harnessing the power of genomics and personalised healthcare mene pangalos festival of genomics21...

Harnessing the power of genomics and personalised healthcare

Mene PangalosFestival of Genomics 21 January 2016

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Outline

Applying PHC across all therapy areas

Our progress in oncology

PHC is integral to AZ strategy

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Outline




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The quality of submitted applications has risen sharply

Exane BNP Paribas Research, Jan 2016

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Our 5R framework has helped us drive quality not quantity

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 Personalized healthcare strategy, including diagnostic and

biomarkers

Right culture Truth seeking versus milestone seeking behaviours

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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Embedding patient stratification and biomarker use early in the R&D process is critical

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>80% of our clinical pipeline has a PHC approach

OncologyRIA CVMD Infection, Neuroscience, Gastrointestinal

Pipeline data correct as of 30 September 2015Includes significant fixed dose combination projects, and parallel indications that are in a separate

therapeutic area# Partnered; ¶ Registrational P2/3 study

Project with PHC Approach

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Outline




10

Case study 1

Osimertinib for non-small cell lung cancer

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The evolution of genomics in lung cancer diagnosis

Unknown EGFR KRAS ROS1 RET

PIK3CA AKT MET BRAF Her2

ALK

201220041987Historical View

Adeno-carinomaSquamousLarge-cell

Unknown KRAS EGFRUnknown KRAS

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The first EGFR inhibitors highlighted the importance of identifying the right patient

0.0

0.2

0.4

0.8

1.0

0.6

0 4 8 12 16 20 240 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Prob

. of p

rogr

essi

on-fr

ee s

urvi

val

Time from randomisation (months)

Unselected Population

Prob

. of p

rogr

essi

on-fr

ee s

urvi

val

Time from randomisation (months)

Selected by EGFRm Status

Gefitinib EGFR M+ Gefitinib EGFR M- C/P M+ C/P M-

Gefitinib C/P

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Structure-based design underpins the accelerated progress of osimertinib

Mutations in EGFR lead to an oncogenic phenotype & acquired resistance

Drugs like gefitinib & Tarceva face resistance with new mutations in EGFR

66% of acquired resistance due to T790M in exon 20 of EGFR (gatekeeper mutation)

Osimertinib designed to target T790M

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IMED Biotech Unit16Presented by Pasi A Janne at the 2015 European Lung Cancer ConferenceD = discontinued from AZD9291

Osimertinib: Overall response rate* 64% in T790M+ Longest response > 9 months and ongoing

IMED Biotech Unit1-3 yr

17

Ground-breaking timelines from discovery to approval together with the world’s first plasma and tissue diagnostic approved

Pre-clinical Phase I Phase II Phase III RegistrationResearch

~8 yr1-3 yr4-5 yr

3.1years

10 months 3.4 years

osimertinibapproved in US Nov 2015

cobas® EGFR mutation test - V2

+

Timespan

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18

We continue to understand resistance mechanisms to osimertinib to prolong patient benefit

Early responses with savolitinib (MET inhibitor) / osimertinib combo in NSCLC

Pre-treatment 4 weeks32-yr female showing neck metastasis

with high MET-amplification

MET amplification (10–15% patients)

MEK/ERK pathway switching

Combination with immune-oncology molecules

Treating EGFRM+ NSCLC with brain metastasis

C797S EGFR (~40% patients) Nature Medicine, Thress et al, 2015

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v

19


v

Eberlein et al. (2015) Cancer Res.

Osimertinib/ selumetinib combo restores tumour regression in EGFR T790M

Tran

sgen

ic m

ouse

Pre-treatment Osimertinib 8W

Osimertinib 12W Combo 20W






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20


EGFR C797S mutation drives osimertinib resistance in the clinic

Thress et al. (2015) Nature Med

Pre-treatment

Osimertinib 6W

Osimertinib 23W

T790M

C797S






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Generation of an EGFR C797S cellular model

Generation of matched cell lines of gefitinib and osimertinib resistance

CRISPR used to generate EGFR C797S cellular model

Enables screening of molecules in C797S model to identify next-generation EGFR inhibitors

EGFR ex19del

PC9 cell line

EGFR ex19 del, T790M

EGFRex19 del,T790M,

C797S

gefitinib sensitive

gefitinib resistant

gefitinib resistant

osimertinib sensitive

osimertinib sensitive

osimertinib resistant

22

Case study 2

DNA damage response therapies

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Our DNA damage response (DDR) portfolio is world leading

PARP inhibitor (olaparib) Approved

Single strand DNA break repair

ATM kinase inhibitor (AZD0156)

Phase I Double strand DNA

break repair Wee1 kinase

inhibitor (AZD1775)Phase I & II

Cell cycle regulator

ATR kinase(AZD6738)

Phase IDNA replication &

double strand break repair

DNA-PKLead optimisationDouble strand end

joiningApproved

Clinical

Pre-clinical (Lead optimisation)

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Olaparib is a first-in-class PARP inhibitor for BRCAm ovarian cancer

Exploits tumours with defective DNA repair mechanism

Initial research by Professor Steve Jackson at University of Cambridge

Discovered and developed by KuDOS and AZ scientists

Approved in US and EU Q4 2014

Clinical benefit in BRCAmovarian cancer

v

Prop

ortio

n of

pati

ents

pro

gres

sion-

free

00

1.0

3 6 9 12 15

0.5

Placebo BRCAm

Olaparib BRCAm

Months

Olaparib, n=74 Placebo, n=62Median 11.2 mo 4.3 mo

HR=0.18 95% CI (0.10, 0.31); P<0.00001

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AZD1775 (Wee1) expands therapeutic opportunity beyond chemo combination for multiple untreatable cancers

Wee1 inhibition drives cell to catastrophic cell death

Ph2 efficacy in platinum resistant ovarian cancer

Emerging data

− Potential in breast, ovarian and lung cancer

− Combination with olaparib or olaparib failures

− Combination with IO molecules

AZD1775 improves on SOC for platinum resistance ovarian cancer

R

R

R

Threshold for response

ORR (CR+PR) = 41%cf SOC ~10%

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AZD1775 (Wee1) expands therapeutic opportunity beyond chemo combination for multiple untreatable cancers

Wee1 inhibition drives cell to catastrophic cell death

Ph2 efficacy in platinum resistant ovarian cancer

Emerging data

− Potential in breast, ovarian and lung cancer

− Combination with olaparib or olaparib failures

− Combination with IO molecules

v

AZD1775 combined with olaparib has superior efficacy in a variety of models

AZD1775 (optimized dose)

Tum

our v

olum

e

vehicle

olaparib 100 mg/kg

dosing stopped on day 28

Days7 14 21 28 35 42 49 56 63 70 77

AZD1775 (NCI dose)

olaparib & AZD1775

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Basket trials will become even more important as we stratify patient segments further

National Lung Matrix trial

Lung Cancer Master Protocol trial

Simultaneous NGS testing of cancer-related genes

Drug identified on tumour specific changes

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Outline




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Extending personalised healthcare beyond oncology

Point of care testing for gout

Clinical trial enrichment for neurodegeneration

Identifying the right patient in severe asthma

Next generation sequencing for disease variants

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No single cognitive test to diagnose prodromal Alzheimer’s Disease (AD)

Amyloid-β peptide (Aβ) production is a key driver in AD pathophysiology

Routes for enrichment - CSF biomarkers, apoE genotype and PET imaging

NAV4694 Aβ PET radioligand


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Castro et al., Lancet 2014

~40-60% of severe asthmatics have elevated eosinophil count

Benraluzimab (anti-IL-5Rα) depletes eosinophils

Greater response in patients with high eosinophil counts from Phase II trials

Ann

ual e

xace

rbat

ion

rate

re

duct

ion

rela

tive

to p

lace

bo

Baseline blood eosinophil count cutoff (cells per µL)

Benraluzimab 2mgBenraluzimab 20mgBenraluzimab 100mg

0 50 100 150 200 250 300 350 400 450 500

100

50

0

-50

-100


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Gout not adequately managed in 40-60% patients

Achieving sustained serum UA lowering would improve patient care

Solution: UA test meter that delivers comparable results to clinical laboratory testing


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Uncovering new diagnostics & treatments - genotyping 100,000 patients with cancer & rare diseases

Insight into diabetes & cardiovascular diseases - genotyping ~80,000 consented AZ trial patients


…will enable us to change the way we treat disease and transform lives

What science can do

Being open for collaboration…

…creating an environment where science thrives

…and challenge conventional thinking

harnessing the power of genomics and personalised healthcare mene pangalos festival of genomics21...

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