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Creating an environment
where science thrives Dr Menelas Pangalos
EVP Innovative Medicines & Early Development
2 July 2014
Stimulate a more collaborative, more
permeable research ecosystem
2
AstraZeneca today: science at the heart of
everything we do
What we will cover today…
Learning from the past to identify the
potential drivers of scientific success
Stimulate a more collaborative, more
permeable research ecosystem
3
Learning from the past to identify the
potential drivers of scientific success
AstraZeneca today: science at the heart of
everything we do
What we will cover today…
We are on an ambitious journey
Return to growth
Acknowledged leaders in our
core TAs
2020 At least 10 new
medicines expected
to be launched since
2013
Rebuild the pipeline
2017 Revenues expected
to be broadly in line
with 2013
2014 Late stage pipeline
rebuilt focused on 3
core TAs
After 2020 Leadership in
core TAs & a balance of
specialty and primary
care
Note: The line is illustrative and is not representative of revenue 4
Neuroscience Infection
& Vaccines CV- Metabolism
Respiratory,
Inflammation
& Autoimmunity
Oncology
Core Therapy Areas Opportunity-focused
Heart disease
17 million
deaths every
year
Cancer
7 million lives
lost every year
Diabetes
350 million people
affected today
Asthma
235 million
sufferers today
We are focused on in our 3 core therapy areas
5
6
We have a growing and accelerating pipeline
MEDI0639
DLL-4 solid tumours
AZD4547
FGFR solid tumours
selumetinib
MEK solid tumours
moxetumomab
CD22 HCL
Volitinib (AZD6094)
MET solid tumours
MEDI-573
IGF MBC
MEDI-565
CEA BiTE solid tumours
olaparib
PARP BRCA
ovarian/gastric/breast
brodalumab
IL-17R psoriasis/psoriatic
arthritis
AZD1775
Wee-1 ovarian
AZD1208
PIM haems
MEDI-551
CD19 CLL/DLBCL
MEDI-550
Panflu library
MEDI9287
H7N9 avian influenza
ATM AVI
BL/BLI SBI
MEDI4893
staph alpha toxin SSI
AZD5847
oxazolidinone TB
AZD0914
GHyrAR serious infection
MEDI-559 (PRVV)
RSV prophylaxis
CXL
BLI/cephalosporin MRSA
AZD2014
mTOR solid tumours
MEDI3617
ANG-2 solid tumours
benralizumab
IL-5R asthma
AZD9150
STAT3 haems
tremelimumab
CTLA-4 mesothelioma
lesinurad
URAT1 gout
MEDI6469
mOx40 solid tumours
AZD9291
EGFRm+ solid tumours MEDI4736
PD-L1 NSCLC
PT003
LABA/LAMA COPD
selumetinib
MEK 2L KRAS-ve NSCLC
PT010
LABA/LAMA/ICS COPD roxadustat (AZD9941)
HIF anaemia CKD/ESRD
MEDI-551
CD19 MS
anifrolumab (MEDI-546)
IFNaR SLE
Epanova
hypertriglyceridaemia
AZD6738
ATR CLL/H&N AZD5069
CXCR2 antagonist asthma
MEDI4736+tremelimumab
PD-L1+CTLA-4 solid tumours
MEDI8968
IL-1R COPD/HS
naloxegol
PAMORA OIC
AZD8848
Inhaled TLR7 agonist asthma
AZD2115
MABA COPD
MEDI4736+dabraf+trametinib
PD-L1+BRAF+MEK
mavrilimumab
GM-CSFR RA
CAZ AVI
BLI/cephalosporin SBI
AZD7624
Inhaled p38 inhibitor COPD
RDEA3170
URAT1 gout
moxetumomab
CD22 pALL
MEDI7183
α4β7 UC/Crohn’s
AZD4721
CXCR2 COPD AZD4901
Hormone modulator PCOS
MEDI5872
B7RP1 SLE
tralokinumab
IL-13 asthma/IPF
AZD1419
TLR9 asthma tenapanor
NHE3 inhibitor ESRD/CKD
MEDI9929
TSLP asthma
MEDI2070
IL-23 Crohn’s
AZD3293
BSECDR Alzheimer's
AZD3241
MPO Parkinson's Disease
MEDI6012
LCAT arterial thrombosis
benralizumab
IL-5R COPD
Pipeline table as of 31st March 2014
AZD6423
NMDA suicidal ideation AZD5213
H3R Tourette’s/neuropathic
pain
brodalumab
IL-17R asthma
MEDI8111
Rh-factor II trauma/bleeding
AZD5363
AKT breast
AZD8186
PI3Kβδ solid tumours MEDI0680
PD-1 solid tumours
sifalimumab (SLE)
IFNa SLE
PT001
LAMA COPD
Phase 1 - 32 NMEs Phase 2 - 28 NMEs Phase 3 / Reg - 11 NMEs
Small molecule Large molecule Small molecule Large molecule Small molecule Large molecule
RIA Oncology Neuroscience CVMD Infection
6
Stimulate a more collaborative, more
permeable research ecosystem
7
AstraZeneca today: science at the heart of
everything we do
What we will cover today…
Learning from the past to identify the
potential drivers of scientific success
1 Compounds / projects excluded for a variety of reasons, for example, investigational compounds, biologics, old projects, or data
not readily available; Active projects were not included in Pre-clinical and Phase I analyses
We reviewed our full IMED portfolio from 2005-2010
36
49
30
622
Ph IIb
21
6 9
Ph IIa
51
21
8
Ph I
106
51
25
Pre-clin
180
106
25
Pre-nom
248
180
32
Successful compounds
Parked + Closed compounds
Active compounds
225 Total compounds/ projects in scope1 142 73 54
▪ > 80% of 2005-2010 portfolio compounds assessed ▪ Compounds assessed in each phase separately
8
Number of small molecule compounds
in portfolio (2005–2010)
Right target
Right safety
Right patients
Right commercial potential
Right tissue
Strong link between target and disease
Differentiated efficacy
Available and predictive biomarker
Adequate bioavailability and tissue exposure
Definition of PD biomarkers
Clear understanding of preclinical and clinical PK/PD
Understanding of drug–drug interactions
Differentiated and clear safety margins
Understanding of secondary pharmacology risk
Understanding of reactive metabolites, genotoxicity, drug–drug interactions
Understanding of target liability
Identification of the most responsive patient population
Definition of risk–benefit for given population
Differentiated value proposition versus future standard of care
Focus on market access, payer and provider
Personalised healthcare strategy, including diagnostic and
biomarkers
Our analysis has driven development of our 5R framework
Right culture Truth seeking versus milestone seeking behaviours
9 Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework Cook et al Nature Reviews Drug Discovery 13, 419–431 (2014)
2012 2004 1987 Historical View
Adeno-
carinoma Squamous
Large-cell KRAS
Unknown Unknown
EGFR
KRAS KRAS
EGFR
Unknown
Lung cancer is a stratified disease
• Worldwide, lung
cancer is the most
common cause of
cancer-related death
(1.3M deaths)
• Traditional
classification used
morphology
• Discovery showed
that NSCLC cells can
harbor a single
specific mutated
KRAS oncogene
• AstraZeneca in
collaboration with
external groups show
that clinical response
to Gefitinib correlates
with EGFR mutations
• Global genomics
initiatives (e.g., TCGA)
identify multiple
additional primary
genetic “drivers”
11
AZD9291 targets the EGFR mutant T790M
Mutations in the EGFR tyrosine kinase
domain leads to an oncogenic phenotype
& acquired resistance
Drugs like Iressa (gefitinib) & Tarseva
face resistance with new mutations in
EGFR
50% of the acquired resistance due to a
secondary mutation, T790M in exon 20 of
EGFR (gatekeeper mutation)
AZD9291 has been designed to target
T790M mutation which drives resistance
to standard of care drugs
12
Mutant EGFR inhibitor builds on gefitinib resistance
Mutations in the EGFR tyrosine kinase
domain leads to an oncogenic phenotype
& acquired resistance
Drugs like Iressa (gefitinib) & Tarseva
face resistance with new mutations in
EGFR
50% of the acquired resistance due to a
secondary mutation, T790M in exon 20 of
EGFR (gatekeeper mutation)
AZD9291 has been designed to target
T790M mutation which drives resistance
to standard of care drugs
13
Mutant EGFR inhibitor builds on gefitinib resistance
Mutations in the EGFR tyrosine kinase
domain leads to an oncogenic phenotype
& acquired resistance
Drugs like Iressa (gefitinib) & Tarseva
face resistance with new mutations in
EGFR
50% of the acquired resistance due to a
secondary mutation, T790M in exon 20 of
EGFR (gatekeeper mutation)
AZD9291 has been designed to target
T790M mutation which drives resistance
to standard of care drugs
14
Dialing out potential liabilities in our compound
Target Assay Type
CO-1686 (IC50 μM) AZD9291 (IC50 μM)
w/tEGFR Phospho/ whole-cell
1.1 0.480
Act mutEGFR Phospho/ whole-cell
0.061 0.017
T790M mutEGFR Phospho/ whole-cell
0.032 0.015
HER2 Phospho/ whole-cell
0.488 0.123
IGF1R Biochemical
0.26 2.9
AZD9291: Overall response rate* 64% in T790M+; Longest response > 9 months and ongoing
Janne P et al ASCO 2014 – Abstract 8009. *Includes confirmed responses and responses awaiting confirmation; # represents imputed values.
Population: all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment and an evaluable response (CR/PR, SD or PD),
N=107 (from 120 T790M+ patients, 13 patients with a current non-evaluable response are not included). QD, once daily; D, Discontinued
40 mg QD
80 mg QD
160 mg QD
240 mg QD
20 mg QD
40
20
-20
-40
-60
-80
0
# #
D D
D D
D
D D D D D D
D D
D D D
Best percentage change from baseline in target lesion T790M+ evaluable patients, expansion cohorts only (n=107)
Overall disease control rate (CR+PR+SD) = 94%
20 mg 40 mg 80 mg 160
mg
240
mg
ORR%
(N)
50%
(5/10)
62%
(18/29)
68%
(23/34)
64%
(18/28)
83%
(5/6)
D D D
D D
D D
The 5R story for AZD9291
16
Right target
Right safety
Right patients
Right commercial potential
Right tissue
Research Candidate
Selection Clinical
17
β-secretase (BACE1) is a key processing enzyme of
amyloid precursor protein
BACE1 activity leads to the release of the
Aβ fragment
Mutations in APP result in increased
BACE activity and Aβ production
Familial AD is linked to mutations in APP
There are also mutations in BACE that
confer protection to AD
Inhibition of BACE1 should reduce
production of Aβ and reduce disease
progression
Highly promising approach to
address unmet medical need in
Alzheimer’s
APP
(b-secretase)
BACE
g-secretase
Ab42
Ab40
Plaque
1
2
AZD4694 PET ligand imaging
18
We are using structure based design
against BACE1
Targeting BACE1 has several challenges:
Large binding pocket
Compound must cross BBB
Potential for off-target effects
AZD3293 is a new chemical series with
pM potency in human cells and long off-
rates with purified protein
Crystal Structure of AZD3893 (yellow)
in complex with BACE1 (gray)
AZD3293 targets the BACE1 enzyme
19
Brain Ab40 (guinea pig)
CSF Ab40
Lowering of Aβ in CSF and brain tissue with AZD3293
(guinea pig)
0
20
40
60
80
100
120
2 4 8 16 24
% Ab40 (30 mol/kg)
% Ab40 (10 mol/kg)
% Ab40 (100 mol/kg)
Hours after dose
Bra
in A
b40
(%
of
veh
icle
)
0
20
40
60
80
100
120
2 4 8 16 24
% Ab40 (30 mol/kg)
% Ab40 (10 mol/kg)
% Ab40 (100 mol/kg)
Hours after dose
CS
F A
b40
(%
of
veh
icle
)
Amyloid-β peptide (Aβ) production is a key
driver in AD pathophysiology
Familial mutations in APP leads to
increased Aβ production and AD
>80% lowering of amyloid in the brain of
two preclinical species
Significant & dose-dependent reduction in
Aβ biomarkers in plasma and CSF in
healthy volunteers & Alzheimer’s patients in
Phase I clinical studies
AZD3293 (Phase 1): BACE1 inhibitor for delayed
progression of Alzheimer’s Disease demonstrates target
engagement in the clinic
Amyloid-β peptide (Aβ) production is a key
driver in AD pathophysiology
Familial mutations in APP leads to
increased Aβ production and AD
>80% lowering of amyloid in the brain of
two preclinical species
Significant & dose-dependent reduction in
Aβ biomarkers in plasma and CSF in
healthy volunteers & Alzheimer’s patients in
Phase I clinical studies
15mg AZD3293
50mg AZD3293
Reduction of Ab in CSF in Healthy
Volunteers – continuous sampling
Placebo
20
21
Study AZD3293 Margins (Cmax free at 50% Aβ reduction)
AZD3839 Margins (Cmax free at 50%* Aβ reduction)
Dog ECG (tox study) (NOEL)
220x 11x
Dog ECG telemetry (NOEL)
45x 5x
hERG IC50 (uM) 15 4.8
BACE1 IC50 (uM) 0.0005 0.036
*20% extrapolated to 50% based on linear relation
Safety margins, reduced hERG and improved potency
against BACE1 diminish QT liability of AZD3293
The 5R story for AZD3293
22
Right target
Right safety
Right patients
Right commercial potential
Right tissue
Research Candidate
Selection Clinical
23
AstraZeneca today: science at the heart of
everything we do
Learn from the past to identify the
potential drivers of scientific success
What we will cover today…
Stimulate a more collaborative, more
permeable research ecosystem
AZ are an active
collaborator with
industry and
academia
24
• University of Strathclyde
• University of Aberdeen
• University of Stirling
• University of Glasgow
• University of Dundee
• University of Edinburgh
• University of Newcastle
• University of York
• University of Belfast
• University of Durham
• University of Huddersfield
• University of Leeds
• University of Liverpool
• University of Sheffield
• University of Manchester
• University of Nottingham
• University of Loughborough
• University of Birmingham
• University of Warwick
• University of Leicester
• University of East Anglia
• University of Swansea
• University of Cardiff
• University of Bristol
• University of Exeter
• University of Oxford
• University of Reading
• University of Southampton
• University of Surrey
• University of Sussex
• University of Cambridge
• Brunel University London
• Imperial College London
• University College London
• Kings College London
• Queen Mary University of
London
We have more than 200 active collaborations with
academic institutions
Here’s a few examples
25
We work openly with UK biotech and academia in a
number of different ways…
Collaboration on the stratified medicines programme with Cancer Research UK
and Pfizer to create a pioneering clinical trial for patients with advanced non-small
cell lung cancer
AZ, GSK and the University of Manchester: Manchester Collaborative Centre for
Inflammation Research - translational research centre for inflammatory diseases
Acquisition of Spirogen, specialist in antibody-drug conjugate technology
for use in oncology
Four-year collaboration with Heptares: challenging G-protein coupled receptor
targets in neuroscience, CV and inflammatory disorders research.
Two-year collaboration with Conformetrix: compound interaction with targets
and delivery of quality compound design and higher probability of success.
26
22 deprioritised AZ
compounds
MRC funding of £10M over
3 years
106 applications submitted
from 37 UK institutions
6 Clinical and 7 pre-clinical
funded proposals
…continuing to progress ground breaking agreements
to be a leader in Open Innovation
Unique joint centre for
research on CVMD
Integrated Cardio Metabolic
Centre located on KI
Campus
Focused on identifying and
validating novel targets on
three strategic research
themes: Cardiac
Regeneration, Islet Health
and Diabetic Nephropathy
AZ one of three industry
founders modeled in
part after AZ/MRC
alliance
14 ‘discontinued’ AZ
compounds (1 biologic)
– all ‘patient ready’
3 of 9 projects funded
with AZ compound
3 additional investigator-
sponsored projects
spawned from the
programme
27
Our new Open Innovation initiatives will help us push the
boundaries of science
openinnovation.astrazeneca.com
Pharmacology Toolbox
Target Innovation
Clinical Compound Bank
New Molecule Profiling
Suggestion Box
R&D Challenges
28
Laboratory of
Molecular Biology
Cambridge Institute
Addenbrooke’s Hospital
The Rosie Hospital
School of Clinical Medicine
Future hospital site
New UK R&D Centre and
Global Corporate Headquarters
Our move to the Cambridge Biomedical Campus
present further opportunties for collaboration
29
View from Papworth Hospital
Our new Cambridge research centre will be designed with openness and collaboration in mind
30
A groundbreaking collaboration will see IMED scientists
work side by side with MRC researchers
Innovative collaboration to create
AstraZeneca MRC UK Centre for Lead
Discovery
MRC-supported researchers working
side-by-side with IMED scientists at CBC
site
Significant investment from AZ and MRC
AZ will gain early access to MRC funded
science and the ability to in-license up to
15 projects/year
AstraZeneca MRC UK
Centre for Lead Discovery
31
32
Conclusions Closing thoughts…
We believe in scientific collaboration and open innovation
We have the strategy, size and focus to succeed
One of the most exciting pipelines in the
industry
Science and innovation is at the heart of our culture
33
Questions