Steve Yang, May 11, 2012. Shanghai Bioforum Translational Medicine, Session S4, Shanghai, China

1. R&D Innovation in China and Asia:
From Translational Science to Drug
Discovery
Bio-Forum 2012 (14th Shanghai International
Forum on Biotechnology & Pharmaceutical
Industry)
I d )
Steve Yang, Vice President
g
R&D Asia & Emerging Markets
11 May 2012

2. Topics
Implement Asia R&D Strategy
Deliver Translational Science
Build Drug Discovery
Drive R&D Innovation in China
1

3. Topics
Implement Asia R&D Strategy
Deliver Translational Science
Build Drug Discovery
Drive R&D Innovation in China
2

4. AstraZeneca Global R&D Strategy
High quality Strong Asia & Culture,
early stage
l t biologics Emerging
E i Capabilities
C biliti Leadership,
L d hi
pipeline pipeline Markets Engagement
• Transform leadership – 60% senior leaders from outside
p
• Payer evidence, Personalized Healthcare, Predictive
sciences, and innovative clinical trial design and
interpretation
• 40% of clinical pipeline is in-licensed
• 8 biologics candidates in phase II development
3

5. AstraZeneca's focus for R&D in Asia
Ensure patients in Asia benefit from
existing products sooner
Deliver innovative new medicines
focusing on diseases more prevalent in Asia
Access R&D innovation
Meet unmet needs of Asian patients
and capabilities in Asia
4

6. Designed for success
Regional strength and experience
• Leading oncology company in Japan and
China
• $2.2 billion sales in Asia Pacific
• Significant regional presence, with
expansions planned in 2012
One of the first global pharma
companies to establish an innovation
innovation-
driven research laboratory in China
One of the few global pharma companies
with substantial internal research
operations in both China and India
ti i b th Chi d I di
5

7. Designed for success
significant world class presence in Asia
i ifi t ld l i A i
…Brings us closer to the patients we
Shanghai, China serve,
serve the scientists and medical
professionals we collaborate with and
the great local talent we can access.
Osaka, Japan
• Innovation Center China
• Clinical Development Operational Hub
• Clinical Development
Bangalore, India
• Clinical Development
p
• Infection iMed
6 • Pharmaceutical Development

8. Innovation Center China: History & Milestones
Moved to Oncology global
the lab translational
facility science center
AZ announced First Became Part of AZ
$100 M R&D project Asia & Emerging
investment in started & Markets R&D with
China delivered a New Mission
2006 2007 2008 2009 2010 2011 2012
7

9. Innovation Center China
Solid
S lid progress on capability build-up
bili b ild
Capabilities
In vitro
pharmacology
In vivo
pharmacology
PK/PD
Target
selection
2007 2008 2009 2010
8

10. Topics
Implement Asia R&D Strategy
Deliver Translational Science
Build Drug Discovery
Drive R&D Innovation in China
9

11. Key translational science questions
• What disease(s) and how to select patients?
• What dose and schedule?
• How to combine with current drugs?
• How do we know the drug works – what to measure
as biomarkers

12. Patient Selection for AZD (1)
Only FGFR2 amplified gastric cancer cells
Sensitivity of Gastric Cancer Cells to AZD4547 in
are sensitive to AZD
MTS assayy
100.000
10.000
M)
GI50 (nM
1.000
0.100
0.010
0.001
GC lines
FGFR2
CEP10
DAPI

13. Patient Selection for AZD (2)
FGFR2 shRNA inhibits Snu16 (FGFR2 amp) tumor growth in vivo
FGFR2 knockdown in SNU-16 inhibit its tumor growth
SNU16 control
800
SNU16 treated with Dox
SNU16-ShRNA3C8 control
700 Doxycycline SNU16-ShRNA3C8 treated with Dox
treatment SNU16-ShRNA2B control
SNU16-ShRNA2B treated with Dox
Tum Volume (mm3)
600 SNU16-shEGFP control
SNU16-shEGFP treated with Dox
500
400
mor
300
200
100
0
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Study period (Day)

14. Patient Selection for AZD (3)
Primary gastric cancer explant model
(FGFR2 amp: FISH 6)
Patient tissue
Dosing stopped at Day 20
Tumor cell line

15. Hepatocellular carcinoma (HCC): disease segments
~30% ~5% ~5-10% ~30-40% ~10%
Barcelona Clinic Liver Cancer (BCLC) algorithm

16. HCC Treatment Through TACE
TACE (Transcatheter arterial chemoembolization) in Clinic
Hepatic
artery
Catheter
Tumor
Femoral artery
• Catheter insertion into hepatic artery and Two cycles of TACE treatment
angiogram
g g
• Local delivery of chemotherapeutic agent
through the catheter
• Hepatic arterial embolization by gelfoam

17. Build the animal model for TACE
(1)
(3)
(2)
necrosis
1. Generation of orthotopic HCC model
2.
2 Injection of chemocytotoxic drug through hepatic
artery/portal vein
3. Hepatic artery ligation

18. TACE model: Histological and molecular changes
Control 7D Post HAL
90% necrosis
H&E
SHCC034 primary orthotopic HCC
pHH3 model
• Over 90% necrosis, 7 days after
treatment
• pHH3 and Aurora B expression in
Aurora B the residual tumor cells
• Ki67 IHC staining in the residual
viable cells
i bl ll
Ki67 Note:
HAL: hepatic artery ligation

19. Tumor response predicts effect of AZD
With response to HAL Without response to HAL
1000
HAL(n=4) 1400
00
HAL+AZD1152 25mg/kg PV,D1(n=9) HAL(n=5)
800 HAL+AZD1152 25mg/kg PV,D8(n=4) 1200 HAL+AZD1152 25mg/kg PV,D1(n=5)
Tumor volum (mm3)
Tumor volum (mm3)
HAL+AZD1152 25mg/kg PV,D8(n=5)
1000
600
me
me
800
400 AZD1152 PV 600 AZD1152 PV
injection, D1 injection, D1
400
200
200
AZD1152 PV AZD1152 PV
0 injection, D8
0 injection, D8
0 8 15 22 29 36 0 8 15 22 29 36
Time after treatment (days)
( y ) Time after treatment (days)
• Tumors without response to HAL did not benefit from AZD
• Recommendations to clinical trial design:
• Exclude patients with disease progression after TACE at the
time of AZD administration

20. Topics
Implement Asia R&D Strategy
Deliver Translational Science
Build Drug Discovery
Drive R&D Innovation in China
19

21. Innovation Center China
New vision and mission
Mission
Deliver candidate drugs and
ultimately, clinical proof of
Vision concepts and valuable
t d l bl
Deliver innovative medicines
medicines
addressing unmet
medical needs in
Asia Maximize commercial
potential of in-line products
Provide strong Translational
Science support
20

22. Innovation Center China
Unique advantages
Focusing on
Disease diseases
area focus important to Asia
Deep expertise in
Scientific
S i tifi Translational Science to
expertise generate clear target
Lean and flexible model
Operating leveraging local
model p
capabilities
External Access to increasing
innovation innovation in China Asia
Talent
T l t pool
l High caliber of talent
with solid experience
21

23. Innovation Center China
Aspirations for the future
2017
beyond
2014 -
2016
2011 - Deliver Proof of
2013 Concepts with
Deliver steady
balanced
candidate
portfolio
Build up core drugs
capabilities
22

24. Topics
Implement Asia R&D Strategy
Deliver Translational Science
Build Drug Discovery
Drive R&D Innovation in China
23

25. Asia Clinical Operational Hub in Shanghai
Celebrates First A i
C l b t Fi t Anniversary
• Supports global, regional and
local studies to deliver the
global portfolio
• An integral part of the
AstraZeneca global clinical
operation hub network
• Concrete progress in recruiting,
capability building, and study
delivery
• Launched in February 2011, plan
for continuous growth in 2012
24

26. AstraZeneca and Hutchison Medi Pharma
Global C ll b
Gl b l Collaboration on V liti ib
ti Volitinib
• Global licensing, co-development, and commercialization
agreement for Volitinib (novel c-Met inhibitor for cancer
treatment, currently in Phase I clinical testing)
)
• $20M USD upfront payment plus $120M USD potential
milestone payments
25

27. AZ - SIMM Preclinical Safety Alliance Received
OECD GLP Certification
C tifi ti
• AstraZeneca and Shanghai Institute of Materia Medica
(SIMM) established the long term strategic alliance in
preclinical safety evaluation in 2007
• Receiving OECD GLP certification is a major milestone for
the AZ SIMM preclinical safety alliance
AZ-SIMM
26

28. Asia R&D Strategy Implementation in China
Key Themes
Drive
1 business in
Asia
Asia Clinical Operational Hub
Deliver
Deli er
2 innovative
medicines
Innovation Center China
Access R&D
3 innovation &
capabilities
27

29. Driving R&D Innovation in China
• A laboratory to understand
the diseases that are
highly prevalent in China
and Asia
dA i
• A laboratory to explore
novel R&D operating
models
• A laboratory to expand
R&D partnership
approaches
28

30. What’s Next for Asia and Emerging Markets R&D?
• Deliver candidates at
Innovation Center China
• Implement Asia R&D strategy
• Identify new R&D
opportunities in other
emerging market countries
29

31. Thank you!
y

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Steve Yang | May 11. 2012 R&D | Asia and Emerging Markets