The Imperial Drug Discovery Centre;

enabling translation ofacademic projects towards clinical

validationCathy Tralau-Stewart PhDHead of Drug DiscoveryDrug Discovery Centre

Imperial College

www.imperial.ac.uk/medicine/drugdiscoverycentre

Drug Discovery Landscape

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Pharma 2020: The Vision PWC 2010

Future of drug discovery

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‘in the next 10 years, pharma spend will continue to decrease and most of pre-clinical candidate drug discovery will be done in academia’

Dr Dave TapolczayCEO MRC Technology 2009

‘>50% of future pipeline will come from outside major pharma’

David Redfern CSO, GSK, Feb 2011

‘Research-led Pharma needs new innovative models’

John LechleiterPresident & CEO Eli LillyFeb 2011

• ‘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’

What future for UK science base?

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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

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Published by AAAS

M. A. Fischbach et al., Science 325, 1089 -1093 (2009)

Between 1962 and 2000, no major classes of antibiotics were introduced

and resistance is a major issue

7AE Clatworthy et al (2007) Nature Chemical Biology p 541

~ 30 years

~ 3 years

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 diseaseReward: Potential for commercial reward and publications

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Academic v Industrial skill base

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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

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

dose10

Licenseable assets

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

Time (years)

Valu

e

6-10

4-6

2-4

2-3

0

Drug Discovery takes 10 years +

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Discovery 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 Industrial expertiseLack of expertise

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)

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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

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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&JCell 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 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 studies- engaging expertise as required

• Synthetic chemistry • Peptide & protein synthesis • DMPK ~ in vitro and in vivo• Receptor/ enzyme selectivity

screens • HTS

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A cost-effective and efficient approach which enables access industry expertise

and capabilities

DDC contribution to projects

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Target IdentificationTarget Valdation

Hit discovery

Hit to Lead Lead optimisation

Candidate Pre-clinicalClinical

Increasing value

Medicinal chemistry/modeling

Synthetic chemistry

Drug metabolism & pharmacokinetics

Assay design/screening (virtual/real)

In vitro/in vivo pharmacology

Grant applications

Project Management

Portfolio by phase Jan 2011

Mlaria

DDC delivery

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Translation in action

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

Traditional drug discovery ‘process’

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Discovery 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 : 24 ……………………………………….…….1

Drug Discovery Cycle

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Click icon to add picture AssetsClinicians who also run research groupsLab work on human tissueBirthplace of new technologies

GapsInter-disciplinary skillsAccess to toolsLack of flexibilityDrug discovery knowledge

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)

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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

Partnership with industry to ensure translation to the clinic

Drug Discovery Centre expertise; from biology to candidate

Imperial College Drug Discovery Centre

www.imperial.ac.uk/medicine/drugdiscoverycentre

7th Floor Biochemistry, South Kensington

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