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

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

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 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

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

The funding system does not support “innovation”

How have we responded to the genome?

Citations as a function of time

1950-2002 2003-2008 2009 HUMAN PROTEIN KINASES (ordered by most citations 1950-2002)

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

35000

Another path emerges from examining the history of nuclear hormone receptor research (1950-2010)

30000 25000 20000 15000 10000 5000 0 NUCLEAR HORMONE RECEPTOR

3000

In 2009, the research is even more biased

2500 2000 1500 1000 500 0 NUCLEAR HORMONE RECEPTOR

3000 2000 1000 0 7000 6000 5000 4000

Pre- and post-genome NR citations

1950-1995 2009 * * * * *

2000 1500 1000 500 0 3000

The power of open access reagents Chemical probe available No chemical probes available

2500 NUCLEAR HORMONE RECEPTOR

Can we be proactive?

Epigenetics – a pioneer area of science and medicine

Number of Citations

The SGC: Delivered(ing) on its core mandate Wellcome Trust GSK Novartis Merck Canada Ontario Sweden

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>2000 purified human proteins

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>1000 human crystal structures Construct Design Cloning Expression & Purification Crystallography

Pushing the pre-competitive boundary Wellcome Trust GSK Novartis Merck Canada Ontario Sweden

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>2000 purified human proteins

•

>1000 human crystal structures Construct Design Cloning Expression & Purification Crystallography Medicinal Chemistry

•

Epigenetics Chemical Probes Consortium

•

Pre-competitive tools for new drug target validation GSK Pfizer Lilly Novartis Oxford: SGC Chemistry Biochemistry Toronto SGC UNC CICBDD OICR More than 50 universitiies

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

Creative commons

Drug Discovery

(re)Screening Chemistry Lead optimization Pharmacology DMPK Toxicology Chemical development Clinical development

Proprietary

Epigenetics Chemical Probes Consortium

Accessing expertise, assays and resource quickly

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

It’s working. The BET probe

Identified Jan 10 100 80 60 40 20 0

Vehicle

797

JQ1 Vehicle

403

JQ1

Published Sep 10 250+ labs across the globe Distributed Jan 11

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

How is this linked to the development of new medicines?

Structural Genomics Consortium SGC Toronto SGC Oxford SGC Stockholm

The Challenge of Pioneer Drug Discovery

Yearly FDA Approvals 1312 10 18 91619 9 7 7 9 17 13 6 7 7

Public Data from Center of Drug Evaluation and Research: www.fda.gov/cder/ 120 100 80 60 40 0 20 New Drug Approvals New Chemical Entities Priority Reviewed NCEs • • • 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

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?

Hypothesis generated Target ID/ Discovery HTS Hit/ Probe/ Lead ID LO Clinical candidate ID 50% 10% Failure rates Toxicology/ Pharmacy 30% Phase I 30% Phase IIa/ b 90+% And tested

And here is how industry currently works

Target ID/ Discovery Target ID/ Discovery Target ID/ Discovery Target ID/ Discovery Target ID/ Discovery Target ID/ Discovery Target ID/ Discovery HTS Hit/ Probe/ Lead ID Probe/ Lead ID Lead ID Probe/ Lead ID Lead ID Hit/ Probe/ Lead ID Lead ID LO Clinical candidate ID Clinical candidate ID candidate ID candidate Clinical candidate ID Clinical candidate ID candidate ID 50% 10% Toxicology/ Pharmacy Toxicology/ Pharmacy 30% Toxicology/ Pharmacy 30% Pharmacy 30% Pharmacy 30% Toxicology/ Pharmacy 30% Toxicology/ Pharmacy 30% 30% Phase I Phase I 30% Phase I 30% I 30% I 30% Phase I 30% Phase I 30% 30% Phase IIa/ b Phase IIa/ b 90+% Phase IIa/ b 90+% IIa/ b 90+% IIa/ b 90+% Phase IIa/ b 90+% Phase IIa/ b 90+% 90+%

One example of the real world Total number of patents on TRPV1

Source: Derwent World Patent Index

Aurora Kinase Inhibitors

>60 • • • • • • • 11

Preclinical

AT9283 PF03814735 AS703569 AMG-900 KW-2449 CYC116 AZD-1152 MLN-8054 VX-667 SU-6668 SNS-314

Phase I

4 MLN-8237 PHA-739358 VX-680 ENMD-981693

Phase 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

What can we do?

Structural Genomics Consortium SGC Toronto SGC Oxford SGC Stockholm

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

Invalid mechanism Publish quickly

80%

POC

20%

Valid mechanism

30%

Developable probe Auction IND & all clinical data to partners

70%

Non developable probe 1 or more partners develop probe * Proceeds to independent research fund Other partners develop proprietary molecules All partners develop proprietary molecules

*Based on existing market exclusivity laws

Commercial opportunities for Canada in the new “open access” drug discovery ecosystem Market size: ~$20B up for grabs Potential opportunities for research and business 1.

2.

3.

4.

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 1.

2.

3.

4.

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