PDF of presentation given at Drug Repositioning Conference on 13.07.11 in San Francisco

1. Drug Repositioning Informatics
Developing Information Analytics & Search
Solutions To Identify, Evaluate and Exploit
New Opportunities For Drug Repositioning
Nick Brown
Informatics Programme Manager
New Opportunities

2. Our Company
Healthcare For People
As one of the world’s leading pharmaceutical companies, our business is
providing innovative, effective medicines that make a real difference to patients.
We focus our skills and resources on six important areas of healthcare, which
include some of the world’s most serious illnesses.
Cardiovascular Gastrointestinal Neuroscience
Respiratory & inflammation Infection Cancer

3. New Opportunities
The Other Disease Areas...
New Opportunities is a fully virtualized R&D unit that brings
medicines to patients in disease areas where AstraZeneca is
not currently conducting research.
Our current interests are in ophthalmology, wound‐healing,
bone disorders, dermatology, women’s health, critical care,
auditory disorders and regenerative medicine.
We are always seeking New Opportunities by
In‐licensing promising late stage assets to strengthen our pipeline
Out‐licensing and co‐development models for internal candidate drugs
Testing and adding value to our compounds through in vivo and clinical models
Forming partnerships with external companies with expertise in specific diseases

4. External Partnerships
Recent Success
In 2009, we signed a deal with Alcon, experts in ophthalmology and in 2011, we
signed a deal with Galderma, experts in dermatology. Partnering with world‐
leaders is the most efficient and effective way to unlock the potential of our
compounds in these rapidly evolving disease areas.

5. Drug Repositioning
Definitions...
Repositioning, Reprofiling, Repurposing, Recycling...
We simply look to systematically consider alternative disease indications for all
of our drugs and compounds, from early discovery to late stage development
compounds, even considering life cycle management opportunities.
We do this through the gathering of different types of information, informatic
analyses, scientific testing and prioritizing our options for a considered portfolio.
Today I will describe some of these approaches.

6. Structure-Based Repositioning
Predictive Modelling
We have experimented with a variety of in‐silico modelling approaches
(Bayesian, QSAR, Random Forest) to identify novel indications for screening our
early Discovery compound library based on structure alone.
positive
negative
We hope to start to use such approaches in earnest to develop new R&D
programmes with a longer term approach to diseases of unmet patient needs.
Always interested in hearing additional approaches that have the ability to
profile entire compound libraries.

7. Launched Drug Repositioning
Life-Cycle Management Indications
One of the easiest opportunities to reposition is with existing, launched drugs,
leveraging literature, clinical and mechanistic information.
▪ Xylocaine (lidocaine) – many literature and medical sources described the potential for
this anesthetic, reformulated for migraine. This has now been tested in clinical trials as
a nasal spray for migraine.
▪ Atacand (candesartan) and similar compounds have the potential to be useful in
hypertension, alcoholic liver disease and aortic valve stenosis. These are also
undergoing clinical testing.
Where compounds have been launched, there is a lot of information that can be
gathered from conference and grants, as well as web‐sources and forums to
provide possible clues to consider further new indications.

8. Mechanistic Repositioning
Building The Foundation
In 2008, we negotiated, licensed and indexed >50 million scientific abstracts.
Our systems use these & aggregated competitive intelligence systems on the fly
Identify Find Alerts & Trends Capture Ideas
Collaborators Repositioning to Breaking For Our
& Companies Opportunities Information Prioritisation
SOLR Web Services
Clinical Trials Publications Patents News
Congress Data Grants PhD theses PhD
Unstructured Scientific Abstracts Structured Comp Intel
We then leverage tools like Pipeline Pilot to build prototypes rapidly

9. Mechanistic Repositioning
Underlying Concept
We systematically process every disease against every mechanism, finding
potential hotspots that we should investigate further.
Potential Potential
Disease terms Mechanism of Actions
Mechanism of Actions
Disease terms
Biological Rational
Competitive Rational
Using a variety of statistical approaches, we can identify new opportunities for
our existing compounds or in‐licensing opportunities for external compounds.

10. Asset Repositioning Matrix
Stitching Information Together
Using this approach, we have identified hundreds of opportunities that connect
druggable target mechanisms to disease indications. e.g. Neglected Tropical Disease
Having evaluated some hits pre‐clinically , we have our first human study this year.
As well as single hits, we also identifies themes for potential franchises, such as
ophthalmology and dermatology, where we seek world leaders to partner with

11. Matrix Reloaded
Extending The Sources
As the system was developed to handle millions of datapoints, from different
data slices, we have started to add additional data from a variety of sources
Biological Potential & Target Efficacy
Competitor Landscape & Patent Position
Safety & Adverse Events Consideration
Patient & Genetic Rationale
Tissue & Cell Rational
Only in combination, can we utilize this information to have a prioritized
view of our assets and those potential repositioning opportunities we
should progress further to evaluation.

12. Web 2.0 Repositioning
Using The Power of People
As a small team, we are unable to triage every potential opportunity, but by
building an intranet based approach, scientists from across AZ can curate
potential hits as well as submit their own ideas in one system.
Reject
hypothesis
Second
Opinion
Evaluate
Pre‐Clinically
Submit New Idea
This also helps to actively consider repositioning opportunities from one disease
area into another existing AZ disease area, as well as those that we consider in
New Opportunities.

13. Influencing R&D Search
Accessing our internal content
Over the past 6 months, I have been working with a team in AstraZeneca (and
external company) to develop new platforms for searching internal R&D content
and surfacing it in bespoke business applications.
By standardizing our internal AZ vocabularies and auto‐tagging our rich, internal
document sources, we have been able to identify around 1700 files that contain
potential new indications that have been hypothesized over the past 10 years.
We aim to increase access to this R&D content, through improved information
policies and knowledge management systems but also by driving it through
demonstrating clear, unequivocal business benefits such as this.

14. Repositioning By Function
Leveraging how our drugs work
Understanding mechanisms and targets is not sufficient.
Working with our scientists, we have recognised that the best repositioning successes are
done by truly understanding how the drugs operate. No target is involved !
For example heart failure / angina
hypertension
Stroke / aneurysms
e.g. lowers blood
AZ compounds pressure
retinopathy
nephropathy
dementia
We have interviewed over 100 scientists to collate information about our
drugs systematically into a single location and biological process maps

15. Biological Process Mapping
Capturing AZ Knowledge
We capture information around where and how the drugs work, down to the
level of the cell, tissue and pathophysiological changes leading to outcomes.

16. Consortium Model ?
We can’t do this alone...
Whilst we can map our own existing AZ development compounds and drugs,
we are working with Thomson Reuters (GeneGO) to launch a new consortium
MetaMiner Mechanism of Action (MMMOA) consortium
Commencing July 2011
Mapping bioprocess maps for FDA approved drugs over 3 years
Manually curated maps, supported by scientific evidence
Benefits ? We are aiming to use this in conjunction with internal approaches
to facilitate our drug repositioning and drug combination initiatives
Interested ? Get in touch… Contact Nick Brown (AZ), Caroline Hellawell (AZ),
or Rob Greenwood (Thomson Reuters)

17. New Opportunities - Virtual iMED
100% Externalisation
With no R&D of our own, New Opportunities always looks to consider the
external world as its laboratory, working with leaders in any field.
We are always interested to work with people on repositioning systems,
computational approaches, disease models, licensing compounds,
collaborative development opportunities…

18. Understanding New Disease Areas
Finding Key Opinion Leaders & Experts
Of course, to rapidly understand new disease areas, we try to work with leading experts.
To find them, we built KOL Miner (with OpenQ) – a system that analyses the 50M
scientific documents on the fly and finds people & companies in seconds.
Top KOLs in GABA across the world. Top 10 KOLs working with leptocytes in GABA field.
It also creates interaction maps and timeline views, that enable us to figure out who is
key, who are rising stars and who has the largest sphere of influence. This also allows us
to rapidly find companies to test our new hypotheses with.

19. Evaluating Our Hypotheses
Finding The Right CRO
As well as working with leading academic experts, we work with many CROs to test our
ideas pre‐clinically. We use a private version of the Assay Depot marketplace to find
services and screens. The private marketplace acts as a single source of information about
internal and external services, and can enable us to easily chat with new CROs about what
models they have, how much they cost and what parameters we are planning to evaluate.
Service marketplace and communication channel for 4000+ CROs
The marketplace helps standardize information about in vivo models that have
previously been difficult to compare directly.

20. New Opportunities
Please come and talk to us !
Hopefully today I have provided a brief overview of how we use a virtual function in a
pharmaceutical company to repositioning our portfolio and evaluate these.
If you would like to work together or want to discuss anything further please get in touch.
nick.brown@astrazeneca.com
Any Questions…

21. Acknowledgements
None of this possible without the help of
Ed Holbrook (AstraZeneca) and some of our collaborators I can name
Mark Robertson (AstraZeneca) Graham Cox (Tessella)
Caroline Hellawell (AstraZeneca) Jerry Campbell (Tessella)
Johanna Sagemark (AstraZeneca) Jamie Kincaid (Accelrys)
Jane Escott (AstraZeneca) Alex Benn (Accelrys)
Marcus Bjäreland (AstraZeneca) Julie Bryant (GeneGO)
Ian Barrett (AstraZeneca) Svetlana Bureeva (GeneGO)
Amy McDonough (AstraZeneca) Ruben Jimenez (OpenQ)
Graeme Wilkinson (AstraZeneca) Otavio Freire (OpenQ)
Hitesh Sanganee (AstraZeneca) Kevin Lustig (AssayDepot)
Elaine Anderson (AstraZeneca) Corey Jacklin (AssayDepot)
Lisa Taylor (AstraZeneca)