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Harnessing the power of genomics and personalised healthcare
Mene PangalosFestival of Genomics 21 January 2016
IMED Biotech Unit2
Outline
Applying PHC across all therapy areas
Our progress in oncology
PHC is integral to AZ strategy
IMED Biotech Unit3
Outline
Applying PHC across all therapy areas
Our progress in oncology
PHC is integral to AZ strategy
IMED Biotech Unit4
The quality of submitted applications has risen sharply
Exane BNP Paribas Research, Jan 2016
IMED Biotech Unit
IMED Biotech Unit6
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)
IMED Biotech Unit7
Embedding patient stratification and biomarker use early in the R&D process is critical
IMED Biotech Unit8
>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
IMED Biotech Unit9
Outline
Applying PHC across all therapy areas
Our progress in oncology
PHC is integral to AZ strategy
10
Case study 1
Osimertinib for non-small cell lung cancer
IMED Biotech Unit11
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
IMED Biotech Unit12
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
IMED Biotech Unit13
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
IMED Biotech Unit14
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
IMED Biotech Unit15
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
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
IMED Biotech Unit
v
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
IMED Biotech Unit
v
19
We continue to understand resistance mechanisms to osimertinib to prolong patient benefit
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
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
IMED Biotech Unit
v
20
We continue to understand resistance mechanisms to osimertinib to prolong patient benefit
EGFR C797S mutation drives osimertinib resistance in the clinic
Thress et al. (2015) Nature Med
Pre-treatment
Osimertinib 6W
Osimertinib 23W
T790M
C797S
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
IMED Biotech Unit21
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
IMED Biotech Unit23
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)
IMED Biotech Unit24
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
IMED Biotech Unit25
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%
IMED Biotech Unit26
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
IMED Biotech Unit27
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
IMED Biotech Unit28
Outline
Applying PHC across all therapy areas
Our progress in oncology
PHC is integral to AZ strategy
IMED Biotech Unit29
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
IMED Biotech Unit30
Clinical trial enrichment for neurodegeneration
Identifying the right patient in severe asthma
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
Extending personalised healthcare beyond oncology
IMED Biotech Unit31
Clinical trial enrichment for neurodegeneration
Identifying the right patient in severe asthma
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
Extending personalised healthcare beyond oncology
IMED Biotech Unit32
Point of care testing for gout
Next generation sequencing for disease variants
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
Extending personalised healthcare beyond oncology
IMED Biotech Unit33
Point of care testing for gout
Next generation sequencing for disease variants
Uncovering new diagnostics & treatments - genotyping 100,000 patients with cancer & rare diseases
Insight into diabetes & cardiovascular diseases - genotyping ~80,000 consented AZ trial patients
Extending personalised healthcare beyond oncology
…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