Creating an environment where science thrives - … · Creating an environment where science...

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Creating an environment where science thrives Dr Menelas Pangalos EVP Innovative Medicines & Early Development 2 July 2014

Transcript of Creating an environment where science thrives - … · Creating an environment where science...

Page 1: Creating an environment where science thrives - … · Creating an environment where science thrives ... all dosed centrally confirmed T790M+ patients with a baseline RECIST assessment

Creating an environment

where science thrives Dr Menelas Pangalos

EVP Innovative Medicines & Early Development

2 July 2014

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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

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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…

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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

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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

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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

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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

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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)

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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)

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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”

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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

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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

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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

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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

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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

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The 5R story for AZD9291

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Right target

Right safety

Right patients

Right commercial potential

Right tissue

Research Candidate

Selection Clinical

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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

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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

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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

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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

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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

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The 5R story for AZD3293

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Right target

Right safety

Right patients

Right commercial potential

Right tissue

Research Candidate

Selection Clinical

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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

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• 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

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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.

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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

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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

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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

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View from Papworth Hospital

Our new Cambridge research centre will be designed with openness and collaboration in mind

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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

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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

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Questions