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