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

Established 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 The SGC: A model for sharing in experimental science

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

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 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 ( ); 1,100 achieved to date No IP

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

The funding system does not support “innovation”

HUMAN PROTEIN KINASES (ordered by most citations ) CITATIONS (normalized) Citations as a function of time How have we responded to the genome?

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

Others also feel trapped by the system

What should the scientific community do? 1.Pay less attention to the literature 2.Be more daring when funding research 3.Support young scientists to dream bigger

NUCLEAR HORMONE RECEPTOR CITATIONS Another path emerges from examining the history of nuclear hormone receptor research ( )

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

Pre- and post-genome NR citations ***** ** *

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

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

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

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

Industry Public Domain Public/Private Partnership 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 Our Model for Pre-Competitive Chemistry Creative commons Proprietary

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

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

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

SGC OxfordSGC TorontoSGC Stockholm How is this linked to the development of new medicines? Structural Genomics Consortium

The Challenge of Pioneer Drug Discovery Number of pioneer drugs (Priority Reviewed NCEs) has not increased from 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 New Drug Approvals New Chemical Entities Priority Reviewed NCEs Public Data from Center of Drug Evaluation and Research:

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”

How industry acceses “innovation”

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

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

One example of the real world Total number of patents on TRPV1 Source: Derwent World Patent Index

Aurora Kinase Inhibitors AT9283 PF AS AMG-900 KW-2449 CYC116 AZD-1152 MLN-8054MLN-8237 VX-667PHA SU-6668VX-680 SNS-314ENMD PreclinicalPhase IPhase II 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 >

SGC OxfordSGC TorontoSGC Stockholm What can we do? Structural Genomics Consortium

Why not change the system?

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

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

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

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

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

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

Market size: ~$20B up for grabs Potential opportunities for research and business 1.Academic partnerships that deliver new targets 2.High value clinical trials 3.Contract research organizations with leading edge science 4.Biotech companies with compounds and technologies Potential impact 1.More industry funding for University and Hospital-based research 2.A business community built on high value service 3.A clinical trial network that works on innovative targets 4.Better business climate for biotech due to enhanced links with industry Commercial opportunities for Canada in the new “open access” drug discovery ecosystem