertise as required
•
•
•
•
Synthetic chemistry
Peptide & protein synthesis
DMPK ~ in vitro and in vivo
Receptor/ enzyme selectivity
screens
• HTS
A cost-effective and efficient approach
which enables access industry expertise
and capabilities
17
DDC contribution to projects
Target
Identification
Target
Valdation
Hit discovery
Hit to Lead
Lead
optimisation
Candidate
Pre-clinical
Clinical
Increasing value
In vitro/in vivo pharmacology
Medicinal chemistry/modeling
Assay design/screening (virtual/real)
Synthetic chemistry
Drug metabolism & pharmacokinetics
Project Management
Grant applications
18
Portfolio by phase Jan 2011
Mlaria
DDC delivery
Tool
compounds
•Malaria
•Heart failure
•Kidney
fibrosis
Hit discovery
•Malaria
•5 cancer
projects
•Transplant
rejection
Hit to Lead
•Biological
therapeutic
(breast cancer)
•Solid tumors
Lead
optimisation
•Ovarian cancer
•Rheumatoid
arthritis
•Multiple
myeloma
Pre-clinical
•Breast
cancer
(BS194 and
back ups)
Spin out
•Navion external
investment,
biological
(breast
cancer)
Increasing value
Translation in action
20
Traditional drug discovery ‘process’
Discovery
Pre-Clinical:
years 4-6
Basic research:
years 0-3
1000’s
Disease
Target
Hypothesis
Projects :
Development
Protein, Assay,
Screen, Hit
100’s
Clinical:
years 7-10
10’s
Lead, Med Chem,
Pharmacology, ADMET,
Candidate, Tox, FTIH
Drug to public:
years 11+
1’s
PoC (Phase 2), Phase 3,
File
DRUG
24 ……………………………………….…….1
21
Drug Discovery Cycle
Assets
Clinicians who also run
research groups
Lab work on human tissue
Birthplace of new
technologies
Gaps
Inter-disciplinary skills
Access to tools
Lack of flexibility
Drug discovery knowledge
22
Drug discovery linking directly to the clinic
Benefit of phenotypic human based assays
eg;
• Identified compounds which reverse the
resistant phenotype in paired human platinum
sensitive & resistant ovarian tumour cell lines
(Hani Gabra & Euan Stronach)
• Identified compounds which effectively inhibit
TNF in human rheumatoid synovial
membranes using human white blood cells
(Sandra Sacre, Brian Foxwell & Marc
Feldmann)
23
Patient Access – Imperial College
Healthcare NHS Trust
•One million patients pass through our London hospitals each year
•Charing Cross Hospital
•Hammersmith Hospital
•St Mary’s Hospital
•Queen Charlotte’s & Chelsea Hospital
•Western Eye Hospital
•Large patient population for recruitment into clinical trials
•Imperial College Clinical Trials Unit - access to a large and ethnically
diverse patient population in major London hospitals (2.3 million local
population)
The Drug Discovery Centre
translates academic research
Academics discover
novel targets
Drug Discovery Centre
expertise; from biology
to candidate
Partnership with
industry to ensure
translation to the clinic
Imperial College Drug Discovery Centre
www.imperial.ac.uk/medicine/drugdiscoverycentre
7th Floor Biochemistry, South Kensington
26

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