1. Cathy Tralau-Stewart PhD
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

2. Drug Discovery Landscape
Pharma 2020: The Vision PWC 2010

3. Future of drug discovery
‘Research-led Pharma needs new innovative models’
‘Investors will not tolerate sub-optimal 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’
John Lechleiter
President & CEO Eli Lilly
Feb 2011
‘in the next 10 years, pharma spend will continue to decrease and most of pre-clinical candidate drug discovery will be done in academia’
‘>50% of future pipeline will come from outside major pharma’
David Redfern
CSO, GSK,
Feb 2011
Dr Dave Tapolczay
CEO MRC Technology 2009

4. What future for UK science base?

5. 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

6. Between 1962 and 2000, no major classes of antibiotics were introduced
M. A. Fischbach et al., Science 325, (2009)
Published by AAAS

7. and resistance is a major issue
~ 30 years
~ 3 years
AE Clatworthy et al (2007) Nature Chemical Biology p 541

8. Why Do Drug Discovery in Academia ?
Pull: Pharma require products for their pipelines
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

9. Academic v Industrial skill base
Academic/ Clinical
In-depth disease knowledge
Novel pathway knowledge
Clinical expertise & access
Innovative approaches
Industrial
Drug discovery Know-how
Quantitative robust assays
Data security
Candidate definition
Complementary skills and
capabilities

10. 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

11. Licenseable assets 1. Candidate with human PoC or Phase I safety (IP)
Value
6-10
4-6
2-4
2-3
1. Candidate with human PoC or Phase I safety (IP)
2. Pre- Clinical Candidate with required safety/ toxicology/ pharmacokinetics & efficacy profile (IP)
3. Candidate molecule with defined optimised target profile
4. Lead series (+/- backup)
5. Novel target or effect

12. Drug Discovery takes 10 years +
Development
Basic research:
years 0-3
Pre-Clinical:
years 4-6
Clinical:
years 7-10
Drug to public:
years 11+
1000’s
100’s
10’s
1’s
Disease
Target Hypothesis
Protein, Assay, Screen, Hit
Lead, Med Chem, Pharmacology, ADMET, Candidate, Tox, FTIH
PoC (Phase 2), Phase 3, File
DRUG
Academic expertise
Lack of expertise
Industrial expertise

13. 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)

14. A flexible cost efficient academic virtual biotech
Projects sourced from Imperial’s 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

15. DDC team: respected, expert, multi-disciplinary
Expertise
Background
Pharmacology
Cathy Tralau-Stewart PhD
20 years Glaxo,
GlaxoWellcome, GSK
Medicinal Chemistry
Albert Jaxa-Chamiec PhD
30 years Pfizer, Searle, SK&F, Glaxo, GSK
Molecular Modeling & Medicinal Chemistry
Caroline Low PhD
20 years James Black Foundation / J&J
Cell Biology & Project Management
Hayley Cordingley PhD
10 years GSK
Assay Development & Screening
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

16. 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 year timeframe from the bench to the clinic
Tackle the hard problems - no “low hanging fruit” left
Create the next generation of drugs

17. Contract studies- engaging 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

18. 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

19. Portfolio by phase Jan 2011 Mlaria
add in info here about # projects worked on since inception - total number of projects not just current???

20. Translation in action DDC delivery Increasing value Tool compounds
Malaria
Heart failure
Kidney fibrosis
Hit discovery
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

21. Traditional drug discovery ‘process’
Development
Basic research:
years 0-3
Pre-Clinical:
years 4-6
Clinical:
years 7-10
Drug to public:
years 11+
1000’s
100’s
10’s
1’s
Disease
Target Hypothesis
Protein, Assay, Screen, Hit
Lead, Med Chem, Pharmacology, ADMET, Candidate, Tox, FTIH
PoC (Phase 2), Phase 3, File
DRUG
Projects : ……………………………………….…….1

22. 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

23. 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)

24. 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)

25. 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

26. Imperial College Drug Discovery Centre
7th Floor Biochemistry, South Kensington