Pre-competitive projects can work to deliver science and change culture

1. Pre-competitive projects can work to deliver science and change culture

2. The SGC: A model for sharing in experimental science • Established 2003 • 200 scientists; labs in Toronto, Oxford and Stockholm • Funded by - Private: GSK, Merck, Novartis, Lilly, Pfizer, Life Tech - Govt: Canada, Ontario, Sweden - Charities: Wellcome Trust, Wallenberg Foundation

3. SGC: open access works • 1000 human protein structures– all available without restriction • ~30% of novel human proteins in PDB per annum • Structures used to be “competitive” • >100 structures of proteins from parasitic protozoa • Chemical validation for drug targets in toxoplasmosis (Nature, 2010) and sleeping sickness (Nature, 2010) • 500 cDNA clones distributed freely every year (academia, biotech, pharma) • 75 visiting scientists per annum

4. Why does the SGC model work? • SGC model allows opportunity to work with the very best • 200+ collaborations • SGC model drives fast data dissemination • On average, each SGC structure enters public domain 18-24 months in advance of academic norms • SGC model promotes collaboration • Average of >3 non-SGC authors for each paper • SGC model focuses on milestones • 1000 structure target (2004-2011); 1,100 achieved to date • No IP

5. In biomedicine, the system is the greatest hurdle to the discovery of innovative medicines

6. The funding system does not support “innovation”

7. How have we responded to the genome? Citationsas a function of time 1950-2002 2003-2008 CITATIONS (normalized) 2009 HUMAN PROTEIN KINASES (ordered by most citations 1950-2002)

8. Another way of looking at it • 65% of 2009 kinase publications on the 10% of the kinome that was “hot” in early 1990’s • 5% of 2009 kinase publications on the 300 kinases that were the least studied in 2002

9. Others also feel trapped by the system

10. What should the scientific community do? • Pay less attention to the literature • Be more daring when funding research • Support young scientists to dream bigger

11. Another path emerges from examining the history of nuclear hormone receptor research (1950-2010) CITATIONS NUCLEAR HORMONE RECEPTOR

12. In 2009, the research is even more biased CITATIONS NUCLEAR HORMONE RECEPTOR

13. Pre- and post-genome NR citations 1950-1995 2009 * * * * * * * *

14. The power of open access reagents Chemical probe available No chemical probes available CITATIONS NUCLEAR HORMONE RECEPTOR

15. Can we be proactive? Epigenetics – a pioneer area of science and medicine Family member Number of Citations

16. The SGC: Delivered(ing) on its core mandate Wellcome Trust Canada Ontario • >2000 purified human proteins • >1000 human crystal structures GSK Novartis Merck Sweden Construct Design Cloning Expression & Purification Crystallography

17. Pushing the pre-competitive boundary Wellcome Trust Canada Ontario • >2000 purified human proteins • >1000 human crystal structures GSK Novartis Merck Sweden Construct Design Cloning Expression & Purification Crystallography Medicinal Chemistry GSK Pfizer Lilly Novartis Toronto SGC UNC CICBDD OICR • Epigenetics Chemical Probes Consortium • Pre-competitive tools for new drug target validation Oxford: SGC Chemistry Biochemistry More than 50 universitiies

18. Our Model for Pre-Competitive Chemistry Public/Private Partnership Public Domain Industry Chemical Probes Screening Chemistry Structure Bioavailability Target Validation No IP No restrictions Publication Drug Discovery (re)Screening Chemistry Lead optimization Pharmacology DMPK Toxicology Chemical development Clinical development Creative commons Proprietary

19. Epigenetics Chemical Probes Consortium Accessing expertise, assays and resource quickly July 11 June 09 April 09 Jan 09 Well. Trust (£4.1M) NCGC (20HTSs) GSK (8FTEs) Lilly, Pfizer (8FTEs) OICR (2FTEs) UNC (3FTEs) Novartis (8FTEs) Ontario ($5.0M) 15 acad. labs Sweden ($3.0M) ….more than $50M of resource

20. It’s working. The BET probe 250+ labs across the globe Identified Jan 10 Published Sep 10 Distributed Jan 11

21. Take home message: SGC and its pharma partners have moved the pre-competitive boundary to medicinal chemistry

22. SGC Toronto SGC Oxford SGC Stockholm How is this linked to the development of new medicines? Structural Genomics Consortium

23. Number of pioneer drugs (Priority Reviewed NCEs) has not increased from 1993-2008 Investment in pharmaceutical R&D has risen dramatically over this period >90% failure rate in clinical trials for pioneer drugs due to lack of efficacy Yearly FDA Approvals 120 100 80 60 13 18 12 40 10 16 19 9 New Drug Approvals New Chemical Entities Priority Reviewed NCEs 9 1993 7 17 1994 20 7 1995 9 1996 13 1997 1998 1999 2000 6 2001 7 0 2002 7 2003 2004 2005 2006 2007 2008 The Challenge of Pioneer Drug Discovery Public Data from Center of Drug Evaluation and Research: www.fda.gov/cder/

24. Impact on pharma and biotech in 2009 • $100B in R&D • 21 drugs approved (7 truly novel) • 70,000 pharma employees let go • Investment houses writing that pharma should “get out of R&D” • Industry relying on academia for “innovation”

25. How industry acceses “innovation”

26. What’s the “innovative” drug discovery process? Hypothesis generated Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery HTS LO 50% 10% 30% 30% 90+% Failure rates And tested

27. And here is how industry currently works Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery HTS LO Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery 30% 30% 90+% Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery 30% 30% 90+% Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery 30% 30% 90+% Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery 30% 30% 90+% Hit/ Probe/ Lead ID Clinical candidate ID Toxicology/ Pharmacy Phase I Phase IIa/ b Target ID/ Discovery 30% 30% 90+% 30% 30% 90+% 50% 10% 30% 30% 90+%

28. One example of the real worldTotal number of patents on TRPV1 Source: Derwent World Patent Index

29. Aurora Kinase Inhibitors • Antimitotic kinase – potential treatment for numerous cancer types • Will also affect healthy proliferating cells – risk of low TI • >60 separate organizations have pre-clinical programs with patents • 11 compounds in Phase I • Further 4 compounds in Phase II • Estimated total expenditure >£200M • No data available on outcomes of clinical studies, apart from rumours >60 11 4

30. SGC Toronto SGC Oxford SGC Stockholm What can we do? Structural Genomics Consortium

31. Why not change the system?

32. Let’s imagine…. A steady stream of pioneer targets whose links to disease have been validated in humans Engagement of top scientists and clinicians A process in which regulators can fully collaborate to solve key scientific problems An engaged citizenry that promotes science and acknowledges risk Mechanisms to avoid bureaucratic and administrative barriers Sharing of knowledge to more rapidly achieve understanding of human biology

33. Imagine… Pooled public and private sector funding into independent organization Public sector provides stability and new ideas Private sector brings focus and experience Funding can focus explicitly on high-risk targets A pre-competitive model to test hypotheses Disassociates science from financial gain Will attract top scientists and clinicians Will allow regulators to participate as scientists Will reduce perceived conflicts of interests – engages citizens/patients Will reduce bureaucratic and administrative overhead Will allow rapid dissemination of information without restriction - informs public and private sectors and reduces duplication

34. Progress arch2POCM concept University of Toronto, University of Oxford, University of California, San Francisco committed CIHR and Genome Canada helping drive Six large pharma engaged (none committed yet!) Regulators (FDA) keen to be involved as participants Patient groups fully engaged Therapeutic foci selected Oncology, neuroscience and inflammation Business plan being written

35. What is needed A set of public funders keen to take the “risk” and drive the concept (Canada???) Leadership identified A core set of pharmaceutical funders

36. And when we succeed? • Less duplication • Broader scientific assessment • Faster dissemination of data • Pool academic and multiple pharma strengths and funding – shared risk • Increasing knowledge of human biology (which will in turn reduce attrition?) More clinical POCs on novel targets….more clinically validated targets …..more novel drugs

37. How it might play out Invalid mechanism Publish quickly 1 or more partners develop probe * 80% Developable probe Proceeds to independent research fund Auction IND & all clinical data to partners POC 30% 20% Other partners develop proprietary molecules Valid mechanism Non developable probe All partners develop proprietary molecules 70% *Based on existing market exclusivity laws

38. Commercial opportunities for Canada in the new “open access” drug discovery ecosystem Market size: ~$20B up for grabs Potential opportunities for research and business • Academic partnerships that deliver new targets • High value clinical trials • Contract research organizations with leading edge science • Biotech companies with compounds and technologies Potential impact • More industry funding for University and Hospital-based research • A business community built on high value service • A clinical trial network that works on innovative targets • Better business climate for biotech due to enhanced links with industry