Cathy Tralau -Stewart PhD Head of Drug Discovery Drug Discovery Centre Imperial College

1. The Imperial Drug Discovery Centre; enabling translation ofacademic projects towards clinical validation Cathy Tralau-Stewart PhD Head of Drug Discovery Drug Discovery Centre Imperial College www.imperial.ac.uk/medicine/drugdiscoverycentre

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, 1089 -1093 (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 6-10 4-6 2-4 2-3 0 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 Value

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

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 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

15. DDC team: respected, expert, multi-disciplinary

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 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

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 IdentificationTarget Valdation Hit discovery • Hit to Lead Lead optimisation Candidate Pre-clinicalClinical In vitro/in vivo pharmacology Medicinal chemistry/modeling Increasing value Assay design/screening (virtual/real) Synthetic chemistry Drug metabolism& pharmacokinetics Project Management Grant applications

19. Portfolio by phase Jan 2011 Mlaria

20. 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

21. Traditional drug discovery ‘process’ Discovery Development Pre-Clinical: years 4-6 Clinical: years 7-10 Drug to public: years 11+ Basic research: years 0-3 100’s 10’s 1’s 1000’s Lead, Med Chem, Pharmacology, ADMET, Candidate, Tox, FTIH Disease Target Hypothesis PoC (Phase 2), Phase 3, File DRUG Protein, Assay, Screen, Hit Projects : 24 ……………………………………….…….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 & EuanStronach) • 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 Centretranslates academic research Academicsdiscover 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 www.imperial.ac.uk/medicine/drugdiscoverycentre 7th Floor Biochemistry, South Kensington