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The next wave of
scientific innovation
Innovative Medicines & Early Development Biotech Unit
2015 – a year in review
Oncology combination therapies
AstraZeneca is investigating combinations
of biologic and small-molecule therapies for
the treatment of cancer. These combinations
target the tumour directly and some help boost
the body’s own immune system to induce
tumour cell death.
Contents
Introduction
2The next wave of scientific innovation
An introduction from Mene Pangalos
4
IMED 2015 in numbers
6The story of osimertinib (or AZD9291)
Our 5R framework in action
Biologics in the
treatment of asthma
The next wave of scientific innovation 1
An environment where
science thrives
An environment where science thrives
92 People: Inspiring great scientists
96Our strategic science centres
98 Building our future in Cambridge
100Case study: The next wave of innovation
in DNA damage response
104 Our reputation for scientific leadership
108Preparing for the future with our ‘IMED
Futures’ teams
Collaborating for
science innovation
CGI image of
AstraZeneca’s new
Global R&D Centre
and Corporate
Headquarters,
Cambridge, UK
Collaborating for science innovation
82Case study: Partnering to develop new
medicines for neurodegenerative diseases
84 Three science units with one shared goal
86Partnering to redefine the future of
drug discovery
90Case study: Partnering to develop the next
generation of antisense-based therapeutics
IMED functions
IMED functions
46 Discovery Sciences
52Case study: The technology
supporting our science – Acoustic
mass spectrometer
54 Drug Safety & Metabolism
62Personalised Healthcare & Biomarkers
72 Early Clinical Development
80 Shaping drug development in Asia
Therapy area progress
Therapy area progress
10 Oncology iMed
18Case study: The technology supporting
our science – Confocal Microscope
20Respiratory, Inflammation &
Autoimmunity iMed
30Case study: PT010 triple combination
speeds into Phase III
32 Cardiovascular & Metabolic Diseases iMed
40 Neuroscience iMed
Introduction
Delivering the next wave
of scientific innovation
The next wave of scientific innovation
An introduction from Mene Pangalos
In the last 12 months, we have continued to demonstrate the
strength of our science, setting new records to deliver lifechanging medicines to patients around the world. All of this has
been made possible through the dedication and commitment
of our amazing people, and their relentless passion for science
and innovation.
2015 also saw further progress in our pioneering approach to
open innovation. Thanks to the outstanding work of a small
team of people from our Strategic Partnering & Alliances group,
working alongside colleagues from our iMeds and Functions,
we have built a virtual pipeline supporting more than 20 clinical
and 80 pre-clinical studies. Since the launch of our IMED Open
Innovation portal in October 2014, we have seen >10,000 visits
and reviewed >350 proposals for new drug projects. It’s a
great example of how our scientists are being entrepreneurial,
creating an environment that is open for collaboration and
challenging conventional thinking.
In the last quarter, our organisation entered into an exclusive
agreement with the Wallenberg Centre for Protein Research to
identify new targets for disease research in the groundbreaking
area of the Secretome – research into all proteins that are
secreted by a cell or that are exposed to the outside of the cell
from within the cell membrane. The momentum continued right
up to the end of the year. In December, our IMED scientists
played a pivotal role, delivering the agreement to acquire a
majority equity stake in Acerta Pharma, which gives us access
to acalabrutinib (ACP-196), a potential best-in-class, smallmolecule oral BTK inhibitor.
Left
Mene Pangalos,
Executive Vice
President, IMED
Biotech Unit
Above
CGI images of
AstraZeneca’s new
Global R&D Centre
and Corporate
Headquarters,
Cambridge, UK
2 ©AstraZeneca 2016
Although not possible to capture all of the details of the incredible
contributions of our people across the IMED Biotech Unit in
2015, I hope this report gives you a flavour of the work we
have done and the role we have played in helping to ensure
AstraZeneca continues to push the boundaries of science.
Mene Pangalos
Executive Vice President,
IMED Biotech Unit
The next wave of scientific innovation 3
An environment where
science thrives
Throughout the year, our teams continued to look to the
future – exploring and investing in the next wave of scientific
innovation. We supported recommendations for investment
for our IMED Futures teams to explore emerging technologies
and innovations that have the potential to redefine the future
of healthcare. We invested in organs-on-a-chip technology
that could one day become an entire human body on a chip,
bringing us closer to our goal of reducing, refining and replacing
the use of animals in research. We also made significant
discovery investments to enhance the use of CRISPR precision
DNA-editing technologies across our discovery platforms,
and we are looking forward to further understanding its
application as a therapeutic option in our main therapy areas.
Collaborating for
science innovation
Another personal highlight is our progress in personalised
healthcare (PHC), developing targeted treatments matched using
diagnostics to the patients most likely to benefit, which has
been rapid by industry standards. In 2015, we launched seven
diagnostic tests and signed 13 diagnostic partnerships. These
achievements position AstraZeneca as a leading company in
personalised healthcare amongst our peers – a tremendous
accomplishment since the formation of our Personalised
Healthcare & Biomarkers group in 2011. We also announced a
collaboration with the Montreal Heart Institute (MHI) to search the
genomes of up to 80,000 patients for genes associated with
cardiovascular diseases and diabetes to support the discovery
of new targeted treatments for these serious conditions.
The AstraZeneca Senior Executive Team further demonstrated
the company’s commitment in this area at the end of 2015 by
agreeing a broader genomics strategy across the spectrum of our
discovery and development activities, something we look forward
to sharing more about in 2016.
IMED functions
“In the last 12 months,
we have continued
to demonstrate the
strength of our science,
setting new records to
deliver life-changing
medicines to patients
around the world.”
Secondly, our Respiratory, Inflammation and Autoimmune
team achieved a Phase III investment decision for PT010,
our triple combination inhaler for the treatment of patients with
COPD. The combination builds on the previously successful
Phase III outcome of our dual-LAMA/LABA combination
The quality of our science was also demonstrated with
our teams setting new records for scientific publications.
Our transformation in the last five years is nothing short of
exceptional, moving from a single high-impact publication
in 2010 to a record of 29 high-impact publications in 2015.
This not only reflects the quality of the research conducted
in our laboratories, but also demonstrates how our sciencedriven culture is helping to build the scientific reputation
of AstraZeneca.
Therapy area progress
During the year, our teams progressed a number of important
projects within our main therapy areas, helping to further
strengthen the AstraZeneca pipeline. While it is difficult to
pick out highlights, I will call out three key progressions:
Firstly, in oncology, where we saw the approval of osimertinib
(AZD9291) and the accompanying companion diagnostic in the
US in lung cancer. This is one of the fastest, if not the fastest,
drug approvals from first-time-in-human to launch in less than
three years. Adding a positive CHMP opinion towards the
end of the year rounded off an incredible achievement by our
teams, of which I am incredibly proud.
Finally, in CVMD, it was great to see the anti-microRNA from
our Regulus partnership, AZD4076 (anti-miR103/107) for nonalcoholic steatohepatitis, reach the clinic. Oligonucleotides play
an increasingly important role in our research portfolio, seeking
to target novel proteins at the desired tissue more effectively,
so these were important achievements for our team.
Introduction
2015 has been a remarkable year for our company, and for the
IMED Biotech Unit.
(PT003), and will also include the anti-inflammatory inhaled
corticosteroid budesonide. Our proprietary porous particle
co-suspension technology in the pMDI, developed by our
colleagues at Pearl Therapeutics, allows aerodynamically
efficient drug delivery.
IMED Biotech Unit by numbers in 2015
Around
60
Over
120
60
12
clinical project
combinations in
oncology
major
collaborations
post-docs
Phase I and
Phase II starts
90%
29
high-impact
publications
projects with
Personalised
Healthcare
approach
Over
29
$1bn
investment in
scientific research
clinical projects
7
2
2500
positive Phase
III investment
decisions
Nearly
$50m
generated through
Open Innovation
4 ©AstraZeneca 2016
companion
diagnostics
launched
people with
a passion for
science
Almost
450
peer-reviewed
publications
The next wave of scientific innovation 5
The story of osimertinib (or AZD9291)
Our 5R framework in action
AZD9291 – or osimertinib as it is now known – received Food
and Drug Administration (FDA) approval in November.
The stats
Positive data on osimertinib in
first-line EGFR mutated lung cancer
at the American Society of Clinical
Oncology (ASCO) meeting 2015:
– 81% patients on a once-daily
dose of osimertinib were
progression free at nine months
– Overall response rate 73%
– Longest duration of response was
ongoing at 13.8 months at the
time of data cut-off
Therapy area progress
1.59 million people die of lung cancer every year, one of the
biggest cancer killers in the world. Around 80-85% of lung
cancers are non-small cell (NSCLC) and its five-year survival rate
is less than 10%. Osimertinib was approved in the US for the
treatment of patients with metastatic EGFRm T790M non-small
cell lung cancer who have received prior EGFR-TKI therapy.
The T790M ‘gatekeeper’ mutation is prevalent in approximately
two-thirds of cases of EGFRm advanced NSCLC. This was
our biological target, and data from our clinical trials gave us
confidence that osimertinib would have a clinically meaningful
benefit and address an area of high unmet medical need.
“The science in our labs that generated
AZD9291 has been absolutely fantastic.
I still remember the first time our
scientists showed me our molecules
binding to the T790M mutated receptor
in 2010. The understanding of that
science, the quality of the chemistry
that we were doing, the biology, to
enable us to progress the molecule so
quickly through the research phase
and ultimately get the candidate out in
March 2013 was very, very impressive.
This is something that I think all our
scientists can be extremely proud of.”
Mene Pangalos, Executive Vice
President, IMED Biotech Unit
Introduction
The story of osimertinib or AZD9291 is a story of the fastest ever drug to make it from
discovery to market. And it all began right here with our IMED Biotech team, living our
values to follow the science, and challenge everything.
“I arrived at AstraZeneca in September
2010, and one of the first jobs that I had
to do was go through and review the
portfolio to rank and prioritise projects.
AZD9291 was in discovery at the time
and I think it’s helpful to go back to the
origins of thinking ‘why would we want
a drug like this?’ because at the time
it wasn't as obvious as it is now that
you have the data. I think you have to
recognise that the scientists that came
forward with this idea had to struggle
against some prevailing wisdom that
this might not be a useful thing to do.”
Susan Galbraith, Head of Oncology
iMed
Our 5R framework in action
Quality – not quantity
designed to overcome a common resistance mechanism,
‘gatekeeper’ mutation T790M
IMED functions
Right target
Osimertinib was one of the first
examples where we applied
the 5R approach, when it was
identified as a ‘must-win’ project.
Right tissue
good bioavailability and widely distributed in tissues, potential
objective response rate of 66%
Right safety
good tolerability profile, minimised hyperglycaemia risk and
unwanted activity on the receptor which causes rash and diarrhoea
Right patient
Collaborating for
science innovation
companion diagnostic – cobas® EGFR Mutation Test v2 for the
detection of T790M mutations in both tumour tissue and blood –
developed in partnership with Roche Molecular Systems
Right commercial opportunity
defining the value, understand more quickly and deeply the patient
subgroups and future viability
Plus… Right culture
team speed and flexibility to capitalise on the opportunity, and
drive innovation in every aspect of how we discover and develop
new therapies
6 ©AstraZeneca 2016
The next wave of scientific innovation 7
An environment where
science thrives
Innovation in the clinic
A clear vision
Needless to say, screening hundreds of lung cancer patients
to find the few with the correct genetic driver is slow and
expensive, challenging for physicians, and frustrating for the
patients – who have a lower probability of having the correct
genetic driver for the single targeted drug being tested.
This approach puts the patient at the centre of the trial,
offering more drug options for the patient through a single
trial process and a better chance of getting on the trial, while
allowing us to test the drugs more quickly and effectively.
Basket trials speed up the discovery of new medicines
making it possible to offer better medicines, to more patients,
more quickly.
13
Genetic drivers
of disease
ATM
Drug
AZD6738
5
14
3
38
15
30
7
4
13
MET
PIK3CA
pathway
LKB1
or TSC1/2
FGF2/3
KRAS
or NF1
EGFRm+
PIK3CA
pathway
LKB1
or TSC1/2
FGF2/3
KRAS
or NF1
savolitinib
AZD5363
AZD2014
AZD4547
Selumetinib
Osimertinib
or Gefitinib
AZD5363
AZD2014
AZD4547
Selumetinib
5
Figure highlighting % of patients with different genetic drivers of lung cancer and the
variety of drugs included in the basket trial to attack each of those specific genetic drivers.
What next for osimertinib?
Our teams continue to keep driving and keep looking for
novel and next-generation strategies to benefit patients
– from exploring potential benefits in other settings,
combination therapies and first-line therapy. We are also
starting to see that the same type of science and the same
type of approach can be used in other patients with other
diseases beyond oncology.
“The future is very exciting and osimertinib highlights a
key milestone in building our oncology pipeline. We’ve
launched olaparib, we have gefitinib, now osimertinib, and
we are keeping our eyes to the big milestone, launching
our immuno-oncology pipeline. This is a great time to be in
oncology in AstraZeneca.”
Mene Pangalos, Executive Vice President,
IMED Biotech Unit
The importance of collaboration
The companion diagnostic for
osimertinib was developed in
partnership with Roche Molecular
Systems (RMS). For patients who
may not be able to provide a biopsy
or whose test result based on a
tissue sample is unknown, then
circulating tumour DNA (ctDNA)
offers a solution in terms of a
source of DNA that can be analysed
for mutations. In this case, the
diagnostic approach developed with
RMS was especially important, as
assay development for the T790M
mutation that we were looking to
detect is challenging because of
the sequence surrounding that
mutation. Our early exploratory
work enabled us to find the test that
could detect the mutation in plasma
as well as tissue.
“To move so fast, you have to start from a very solid
foundation. In this case the solid foundation was really,
really excellent science. There was scientific purpose, there
was excellence by design if you will. The drug was designed
to do a job, and it did it.”
Flavia Borellini, Global Medicine Leader AZD9291,
Global Medicines Development
8 ©AstraZeneca 2016
The next wave of scientific innovation 9
An environment where
science thrives
“It was just amazing to sit in a room and actually see a slide
of a patient before and a patient after six weeks of treatment
and the tumour’s shrunk by 60%. It just doesn’t get any
better in terms of the science that we do here. For me it
was incredibly rewarding. Susan Galbraith came into the
office and I’ve never seen her so excited, she was practically
dancing. It was amazing!”
Ray Finlay, Medicinal Chemistry, IMED Biotech Unit
% of population
Collaborating for
science innovation
“From the first time this molecule went into patients we were
seeing a clinical response and that was just fantastic news for
patients, for the team who worked on the molecule and for
the organisation as a whole.”
Mark Anderton, Discovery Toxicologist Drug Safety &
Metabolism, IMED Biotech Unit
Squamous NSCLC
Adenocarcinoma NSCLC
IMED functions
An emerging solution to these challenges, which leverages
our broad portfolio in lung cancer, are ‘basket’ trials. These
are trials that don’t test a single drug, but a ‘basket’ of drugs,
each one targeting a specific molecular or genetic driver of
disease. Rather than screening for a single genetic driver in
a patient population, we can then screen patients for drivers
of their disease and match the right patient to the right drug
in the ‘basket’.
Patient cohort on trial
Therapy area progress
“In a project, you keep on making
compounds, testing compounds,
really until you’re absolutely sure
you have a high-quality compound,
clinical candidate. We had some
early compounds that looked
interesting. Unfortunately, when
we looked at them in more detail
we thought some of them had an
issue with hyperglycaemia, which
we believe is caused by off-target
inhibition of the insulin receptor.
As a chemistry team we were
able to design out that activity
with AZD9291, so AZD9291 came
through and didn’t have that liability
– this is something that we’re really
proud of as a chemistry team.”
Richard Ward, Principal Scientist
Chemistry, IMED Biotech Unit
Traditional clinical trials use a single drug for a given patient
population. If that population is small (for example, genetically
defined as 1% of the population), we would need to screen
100 patients to find the one patient that will benefit from
the targeted drug.
Basket trial
Introduction
“The early project team were a
fantastic group of people to work
with. I think what really helped
was we had a really clear vision of
what we wanted to do. We’d done
a lot of discussion and a lot of
consultation about what the profile
of the molecule needed to be and
we’d expanded it from its original
vision and then we were really
clear. The molecule needed to look
like this. It needed to have these
properties and this kind of potency,
not this kind of toxicity. I think that
really helps and the team really
gelled. Initially we weren’t under the
spotlight that AZD9291 is today.
It was a bit of a slow burner if you
like, but we delivered it very, very
quickly.”
Teresa Klinowska, Early Project
Leader Oncology iMed, IMED
Biotech Unit
Our increasing ability to identify the molecular or genetic
mechanisms that drive cancer, such as non-small cell lung
cancer (NSCLC), has allowed us to recognise and select
defined patient subgroups where an individual’s cancer
(disease segmentation) is identified by the molecular or
genetic driver. However, this brings new challenges in drug
development as patient subpopulations consequently
become smaller.
Oncology iMed
Our vision is clear. To help patients
by redefining the cancer-treatment
paradigm, with the aim of bringing
six new cancer medicines to patients
between 2013 and 2020. A broad
pipeline of next-generation medicines
is focused principally on four disease
areas – breast, ovarian, lung and
haematological cancers.
10 ©AstraZeneca 2016
The next wave of scientific innovation 11
Oncology iMed
Susan Galbraith, VP Oncology iMed
Opposite
Cancer cells
Top
Susan Galbraith,
VP Oncology iMed
The iMed saw significant progress in
its early discovery phase and clinical
phase portfolio. In addition to nominating
three new candidate drugs, we started
Oncology also provided extensive support
for the late-stage and Phase III pipeline:
Osimertinib: Provided data supporting
the potential for osimertinib in early-stage
disease, supported circulating tumour
DNA testing and generated exciting
efficacy data in leptomeningeal disease.
Olaparib: Provided scientific foundation
for expanding the use of olaparib beyond
germline BRCA for Solo 2 (ovarian
cancer) trial and gastric trials as well
as to support the Phase III investment
decision in prostate cancer.
Faslodex: Delivered data showing
activity of Faslodex in tumours with
ESR1 mutations.
Therapy area progress
Beyond these exciting data, there
were a total of 11 oral and 19 poster
presentations with iMed authors at
ASCO 2015.
clinical development of an ATM inhibitor
(AZD0156) and an aurora kinase inhibitor
(AZD2811). We moved three projects into
Phase II clinical trials and made significant
progress with our existing Phase II assets.
Introduction
“We have made a huge amount of progress in a short time while moving to our new location
in Cambridge this year, including supporting Phase III investment decisions for osimertinib
in the adjuvant setting, and expansion in leptomeningeal disease, and olaparib in prostate
cancer. We also achieved three candidate drug investment decisions and two compounds
entering first time in human trials. There was great progress in the Discovery phase, setting
us up for exciting candidate drug progressions in 2016 and 2017. We now have over half our
UK-based staff in Cambridge, and I would like to thank everyone involved in making this
transition successful.”
The approval of osimertinib towards
the end of the year was a key highlight,
just 32 months after first-dosing in
patients. At the American Society of
Clinical Oncology (ASCO) meeting
2015, AstraZeneca presented positive
data on osimertinib in first-line EGFR
mutated lung cancer. Data showed that
81% of patients on a once-daily dose of
osimertinib were progression-free at nine
months, with an overall response rate of
73%. The longest duration of response
was ongoing at 13.8 months at the time
of data cut-off.
Highlights
Opportunities with Starpharma and Heptares Therapeutics. For Starpharma, this was for the
use of their dendrimer drug delivery technology in the development and commercialisation
of one of our oncology compounds with the potential to add additional compounds later.
Heptares Therapeutics – we have gained exclusive global rights to develop, manufacture and
commercialise HTL-1071 (now AZD4635), an adenosine A2A receptor antagonist.
Demonstrate progress in at least two
scientific areas based on external
collaboration.
22 papers derived from collaborations published /accepted in 2015. This included several
publications in impactful journals, including on PI3K inhibition in Cancer Cell and on
blockade of AKT and MEK in Ras-driven tumours in Clinical Cancer Research
Deliver new portfolio opportunities in an
Emerging or Asian Oncology Market.
Collaboration with China team on osimertinib; three Korean master agreements; launch of Taiwan
translation fellowship programme; Koc University (Turkey) studentship for target validation.
Build a credible small-molecule drug
discovery effort around immunooncology targets.
A strategic push to explore possibilities for small-molecule drugs and relevant targets in
the exciting immuno-oncology arena with the idea of integrating with and complementing
the checkpoint antibodies and other biologics coming from our MedImmune colleagues.
We developed key capabilities and hired staff with strong backgrounds in immunology.
We focused on factors that promote the immunosuppressive microenvironment that exists in
many tumours. We now have two ongoing clinical trials with antagonists of STAT3 signalling
and CXCR2, both combined with durvalumab and we recently licensed a clinical phase
Adenosine A2a antagonist (AZD4635).
Refresh our early-stage
discovery strategy.
Focused effort into three main areas – oncogenic drivers and resistance mechanisms,
DNA damage response biology and finally immuno-oncology.
To deliver a comprehensive solution for
patients with EGFR-driven non-small cell
lung cancer.
A drug combination strategy to drive deeper and more durable responses and have ongoing
clinical studies combining our EGFR inhibitors with inhibitors of both MEK and cMet, as well
as a collaboration with Incyte to explore JAKi, all pathways that have been shown pre-clinically
and/or clinically to contribute to drug resistance. Finally, while osimertinib represents an
important solution for patients with T790M resistant disease we are committed to exploring
resistance mechanisms that arise in patients and initiating efforts to address those events.
The next wave of scientific innovation 13
An environment where
science thrives
Close two licensing deals.
Collaborating for
science innovation
We delivered
IMED functions
12 ©AstraZeneca 2016
We set out to
Highlights
We delivered
Enhance AstraZeneca’s capability to
perform Next Generation Sequencing
programmes.
Augmented laboratory and computational Next Generation Sequencing (NGS) capabilities,
which increased throughput and delivery for oncology projects. NGS support of pre-clinical
and clinical programmes resulted in programme line-of-sight, targets, PHC, biomarker
assays, CDx development, model characterisation, genetic drivers, and mechanisms
of resistance. As we work to build an integrated sample-to-answer workflow, Oncology
NGS Lab and Production Informatics’ efforts have matured from methods development
to methods optimisation and scale-up. These new tools will enable biologists to more
seamlessly integrate sample and patient data to explore and understand genotype and
phenotype and begin to deliver on the promise of precision medicine.
Build our Phase II pipeline.
– Data sets that showed AZD1775 (Wee1 inhibitor) has activity in combination with
platinum-based chemotherapy in ovarian cancer. Data from a single-centre study in
Platinum-resistant and refractory disease demonstrated a 41% response rate and was
presented at the ASCO meeting. Importantly, combination dosing of AZD1775 with both
durvalumab and olaparib was initiated in 2015
– Three compounds into Phase II clinical trials. AZD9150 is a STAT3 antisense
oligonucleotide, which started a Phase II trial dosing in combination with anti-PD-L1
durvalumab. The trial also allows us to evaluate the combination of durvalumab with
AZD5069, a small-molecule inhibitor of the chemokine CXCR2. The third compound was
AZD3759, an EGFR inhibitor designed to have increased brain penetration. AZD3759 met
the predetermined PoM criteria
An approved companion diagnostic for osimertinib, and worked to identify and characterise
mechanisms of clinical resistance. In addition, the team led work to support potential for
olaparib beyond germline BRCA in ovarian, gastric and prostate cancers.
Create the Cambridge Cancer Science
Symposium with MedImmune.
A successful event with 286 attendees, 12 topics, 75 talks, 136 posters, 17 academic
institutes that has encouraged early project openness and identified many immunooncology and combination approaches.
Olaparib
In 2015, the Phase III investment decision was made for
olaparib in metastatic castrate resistant prostate cancer
(mCRPC). There is a high unmet need and an opportunity
to advance standard of care (SOC) with personalised
medicine. Prostate is the most common cancer in men
and the sixth leading cause of cancer death among men.
New hormonal agents (abiraterone and enzalutamide) and
taxanes (docetaxel and cabazitaxel) are SOC. Although the
heterogeneity of mCRPC is well recognised; treatment to
date has not been driven by companion diagnostics (CDx). In
2015, we have generated limited but very encouraging data
14 ©AstraZeneca 2016
from TOPARP A (biomarker +ve N=16) with an 88% response
rate and mean progression-free survival of 9.8 months.
Studies are ongoing with the new data expected towards the
end of 2016. FDA provided useful insights, which will support
our development plan and innovative trial design given the
rarity of the patient population.
In addition, the translational science team have provided
support for broadening the opportunity for olaparib beyond
germline BRCA by developing the SOLO2 (confirmatory
Phase III trial in second-line ovarian cancer) for somatic
tumour-based BRCA testing plan, and by running a successful
concordance study for other mutations in genes involved in
Homologous Recombination Repair (HRR) with Myriad and
Foundation Medicine.
Dan Stetson was a major contributor
to the introduction of Next Generation
Sequencing and has continued to
drive the development of methodology
for projects and novel technologies.
Dan led the validation of the Illumina
platform for NGS.
As a member of the KRAS team,
Sarah Ross provided a significant
contribution to the strategy for
candidate nomination. Sarah saved
significant investment on an HTS
through detailed biochemistry. This was
achieved in a year when Sarah moved
to Cambridge, has taken on some line
accountability and still delivers from
the bench.
Paul Lyne completed a phenomenal
achievement this year – successfully
leading all three projects that delivered
Candidate Drugs for the iMed. The
AZD4785 (Kras), AZD4635 (A2aR)
and AZD4205 (JAK1) projects all
progressed into the Pre-clinical stage
of development in 2015. These novel
targets required the team to build
creative development plans. In addition,
Paul has made major contributions to
the development of the next generation
of immune-modulatory agents
through the delivery of the Phase
II starts for AZD9150 (STAT3) and
AZD5069 (CXCR2) as well as working
with MedImmune to coordinate the
portfolio of small-molecule-largemolecule combination studies.
The next wave of scientific innovation 15
An environment where
science thrives
Powering the
Phase III pipeline
People spotlight
Collaborating for
science innovation
Support the late stage and Phase III
pipeline.
AZD9291 ADAURA study
Development of AZD9291 for early stage EGFRm disease
is a key component of the AstraZeneca lung cancer
strategy. The opportunity in adjuvant EGFRm NSCLC has
many compelling aspects. Firstly, there is an unmet need
to address the high relapse rate and impact long-term
survival through long treatment duration. This is possible
due to AZD9291 tolerability profile. AstraZeneca is ideally
placed to strengthen its scientific leadership in NSCLC
and personalised medicine as the adjuvant population is
expected to increase, especially in the US and Japan, due
to improved screening and early detection. We are now
embracing the next wave of scientific innovation and enrolling
EGFRm patients in the adjuvant setting to meet recruitment
targets to development this new modality.
IMED functions
– Encouraging response rate data with AZD5363 (AKT) monotherapy in AKT1 mutant breast
cancer; to drive increased durability of response the first patients have been dosed with a
combination of AZD5363 and Faslodex
The primary objective was to assess the safety and tolerability
of osimertinib in patients with LM. All 13 patients were Asian
with adenocarcinoma. Three of eight patients had improved
neurological exam per investigator; of five patients with normal
neurological exam at baseline, four had no change. Eight
patients are continuing treatment with osimertinib beyond
four months. One patient with neurological improvement was
This initial data has been very well received at global and
US Advisory Boards and we are now enrolling a larger
expansion cohort.
Therapy area progress
– Full recruitment of the Phase II trial for savolitinib (AZD6094; a cMet inhibitor) in papillary
renal cell carcinoma and preliminary data from the TATTON trial was presented at the ASCO
meeting, which supports combination therapy in patients with a cMet amplification who lack
the T790M secondary mutation
There is no established effective treatment for LM disease.
Different treatment approaches are used such as radiation,
systemic or intrathecal chemotherapy with limited success.
The overall survival is 7-14 months with LM from EGFRm
NSCLC previously treated with an EFGR tyrosine kinase
inhibitor (EGFR-TKI). However, through collaboration with
our Innovation Center in China, we have established a
preclinical rationale for osimertinib activity in CNS disease
and low incidence of progression in the brain among patients
without brain metastases suggests potential for CNS control.
Addressing an important unmet need, the opportunity for
differentiation was highlighted at Portfolio Review in June 2015
to support the case for an expansion study in Q4.
a 62-year-old Korean male, diagnosed with advanced nonsmall cell lung cancer (Ex19del, T790M) in March 2012 with
most recent progression due to LM spread in March 2015.
Prior therapy included multiple courses of chemotherapy, an
EGFR-TKI and WBRT in 2014. He presented with right lower
extremity weakness, headache and dyspnea. He started with
160 mg AZD9291 in April 2015. The LM response was ongoing
from week six, as was his extracranial disease. He showed
improved motor function while on treatment, progressing from
wheelchair bound to being able to walk with cane.
Introduction
We set out to
Osimertinib
The case was also successfully made to expand the osimertinib
cohort in a CNS disease study, to characterise and explore
label inclusion for leptomeningeal disease. Leptomeningeal
Metastasis (LM) is a devastating complication of NSCLC and
has been reported in 4–15% of NSCLC patients, resulting in
a very poor prognosis. An increased risk of CNS involvement
has been reported among patients with EGFRm NSCLC, in
particular those treated with a first-generation EGFR-TKI.
Oncology iMed small-molecule pipeline end of 2015
Phase I
Phase II
Phase III / Launch
AZD4635/A2aR
AZD4547 / FGFR
AZD5363 / AKT
Selumetinib / MEK
AZD4785/KRAS ASO
AZD8186 / PI3Kb
AZD2014 / TOR
AZD9291 / EGFR
AZD4205/JAK1
AZD6094 / cMet
AZD9496 / SERD
AZD9150 / STAT3
AZD5069/ CXCR2
AZD0156 / ATM
AZD3759/EGFR-BBB
Schug Z, Peck B, Zhang Q, Jones DT, Grosskurth S,
Alam I, Smethurst E, Mason S, Byth K, McGarry L, James
D, Shanks E, Kalna G, Saunders B, Jiang M, Howell M,
Lassailly F, Thin MZ, Spencer-Dene B, Stamp G, Harris A,
Abogaye E, Critchlow S, Wakelam M, Schulze A, Gottlieb E
Cancer Cell
Feedback suppression of PI3Ka signalling
in PTEN-mutated tumours is relieved by
selective inhibition of PI3Kβ
Schwartz S, Wongvipat J, Trigwell CB, Hancox U,
Carver BS, Rodrik-Outmezguine V, Will M, Yellen P, de
Stanchina E, Baselga J, Scher HI, Barry ST, Sawyers CL,
Chandarlapaty S, Rosen N
Nature Reviews Drug
Discovery
An analysis of the attrition of drug candidates
from four major pharmaceutical companies
Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrel
S, Owen RM, Pairaudeau G, Pennie WD, Pickett SD, Wang
J, Wallace O, Weir A
Nature
Patient-centric trials for therapeutic
development in precision oncology
Biankin AV, Piantadosi S, Hollingsworth SJ
Nature Medicine
Acquired EGFR C797S mutation mediates
resistance to AZD9291 in non-small cell lung
cancer harbouring EGFR T790M
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D,
Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan
D, Matthews SE, Cantarini M, Barrett JC, Janne P, Oxnard G
Journal of Clinical
Oncology
Randomized, double-blind Phase II trial with
prospective classification by ATM protein
level to evaluate the efficacy and tolerability
of olaparib plus paclitaxel in patients with
recurrent or metastatic gastric cancer
Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim
YH, Park JO, Chun HG, Zang DY, Fielding A, Rowbottom J,
Hodgson D, O'Connor MJ, Yin X, Kim WH
Samsung Medical Centre, Seoul,
South Korea
Oregon Health Sciences University,
Portland, Oregon and the Leukemia and
Lymphoma Society, New York, US
Bind Therapeutics, Boston, US
Gastric Cancer Alliance. Basket study
with selumetinib, savolitinib, AZD1775,
AZD5363, and AZD2014 plus paclitaxel
in second-line Gastric Cancer,
with biopsies.
Test primary AML samples with
biomarker/genetic association follow-up.
Development of AZD2811 nanoparticle
aurora B kinase inhibitor. Nanoparticle
approach provides a slow release
profile so a single infusion will give
multiple-day efficacious cover of
the target and delivered improved
therapeutic index in pre-clinical models.
Nature Reviews Cancer
MEK1 and MEK2 inhibitors and cancer
therapy: the long and winding road
Caunt CJ, Sale MJ, Smith PD, Cook SJ
Nature Reviews Molecular
Cell Biology
Targeting the DNA damage response
in cancer
O’Connor MJ
Cell Metabolism
Leptin, BMI and metabolic gene expression
signature are associated with clinical outcome
to VEGF inhibition in colorectal cancer
Pommier AJC, Farren M, Patel B, Wappet M, Michopoulos
F, Smith NR, Kendrew J, Frith J, Hubby R, Eberlein C,
Campbell H, Womack C, Smith PD, Robertson J, Morgan
S, Critchlow SE, Barry ST
Vall d’Hebron Institute of Oncology,
Barcelona, Spain
Driving open innovation through clinical
partnerships with 16 French Centres.
Effective working across IMED, GMD,
MedI and AstraZeneca France.
Genetic Determinants of Wee1 and
Parp inhibitor sensitivity. Identify
genetic backgrounds that correlate with
sensitivity to olaparib and AZD1775 and
the effectiveness of the combination.
An environment where
science thrives
Institut National du Cancer,
Luxembourg City, Luxembourg
Collaborating for
science innovation
Acetyl-coA synthetase 2 promotes acetate
utilization and maintains cancer cell growth
under metabolic stress
IMED functions
Cancer Cell
AZD1775 / Wee1
Key Oncology iMed collaborations in 2015
16 ©AstraZeneca 2016
Authors
Olaparib / PARP
AZD8835 / PI3Ka
AZD2811 / AUR-N
Title
Therapy area progress
AZD6738 / ATR
Publication
Introduction
Pre-clinical
Key Oncology iMed publications in 2015
The next wave of scientific innovation 17
Case study
Behind the scenes
Automated confocal microscope
Our technique of choice for high resolution microscopy
The technology supporting our science
The stats
– High throughput, fast, automated confocal imaging of live
and fixed cells and tissue
– Faster than any other automated microscope that we had
previously. For example, it can image a 384 well plate in
three colours (one field of view) in around five minutes.
Compare this to other widefield microscopes that we have,
which can take ten times longer to image the same plate.
– Imaging with spatial cellular resolution (to monitor cellular
trafficking, for example)
– Imaging in multiple formats from slides to 1536 MTP plates
"This instrument promises
new capability with
improved assay quality
at fast acquisition rates
and will enable Discovery
Sciences to expand their
assay portfolio to support
all of the IMED Biotech Unit."
– Enabling capabilities that we didn’t have before – confocal
imaging at higher throughput. The only true confocal
platform that we had previously was a stand-alone
microscope which was only capable of processing single
samples and so imaging a 384 well plate could take a
scientist several days, now this can be achieved in as
little as five minutes.
Case study
The facts
The Automated confocal microscope (CV7000) is an automated confocal
fluorescence microscope that can acquire images from live or fixed cells
and tissue samples. Confocal microscopy is an imaging technique widely
used for increasing cellular spatial resolution by eliminating out-of-focus
light through the use of pinholes placed at the confocal plane of the lens.
Confocal microscopy has become an essential tool for the life sciences
and is the technique of choice for high resolution microscopy.
The scientist perspective
“The use of more physiological, cellular and tissue models including primary
cells, stem cells and multicellular systems in preclinical drug discovery
is now commonplace. Such models are often 3D in nature and therefore
cannot be effectively imaged by traditional wide-field systems. In addition,
AstraZeneca has invested heavily in phenotypic screening initiatives and
precise genome editing. Having access to powerful detection microscopes
that can detect subtle cellular phenotypic changes is critical to realising the
full potential of such investments.
We evaluated current and future project demand and it was clear that there
were many projects spanning our R&D functions that could benefit from
the purchase of the CV7000. This instrument promises new capability
with improved assay quality at fast acquisition rates and will enable
Discovery Sciences to expand their assay portfolio to support all of
the IMED Biotech Unit. The ability to image and extract data from more
complex cellular models with improved physiological relevance early in
drug discovery will speed up the discovery process and reduce attrition.
The microscope was installed at the latter end of 2015 and we have
already started to use the system to impact projects where cellular spatial
resolution is a requirement and for use with thicker tissue specimens.
We are open to collaboration and would encourage interested parties to get
in touch if they are interested in getting access to our microscopes.”
Samantha Peel, Senior Research Scientist, Discovery Sciences
Confocal imaging
of a 384 well
plate could take a
scientist several
days, now this can
be achieved in as
little as five minutes
18 ©AstraZeneca 2016
The next wave of scientific innovation 19
Respiratory,
Inflammation
& Autoimmunity
iMed
AstraZeneca holds a unique position in
respiratory disease, including asthma,
chronic obstructive pulmonary disease
(COPD) and idiopathic pulmonary fibrosis
(IPF), with a range of differentiated,
potential medicines in development
by leveraging novel combinations,
biologics and devices. The pipeline also
has a number of promising assets in
inflammatory and autoimmune diseases
within areas such as psoriasis, psoriatic
arthritis, gout, systemic lupus and
rheumatoid arthritis.
20 ©AstraZeneca 2016
The next wave of scientific innovation 21
Respiratory, Inflammation
& Autoimmunity iMed
Introduction
“2015 has been a transformative year where we have become fully staffed with the optimal
scientific profile. The right mix of scientists is now breathing science and working on
the RIA iMed portfolio, which aims to transform the lives of patients with respiratory,
inflammatory and autoimmune diseases.”
Maarten Kraan, VP RIA iMed
Therapy area progress
Our third breakthrough was discovering
a vastly improved approach to access
crystalline material in the early phase
of inhaled delivery projects. This allows
crystallisation conditions to be identified
in a reproducible and controlled way,
and consume only small amounts
of compound. Multiple studies can
be automated and processed in
parallel, effectively removing one of
the major bottlenecks in inhaled drug
discovery projects.
An environment where
science thrives
By polarising human alveolar
macrophages ex-vivo, we have been
able to identify unique COPD-specific
gene signatures. The identification of
novel gene signatures for polarisation
status has led to new understanding
of potential disease-relevant functions
of alveolar macrophages in COPD.
In addition, the experiments uncovered
a remarkable cell plasticity independent
of disease severity, opening up the
potential for new therapeutic strategies
targeting alveolar macrophages
polarisation in COPD.
Collaborating for
science innovation
Our ambition is to drive the scientific
excellence agenda and lead the
development of game-changing,
inhaled, immuno-modulatory treatments
for asthma and COPD patients. All core
functions work together to provide the
necessary scientific innovation, patient
insight and technology to achieve
that goal. Some significant, industryleading breakthroughs in 2015 included:
characterisation of gene signatures
for subsets of alveolar macrophages
towards modulation of innate immunity
in COPD; first ever measurement of in
vivo lung receptor occupancy and early
exploration of crystallisation conditions
to fundamentally change inhaled drug
dose estimation.
We have created a new paradigm in
inhalation drug discovery. Without
the means to assess the relationship
between local tissue exposure and
unbound pharmacologically active
drug after inhalation, it has been
notoriously difficult to establish solid
PK/PD understanding for inhaled
drugs. Our Drug Metabolism and
Pharmacokinetics group has developed
a new methodology to determine
receptor occupancy in the lung,
thus providing an elegant solution
for describing PK/PD relationships.
This was accompanied by a novel and
sophisticated mathematical model,
which gave input into drug design
strategies and a way to better predict
clinical outcome.
Above
Maarten Kraan,
VP RIA iMed
22 ©AstraZeneca 2016
The next wave of scientific innovation 23
IMED functions
Transforming clinical practice
and patient outcomes in
chronic respiratory diseases
Highlights
We delivered
– Collaboration results that
significantly contributed
to several projects in our
portfolio (PI3K, MALT1
andRORg, as well as LTC4S
(with our partner Orexo)
– Three major new
collaborations
– 12 publications from
collaborations
We delivered
– Recruitment of a Chief
Scientist with worldleading scientific record
(Gary Anderson)
– 10 out of 12 new recruits
directly from academia with
strong science background
– 71 publications in major
peer-reviewed journals
We delivered
– Solid portfolio progress in
all phases of development
(from target selection to end
of Phase II)
– Two projects with positive
Phase II data out of which
one was chosen for internal
progression into Phase III
(PT010 Triple COPD)
Transformation timeline
Today
2015+
Win in Inhaled
The future
2020+
Transform
disease
management
Lead with innovative precision
This year, we started to research a firstin-class, inhaled on-demand treatment
to prevent exacerbations. As a result,
the inhaled immunomodulator AZD9412
(recombinant IFN-β1a) progressed
to Phase II evaluation in severe
asthmatics. In-licensed from Synairgen,
AZD9412 is being developed as
an inhaled, on-demand therapy for
patients with a history of exacerbations
following respiratory viral infection
symptoms. Such a targeted treatment
approach could provide a major
breakthrough in preventing morbidity in
asthma, and potentially COPD patients.
People spotlight – a new generation of RIA iMed scientists
Our first rising star is Madelene
Lindqvist, who joins us after four
years as a postdoctoral fellow at
Harvard Medical School, bringing
with her profound expertise in
adaptive immune mechanisms.
Madelene has worked on T
follicular helper cells and their role
in context of HIV infection, which
resulted in several publications
in high-impact journals including
Science Translational Medicine,
Journal of Clinical Investigation,
Nature Medicine and Nature
Communications.
The recruitment of Kumar
Krishnaswamy from Yale University
School of Medicine even further
strengthens the immunomodulation
research in RIA. At Yale, Kumar’s
postdoctoral research over the last four
years was on innate-adaptive immune
crosstalk with a particular focus on the
role of dendritic cell subsets driving
respiratory diseases like asthma. This
generated key papers published in
journals such as Proceedings of the
National Academy of Science of the
United States of America.
A major aspect of drug discovery and
development is to impact on clinical
outcome through predictive science.
In RIA iMed DMPK, key approaches to
prediction are mathematical modelling
and Quantitative Systems Biology.
In this context, Hoda Sharifian joins
us from ETH Zürich (Swiss Federal
Institute of Technology in Zurich)
and brings a unique skill set to
mathematically describe key biological
processes against an overlay of
relevant drug pharmacokinetic data.
Her PhD at ETH modelled feedback
regulations in the HOG MAPK pathway
based on single cell measurements,
resulting in high-quality publications
in Molecular Systems Biology and
Integrative Biology.
The next wave of scientific innovation 25
An environment where
science thrives
24 ©AstraZeneca 2016
Tomorrow
2017+
Lead with
innovative
“Precision”
approaches
Following last year’s groundbreaking
respiratory deal with Almirall, in 2015
we have advanced two dual-muscarinic
antagonist/β2 agonist bronchodilators
(MABAs, AZD8999 and AZD8871) into
Phase Ib evaluation in asthma and
COPD patients, with an intent to select
the best combination partner for SGRM
in COPD. These MABAs are in addition
to AZD2115 and others arising from
our long-standing collaboration with
Pulmagen Therapeutics.
2015 also saw pre-clinical development
of RIA’s first small-molecule in
development in a niche indication
with AZD5634 – an inhaled epithelium
sodium channel blocker (iENaC).
Collaborating for
science innovation
– Two progressions into Phase
II (Inhaled SGRM and Inhaled
IFNβ) the first of which
will enable future inhaled
combination treatments
2016 will see RIA’s continued scientific
innovation to address significant disease
severity and unmet medical need in
respiratory disease beyond asthma
and COPD.
Focused on the
enhancement
of inhaled
therapeutics,
stage one of RIA’s
research strategy
saw a number
of successful
developments
in 2015.
IMED functions
We set out to progress the RIA
project portfolio.
August saw the progression of an
inhaled, dry powder formulation of
AZD7594 into Phase II in asthma
patients. The inhaled non-steroidal
glucocorticoid receptor modulator
(iSGRM) potentially provides a
once-daily platform for novel antiinflammatory combinations that
may induce disease modification in
obstructive airway diseases. A coformulation of iSGRM with abediterol
has also advanced as a ‘best-inclass’ once daily future maintenance
treatment for asthma patients.
This paves the way for clinical evaluation
focused on restoring airway hydration,
mucociliary clearance (MCC) and
improving lung function in cystic fibrosis
(CF), an ultimately lethal respiratory
condition resulting from the genetic
dysfunction of the Cystic Fibrosis
Transmembrane Conductance Regulator
(CFTR). In pre-clinical evaluation,
AZD5634 increases airway surface
liquid (ASL) in vitro, improves MCC
in vivo, and thus, has the potential to
rehydrate the airways, restore primary
innate defence and impact upon
disease progression in CF patients.
Therapy area progress
We set out to strengthen our
scientific leadership in the
Respiratory, Inflammation and
Autoimmunity area.
Progress the portfolio
Focused on the enhancement of
inhaled therapeutics, stage one
of RIA’s research strategy saw a
number of successful developments
in 2015. In June, the advancement of
PT010 (a MDI-inhaled, combination
of budesonide, glycopyrronium and
formoterol) into Phase III clinical trials
for chronic obstructive pulmonary
diseases (COPD) marked a major step
forward for the portfolio. This was
made possible through our unique
technology that creates stable
co‑suspensions of drug crystals in
HFA propellants using lipid-based
porous particles.
Transform disease management
A key project in 2015 focused on
modifying the underlying pathology of
disease is the inhaled toll-like receptor
9 (TLR9) agonist project in asthma.
AZD1419 is an immune-stimulatory
oligonucleotide analogue identified
through collaboration with Dynavax
Technologies in California. Pre-clinical
studies have shown that stimulation of
TLR9 in mice induces a long-standing
protection against allergic inflammation
in the lung. In healthy volunteers,
inhaled AZD1419 was safe and able
to stimulate the local production of
Type 1 interferons in the lung, the first
step in the modulation of the immune
response. AZD1419 generates an
interferon signal in human lung at doses
lower than those causing influenzalike symptoms.
Introduction
We set out to ensure impact
from new and existing
collaborations.
Transforming clinical practice
and patient outcomes in
chronic respiratory diseases
Key RIA iMed publications in 2015
RIA iMed small-molecule pipeline end of 2015
Phase IIa
Phase IIb
Phase III
AZD7594/Abediterol
SGRM/LABA
AZD1419
Inhaled TLR9
AZD9412
Inhaled IFN-beta
Abediterol
LABA
PT010
Triple MDI (COPD)
AZD7594/tbd
SGRM/MABA
AZD7986
DPP1
AZD7594
Inhaled SGRM
PT010
Triple MDI (Asthma)
PT001
LAMA
AZD5634
iENaC (CF)
AZD8871
MABA
AZD7624
Inhaled P38
RDEA3170
URAT1 (Gout)
PT003
LABA/LAMA
AZD0284
RORg (LN)
AZD8999 MABA
Lesinurad
URAT1 (Gout)
AZD9567
Oral SGRM
Seys L, Verhamme F, Schinwald A, Hammad H,
Cunoosamy D, Bantsimba-Malanda C, Sabirsh A, McCall
E, Flavell L, Herbst R, Provoost S, Lambrecht B, Joos G,
Brusselle G, Bracke K
Clinical Pharmacology
and Therapeutics
Physiologically based pharmacokinetic
modelling in drug discovery and
development. A pharmaceutical
industry perspective
Jones HM, Chen Y, Gibson C, Heimbach T, Parrott N.J,
Peters SA, Snoeys J, Upreti VV, Zheng M, Hall SD
Journal of Controlled
Release
Specific accumulation of orally administered
redox nanotherapeutics in the inflamed
colon reducing inflammation with doseresponse efficacy
Vong LB, Mo J, Abrahamsson B, Yukio N
Mucosal Immunology
The Axl receptor tyrosine kinase is a
discriminator of macrophage function in
the inflamed lung
Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook
PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D,
Hussell, T
Structure
Ligand binding mechanism in steroid
receptors: from conserved plasticity
to differential evolutionary constraints
Köhler C
Journal of
Cheminformatics
Target prediction utilising negative bioactivity
data covering large chemical space
Mervin LH, Afzal AM, Drakakis G, Lewis R, Engkvist O,
Bender A
Molecular Pharmaceutics
Fast and general method to predict the
physicochemical properties of drug-like
molecules using the integral equation
theory of molecular liquids
Palmer DS, Misin M, Fedorov MV, Llinas A
Journal of Leukocyte
Biology
Targeting neutrophilic inflammation in severe
neutrophilic asthma: can we target the
disease-relevant neutrophil phenotype
Bruijnzeel PL, Uddin M, Koenderman L
American Journal of
Respiratory Cell and
Molecular Biology
Temporal and spatial expression of
transforming growth factor-beta following
progressive exposure to tobacco smoke in
spontaneously hypertensive rats
Hoang L, Bolton S, Wang L, Kenyon N, Nguyen Y,
Smiley-Jewell S, Pinkerton K
Journal of Pharmacology
and Experimental
Therapeutics
A novel in vivo receptor occupancy
methodology for the glucocorticoid receptor:
toward an improved understanding of
lung pharmacokinetic/pharmacodynamic
relationships
Boger E, Ewing P, Eriksson UG, Fihn BM, Chappell M,
Evans N, Fridén M
Disease Area
Asthma
RA
COPD
Other
Key RIA iMed collaborations in 2015
Introduced in 2015
Ongoing with 2015 achieved milestones
University of Southampton, UK
State Key Lab of Respiratory Disease,
Guangzhou Medical College, China
Catholic University of Leuven,
Belgium
Access to a large number of clinically
well-characterized patients to help map
somatic mutations in COPD patients.
Aims to identify trigger factors for COPD
exacerbations as well as exacerbation
phenotypes/endotype. Provides ‘real
world’ COPD cohort and information
on true exacerbations rates future
clinical trials.
Determine in vitro and in vivo role
of MALT1’s protease activity and
scaffolding role in immune cell’s
function. Key high-impact papers
published in 2015.
University of Helsinki, Finland
Uppsala University, Sweden
GLAZGo Discovery Centre,
Glasgow, UK
Insights into how RORg inhibitors
modulate the function and plasticity
of Th17 cells isolated from both
patients with autoimmune diseases
and healthy individuals.
Development of a lung slice methodology
to study mechanisms of inhaled drug
retention in the lung and allow tailoring of
inhalation pharmacokinetics to provide
long-lasting duration of effect. Contributing
fundamental knowledge and leadership in
the field of inhalation science.
The RIA iMed’s collaboration with
Glasgow University’s Institute of
Infection, Immunity and Inflammation is
breaking new ground in this area. This
collaborative enterprise has been fully
functional for the last 18 months, and
has already yielded 15 joint projects.
26 ©AstraZeneca 2016
The next wave of scientific innovation 27
An environment where
science thrives
Role of B cell activating factor (BAFF) in
chronic obstructive pulmonary disease
Collaborating for
science innovation
American Journal of
Respiratory and Critical
Care Medicine
IMED functions
Authors
Therapy area progress
Phase I
Title
Introduction
Pre-clinical Dev
Publication
Key RIA iMed publications in 2015
Nicholls DJ, Wiley K, Dainty I, MacIntosh F, Phillips C, Gaw
A, Mårdh CK
British Journal of Clinical
Pharmacolology
The effect of a selective CXCR2 antagonist
(AZD5069) on human blood neutrophil count
and innate immune functions
Jurcevic S, Humfrey C, Uddin M, Warrington S, Larsson B,
Keen C
Drug Metabolism and
Disposition
Lipid peroxide mediated oxidative
rearrangement of the pyrazinone
carboxamide core of neutrophil elastase
inhibitor AZD9819 in blood plasma samples
Gu C, Lewis RJ, Wells AS, Svensson PH, Hosagrahara VP,
Johnsson E, Hallström G
Respiratory Medicine
Neutrophil extracellular trap formation
and extracellular DNA in sputum of stable
COPD patients
Pedersen F, Marwitz S, Holz O, Kirsten A, Bahmer T,
Waschki B, Magnussen H, Rabe KF, Goldmann T, Uddin M,
Watz H
ChemMedChem
Benzoxazepines achieve potent suppression
of IL-17 release in human T-Helper 17 (TH17)
cells through an induced-fit binding mode to
the nuclear receptor RORγ
Olsson RI, Xue Y, von Berg S, Aagaard A, McPheat
J, Hansson EL, Bernström J, Hansson P, Jirholt J,
Grindebacke H, Leffler A, Chen R, Xiong Y, Ge H, Hansson
TG, Narjes F
Journal of Pharmaceutical
Sciences
Development of a novel lung slice
methodology for profiling of inhaled
compounds
Bäckström E, Lundqvist A, Boger E, Svanberg P, Ewing
P,Hammarlund-Udenaes M,Fridén M
Bioorganic and Medicinal
Chemical Letters
Discovery and evaluation of a novel
monocyclic series of CXCR2 antagonists
Austin RP, Bennion C, Bonnert RV, Cheema L, Cook AR,
Cox RJ, Ebden MR, Gaw A, Grime K, Meghani P, Nicholls
D, Phillips C, Smith N, Steele J, Stonehouse JP
Expert Review of
Respiratory Medicine
Immunology, genetics and microbiota in the
COPD pathophysiology: potential scope for
patient stratification
Malhotra R, Olsson H
Journal of Thoracic
Disease
Study on risk factors and phenotypes of
acute exacerbations of COPD in Guangzhou,
China – design and baseline characteristics
Zhou Y, Bruijnzeel PLB, McCrae C, Zheng J, Nihlen U, Zhou
R, Van Geest M, Nilsson A, Hadzovic S, Huhn M, Taib Z,
Gu Y, Xie J, Ran P, Chen R, Zhong N
Science Translational
Medicine
Antibodies to influenza nucleoprotein crossreact with human hypocretin receptor 2
Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M,
Pezzicoli A, Karle A, Rigat F, Rappuoli R, Narasimhan
V, Julkunen I, Vuorela A, Vaarala O, Nohynek H, Pasini
FL, Montomoli E, Trombetta C, Adams CM, Rothbard J,
Steinman L
Science
Infectious disease. Life-threatening influenza
and impaired interferon amplification in
human IRF7 deficiency
Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y,
Volpi S, Lafaille FG, Trouillet C, Schmolke M, Albrecht RA,
Israelsson E, Lim HK, Casadio M, Hermesh T, Lorenzo L,
Leung LW, Pedergnana V, Boisson B, Okada S, Picard C,
Ringuier B, Troussier F, et al
28 ©AstraZeneca 2016
An environment where
science thrives
Pharmacological characterisation of
AZD5069, a slowly reversible CXC
chemokine receptor 2 antagonist
Collaborating for
science innovation
Journal of Pharmacology
and Experimental
Therapeutics
IMED functions
Authors
Therapy area progress
Title
Introduction
Publication
The next wave of scientific innovation 29
Case study
A major innovation for
respiratory medicine research
PT010 speeds into Phase III
The secret behind the
co‑suspension technology
Global burden, personal struggle
The Pearl within
The idea behind the co-suspension
technology used in PT010 employs
tiny porous floating particles, to which
the crystals associate. With the floating
particles holding their stability, there is
no interaction between the medicines,
which remain in a uniform suspension
long after the simple inversion of the
inhaler, meaning a consistent and
correct dosage is inhaled every time.
With the co-suspension technology,
all strengths and combinations of
a drug delivers the same aerosol
performance. This attribute is very
important to regulatory agencies and is
a requirement for interpreting whether
pivotal clinical data have met the
'combination rule', which requires that
the combination product be superior to
its components.
There is a major global and individual
unmet medical need in COPD.
The World Health Organisation predicts
the fast-growing lung disease to
become the third leading cause of
death by 2030, and it can severely
affect quality of life for those in its grip.
In June 2013, AstraZeneca completed
the acquisition of Pearl Therapeutics,
which is focused on the development
of inhaled small-molecule
therapeutics for respiratory disease.
Pearl brought to the AstraZeneca
family the innovative co‑suspension
technology used in PT010.
When symptoms worsen, patients
become so short of breath they’re
unable to undertake day-to-day tasks;
struggling to climb the stairs, do the
laundry, or participate in family life.
The fast disease progression and
often late diagnosis means that many
sufferers find current treatments
inadequate – failing to open the airways
sufficiently to relieve the distressing
effects of COPD.
Case study
August 2015 brought a positive Phase III investment decision for PT010;
AstraZeneca’s fixed dosed triple for the treatment of COPD using Pearl’s
innovative co-suspension technology. If successful, this will offer an
improvement for patients suffering from a debilitating disease where true
advances have been few and far between. PT010 combines three wellestablished compounds – a LABA (formoterol), LAMA (glycopyrronium)
and an inhaled corticosteroid (ICS) (budesonide) in a totally new way that
aims to enhance patient adherence and improve clinical outcomes.
The inhaler challenge
In respiratory disease, inhalers are crucial to ensure delivery of the
drug into the lung tissue, but persistent problems limit their therapeutic
potential. To ensure consistency and interpretation of clinical outcomes,
the products must have consistent in-vitro delivered dose and
aerosolization properties, such as particle size distribution of the active
drug. Historically, achieving this consistency has been particularly
challenging for both dry powder inhalers (DPI) as well as with conventional
formulations of pressurized metered-dose inhalers (pMDI) that combine
multiple drugs. The co-suspension crystal technology for pMDIs was
developed to address exactly this challenge.
From dual to triple in record time
Patients with moderate or severe COPD commonly need two or three
different medicines to effectively relieve their breathlessness. Adherence
is key, and Pearl’s co-suspension technology seems to offer a solution
to the delivery challenge for fixed-dose combinations. The first step was
to test the technology for PT003, a dual-combination pMDI of the two
bronchodilators LABA and LAMA. This successful clinical development
programme led to an NDA in June 2015 and the results paved the way for
taking the technology one step further – to develop a fixed dose triple for
COPD patients containing a LABA, a LAMA and a corticosteroid.
PT010 combines – in a single inhaler – crystals of two long-acting
bronchodilators, LABA and LAMA with the ICS budesonide for immediate
relief of symptoms. Relying on the extensive evidence for the three monotherapies coupled with the positive data on PT003, the clinical team were
able to design a Phase III programme that was able to select and confirm
the doses for the individual components, enhancing it with dose-ranging
studies that included budesonide. The Phase II studies were executed
quickly due to the flexible approach of the teams, and by relying on the
porous particle technology that allowed for such speed.
“As a physician it’s great to see how innovative technology can breathe
new life into long-established medicines for the benefit of patients. As
a scientist, I’m envisioning a future treatment paradigm where we marry
this technology with novel pathways and compounds which tackles
different aspects of the underlying cause of the disease. To me, that’s
the essence of ‘What science can do’.”
Maarten Kraan, VP RIA iMed
“The journey so far with Pearl and the cosuspension technology has
been a tremendous experience. We have successfully combined
the know-how and muscle of the big, with the speed, agility and
courageousness of the small. I’m really excited to bring the results to
patients and physicians”
Martin Olovsson, VP Inhaled Respiratory, GPPS
“There is a huge unmet
medical need in COPD.
The beauty of the cosuspension technology
is that we’ve been able
to do what others have
tried and failed to do –
to combine three drugs
in one inhaler while
retaining their efficacy.
I believe that with this
technology, AstraZeneca
once again proves their
ambition to lead the way
in respiratory medicine,
and others will have
to follow”
olin Reisner, Head of Respiratory GMed & Chief
C
Medical Officer, Pearl Therapeutics
30 ©AstraZeneca 2016
The next wave of scientific innovation 31
Cardiovascular
& Metabolic
Diseases iMed
AstraZeneca’s strategy in CVMD
focuses on ways to reduce morbidity,
mortality and organ damage by
addressing multiple risk factors
across cardiovascular (CV) disease,
diabetes and chronic kidney disease
indications. The patient-centric
approach is reinforced by science-led
lifecycle management programmes and
technologies, including early research
into regenerative methods.
R
32 ©AstraZeneca 2016
The next wave of scientific innovation 33
Cardiovascular & Metabolic Diseases iMed
Marcus Schindler, VP CVMD iMed
Opposite
Cardiac-regenerating
muscle cells
Amongst this year’s achievements
is the continued improvement of
the quality and breadth of our key
collaborations that provides us with
Therapy area progress
Top
Marcus Schindler,
VP CVMD iMed
the opportunity to expand into novel
scientific areas whilst maintaining a
clear scientific focus. As an example;
together with Regulus Therapeutics
our CVMD scientists successfully
progressed the novel anti-microRNA
compound AZD4076 for the treatment
of non-alcoholic steatohepatitis (NASH)
into first-time-in-man (FTIM). At the
same time, our strategic collaboration
with Ionis Pharmaceuticals provided
us with the complementary toolbox
of antisense oligonucleotides to
address targets unsuitable for smallmolecule drug discovery in CVMD.
Our continued collaboration with
Moderna Therapeutics showed
promising results of the effect of VEGF-A
modRNA in cardiac regeneration.
Introduction
“2015 was a year of achievements for CVMD iMed. We delivered exciting progress in
our pipeline, continued to strengthen our new modalities platform and enhanced our
capabilities with new collaborations with world-leading academic institutions and biotech
companies. Our work is beginning to show the therapeutic potential of regenerative
approaches in cardiovascular and metabolic diseases.”
Throughout 2015, CVMD iMed
continued to advance and break new
ground with new and established
projects, creating the next wave of
scientific innovation. By making use of
our extensive knowledge and expertise
in the discovery and development
of small molecules we have further
expanded into a ‘new modalities’
platform of modified mRNA, micro RNA,
and antisense oligonucleotides. CVMD
iMed is now pursuing drug targets using
all of these modalities, small molecules
and combinations thereof.
IMED functions
We established 13 new collaborations that gave us the opportunity to work with new
techniques, and that enhanced our capabilities and expertise. Our collaborations make a
significant impact on our R&D pipeline in CVMD and we are looking forward to sharing and
advancing our findings in 2016.
We set out to enhance our scientific
reputation and demonstrate scientific
leadership.
We delivered 93 new publications in major peer-reviewed journals of which 50 in high-quality
journals and three in the world’s leading journals with particularly high-impact factor. Two of
our collaborations (with Shanghai Institutes for Biological Sciences and with University of
Michigan) each resulted in high-impact publications strengthening our scientific reputation.
Our impact on the scientific community could also be seen by the degree of citations of our
publications as well as attention from social media. Significant results reflecting the impressive
advancement of our discovery and clinical stage programmes were presented at key
conferences in 2015 including European Society of Cardiology (ESC), European Association
for the Study of Diabetes (EASD), American Diabetes Association (ADA), American Chemical
Society (ACS) and American Society of Nephrology (ASN).
We set out to strengthen our diabetes
research and pipeline.
We initiated an exciting five-year collaboration with Harvard Stem Cell Institute to bring in their
novel breakthrough technique which creates human insulin producing β-cells from stem cells.
In record time our CVMD scientists successfully set up and mastered this technique, which
is an immense achievement. The cells will be used in screens of AstraZeneca’s compound
library and in the search for new treatments for diabetes. The collaboration also aims to better
understand how the function of β-cells declines in diabetes and research findings will be made
available to the broader scientific community through peer-reviewed publications.
The next wave of scientific innovation 35
An environment where
science thrives
34 ©AstraZeneca 2016
We set out to expand our scientific
leadership in CVMD by collaborating
with the best science outside
AstraZeneca.
Collaborating for
science innovation
Highlights
Taking the road less travelled by
making a difference with regenerative
medicine and RNA therapeutics
2015 was an exciting year and we are looking
forward to further developing our science in 2016.
Every member of CVMD iMed can be proud of
our leaps forward.
An environment where
science thrives
36 ©AstraZeneca 2016
Diabetes/NASH
Non-alcoholic steatohepatitis (NASH) is
inflammation and damage to the liver caused by
a build up of fat in the liver. It is part of a group
of diseases known as non-alcoholic fatty liver
diseases. Some people with NASH have no
symptoms while in others, the fat build-up causes
inflammation, cell damage and in some cases
cirrhosis, to a point where the liver cannot work
properly. It is not known exactly what causes
NASH, but it is thought be caused by any number
of factors, including environmental, lifestyle and
genetics. NASH risk factors include obesity, insulin
resistance (type 2 diabetes) high cholesterol, high
triglycerides, and metabolic syndrome. Currently,
there are no approved drugs for NASH despite the
imminent progress to liver failure of these patients
if left untreated. Our scientists are aiming to bridge
this unmet medical need with the new modalities
drug AZD4076.
Dr Magnone’s expertise is a crucial part of the
research for CVMD iMed. With the ongoing
paradigm shift from ‘blockbuster’ therapies
towards a more personalised form of medicine,
based on sophisticated patient stratification
where prescribed drugs are based on specific
biological phenotypes rather than clinical
characteristics, her expertise is right on target.
Chiara has led several programmes aimed at
identifying patients’ molecular phenotypes
predictive of disease progression and in
response to investigational treatments as well
as pre-clinical programmes for the development
of novel personalised healthcare drugs. In
addition, her experience from the fields of
insulin resistance, obesity, type 2 diabetes,
NASH and chronic kidney disease truly
underlines the value she brings to CVMD iMed.
Collaborating for
science innovation
In parallel, the team is using cardiac stem cells
for screening of drug candidates; the aim is
to identify targets and pathways involved in
inducing and augmenting the human body’s
ability to regenerate and repair damaged cardiac
tissues. From these screens small-molecule
programmes were identified and are now being
validated using human cells and animal models
of heart failure. The broad range of modalities
including small and large molecules, antisense
technology, CRISPR and modified mRNA
available to our scientists enables investigation
and targeting new potential and previously
undrugable targets.
Top
Dividing pancreatic
beta cells
To further explore the possibilities of identifying
new treatments for diabetes a collaboration with
the Harvard Stem Cell Institute was initiated.
In diabetes, pancreatic β-cells are destroyed by
an autoimmune response (type 1) or the β-cells
either fail to function properly or their numbers
decrease (type 2). In the search for diabetes
treatments, human β-cells are a great asset;
however, these cells are extremely limited in
number and availability. With this collaboration
led by HSCI co‑chairman and Howard Hughes
Medical Institute Investigator, Professor Doug
Melton, our CVMD scientists have access to
a technique which allows potentially limitless
quantities of β-cells to be produced from humaninduced pluripotent stem cells generated directly
from adult cells. These cells would be similar in
all important aspects to those found in healthy
individuals and can be utilised for a multitude of
research purposes.
Maria Chiara Magnone joined AstraZeneca
in 2014 as Head of Translational Sciences,
CVMD iMed where she is responsible for
delivering human target validation, biomarkers
and personalized healthcare (PHC) hypothesis
generation across the CVMD portfolio. Chiara
brings over 12 years’ experience in the area
of CVMD biomarkers, personalized healthcare
and target translation and was recruited to
CVMD iMed from her position as Translational
Medicine/Biomarker Lead at Roche and has
previously held positions at Serono research
and Novartis Pharma.
IMED functions
In collaboration with Moderna Therapeutics,
our scientists have access to modified mRNA
(modRNA), which is an attractive modality for
the investigation of the local production of
paracrine factors known to be important for stem
cell activation and differentiation. If successful,
this approach has the potential to stimulate the
generation of new cardiac tissue and reverse
disease in patients with heart failure. One of
the lead modRNA projects, VEGF-A has shown
promising results in animal models. A single
injection of VEGF-A modRNA significantly
increased vascular density, reduced scar area
and improved the cardiac function in mice.
In addition, VEGF-A stimulated cardiac stem cells
(EPDCs) and induced a fate switch in these cells
towards endothelial cells and to some extent to
cardiomyocytes. These data demonstrate the
regenerative potential of VEGF-A modRNA in
the heart. The VEGF-A project is now moving to
first-time-in-man to assess safety and tolerability
as well as pharmacokinetics and local blood
flow response, a key biological mechanism
of VEGF-A.
Our pre-clinical studies have shown that inhibition
of miR-103/107 by AZD4076 in mouse models,
dramatically decreases liver triglyceride content
and improves insulin sensitivity in both liver and
peripheral tissues. AZD4076 has, therefore, the
potential to act as an efficacious insulin sensitising
therapy for NASH in patients with type 2 diabetes.
With the collaborative effort of CVMD scientists
and our partner Regulus Therapeutics Inc,
we have just initiated dosing in a first-time-in-man
Phase I clinical study. If successful, our compound
would be a first-in-class treatment for NASH.
People spotlight
Therapy area progress
Heart failure
In the cardiovascular arena CVMD scientists
are targeting the growing challenge of cardiac
dysfunction and heart failure. In heart failure the
heart’s capacity deteriorate over time and there
are currently no treatment options to reverse or
even address its severe and progressive nature.
A key feature of heart failure is damage due to
the gradually increasing loss of cardiac tissue
such as cardiomyocytes and blood vessels and
the aim of the CVMD research in this area is to
find a way to help the damaged heart to repair
itself. It was recently shown that progenitor
cells, which may play a role in cardiac repair, are
present in the adult heart. Our focus is to identify
targets and pathways involved in the activation
and differentiation of these progenitor cells.
Right
Maria Chiara Magnone
Introduction
or function, has been shown to be significantly
altered or dysregulated in many disease states,
including oncology, fibrosis, metabolic diseases,
and immune-inflammatory diseases. Targeting
microRNAs with anti-miRs – chemically modified
single-stranded oligonucleotides such as
AZD4076 – offers a unique approach to treating
disease by modulating entire biological pathways
and may become a new and major class of drugs
with broad therapeutic application.
AZD4076 is a GalNAc-conjugated antimiR-103/107 oligonucleotide which was
originally discovered in an alliance with Regulus
Therapeutics. MicroRNAs (miR) are small RNA
molecules, typically 20 to 25 nucleotides in
length that do not encode proteins but rather
regulate gene expression. More than 800 miRs
have been identified in the human genome, and
over two-thirds of all human genes are believed
to be regulated by miRs. MiR expression,
The next wave of scientific innovation 37
CVMD iMed small and large-molecule
pipeline end of 2015
Key CVMD iMed publications in 2015
Phase I
Phase II
AZD4831 (MPO)
HFpEF
MEDI8111
(Rh Factor II)
Trauma/Bleeding
AZD5718 *
Cardiovascular
AZD4076
(miR103/107) *
NASH
AZD4901 (hormone
modulator)
Polycystic Ovarian
Syndrome
* Project progressed to current
Phase in 2015
Key CVMD iMed collaborations in 2015
Moderna Therapeutics,
Cambridge, US
Harvard Stem Cell Institute, a
collaboration with Prof. Dough
Melton aimed at finding regenerative
drugs using inducible pluripotent
stem cells and this year started
differentiation protocol to utilise in
industrial applications.
A strategic collaboration to discover
and develop antisense oligonucleotide
(ASO) therapies for cardiovascular,
metabolic and renal diseases.
AstraZeneca and Ionis also continue
their collaboration to discover new
targeted-delivery approaches to access
more disease-relevant tissues for
oligonucleotide therapeutics. The new
CVMD collaboration further supports
AstraZeneca’s strategic approach in
these therapeutic areas in developing
novel RNA-targeted treatments.
An alliance initiated in 2013 to discover
and develop mRNA therapeutics for the
treatment of cardiovascular, metabolic
and renal diseases as well as cancer.
The first project in the alliance, a
VEGF-A encoding modRNA, is on track
to enter into clinical phase in 2016 as
a potential therapy for patients with
cardiovascular disease.
INSERM, Paris, France
The Alliance established in 2012 to
discover and develop microRNA
therapeutics in CVMD and Oncology
has delivered a candidate drug,
AZD4076. AZD4076 is a GalNAc
conjugated anti-miRNA 103/107
oligonucleotide being developed for
treatment of NASH in diabetic patients.
The aim of the collaboration is to advance
understanding of type 2 diabetes and
chronic kidney disease (CKD) and
develop new treatments based on this
knowledge. The first collaboration with
Professor Frédéric Jassier will aim at
better understanding the complexities of
mineral corticoid receptor activity as a
potential treatment for CKD. The second
collaboration with Professor Dominique
Langin will explore pharmacological
ways to prevent adipose tissue release of
lipid into the circulation, to normalize fat
deposition and increase insulin sensitivity
in peripheral tissues. And thirdly, we will
collaborate with Dr Raphaël Scharfmann
to develop models of human β-cells
which have lost their ability to produce
and release insulin, to better understand
the biology of this effect and how it can
be corrected through treatment.
38 ©AstraZeneca 2016
Li Q, Yang R, Huang X, Zhang H, He L, Nie Y, Hu S, Yan Y,
Wang QD, Lui KO, Zhou B
Blood
Structural and functional characterisation of
a specific antidote for ticagrelor
Buchanan A, Newton P, Pehrsson S, Inghardt T, Antonsson
T, Svensson P, Sjögren T, Öster L, Janefeldt A, Sandinge
AS, Keyes F, Austin M, Spooner J, Gennemark P, Penney M,
Howells G, Vaughan T, Nylander S
Development
How to make a cardiomyocyte
Spaeter D, Hansson EM, Zang L, Chien KR
Stem Cells Translational
Medicine
Human iPSC-derived cardiac progenitor
cells in phenotypic screening: a transforming
growth factor-B type 1 receptor kinase inhibitor
induces efficient cardiac differentiation
Drowley L, Koonce C, Peel S, Jonebring A, Plowright AT,
Kattman SJ, Andersson H, Anson B, Swanson BJ, Wang
QD, Brolen G
Nature Medicine
c-kit+ cells adopt vascular endothelial but not
epithelial cell fates during lung maintenance
and repair
Liu Q, Huang X, Zhang H, Tian X, He L, Yang R, Yan Y,
Wang QD, Gillich A, Zhou B.
Cell Metabolism
SerpinB1 promotes pancreatic B cell
proliferation
El Ouaamari A, Dirice E, Gedeon N, Hu J, Zhou JY,
Shirakawa J, Hou L, Goodman J, Karampelias C, Qiang
G, Boucher J, Martinez R, Gritsenko MA, De Jesus DF,
Kahraman S, Bhatt S, Smith RD, Beer HD, Jungtrakoon P,
Gong Y, Goldfine AB, Liew CW, Doria A, Andersson O,
Qian WJ, Remold-O’Donnell E, Kulkarni RN
Science Translational
Medicine
Tissue transcriptome-driven identification of
epidermal growth factor as a chronic kidney
disease biomarker
Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PXK, Mariani
LH, Eichinger FH, Berthier CC, Randolph A, Yi-Chun Lai J,
Zhou Y, Hawkins JJ, Bitzer M, Sampson MG, Thier M,
Solier C, Duran-Pacheco GC, Duchateau-Nguyen G,
Essioux L, Schott B, Formentini I, Magnone MC, Bobadilla
M, Cohen CD, Bagnasco SM, Barisoni L, Lv J, Zhang H,
Wang HY, Brosius FC, Gadegbeku CA, Kretzler M
Angewandte Chemie
Scalable synthesis of piperazines enabled
by visible-light irradiation and aluminium
organometallics
Suárez-Pantiga S, Colas K, Johansson MJ, Mendoza A
Kidney International
Inhibition of the purinergic P2X7 receptor
improves renal perfusion in angiotensin-IIinfused rats
Menzies RI, Howarth AR, Unwin RJ, Tam FW, Mullins JJ,
Bailey MA
Structure
Ligand binding mechanism in steroid
receptors; from conserved plasticity to
differential evolutionary constraints
Edman K, Hogner A, Hussein A, Bjursell M, Aagaard A,
Bäckström S, Wissler L, Jellesmark-Jensen T, Cavallin A,
Karlsson U, Nilsson E, Lecina D, Takahashi R, Grebner C,
Lepistö M, Guallar V
Journal of Medicinal
Chemistry
Discovery of AZD6642, an inhibitor of
5-lipoxygenase activating protein (FLAP) for
the treatment of inflammatory diseases
Lemurell M, Ulander J, Winiwarter S, Dahlén A, Davidsson
Ö, Emtenäs H, Broddefalk J, Swanson M, Hovdal D,
Plowright A, Pettersen A, Landergren M, Barlind J, Llinas A,
Herslöf M, Drmota T, Sigfridsson K, Moses S, Whatling C
Diabetes Care
Contemporary risk estimates of three HbA1c
variables for myocardial infarction in 101,799
patients following diagnosis of type 2 diabetes
Olsson M, Schnecke V, Cabrera C, Skrtic S, Lind M
Drug Discovery Today
Targeting the podocyte to treat kidney disease
Lal M, Young K, Andag U
Arteriosclerosis,
Thrombosis, and
Vascular Biology
Ticagrelor protects the heart against
reperfusion injury and improves remodelling
after myocardial infarction
Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK,
Nylander S, Birnbaum Y
University of Michigan, US
A collaboration with Professor Matthias
Kretzler in the area of chronic kidney
disease (CKD). The collaboration
will tackle the challenging area of
identifying novel therapeutic targets
for the treatment of CKD, focusing on
the use of patient tissue and validation
of pre-clinical models. We will also
seek translatable animal models and
predictive biomarkers for patient
segmentation in-clinic, through a
world-leading source (covering >2500
patients and seven animal models).
Deliveries: human target validation data
package for all portfolio projects and
pre-TSID project, supporting decisions
on project progression and animal
models selection.
The next wave of scientific innovation 39
An environment where
science thrives
Regulus Therapeutics,
San Diego, US
Genetic lineage tracing identifies in situ
kit‑expressing cardiomyocytes
Collaborating for
science innovation
Ionis Pharmaceuticals,
Carlsbad, US
Cell Research
IMED functions
Harvard University, Boston, US
Authors
Therapy area progress
AZD8601 *
Cardiovascular
Title
Introduction
Pre-clinical
Publication
Neuroscience iMed
The Neuroscience iMed model is unique
in that it is dynamic and fully externalised,
forming partnerships with leading-edge
academic researchers, foundations
and companies to create a portfolio
of discovery and early development
projects in neurological disease.
40 ©AstraZeneca 2016
The next wave of scientific innovation 41
Neuroscience iMed
John Dunlop, VP Neuroscience iMed
Opposite
Brain scan
Top
John Dunlop,
VP Neuroscience iMed
PEOPLE SPOTLIGHT
To date, MEDI1814 has a good safety
profile and is well tolerated. No serious
adverse events have been reported
and there is dose-proportional serum
PK, as predicted for IgG1. Most
importantly, is the demonstration of
selectivity for Aβ42 versus Aβ40 in CSF.
The study continues into 2016 with
single and multiple dose cohorts by
intravenous and subcutaneous route
of administration.
In parallel, clinical trials of AZD3293,
an oral potent small-molecule inhibitor
of β secretase cleaving enzyme
(BACE), have continued to progress.
A co-development effort between
AstraZeneca and Eli Lilly and Company
(Lilly), AMARANTH is Phase II/III
study of a BACE inhibitor currently in
development as a potential treatment
for Alzheimer’s disease. AZD3293 has
been shown in Phase I studies to reduce
levels of amyloid-beta in the CSF of
Alzheimer’s patients. Inhibiting BACE
is predicted to prevent the formation of
amyloid plaque and eventually slow the
progression of the disease. The studies
are examining the safety and efficacy of
AZD3293 compared with placebo in the
treatment of early Alzheimer’s disease.
The study is progressing toward a Phase
III ID in 2016.
Deposition of beta amyloid (Aβ) in
the brain is a pathological hallmark of
Alzheimer’s disease. There are two major
Aβ isoforms: the 42-residue Aβ42 and
the 40-residue Aβ40. Several studies
have demonstrated that the Aβ42
species is both more toxic to neurons
and more aggregate prone, despite the
Aβ40 species being more predominant.
AstraZeneca has been developing our
selective monoclonal antibody against
Aβ42, MEDI1814, and our most recent
data demonstrate a selective and
dose-dependent suppression of CSF
Abeta1-42 but not Aβ40 in Phase 1
studies in Alzheimer’s disease patients.
This is a compelling demonstration of
mechanism of action and potential for
therapeutic differentiation.
An environment where
science thrives
42 ©AstraZeneca 2016
– Dose-dependent decrease in free Aβ42
in CSF following single IV doses
Collaborating for
science innovation
Mike Perkinton in our Discovery
team has been a key individual in the
collaboration with Eliezer Masliah
at UCSD and also in driving our
synuclein programme. Mike has
demonstrated scientific innovation
with the leading emergent hypothesis
of protein spreading, or cell-to-cell
transmission, as a key pathological
driver of disease progression in
chronic neurodegenerative diseases
including Parkinson’s disease. Mike’s
work in providing the critical validation
data supporting this hypothesis for
our synuclein-targeted agent, which
resulted in a key portfolio transition for
this programme in 2015.
AstraZeneca has a unique, externalised
approach to neuroscience drug
discovery and development, partnering
to advance the most exciting scientific
opportunities in areas of high unmet
medical need. In November, the team
presented new data on MEDI1814,
a humanised monoclonal antibody
(mAb) selectively targeted to Aβ42,
at the Clinical Trials on Alzheimer’s
Disease (CTAD) 2015 conference in
Barcelona. This event brought together
world leaders in Alzheimer’s disease
to discuss new results, candidate
therapeutics, and methodological issues
important to the development of the
next generation of therapies.
– Selective target engagement following
single IV doses
IMED functions
Making headway in tackling
Alzheimer’s disease
– Dose-dependent increase in total
plasma Aβ42 following single IV doses
Therapy area progress
Bottom
Receptor in the
human brain
The team presented at CTAD the
findings of tolerability and preliminary
pharmacodynamics studies after single
doses of MEDI1814 in mild-moderate
Alzheimer’s disease. MEDI1814 shows:
Introduction
“In 2015, we continued to embrace our entrepreneurial and externalised approach with
a number of new partnerships. These are particularly in the early portfolio and use our
unique model to build for sustained delivery.”
2015 has been a year where we have
really seen the benefit and impact of the
AstraZeneca Tufts Laboratory for Basic
and Translational Neuroscience. This
unique collaboration, established just
two years ago, exemplifies our model
of collaboration and externalisation. In
this case, it is with a local group based
in Boston, just a short distance from
our Cambridge (MA) office. We now see
tangible impact on both our portfolio
and our science. This is best illustrated
by the target validation and screening hit
characterisation for the KCC2 modulator
programme, performed in close
collaboration with our IMED Discovery
Sciences colleagues. KCC2 is a critical
determinant of neuronal excitability in
the brain and implicated in epilepsies
and Amyotrophic Lateral Sclerosis (ALS).
In addition to project support, the lab
has delivered high-quality publications
in the Journal of Neuroscience and the
Proceedings of the National Academy
of Sciences characterising the basic
biology of this target.
The next wave of scientific innovation 43
Neuroscience iMed clinical pipeline end of 2015
Phase I
MEDI7352
Analgesia
AZD8108 NMDA
antagonist
Suicidal ideation
Application of cross-species PET imaging to
assess neurotransmitter release in brain
Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E,
Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C,
Grimwood S
MEDI1814 amyloid
beta mAb
Alzheimer’s disease
AZD3241
myeloperoxidase
inhibitor
Multiple System
Atrophy
Brain
Effect of the myeloperoxidase inhibitor
AZD3241 on microglia: a PET study in
Parkinson’s disease
Jucaite A, Svennigsson P, Rinne JO, Cselényi Z, Varnäs K,
Johnström P, Amini N, Kirjavainen A, Helin S, Minkwitz M,
Kugler AR, Posener JA, Budd S, Halldin C, Varrone A, Farde L
Molecular Psychiatry
Misassembly of non-mutant disrupted-inschizophrenia 1 (DISC1) protein is linked
to altered dopamine homeostasis and
behavioral deficits
Brandon N
Molecular Psychiatry
Early postnatal GABAA receptor modulation
reverses deficits in neuronal maturation in
a conditional neurodevelopmental mouse
model of DISC1
Saito A, Taniguchi Y, Rannals M, Merfeld E, Ballinger M,
Minori K, Ohtani Y, Gurley D, Sedlak T, Cross A, Moss S,
Brandon N, Maher B, Kamiya A
Neuron
BrainSeq: neurogenomics to drive novel target
discovery for neuropsychiatric disorders
Schubert C, O’Donnell P, Quan J, Wendland J, Hualin
S, Domenici E, Essioux L, Kam-Thong T, Didriksen M,
Matsumoto M, Saito T, Brandon N, Cross A, Wang Q, Heon
Shin J, Jaffe A, Jia Y, Straub R, Deep-Soboslay A, Hyde T,
Kleinman J, Weinberger D
Journal of Alzheimer’s
Disease
AZD3293: a novel, orally active BACE1
inhibitor with high potency and permeability
and markedly slow off-rate kinetics
Eketjäll S, Janson J, Kaspersson K, Bogstedt A, Jeppsson
F, Fälting J, Budd Haeberlein S, Kugler AR, Alexander RC,
Cebers G
Nature Neuroscience
The cellular targets of antidepressants
Brandon N, McKay R
Cellular Signalling
Uncovering the function of disrupted in
schizophrenia 1 through interactions with the
cAMP phosphodiesterase PDE4: contributions
of the Houslay lab to molecular psychiatry
Brandon N
Biological Psychiatry
The novel metabotropic glutamate receptor
2 positive allosteric modulator, AZD8529,
decreases nicotine self-administration and
relapse in squirrel monkeys
Justinova Z, Panlilo L, Secci M, Redhi G, Schindler C,
Cross A, Mrzljak L, Medd A, Shaham Y, Goberg S
Neuropharmacology
State-dependent alterations in sleep/wake
architecture and antipsychoticlike activity
by the M4 Positive Allosteric Modulator
VU0467154
Gould R, Nedelcovych M, Gong X, Tsai E, Bridges T, Wood
M, Bubser M, Daniels J, Duggan M, Brandon N, Dunlop J,
Wood M, Ivarsson M, Noetzel M, Niswender C, Lindsley C,
Conn P, Jones C
British Journal of
Pharmacology
Quetiapine and its metabolite norquetiapine
translation from in vitro pharmacology to in
vivo efficacy in rodent models
Cross A, Widzowski D, Maciag C, Zacco A, Hudzik T, Liu J,
Nyberg S, Wood M
Journal of Clinical
Psychopharmacology
AZD6280, a novel partial GABA-A
receptor modulator, demonstrates a
pharmacodynamically selective effect
profile in healthy male volunteers
Chen X, Jacobs G, de Kam M, Jaeger J, Lappalainen J,
Maruff P, Smith M, Cross A, Cohen A, van Gerven J
Proceedings of the
National Academy of
Sciences of the United
States of America
KCC2 activity is critical in limiting the onset
and severity of status epilepticus
Silayeva L, Deeb T, Hines R, Kelley M, Munoz M, Lee H,
Brandon N, Dunlop J, Maguire J, Davies P, Moss S
The Journal of
Neuroscience
Selective inhibition of KCC2 leads to
hyperexcitability and epileptiform discharges
in hippocampal slices and in vivo.
Sivakumaran S, Cardarelli RA, Maguire J, Kelley MR, Silayeva
L, Morrow DH, Mukherjee 2, Moore YE, Mather RJ, Duggan
ME, Brandon NJ, Dunlop J, Zicha S, Moss SJ, Deeb TZ
MEDI1341
Parkinson’s disease
AZD3293*
beta-secretase
inhibitor
Alzheimer’s disease
*Partnered project
Key Neuroscience iMed collaborations in 2015
University of Pennsylvania and
Stanford University, US
Eolas Therapeutics & NIH,
Carlsbad, US
Trinity College Dublin, Ireland
Partnership funded by Target-ALS to
discover new targets modifying the
toxicity of ALS causative and risk genes.
Three-way partnership with biotech
company Eolas and the NIH to advance
orexin1 receptor antagonists in the area
of addiction disorders, funded by the NIH
Blueprint Neurotherapeutics network.
Generation of new mechanistic data on
human Aβ and physiological measures
of cognition.
Imperial College London, UK
University of Sussex, UK
Eli Lilly, Indianapolis, US
Preclinical data characterizing novel
bifunctional mAb in analgesia.
Working with the university’s
Translational Drug Discovery Group
to explore novel GABA receptor
modulators in Huntington’s disease and
anxiety disorders, funded by the MRC
and Wellcome Trust.
Phase II/III trial of AZD3293, an oral
potent small-molecule inhibitor of BACE
– good progress towards Phase III ID
in 2016.
44 ©AstraZeneca 2016
The next wave of scientific innovation 45
An environment where
science thrives
Psychopharmacology
Phase II
Collaborating for
science innovation
Authors
IMED functions
Title
Therapy area progress
Journal/publication
Introduction
Pre-clinical
Key Neuroscience iMed publications in 2015
Discovery Sciences
Applying world-leading expertise to
drive the identification of quality targets,
hits, leads and drug candidates that will
be safe and efficacious in the clinic.
46 ©AstraZeneca 2016
The next wave of scientific innovation 47
Discovery Sciences
Highlights
Mike Snowden, VP Discovery Sciences
Engineered cell lines to selected IMED projects, e.g. the SIK (salt-induced kinase) project
for use in evaluating which one of three isoenzymes was the drug target and secondly,
provided a mutant form of EGFR (C797S) to support that project.
Conduct a phenotypic screen using a
larger collection of compounds than
typically used for such assays.
A phenotypic screen that used 120,000 compounds that is about ten-fold more than typically
used. We executed this technically challenging screen using a seven-day proliferation assay
that involved more than 50 steps using a novel beta cell, EndoC-βH1 and a high-throughput
flow cytometry readout. The output from this screen will provide chemical equity for the
Melton collaboration, which is seeking modulators of beta cell growth.
Enhance the compound collection at
AstraZeneca by the exchange of chemical
equity with peer companies.
A first-in-world exchange of 210,000 compounds between AstraZeneca and Sanofi, and a
further 25,000 compounds exchanged with a leading agrochemical company.
Deliver the strategy for compound
management in Cambridge
Biomedical Campus.
A first-class strategy aligned with several exciting collaborations. The first stage is the
relocation of our solid store from Alderley Park to a world-renown expert, located in Europe.
The temperature-controlled stores that house our liquid compound collection are being
developed in collaboration with Brooks. With another partner, LabCyte, AstraZeneca is
working on groundbreaking technology that will deliver compounds from tubes to plates
using acoustic technology.
Establish a world-class HTS capability at
Cambridge Biomedical Campus.
A strategic collaboration with HiRes of Boston to deliver a modular automation solution for
HTS. Such systems provide a high degree of flexibility as the units are mounted on carts
that can be moved around; to be easily reconfigured to fit the screening modality required.
Provide computational biology and
mathematical modelling work packages
to support IMED projects.
A tailor-made image analysis software package for a novel hepatotoxicity model that used
cells grown in 3D, as spheroids. The package calculated the size/volume of these cell
clusters, which was a critical measurement parameter that relied completely on the experts
in-house, as there was not an off-the-shelf solution. In addition, we continue to explore
statistical methods that reduce the number of animals used in experiments. The use of
micro-sampling that takes ‘snapshots’ of the experimental design is reducing the number
of animals required.
To deliver more predictive liver
toxicity assays.
A novel hepatotoxicity model that cultures HepG2 cells grown in 3D rather than the
conventional 2D/flat dish system. Cells grown under 3D conditions form spheroids
rather than a monolayer, this 3D phenotype is more liver-like with cells expressing drugmetabolising enzymes (cytochrome p450s) unlike those grown in 2D conditions. The assay
has been validated with known liver toxins and compares very favourably against the gold
standard assay primary human liver cells. The new assay is about three times faster than
the outsourced human liver assay and ten-fold cheaper.
Collaborating for
science innovation
Investigate the use of precise genome
editing (CRISPR/Cas9) to deliver
genetically engineered cell lines to
IMED and external collaborators.
IMED functions
To complement our Hit Identification platforms, and to ensure
that we reserve them for the most validated drug discovery
projects, we pushed ahead at pace with our ambitious plans
to revolutionise our pre-clinical target validation capabilities
through the widespread use of precise genome editing in both
cellular and in pre-clinical animal model systems. Through
collaboration with the very best external scientists in the world,
and through significant internal investment we delivered an
unprecedented number of both cellular and animal models
to AstraZeneca projects and, importantly, developed the
technological platform to optimise gene knockout generation,
resulting in two patent filings and the potential for a number
of high-impact publications in 2016. 2015 was a bumper year
for publication for Discovery Sciences, with over 120 peerreviewed papers, including over 50 high-quality and seven
high-impact publications.
We delivered
Therapy area progress
2015 has been an incredible year for Discovery Sciences.
We continued with the development of our small-molecule
Hit Identification capabilities and employed plate-based
high-throughput screening (HTS), DNA encoded libraries and
fragment-based screening to more of our internal projects than
ever before. We made our HTS compound collection available
to a record number of academic collaborators, and initiated
exciting projects with Brooks, Labcyte and HiRes to bring
state-of-the-art robotic compound management and screening
platforms to AstraZeneca as we prepare for the move of our
HTS capability to the Cambridge Biomedical Campus, and
to our partners in the Centre for Lead Discovery, Cancer
Research UK and the Medical Research Council.
We set out to
Introduction
“Discovery Sciences goes from strength to strength with another year of exceptional
delivery and innovation. The Hit Identification platforms we developed in 2014 continue to
provide world-class support for IMED small-molecule discovery, and we augmented this
capability with the development of one of the most advanced genome editing-based target
validation platforms in the industry. An incredible year indeed!”
An environment where
science thrives
Left
Mike Snowden,
VP Discovery Sciences
48 ©AstraZeneca 2016
The next wave of scientific innovation 49
Key Discovery Sciences collaborations in 2015
People spotlight
Use of cryoEM to determine the
structure of large protein complexes.
AstraZeneca is part of ten-partner
consortium.
Collaboration to deliver tube-to-plate
compound dispensing using acoustic
technology (Labcyte) and tailor-made
plastic ware (Brooks).
Research agreement that allows
AstraZeneca access to Pelago’s
thermal shift technology for use
in target engagement and target
identification studies.
HiRes, Boston, US
Labcyte and Waters, Sunnyvale, US
and Elstree, UK
Knut and Alice Wallenberg Foundation
and Royal Institute of Technology,
Stockholm, Sweden
Collaboration to design and deliver
modular, flexible HTS automation
solutions for the Lead Discovery Centre
at CBC.
Collaboration to use acoustic liquid
dispensing technology (Labcyte) to
add samples to a mass spectrometer
(Waters) for use in biochemical and
cellular assays.
Explore new targets for disease research
through the area of secretomics.
Key Discovery Sciences publications in 2015
Authors
Nature Communications
Responding to the challenge of untreatable
gonorrhea: ETX0914, a first-in-class agent
with a distinct mechanism-of-action against
bacterial Type II topoisomerases
Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K,
Vishwanathan K, Alm RA, Doig P, Gardner H, Gowravaram
M, Huband M, Kutschke A, Lahiri SD, Tommasi R, Newman
J, Schuck V, Singh R, Kimzey A, Morningstar M, Barvian K
Nature Communications
Structural and dynamic insights into the
energetics of activation loop rearrangement
in FGFR1 kinase
Klein T, Vajpai N, Phillips J, Davies G, Holdgate G, Phillips C,
Tucker J, Norman R, Scott A, Higazi D, Lowe D, Breeze A
Nature Communications
Oxidation of the alarmin IL-33 regulates ST2dependent inflammation
E. Suzanne Cohen, Ian C. Scott, Jayesh B. Majithiya, Laura
Rapley, Benjamin P. Kemp, Elizabeth England, D. Gareth
Rees, Catherine L. Overed-Sayer, Joanne Woods, Nicholas
J. Bond, Christel Séguy Veyssier, Kevin J. Embrey, Dorothy
A. Sims, Michael R. Snaith, Katherine A. Vousden, Martin
D. Strain, Denice T. Y. Chan, Sara Carmen, Catherine
E. Huntington, Liz Flavell, Jianqing Xu, Bojana Popovic,
Christopher E. Brightling, Tristan J. Vaughan, Robin Butler,
David C. Lowe, Daniel R. Higazi, Dominic J. Corkill, Richard
D. May, Matthew A. Sleeman,* and Tomas Mustelin*
Nature Reviews
Drug Discovery
An analysis of the attrition of drug candidates
from four major pharmaceutical companies
Michael J. Waring, John Arrowsmith, Andrew R. Leach,
Paul D. Leeson, Sam Mandrell, Robert M. Owen, Garry
Pairaudeau, William D. Pennie, Stephen D. Pickett, Jibo
Wang, Owen Wallace, Alex Weir
Nature Reviews
Drug Discovery
Towards a hit for every target
Rees S, Janzen W, Gribbon P, Pairaudeau G, Birmingham K
Science Advances
Structural basis of Lewisb antigen binding by
the Helicobacter pylori adhesin BabA
Hage N, Howard T, Phillips C, Brassington C, Overman R,
Debreczeni J, Gellert P, Stolnik G, Winkler G, Falcone F
The next wave of scientific innovation 51
An environment where
science thrives
Title
Collaborating for
science innovation
Publication
IMED functions
Jon Wingfield joined AstraZeneca
in 2000 as part of the oncology
function, tasked with the delivery of
automation to support secondary
screening activities. After building
delivery-focused screening teams,
he moved into Discovery Sciences
upon its formation in 2010. As a
Principal Scientist, he is responsible
for the strategic delivery of objectives
and ensuring the projects have
high visibility with both internal and
external scientific communities.
Jon uses his experience of drug
discovery to showcase the potential
value of this revolutionary technology
platform with collaborative partners.
Pelago, Stockholm, Sweden
Therapy area progress
50 ©AstraZeneca 2016
Martin Bachman is a postdoc
within Discovery Sciences, joining
AstraZeneca in April 2015 after
completing his DPhil at Cambridge
University. Martin’s main area of
research, prior to AstraZeneca, was
in the role of DNA modifications in
epigenetics. He already has published
in Nature Chemistry and Proceedings
of the National Academy of Sciences,
showing the use of mass spectrometry
as a tool to test biological hypotheses.
Martin supports the delivery of data
for potential scientific applications
and is currently building assays to
demonstrate the system’s potential as a
high-throughput screening platform.
Labcyte and Brooks, Cambridge, UK
Introduction
Ian Sinclair joined AstraZeneca
from Waters in 1999 to manage and
develop the growth of Open Access
LCMS across Alderley Park. Since
2007, he has examined the use of
charged aerosol detection (CAD)
for use in compound management
quality assurance. More recently, he
has studied strategies to measure
and improve quality within large
compound collections. Ian brings
an invaluable technical depth of
knowledge while managing the
project and liaison with our technical
counterparts at Labcyte and Waters.
Laboratory of Molecular Biology,
Cambridge, UK
Case study
Behind the scenes
Acoustic mass spectrometer
Our technique of choice for high-resolution microscopy
The technology supporting our science
The stats
– High throughput: 10,000 data points generated per hour,
with three samples per second going into the acoustic
mass spectrometer versus one sample every ten
seconds with a standard mass spectrometer platform
– Allows us to generate data points at 10,000 data
points per hour
– Small sample volumes required: only 2µl samples needed,
meaning it is possible to get multiple samples more easily
– No cross-contamination: Using acoustics to move
samples means no cross-contamination risk as nothing
touches any surfaces
–T
he acoustics fire at 500Hz frequency (500 times per
second) – that means we fire in 500 bursts of droplets
every second
– For some analytes, we only need ~160 droplet bursts
from a sample to generate enough ions – this means we
can deliver samples to the acoustic mass spectrometer
at a rate of three per second. Currently, the best highthroughput screening platform only sends one sample
every ten seconds to the acoustic mass spectrometer
Case study
The facts
Mass spectrometry (or mass spec) is an analytical chemistry technique that
helps identify the amount and type of chemicals present in a sample by
measuring the mass-to-charge ratio and abundance of gas-phase ions. As
standard, mass specs have three components – a component to convert
sample from liquid to gaseous form. Then a component to ionise the
sample (hit with high energy to turn to +ve or –ve ions), then the component
to detect quantities of each ion (peaks of each ion seen). Instead of using a
needle to aspirate and spray the samples as with standard mass specs, the
acoustic mass spectrometer sends a sonic pulse through liquid creating a
‘mountain of liquid on the surface’. For compound handling, a 2.5 nanoLitre
droplet is generated and fired from the liquid surface. For acoustic mass
spectrometer we send a second pulse through the mountain of liquid and
this explodes the 2.5nL droplet into hundreds of femtoLitre droplets. In
effect, sending a tornado of droplets through a charged field to generate a
stream of ionised particles into the acoustic mass spectrometer.
The scientist perspective
“When you see the droplets flying and you see the science behind
it – it’s astonishingly cool. It’s revolutionary. It allows us to work at very
high throughput and with very small sample volumes – we only need 2µl of
sample. Using this screening system we can screen more compounds or
more targets for the same cost. For some assays we could reduce the cost
of high-throughput screening by 80%.
AstraZeneca has brought together a world leading supplier of mass spec
technology (Waters) and the global leader in acoustic droplet ejection
technology (Labcyte) to deliver this revolutionary platform. It required
the vision of AstraZeneca’s scientific leaders to recognise the potential
of this system. We took the idea to the partners, suggesting that it is
possible to use acoustics in a different way in mass spec. Being open
about the work we are doing has shown the wider scientific community
that AstraZeneca is prepared to invest in groundbreaking science,
we are not just making a small change in mass spec, but we are
leading a potential revolution in mass spec screening. As with any novel
area of research this project carries an element of risk. Again, our openness
shows that AstraZeneca is prepared to take scientific risks. We’re engaging
the broader scientific community early in the process, and delivering real
benefit to the community overall.
The acoustic mass spectrometer platform won the 2015 Innovation
Award from the Society for Laboratory Automation and Screening.
This is awarded to the podium presentation at the annual
conference that shows the most innovation and impact in screening.
AstraZeneca is the first non-US-based company to receive this award.
The webcast of the podium presentation was made available to members
after the meeting, and the society received so many requests to access
this presentation that they made it free to non-members for a period,
which is unprecedented. Subsequently, the society has decided to make
the presentation available for free to the science community for two
years. We have also had a paper about the platform accepted in a peerreviewed journal (Journal of Laboratory Automation).”
Jonathan Wingfield, Principal Scientist, Discovery Sciences
Opposite
Acoustic mass
spectrometer
1
1nL is 1 millionth of a millilitre (or 1 trillionth of a litre). One femtolitre is
1 millionth of a nanolitre (or 0.000000000000001 litre)
52 ©AstraZeneca 2016
Above
Jonathan Wingfield,
Principal Scientist
Discovery Sciences
The next wave of scientific innovation 53
Drug Safety &
Metabolism
Driving our science to bring better, safer
medicines to patients sooner.
54 ©AstraZeneca 2016
The next wave of scientific innovation 55
Drug Safety & Metabolism
Introduction
“2015 was an exceptional year for DSM. On top of delivering against all project timelines in
the IMED and Global Medicines Development portfolio, I’ve been amazed with the progress
of our teams, who have made particularly great progress with oligonucleotide-based
therapies this year where we are already seeing really encouraging results.”
Stefan Platz, VP Global Drug Safety & Metabolism
Opposite
DNA Holliday junction
molecular model
56 ©AstraZeneca 2016
We continue to build our network within
the local Cambridge community, and as
well as hosting and sponsoring a number
of local seminars and conferences,
in 2015 we formed a pre-competitive
alliance with Cambridge University and
GlaxoSmithKline on medicines safety.
In addition to supporting the complete
IMED pipeline, and through a time of
significant footprint change, 2015 was an
exceptional year for DSM; here are some
of our key highlights:
– Enabling Technologies
Next Generation Sequencing
and health patch pilots initiated,
a human tissue lead appointed and
increased bioinformatics support
– People and Organisation
Introduction of a PCRA
engagement programme for
DSM employees to help embed
our PCRA strategy
– CKD Pilot – CKD is the newest
core disease area within CVMD
and the pilot offers the opportunity
to build a patient-centric safety
foundation to identify key areas of
concerns and map the potential
need of new capabilities
– COPD Pilot – The COPD pilot
offers an exciting opportunity to
develop a more proactive approach
to assessing risk pre-clinically
– Internal and External Influence
The launch and implementation
of pilot studies in two key disease
areas in collaboration with the
wider IMED organisation
– Data Information and Integration
The agreement to recruit a Lead
Information Officer, as well as
extensive analysis of data capture
and flow of information
The next wave of scientific innovation 57
An environment where
science thrives
We also initiated several key academic
collaborations to strengthen our
scientific reputation in the area of safety
science, including one with the MRC
Toxicology Unit (“Investigations into the
interference of nucleotide modalities
and their delivery systems on the
translational machinery, nucleotide stress
and immune signalling pathways”),
and another with Uppsala University
on expanding molecular imaging
technologies to improve drug safety and
efficacy understanding.
The global DSM team also worked
to define, build and lead the Patient
Centric Risk Assessment (PCRA)
strategy. 35 DSM colleagues,
approximately 10% of the department,
in four PCRA workstreams aimed
to bring to life a common purpose,
the patient, across DSM.
The four Patient Centric Risk
Assessment workstreams
and key 2015 outcomes
Collaborating for
science innovation
Collaborative working was a focus
for DSM in 2015. Within the ‘New
Modalities’ space, a key strategic
area for DSM, we worked with
external partners to establish deeper
understanding of oligonucleotide and
modRNA therapeutics.
In Cambridge, our Laboratory Animal
Sciences team, who provide invaluable
support across IMED, became part of
the new Research Support Facility (RSF),
a combined IMED and MedImmune
team, which is setting the direction for
future collaborative working between
the two groups. Our team also helped
transition the Medical Research Council
Laboratory of Molecular Biology to their
new base in Cambridge.
IMED functions
Drug Safety and Metabolism (DSM) is an
IMED function contributing to the entire
value chain. Structured into six functions
and with a purpose to drive science
to bring better, safer medicines to
patients sooner, we support and enable
pipeline progression in AstraZeneca’s
core therapeutic areas. With our vast
range of expertise we deliver in silico,
in vitro and in vivo data to deliver target
and chemical risk assessments as well
as metabolic quantitative translational
safety models, including imaging for
functional and pathological safety
signals. We design and deliver tailored
safety pharmacology and toxicology
packages to support project decisionmaking and enable safe progression
through clinical development.
Therapy area progress
Top
Stefan Platz,
VP Globa Drug Safety
& Metabolism
Highlights
We delivered
Consider the safety implications of
CRISPR as a therapeutic modality and
the use of CRISPR technologies for
safety model build.
Collaborations with world-leading scientists for animal model builds, off-target analysis,
DNA repair and targeted delivery. Our scientists have presented both nationally and
internationally on the safety concerns associated with CRISPR and we have set up a crosscompany workgroup with key leaders to consider CRISPR safety.
Become the industry leaders in the
application of modelling and simulation
(M&S) to address drug safety.
A strong translational M&S team with a demonstrated track record of project impact,
particularly in oncology. In addition, we have begun to construct novel safety modelling
platforms in-house and through collaborations. Finally, we have increased our level of
visibility and leadership among industry peers by, for example, chairing the platform
session at the American Conference of Pharmacometrics (premier society meeting)
on systems modelling for drug safety.
Support the progression of the first
AstraZeneca modRNA therapeutic to
candidate drug stage.
Progression with AZD8601 to candidate drug stage in October of 2015, and with the drug
entering GLP toxicology studies in Q1 2016, we will enable first-in-human trials later in 2016.
Progress the first anti-microRNA
oligonucleotide drug into man.
Safety data and documentation that enabled the first human dose to be administered in
Phase I less than nine months from candidate drug identification.
– Flexible – can be encoded to produce
any protein
– Adaptable – proteins can act
intracellularly or be secreted
– Functional – diverse and potent
therapeutic potential
58 ©AstraZeneca 2016
From his experience in this US
biotech environment, Patrik
learnt the importance of sharing
challenges through continuous and
open debate. Acknowledging team
efforts, working together, celebrating
achievements and daring to try new
things were prevalent traits in this
professional environment. Equally
applicable to scientific research and
the Californian surf culture, Patrik
realised that you need to lose your
preconceptions and engage with the
experts – what may at first appear
simple may in fact have a more
complex reality.
Since his return to Sweden, Patrik
has contributed to the strategic
Ionis collaborations in the CVMD
and targeted delivery areas and with
new ideas for the Moderna platform.
The next wave of scientific innovation 59
An environment where
science thrives
The new modelling approach that has
been developed generates accurate
predictions for both intravenous
and subcutaneous dosing and the
biodistribution of LNPs. Unlike classical
pharmacokinetic models, these
mechanistic PBPK models are capable
of describing the biodistribution of LNPs.
Their ability to predict tissue/targetspecific concentration profiles provides
a model-based framework that can be
used to maximise therapeutic index. Of
particular significance is the fact that
their physiological basis allows for more
sophisticated approaches for model
translation from one species to another.
As the potential delivery method of
choice for oligo therapies, exosomes are
critical for the successful development
of CRISPR, enabling efficient transfer
of Cas9 and guide-RNA. However,
endogenous exosomal protein and RNA
contamination raises safety concerns.
Led by Mick Fellows, the DSM Discovery
Safety department has set up a new
collaboration in 2015 with leaders
in the field to research and develop
technologies that enable clean exosome
preparation and to assess the risk
from contamination whilst maintaining
delivery efficiency. This is expected to
significantly contribute to the translation
of exosomes from the lab to the clinic
and will place AstraZeneca in a unique
position to lead in new modality delivery
systems for the next generation of
therapeutics.
Collaborating for
science innovation
DSM have been investigating the
physiologically-based pharmacokinetic
(PBPK) modelling approach for predicting
biodistribution of mRNA-loaded lipid
nanoparticles (LNPs) from a safety
testing perspective. PBPK models are
particularly well-suited for supporting
model-translation from one scenario to
another, e.g. species, exposure route,
dose. This is because LNP kinetics differ
from that of small molecules and are
typically very non-linear and impacted
distinctly through interactions with
different tissues and cells.
In August 2014, Patrik Andersson
moved his Gothenburg family of
five to the biotech cluster in San
Diego for a 12-month secondment
to learn more about oligonucleotide
therapeutics. This drug platform
has different properties to small
molecules and they target RNA
rather than proteins, leading to
different challenges, approaches
and screening cascades. Patrik’s
objectives were to support ongoing
projects in CVMD and Oncology
and identify new collaboration
opportunities for DSM.
IMED functions
Successful development and delivery of these models as well as securing a key
collaboration with a German biotech company, TissUse, to explore the next wave of
scientific innovation, which will connect individual organ units together.
CRISPR (clustered regularly interspaced
short palindromic repeats) is a genomeediting tool that allows fast and precise
changes to be made in specific genes.
The technology has two components
– a homing device to a specific section
of DNA (guide-RNA) and enzymatic
‘scissors’ that cut DNA (Cas9 nuclease).
In the cell nucleus, the guide-RNA
sequence directs the Cas9 nuclease to
cause double-stranded breaks in the
target DNA sequence. By harnessing
the cell’s own DNA-repair apparatus, the
gene being targeted can be altered either
by deleting it, adding nucleotides to it or
by turning its activity on or off.
People spotlight
Therapy area progress
Create rat and dog liver-on-a-chip
models as part of our ongoing organson-a-chip development.
AstraZeneca has been partnering with
Moderna Therapeutics since 2013 to
discover, develop and commercialise
pioneering mRNA Therapeutics™. This
unique approach uses proprietary mRNA
containing nucleotide analogues, which
are designed to stimulate the body’s
natural ability to produce intracellular and
secreted therapeutic proteins without
triggering an innate immune response.
Modified mRNA may dramatically reduce
the time and expense associated with
creating therapeutic proteins using
current recombinant technologies.
Moreover, as a therapeutic device,
modified mRNA are:
Another line of investigation that has
begun in 2015 is the use of exosome
delivery systems to explore potential
safety concerns. Exosomes are
endogenous nanocarriers of RNA and
proteins that mediate communication
between cells. As many cancers are
characterised by exosome-associated
alterations, exosomes are considered
to be relevant drug delivery vehicles for
cancer treatment.
Introduction
We set out to
Thinking differently about
safety using CRISPR and
mRNA modelling
Key Drug Safety & Metabolism collaborations in 2015
University of Cambridge, UK
University of Cambridge, UK
Strengthening the IMED futures
workstream, the TissUse collaboration
has been established to explore the
value of human bone marrow-on-achip model to predict drug-induced
hematotoxicity and genotoxicity.
Andreas Bender in Chemistry.
The project will explore bioinformatics
algorithms for predicting drug-drug
interactions based on clinical adverse
event database mining.
Experimental Medicine Ph.D. student.
This proposal was selected as the first
clinical PhD post of the ‘Experimental
Medicine’ initiative and is on the subject
of quantitative systems models of
human cardiovascular physiology.
Ludwig Maximillians University,
Munich, Germany
Uppsala University, Sweden
This collaboration aims to develop and
validate a new fast-responding and
non-invasive CYP3A biomarker in urine,
1B hydroxydeoxycholic acid, for CYP3A
inhibition DDI studies.
This collaboration will look to generate
pig models with inducible expression of
Cas9 and with transgenic expression of
humanised PCSK9.
This collaboration is expanding
molecular imaging technologies to
improve drug safety and efficacy
understanding and to discover and
develop pathology biomarkers.
University of Cambridge, UK
AZD9150, a next-generation antisense
oligonucleotide inhibitor of STAT3, with early
evidence of clinical activity in lymphoma and
lung cancer
Hong D, Kurzrock R, Kim Y, Woessner R, Younes A,
Nemunaitis J, Fowler N, Zhou T, Schmidt J, Jo M, Lee SJ,
Yamashita M, Hughes SG, Fayad L, Piha-Paul S, Nadella
MVP, Mohseni M, Lawson D, Reimer C, Blakey DC, Xiao X,
Hsu J, Revenko A, Monia BP, MacLeod AR
Nature Communications
Triaminopyrimidine is a fast-killing and longacting antimalarial clinical candidate
Hameed S, Solapure S, Patil V, Henrich P, Magistrado P,
Bharath S, Murugan K, Viswanath P, Puttur J, Srivastava A,
Bellale E, Panduga V, Shanbag G, Awasthy D, Landge S,
et al
British Journal of
Pharmacology
Effects of acute and chronic sunitinib
treatment on cardiac function and calcium/
calmodulin dependent protein kinase II
Mooney L, Skinner M, Coker SJ, Currie S
Molecular Pharmaceutics
Flagging drugs that inhibit the bile salt
export pump
Montanari F, Pinto M, Khunweeraphong N, Wlcek
K, Sohail MI, Noeske T, Boyer S, Chiba P, Stieger B,
Kuchler K, Ecker GF
British Journal of
Pharmacology
Future technology insight: mass spectrometry
imaging as a tool in drug development
Cobice D, Goodwin R, Andren P, Nilsson A, Mackay C,
Andrew R
Archives of Toxicology
Hepatic effects of repeated oral
administration of diclofenac to hepatic
cytochrome P-450 reductase null (HRN?)
and wild type mice
Akingbasote J, Foster A, Wilson I, Sarda S, Jones H, Gerry
Kenna J
Analytical Chemistry
Mapping drug distribution in brain tissue
using liquid extraction surface analysis mass
spectrometry imaging
Swales J, Tucker J, Spreadborough M, Iverson S, Clench M,
Webborn P, Goodwin R
CPT: Pharmacometrics &
Systems Pharmacology
Modeling and simulation approaches for
cardiovascular function and their role in
safety assessment
Collins TA, Bergenholm L, Abdulla T, Yates JWT, Evans N,
Chappell MJ, Mettetal JT
Toxicological Sciences
Re-evaluation of the mutagenic response
to phosphorothioate nucleotides in human
lymphoblastoid TK6 cells
Saleh A, Priestley C, Gooderham N, Fellows M
Toxicological Sciences
Correlation of in vivo versus in vitro benchmark
doses (BMDs) derived from micronucleus test
data: a proof of concept study
Soeteman-Hernández L, Fellows M, Johnson G, Slob W
Chemical Research in
Toxicology
Aortic binding of AZD5248, mechanistic
insight and reactivity assays to support
lead optimzation
Bragg R, Brocklehurst S, Gustafsson F, Goodman J,
Hickling K, MacFaul P, Swallow S, Tugwood J
The next wave of scientific innovation 61
An environment where
science thrives
Science Translational
Medicine
Collaborating for
science innovation
60 ©AstraZeneca 2016
Authors
IMED functions
This collaboration will study genetic
variability in myocyte calcium handling
and the consequences for drug-induced
toxicity.
Title
Therapy area progress
Karolinska Institute, Stockholm, Sweden
Publication
Introduction
TissUse, Berlin, Germany
Key Drug Safety & Metabolism publications in 2015
Personalised
Healthcare
and Biomarkers
Personalised Healthcare is an integral
part of our approach to discovering
and developing new medicines;
we use diagnostics and biomarkers
to target our treatments to patients
most likely to benefit.
62 ©AstraZeneca 2016
The next wave of scientific innovation 63
Personalised Healthcare and Biomarkers
“We see Personalised Healthcare as the future of medicine –
it shows us what science can do.”
Ruth March, VP PHB
Opposite
DNA sequence
To stay at the forefront of Personalised
Healthcare science, we are constantly
looking for novel diagnostic technologies
that can help us deliver better solutions
to patients. For example, the EGFR
Highlights
We delivered
Deliver PHC to patients: enable launch
of AstraZeneca drug products linked
to diagnostic tests.
Seven diagnostics launched with our diagnostic partners linked to four AstraZeneca products:
– Myriad’s tumour BRCA analysis (EU) for olaparib
– Qiagen’s EGFR companion diagnostic test (US), and circulating tumour DNA EGFR
plasma test (EU) for gefitinib
IMED functions
We set out to
Therapy area progress
Top
Ruth March, VP PHB
In 2015, we have launched seven
diagnostic tests linked to our products
(see highlights) and led companion
diagnostic development for AstraZeneca’s
three FDA-approved PHC drugs.
mutation test launched in the EU for
osimertinib (AZD9291) is the world’s
first diagnostic test intended for both
circulating tumour DNA (ctDNA) derived
from plasma and tumour DNA derived
from solid tissue. Indeed, we are now
able to include diagnostic testing based
on plasma for many drug projects,
achieving a label update in China for
gefitinib in 2015. Such use of plasma for
testing enables up to 25% more patients
without evaluable solid tumour samples
to access the right treatment. In addition,
we are continuing to explore diagnostics
based on next-generation sequencing
in several of our drug programmes,
through partnerships with Illumina and
Foundation Medicine. This year we have
started to explore the potential of Droplet
Digital PCR (ddPCR) in partnership
with Sysmex-Inostics, a highly sensitive
diagnostic technology.
Introduction
Personalised Healthcare is an integral
part of our approach to discovering
and developing new medicines; we use
diagnostics and biomarkers to target
our treatments to patients most likely to
benefit. More than 80% of AZ’s clinical
pipeline, and 95% of our small-molecule
IMED pipeline, is following a Personalised
Healthcare approach, with over 50
planned drug launches in the next eight
years requiring a linked diagnostic test.
– Roche Molecular System’s EGFR tissue and plasma test (EU) – the world’s first diagnostic
test for both circulating tumour DNA and tumour tissue, and EGFR companion diagnostic
test (US) for osimertinib
– Ventana’s PD-L1 diagnostic test (Class I in vitro diagnostic test) in US and in EU for
durvalumab – first FDA regulated PD-L1 diagnostic
– Exploration of novel diagnostic technologies, such as ctDNA, NGS and ddPCR,
in nine drug projects for biomarkers, including FGFR, Akt, MET, TP53, KRAS and EGFR
as well as gene panels
– Shaping of the diagnostic landscape through industry-wide collaborative initiatives, such
as the Stratified Medicines Innovation Working Group, ICH E18 Genomics Working Group
and European Biopharmaceutical Enterprises
Collaborating for
science innovation
Achieve leadership in PHC science.
– Advancing new diagnostics and treatments arising from the 100,000 Genomes project
through the Genomics England public-private GENE consortium
Bring the benefits of PHC to all
core therapy areas.
We are now making significant progress in extending the benefits of PHC to patients in
all therapy areas:
– In inflammatory disease, we are developing a handheld uric acid diagnostic test for
patients with inflammatory disease
– In cardiovascular and metabolic disease, we are collaborating with the Montreal
Heart Institute to search the genomes of up to 80,000 patients for genes associated
with cardiovascular and diabetes disease, their complications and treatment outcomes
Invest in strategic collaborations.
– 14 new collaboration agreements signed with diagnostic companies, increasing our
investment to >$130m
– Partnerships with leading academic centres, including the Karolinska Institute,
Cambridge University, Montreal Heart Institute, and The Wellcome Trust Sanger Institute
64 ©AstraZeneca 2016
The next wave of scientific innovation 65
An environment where
science thrives
– Over 30 new staff hired to enhance our diagnostic and biomarker expertise
Developing a companion diagnostic
test for a breakthrough therapy
Osimertinib achieved
one of the fastest
clinical development
programmes on record,
taking less than three
years from first-time-inman to first launch.
Introduction
Therapy area progress
Non-small-cell lung cancer (NSCLC) is the most
common form of cancer worldwide. Patients that
have activating mutations of the Epidermal Growth
Factor Receptor (EGFR) gene are more likely to
benefit from EGFR Tyrosine Kinase Inhibitors
(TKIs) such as gefitinib, and diagnostic tests for
these mutations are used to select patients for
first-line treatment. Although EGFR-TKIs are
effective in these patients, the majority develop
resistance after 10-12 months, and in around
60% of these cases, resistance is associated
with the emergence of another EGFR mutation,
known as T790M. Knowledge of the biological
role of these mutations helped AstraZeneca to
design osimertinib (AZD9291), an irreversible
EGFR-TKI that targets both the sensitising
mutations of EGFR and the T790M mutation
that confers resistance.
Osimertinib achieved one of the fastest clinical
development programmes on record, taking
less than three years from first-time-in-man
to first launch. One of the contributing factors
of AZD9291’s success was its ability to use a
companion diagnostic test to select the right
patients for treatment from the earliest stages of
clinical development. AstraZeneca’s PHB function
partnered with Roche Molecular Systems (RMS)
to develop the cobas® EGFR Mutation Test as
a companion diagnostic test to identify the right
patients for treatment, often accelerating delivery of
essential diagnostic modules to enable fast-tracking
of drug development timelines. In November 2015,
osimertinib was approved by the US FDA for the
treatment of patients with metastatic epidermal
growth factor receptor (EGFR) T790M mutation
positive non-small-cell lung cancer (NSCLC), as
detected by an FDA-approved test, who have
progressed on or after EGFR TKI therapy, with
the companion diagnostic being approved on the
same day. Just five weeks later, the Committee for
Medicinal Products for Human Use of the European
Medicines Agency announced a positive opinion for
the same drug.
IMED functions
People spotlight
Craig Barker brings expertise
to PHB from Leica in Tissue
Diagnostics, including regulatory
interactions and commercial
markets. As the new Head of Tissue
Diagnostics and member of PHB
Labs leadership team based in
Cambridge, he has built a team of
dedicated diagnostic scientists who
deliver companion diagnostic assays
that select patients most likely to
benefit from linked AstraZeneca
drugs. Since joining PHB in January
2015, Craig has rapidly established
his group’s ability to manage global
deployment of the diagnostic assays
and work with diagnostic partners to
submit regulatory packages against
tight timelines.
An environment where
science thrives
66 ©AstraZeneca 2016
Carolina Haefliger is the new
Head of Companion Diagnostics for
Cardiovascular and Metabolic Diseases
(CVMD), and is also responsible for
Opportunistic therapy areas such
as Neuroscience. An MD in clinical
genetics with expertise in both CVMD
and oncology translational science
and the leadership of observational
biomarker studies, Carolina joined
PHB from Novartis in July 2015, and
focuses on providing diagnostic options
to our CVMD portfolio as well as
championing strategic collaborations
such as our genomics initiative with
Montreal Heart Institute on behalf of the
CVMD Therapy Area Leadership team.
A member of PHB’s leadership team
based in Gothenburg, Carolina also
serves as PHB’s Medical Adviser.
Collaborating for
science innovation
Joachim Reischl brings expertise
in global biomarker strategy
and development from Bayer,
combined with scientific leadership
in pharmacology and genomics.
As PHB site head in Gothenburg and
member of PHB’s leadership team
since July 2015, Joachim heads
up the new, global Policy, Portfolio
and Externalisation (PPE) group that
drives organisational efficiency within
PHB and provides diagnostic project
management across a growing
portfolio. The PPE group is also
responsible for providing content for
AstraZeneca’s policy initiatives on
Personalised Healthcare.
The next wave of scientific innovation 67
PHC adoption across AstraZeneca pipeline end of 2015
Phase II
25 New Molecular Entities
Phase III
10 New Molecular Entities
Applications under review
5 New Molecular Entities
Small molecule
Large molecule
Small molecule
Large molecule
Small molecule
Large molecule
AZD1419#
TLR9 asthma
MEDI4920
CD40L-Tn3 pSS
AZD7594
Inhaled SGRM asthma
AZD9412#
Inhaled βIFN asthma/COPD
PT010
LAB/LAMA/ICS COPD
anifrolumab# TULIP
IFNaR SLE
AZD7986
DPP1 COPD
MEDI5872#
B7RP1 SLE
abediterol (AZD0548)
LABA asthma/COPD
mavrilimumab#
GM-CSFR rheumatoid arthritis
roxadustat#
HIFPH anaemia CKD/ESRD
Benralizumab#
IL-5R severe asthma
lesinurad
URAT-1 gout
AZD8999
MABA asthma/COPD
MEDI7836
IL-13 asthma
AZD7624
Inhaled p38 inhibitor COPD
MEDI2070#
IL-23 Crohns
selumetinib# SELECT-1
MEK 2L KRAS+ NSCLC
brodalumab#
IL-17R psoriasis
AZD9291 AURA, AURA 2
EGFR T790M NSCLC>2L
AZD9977
MCR diabetic kidney disease
MEDI0382
GLP-1/gluagon diabetes/obesity
RDEA3170
URAT-1 hyperuricemia/gout
tralokinumab
IL-13 severe asthma
Cediranib ICON 6
VEGF PSR ovarian
AZD3759 or AZD9291 BLOOM EGFR NSCLC brain mets
MEDI6012
LCAT ACS
AZD4901
PCOS
abrilumab#
α4β7 Crohns/ulcerative colitis
durvalumab#ATLANTIC
PD-L1 3L NSCLC
AZD5312#
androgen receptor prostate
MEDI8111
Rh-Factor II trauma/bleeding
AZD1775#
Wee-1 ovarian
MEDI9929#
TSLP asthma/atopic dermatitis
moxetumomab#
CD22 HCL
AZD6738
ATR solid tumours
MEDI0562#
hOX40 solid tumours
AZD2014
mTOR 1/2 solid tumours
MEDI-551#
CD19 DLBCL
tremelimumab DETERMINE
CTLA-4 mesothelioma
AZD8186
PI3Kβ solid tumours
MEDI0639#
DLL-4 solid tumours
AZD4547
FGFR solid tumours
MEDI-573#
IGF metastatic breast cancer
MEDI-551#
CD19 neuromyelitis optica
AZD5363#
AKT breast cancer
susatoxumab (MEDI4893)
staph alpha toxin SSI
AZD9150#
STAT3 haems & solids
MEDI3617#
ANG-2 solid tumours
savolitinib#
MET pRCC
MEDI7510
sF+GLA-SE RSV prevention
AZD9496
SERD ER+ breast
MEDI565#
CEA BITE tumours
AZD3241
MPO Multiple System Atrophy
MEDI8897#
RSV passive prophylaxis
ATM AVI#
BL/BLI SBI
AZD8108
NMDA suicidal ideation
AZD3293#
BACE Alzheimer’s
MEDI9447
CD73 solid tumours
AZD5847
oxazolidione TB
MEDI1814
amyloidβ Alzheimer's
CXL#
BLI/cephalosporin MRSA
CAZ AVI #
BLI/cephalosporin SBI/clAl/cUTI
Pipeline data correct as of 30 September 2015.
Includes significant fixed dose combination projects,
and parallel indications that are in a separate therapeutic area
# Partnered; ¶ Registrational Phase II/III study
RIA
Oncology
CVMD
Infection,
Neuroscience,
Gastrointestinal
Project with
PHC Approach
Key PHB collaborations in 2015
Qiagen, Hilden, Germany
Ventana, Tuscon, US
Roche Molecular Systems,
Basel, Switzerland
Master Collaboration Agreement
focussed on non-invasive diagnostic
test using Circulating Free DNA for
Non-small-cell lung cancer.
Agreement focused on prostate cancer:
PTEN biomarker test, gastric cancer:
ATM IHC diagnostic tissue test, and
PD-L1 expression Class I device and
companion diagnostic test.
Master Collaboration Agreement
focused on lung cancer: KRAS mutation
diagnostic test (solid tumour and
plasma), breast cancer: PI3K mutation
test in plasma DNA, and lung cancer:
T790M EGFR mutation test (solid
tumour and plasma).
Myriad, Salt Lake City, US
Illumina, Cambridge, UK
Master Collaboration Agreement
focused on BRCA testing in pancreatic,
lung, breast and ovarian cancers.
Partnership focused on the
development of an Oncogene Panel
and Therapy Selection System, and
the implementation of next-generation
sequencing as an FDA-approved
companion diagnostic.
MEDI3902
PsI/PcrV pseudomonas
MEDI-550
pandemic influenza virus vaccine
MEDI8852
influenza A treatment
68 ©AstraZeneca 2016
The next wave of scientific innovation 69
An environment where
science thrives
MEDI6383#
Ox40 FP solid tumours
Collaborating for
science innovation
MEDI0680
PD-1 solid tumours
PT003 PINNACLE
LABA/LAMA COPD
IMED functions
AZD8835
PI3Kα solid tumours
Large molecule
Therapy area progress
Small molecule
Introduction
Phase I
30 New Molecular Entities
Key PHB publications in 2015
Authors
European Heart Journal
Effect of genetic variations on ticagrelor
plasma levels and clinical outcomes
Varenhorst C, Eriksson E, Johansson Å, Barratt BJ,
Hagström E, Åkerblom A, Syvänen AC, Becker C, James
SK, Katus HA, Husted S, Steg G, Siegbahn A, Voora D,
Teng R, Storey RF, Allentin L
European Journal of
Nuclear Medicine and
Molecular Imaging
(11)C-PBR28 imaging in multiple schlerosis
patients and healthy controls: test-retest
reproducibility and focal visualization of
active white matter areas
Park E, Gallezot JD, Delgadillo A, Liu S, Planeta B, Lin SF,
O’Connor KC, Lim KI, Lee JY, Chastre A, Chen MK, Seneca
N, Leppert Dl, Huang Y, Carson RE, Pelletier D
Nature: Insight
Precision medicine, AstraZeneca’s approach
March R
Journal of Nuclear
Medicine
Fazio P, Svenningsson P, Forsberg A, Jönsson EG, Amini N,
Nakao R, Nag S, Halldin C, Farde L
Nature Communications
Aberrant splicing of U12-type introns is the
hallmark of ZRSR2 mutant myelodysplastic
syndrome
Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A,
Kohlmann A, Sanada M, Grossmann V, Sundaresan J,
Shiraishi Y, Miyano S, Thol F, Ganser A, Yang H, Haferlach
T, Ogawa S, Koeffler HP
A quantitative analysis of 18F-(E)-N-(3Iodoprop-2-Enyl)-2b-carbofluoroethoxy-3b(49-methyl-phenyl) nortropane binding to the
dopamine transporter in Parkinson’s disease
Journal of Cerebral
Blood Flow & Metabolism
Cselény Z, Farde L
Haematologica –
The Hematology Journal
Refractory anemia with ring sideroblasts
and marked thrombocytosis (RARS-T)
cases harbor mutations in SF3B1 or other
spliceosome genes accompanied by
JAK2V617F and ASXL1 mutations
Jeromin S, Haferlach T, Weissmann S, Meggendorfer M,
Eder C, Nadarajah N, Alpermann T, Kohlmann A, Kern W,
Haferlach C, Schnittger S
Quantification of blood flow-dependent
component in estimates of beta-amyloid
load obtained using quasi-steady-state
standardized uptake value ratio
Journal of Leukocyte
Biology
Targeting neutrophilic inflammation in severe
neutrophilic asthma: can we target the
disease-relevant neutrophil phenotype?
Bruijnzeel PL, Uddin M, Koenderman L
Cancer Research
Exploring the biomechanical properties of
brain malignancies and their pathological
determinants in vivo with magnetic resonance
elastography
Jamin Y, Boult JKR, Li J, Popov S, Garteiser P, Ulloa JL,
Cummings C, Box G, Eccles SA, Jones C, Waterton JC,
Barnber JC, Sinkus R, Robinson SP
Chemistry of Materials
Influence of the base on Pd@MIL-101NH2(Cr) as catalyst for the Suzuki-Miyaura
cross-coupling reaction
Yao Q, Bermejo Gómez A, Su J, Pascanu V, Yun Y, Zheng
H, Chen H, Liu L, Abdelhamid HN, Martín-Matute B, Zou X
Brain, Behavior, and
Immunity
Telomere length and outcomes in ischaemic
heart failure: data from the controlled
rosuvastatin multiNAtional trial in heart failure
(CORONA)
Haver V, Mateo Leach I, Kjekshus J, Fox JC, Wedel H,
Wikstrand J, de Boer RA, van Gilst WH, McMurray JJ, van
Veldhuisen DJ, van der Harst P
Cerebrospinal fluid kynurenines in multiple
sclerosis; relation to disease course and
neurocognitive symptoms
Aeinehband S, Brenner P, Ståhl S, Bhat M, Fidock M,
Khademi M, Olsson T, Engberg G, Jokinen J, Erhardt S,
Piehl F
Radiology
Zhang WJ, Cristinacce P, Bondesson E, Nordenmark L,
Young SS, Liu YZ, Singh D, Naish JH, Parker GJM
Circulation: Cardiovascular
Genetics
The NLRC4 inflammasome is an important
regulator of interleukin-18 levels in patients
with acute coronary syndromes: a genomewide association study in the PLATO trial
Johansson Å, Eriksson N, Becker RC, Storey RF,
Himmelmann A, Hagström E, Varenhorst C, Axelsson T,
Barratt BJ, James SK, Katus HA, Steg G, Syvänen AC,
Wallentin L, Siegbahn A
MR quantitative equilibrium signal mapping:
a reliable alternative to CT in the assessment
of emphysema in patients with chronic
obstructive pulmonary disease
Nuclear Medicine and
Molecular Imaging
β-Amyloid binding in elderly subjects with
declining or stable episodic memory function
measured with PET and [11C] AZD2184
Mattsson P, Forsberg A, Persson J, Nyberg L, Nilsson LG,
Halldin C, Farde L
Stem Cells Translational
Medicine
Concise review: workshop review:
understanding and assessing the risks of
stem cell-based therapies
Heslop JA, Hammond TG, Santeramo I, Piella AT, Hopp I,
Zhou J, Mills, Park BK
British Journal of Clinical
Pharmacology
The effect of a selective CXCR2 antagonist
(AZD5069) on human blood neutrophil count
and innate immune functions
Jurcevic S, Humfrey C, Uddin M, Warrington S, Larsson B,
Keen C
Neuropharmacology
A PET study comparing receptor occupancy
by five selective cannabinoid 1 receptor
antagonists in non-human primates
Hjorth S, Karlsson C, Jucaite A, Varnäs K, Wählby Hamrén
U, Johnström P, Gulyás B, Donohue SR, Pike VW, Halldin
C, Farde L
European Journal of
Nuclear Medicine and
Molecular Imaging
Test-retest reproducibility of [(11)C]PBR28
binding to TSPO in healthy control subjects
Collste K, Forsberg A, Varrone A, Amini N, Aeinehband S,
Yakushev I, Halldin C, Farde L, Cervenka S
NeuroImage
Diurnal and seasonal variation of the brain
serotonin system in healthy male subjects
Matheson GJ, Schain M, Almeida R, Lundberg J, Cselényi
Z, Borg J, Varrone A, Farde L, Cervenka S
Molecular Psychiatry
Contribution of non-genetic factors to
dopamine and serotonin receptor availability
in the adult human brain
Borg J, Cervenka S, Kuja-Halkola R, Matheson GJ,
Jönsson EG, Lichtenstein P, Henningsson S, Ichimiya T,
Larsson H, Stenkrona P, Halldin C, Farde L
Brain: A Journal of
Neurology
Effect of the myeloperoxidase inhibitor
AZD3241 on microglia: a PET study in
Parkinson’s disease
Jucaite A, Svenningsson P, Rinne JO, Cselényi Z, Varnäs K,
Johnström NA, Kirjavainen A, Helin S, Minkwitz M, Kugler
AR, Posener JA, Budd S, Halldin C, Varrone A
Radiology
T1-weighted dynamic contrast-enhanced
MR imaging of the lung in asthma:
semiquantitative analysis for the assessment
of contrast agent kinetic characteristics
Zhang WJ, Niven RM, Young SS, Liu YZ, Parker GJM,
Naish JH
Diabetes
Increasing pyruvate dehydrogenase flux as
a treatment for diabetic cardiomyopathy:
a combined 13C hyperpolarized magnetic
resonance and echocardiography study
Le Page LM, Rider OJ, Lewis AJ, Ball V, Clarke K,
Johansson E, Carr CA, Heather LC, Tyler DJ
Cardiovascular Genetics
Differential genetic effects on statin-induced
changes across low-density lipoproteinrelated measures
Chu AY, Guilianini F, Barrratt BJ, Ding B, Nyberg F, Ridker
PM, Chasman DI
Chemistry – A European
Journal
Influence of the base on PD@MIL-101-NH2
(CR) as catalyst for the Suzuki-Miyrua crosscoupling reaction
Carson F, Pascunu V, Bermejo Gomez A, Zhang Y, PlateroPrats AE, Zou X, Martin-Matute B
Nature Science Reports
Adaptation to acetaminophen exposure
elicits major changes in expression and
distribution of the hepatic proteome.
Eakins R, Walsh J, Randle L, Jenkins RE, SchuppeKoistinen I, Rose C, Starkey LP, Vasieva O, Prats N, Brillant
N, Auli M, Bayliss M, Webb S, Res JA, Kitteringham NR,
Goldring CE, Park BK
European Journal of
Heart Failure
70 ©AstraZeneca 2016
The next wave of scientific innovation 71
An environment where
science thrives
Title
Collaborating for
science innovation
Publication
IMED functions
Authors
Therapy area progress
Title
Introduction
Publication
Early Clinical
Development
Where science meets the patient, skilled
transitional clinical scientists who evaluate
whether our research can change lives.
72 ©AstraZeneca 2016
The next wave of scientific innovation 73
Early Clinical Development
A strategy with
three principles
“In 2015, the second year of Early Clinical Development (ECD), we created significant
positive change in our strategy, people, operations and culture. ECD has attracted
world-class talent globally and established a Clinical Discovery Unit (CDU). Operational
simplification was reflected in substantial improvements in clinical trial cycle times,
underpinned by an increasingly entrepreneurial and accountable culture.”
– Design and deliver innovative clinical
studies to progress the pipeline
Tony Johnson, VP Early Clinical Development
Opposite
Immune response
to cancer
– Accelerate human target validation
(HTV) across AstraZeneca core
therapeutic areas
Process improvement has been
another key area of focus, with the
implementation of eight new initiatives
to ensure simplification and improved
operational efficiencies. Compared to
2014, we have reduce our cycle times in
Phase I by 28% and in Phase II by 41%.
These improvements have generated
significant cost reduction and 36%
increased efficiency.
In order to achieve such improvements,
ECD has progressively evolved its
culture to foster agility and accountability
in decision-making coupled with an
entrepreneurial ‘can do’ attitude.
Progress the pipeline across the core
therapeutic areas.
Enrolment of Phase I studies for oncology (e.g. c-met inhibitor, AZD6094 and AKT inhibitor,
AZD5363) were completed with encouraging data thus far; multiple Phase I and Phase
II starts; RIA P38 Phase II trial achieved its interim analysis; CVMD – dosed the MCR
antagonist in humans and completed the MAD study.
Implement innovative study designs.
Over 20 clinical trials incorporated an adaptive design, increasing our ability to be
responsive to the evolving knowledge of our product candidates. Certain respiratory
studies have been initiated with novel early phase endpoints which, in some cases,
halved the required number of patients and reduced the study durations, e.g. P38 MAPK
inhibitor. Scientifically innovative model-based evaluation of biomarker data has also been
incorporated within our adaptive study designs to achieve earlier POM, e.g. DPP1.
Increase patient-centricity.
Real-time data capture from patients (e.g. PROACT) and real-time visualisation of clinical
trial data (e.g. REACT) have guided clinical trial adaptation and more efficiently determined
the right dose/regimen and patient population for our novel medicines. In 2015, REACT was
further improved to become web-based and incorporate safety, efficacy, PK and biomarker
data, a significant industry-leading achievement.
Foster excellence in scientific leadership.
ECD produced 124 publications – 32 of which were high quality and five were high impact,
a 118% improvement from 57 publications in 2014. These demonstrated world-class early
clinical development science in oncology, RIA, CVMD, Quantitative Clinical Pharmacology
(QCP) and Biometrics.
Systematically integrate data from
multiple sources.
QCP developed renal disease models incorporating pharmacokinetics and
pharmacodynamics for lesinurad and the two xanthine oxidase inhibitors, allopurinol and
febuxostat, which included the key documented influence of renal filtration on clearance of
uric acid key components in gout. Using model-based simulations, it was demonstrated that
lesinurad exhibits a positive benefit-risk in key clinical scenarios identified by the FDA.
Be the partner of choice to
external partners.
ECD scored a rating within the top three for our managed relationships with external partners.
The next wave of scientific innovation 75
An environment where
science thrives
We delivered
Collaborating for
science innovation
74 ©AstraZeneca 2016
We set out to
IMED functions
Highlights
Therapy area progress
Top
Tony Johnson,
VP Early Clinical
Development
– Integrate data from multiple sources
systematically to inform research
and development
We have also recruited six exceptional
physician scientists from top universities
to push the translational science agenda
in ECD.
Introduction
ECD’s new strategy reflecting our focus
on ‘where science meets the patient’
was communicated in October 2015.
Skilled translational clinical scientists
evaluate whether our research can
change lives, dependent on three
fundamental principles:
In addition, we have built strategic
alliances with some of the best teaching
hospitals, including Cambridge, Harvard
and Manchester.
Cycle Time (number of months)
41% reduction
Industry benchmark 31
2012-14
2013-15
Rolling years
2014-16
Cycle Time (number of months)
Phase I Cycle Time
25
Industry benchmark 24
28% reduction
20
15
The Experimental Medicines Initiative at the University
of Cambridge is another key collaboration for the CDU.
AstraZeneca funds one PhD and two academic lecturer
positions for clinicians per year. The first PhD scientist has
been appointed and will start work with the Drug Safety
and Metabolism (DSM) team in early 2016. The aim is to
expand this model to other key academic partners.
Importantly, recruitment has been a major focus for ECD
in 2015. We have attracted world-class talent globally
across all departments and disciplines to consolidate our
geographical footprint in Cambridge (UK), Boston and
Gaithersburg (US) and Gothenburg (Sweden). Recruiting
and retaining world-class talent is fundamental to the
innovation, creativity, dedication and execution-focus that
will enable ECD to become industry leaders. During 2015,
we have recruited 66 positions in ECD, 70% in Cambridge
(UK), 20% in Gothenburg (Sweden), 9% in Boston (US)
and 1% in Gaithersburg (US). By the end of 2015, the
permanent ECD headcount was 237, an increase of 12%
compared to 212 at the end of 2014.
10
5
0
2012-14
2013-15
Rolling years
2014-16
The next wave of scientific innovation 77
An environment where
science thrives
76 ©AstraZeneca 2016
80
70
60
50
40
30
20
10
0
The CDU is actively looking to recruit PhD clinical
scientists to further expand the AstraZeneca talent pool.
Two academic clinical lecturers have been seconded from
the University of Cambridge to build collaborative links in
CVMD and oncology respectively. Further secondments
both from within and from outside AstraZeneca are
being explored.
Collaborating for
science innovation
Use of the portfolio power and agility of
AstraZeneca creates the opportunity to search for
early scientific signals from potential therapies,
alone or in combination, targeting niche patient
populations. Taking a modular approach makes
it possible for ECD to truly follow the science, as
different combinations can be added in response
to evolution in each patient’s cancer. Placeholders
are added to the protocol from the outset, to create
the flexibility to test combinations dependent on
the specific molecular cancer drivers detected.
Such an approach is especially effective for
using immunotherapy agents, which are often
administered in combination with targeted agents.
Within the Tatton study, a rolling-arm allocation was
used as a specific design feature to ensure ongoing
parallel recruitment so that patients could always
join an appropriate trial arm in an efficient manner.
The dose-finding phase of Tatton has now been
completed, while the trial is entering the expansion
phase under the supervision of Global Medicines
Development (GMD).
Phase II Cycle Time
People are at the heart of CDU’s function – through
collaboration with leading academic institutions and by
recruiting and developing talented physician scientists
across therapeutic areas. Professor Stephen Rennard is
Chief Clinical Scientist and a respiratory physician whose
key area of interest it to recruit a large cohort of chronic
obstructive pulmonary disease (COPD) patients and to
characterise them fully. This will identify COPD clinical
subsets and allow us to target the right drugs to the
right patients.
IMED functions
We deliver innovative clinical studies
Innovation in fit-for-purpose clinical trial design is a
key strategic pillar for ECD. In 2015, ECD initiated
its first basket trial design in the AZD9291 Tatton
lung cancer study, collaborating with the oncology
IMED. The creativity is reflected in multiple treatment
options for patients within a single trial based on the
molecular driver of each patient’s cancer. In addition,
the design allowed for combinations of therapies
to be tested using the extensive AstraZeneca
portfolio of small and large molecules while also
enabling more efficient progression through trials of
each monotherapy or drug combination regimen.
AstraZeneca has been an early adopter of this
approach from an industry perspective.
We integrate data and inform
research and development
In the context of improving data integration to
knowledge, the second ECD strategic pillar,
significant enhancements have been delivered
at the patient interface using REACT. ECD’s
partnership with Tessella Technology is to develop
innovative new technologies that allow datadriven, scientific decisions during, rather than on
completion, of a clinical trial. This augments R&D
efficiency by earlier discontinuation of those drugs
with a low probability of meeting their predefined
safety and/or efficacy goals. REACT was developed
to enable AstraZeneca researchers to view patient
information from ongoing clinical trials within 24
hours of data reaching AstraZeneca. REACT tracks
laboratory tests, adverse events, and can monitor
biomarker and efficacy data on both population and
subject-specific levels during the course of a clinical
trial. In 2015, REACT has evolved to become much
more user-friendly through conversion to a webbased format. In addition, the ability to incorporate
safety, efficacy, biomarkers and PK in a single
study, as was achieved with a key savolitinib study,
allows many scientific questions to be evaluated.
This enables a data-driven, appropriate adaptation
of the study design during the course of a trial
and is an exciting improvement of real-time data
visualisation capabilities.
The Clinical Discovery Unit was set up in 2015 by
Professor Tim Eisen. Its primary purpose is to expand the
capacity for translational clinical science and accelerate
HTV as a key contribution for ECD.
Therapy area progress
Strategic pillars
Operations
Due to ECD’s disciplined coordination between
operational activity, efficiency and licence to operate,
our clinical operations have improved their overall
efficiency by 36% since being established in 2014.
Clinical Pharmacology Unit (CPU) costs have been
reduced by 12%, laboratory costs by 15% and CPU
protocol deviations by 27%. Most significantly, we set
out to deliver 20% improvement in our Phase I and
Phase II cycle times. We achieved a reduction of 28%
in Phase I (16m v industry 24m) and a reduction of
41% in Phase II (44m v Industry 31m), underscoring the
enabling role of ECD across IMED’s delivery programme.
People spotlight
Introduction
We accelerate human target validation
ECD is focusing increasing effort on accelerating
Human Target Validation (HTV). All functions of ECD
are involved and will increasingly be boosted by the
development of the Clinical Discovery Unit. HTV will
often be achieved in collaboration with academic
partners. For example, in collaboration with Lars
Lund at Karolinska, the CVMD TMU demonstrated
that Myeloperoxidase (MPO)-related biomarkers
outperformed NT-proBNP in predicting NYHA
score. This significantly adds to previous work
suggesting that MPO drives endothelial dysfunction
and mortality in heart failure with preserved ejection
fraction. Other CVMD TMU examples include FLAP
in inflammatory disease and GPR44 in dysfunction of
human pancreatic beta cells. CDU, working with key
ECD partners, commenced work on a study to recruit
a large cohort of patients with COPD who will be very
thoroughly characterised. As well as providing greater
understanding of the different disease phenotypes, this
will enable segmentation of the COPD population and
rapid recruitment of patients to multiple molecularly
targeted Phase II studies using novel portfolio agents.
Key Early Clinical Development collaborations in 2015
National Jewish Health, Denver, US
Boston University School of
Medicine, US
University of Georgia, US
Sarah Cannon Research Institute,
London, UK
Karolinska Institute,
Stockholm, Sweden
Investigator: Professor Johann De
Bono, MD, MSc, PhD, FRCP, FMedSci.
Professor of Experimental Cancer
Medicine, Honorary Consultant
Medical Oncologist at the Royal
Marsden Hospital and Institute
of Cancer Research
Expert at developing molecular
targeted therapies for prostate
cancer patients and the projects have
involved evaluating AstraZeneca novel
therapeutics in prostate cancer.
Investigator: Dr Howard A. Skip
Burris, III, MD, FACP.
President, Clinical Operations and
Chief Medical Officer, Sarah Cannon
Providing AstraZeneca with clinical
development expertise, access to
molecular profiling data and timely,
cost-efficient CRO trial management
for early phase novel oncology clinical
trials with potential for personalised
medicine approaches.
Investigator: Professor Peter
Stenvinkel, MD, PhD Renal Medicine
and Kerstin Brismar, MD, PhD Growth
and Metabolism
Collaboration set up to provide access
to clinical samples and data from several
large cohorts of CKD patients as well
as healthy controls, which were and
will continue to be used to assess HTV
in multiple targets for the management
of CKD, as well as some pre-TSID
CKD projects.
IMED functions
Institute of Cancer Research and
The Royal Marsden Hospital,
London, UK
Therapy area progress
Investigator: Assistant Professor K.
Melissa Hallow, PhD. Joint appointment
in College of Engineering and College
of Public Health, Department of
Epidemiology and Biostatistics
The project involves diabetes disease
modelling in collaboration with DMPK
CVMD and DSM and provides support
to late stage and early diabetes assets
including chronic kidney disease.
Introduction
Investigator: Professor Avrum Spira,
MD, MSc. Division of Computational
Biomedicine, Department of Medicine
This project seeks to find key gene
expression and protein biomarkers that
identify COPD patients with high levels
of p38 MAP kinase and MEK activity in
order to correlate protein kinase activity
with clinical outcomes in COPD and
lung cancer and to identify patients who
might best respond to specific p38 and
MEK inhibitors.
Investigator: Associate Professor
Elena Goleva, PhD. Division of
Pediatric Allergy and Immunology
This project examines the role of p38
MAP kinase in steroid resistant asthma,
and explores the effect of AZD7624
(inhaled p38 inhibitor) in severe steroidresistant asthma.
Title
Authors
The New England Journal
of Medicine
AZD9291 in EGFR inhibitor-resistant nonsmall-cell lung cancer
Jänne PA, Hsin Yang JC, Kim DW, Planchard D, Ohe
Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L,
Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M,
Brown KH, Dickinson PA, Ghiorghiu S, Ranson M
European Heart Journal
Effect of genetic variations on ticagrelor
plasma levels and clinical outcomes
Varenhorst C, Eriksson N, Johansson Å, Barratt B,
Hagström E, Åkerblom A, Syvänen AC, Becker RC, James
SK, Katus HA, Husted S, Steg PG, Siegbahn A, Voora D,
Teng R, Storey RF, Wallentin L
The Lancet Oncology
Lenvatinib, everolimus, and the combination
in patients with metastatic renal cell
carcinoma: a randomised, phase 2, openlabel, multicentre trial
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina
A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B,
Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus
C, Larkin J
Nature Reviews Cancer
VHL, the story of a tumour suppressor gene
Gossage L, Eisen T, Maher ER
Gut
Galectin-3 regulates hepatic progenitor cell
expansion during liver injury
Hsieh WC, Mackinnon AC, Lu WY, Jung J, Boulter L,
Henderson NC, Simpson KJ, Schotanus B, Wojtacha D,
Bird TG, Medine CN, Hay DC, Sethi T, Iredale JP, Forbes SJ
78 ©AstraZeneca 2016
An environment where
science thrives
Publication
Collaborating for
science innovation
Key Early Clinical Development publications in 2015
The next wave of scientific innovation 79
Shaping drug development in Asia
Background
A key growth area for AstraZeneca
We enhanced our external scientific reputation through highimpact publications, presentations at major international
scientific conferences, and collaborations with leading research
institutions. The positive results of olaparib Phase II study
in gastric cancer was published in the Journal of Clinical
Oncology in 2015. Our poster on AZD3759 Phase I study was
selected for oral discussion at ASCO 2015. Several of our
senior scientists have been invited to join leading academic
institutions such as Beijing University as faculty members.
– The dose and schedule for further
clinical studies has been identified
through Phase II clinical studies
initiated in 2015
– China IND filing was accepted by
China FDA in April 2015. This is the first
category 1.1 (China Innovation) filing
by AstraZeneca
Scientific leadership in action
to accelerate delivery of our
innovative medicines to
patients in China
These plans aim to help us accelerate
development of our medicines in this
important market by expanding our
These investments and dedicated R&D
capabilities are aimed at accelerating
Chinese patient access to innovative
medicines to address significant unmet
need in AstraZeneca’s main therapy
areas – respiratory; cardiovascular and
metabolic diseases; and oncology.
AstraZeneca’s commitment to bring
cutting-edge biopharmaceutical
science to China and to partner with
the local science community is aligned
with the Chinese Government’s focus
on increasing innovation to support
economic development and access
to healthcare.
“AZD3759 is an
example of China
innovation for the
global market.
Asia iMed is on
AstraZeneca’s
innovation map.”
Pascal Soriot, CEO
The initiatives and
investments include:
– An investment of $50 million to
build an additional development
and launch facility alongside our
existing manufacturing site in Wuxi
City to support the development
and manufacture of innovative
small molecules discovered in
China and our global R&D sites
– Additional investments include
the creation of a new global hub
for Pharmaceutical Development
– alongside those in the UK and
Sweden – with up to 50 scientists
based in Shanghai and Wuxi
City, to support both China and
global needs. AstraZeneca is
also establishing an integrated
China medicines development
organisation, bringing together
early- and late-stage medicines
development across small
molecules and biologics
– A strategic alliance with WuXi
AppTec, a leading Chinese
biologics manufacturer and
contract research organisation,
to produce innovative biologics
locally in China
– A strategic discovery partnership
with Pharmaron, a leading R&D
service provider based in China.
Pharmaron works closely with our
teams to deliver discovery services
in chemistry, as well as in drug
metabolism and pharmacokinetics
(DMPK)
80 ©AstraZeneca 2016
The next wave of scientific innovation 81
An environment where
science thrives
In December 2015, AstraZeneca,
along with MedImmune, its global
biologics research and development
arm, announced a range of strategic
initiatives to accelerate the delivery
of medicines to patients in China,
the company’s second largest market
globally and a key growth platform.
clinical development activities, including
all clinical development phases, and
further developing local capabilities
in drug substance synthesis and drug
product development.
Collaborating for
science innovation
Xiaolin Zhang, VP Asia iMed
AZD3759 is the first investigational drug
discovered by Asia iMed and targets
EGFR mutation positive advanced
stage non-small cell lung cancer.
– Clinical activities have been
demonstrated in patients with CNS
metastasis. Patients who have failed
multiple lines of therapies showed
benefit from AZD3759 treatment
IMED functions
“We have advanced our oncology
portfolio significantly in 2015.
Building on our expertise from
AZD3759, we have identified the
drug candidates that can penetrate
the blood-brain barrier for the
treatment of tumours that have
metastasised to the brain.”
Above
Xiaolin Zhang,
VP Asia iMed
Therapy area progress
One of our strategic objectives is to realise the benefit of
our new drugs for Chinese and Asian patients as quickly as
possible. Asia iMed worked closely with global teams during
2015, and actively explored new potential drugs for the
treatment of diseases that are most prevalent in China and
Asia. Building on our pre-clinical findings, the olaparib team
has initiated AstraZeneca’s first Phase III study in gastric
cancer. To ensure clinical studies in China are efficiently
executed, the biomarker team also delivered essential
biomarker studies for osimertinib, olaparib, volitinib, and
MEDI4736 in 2015.
Introduction
Our drug discovery programmes in the chronic kidney
disease area are progressing as planned. We prioritise kidney
disease targets with a strong human genetic link, followed by
animal models to establish causal relationship between the
genetic change and disease phenotype. Realising the huge
and increasing unmet medical needs, especially in China,
we started our investment in the respiratory disease area, with
a focus on chronic obstructive pulmonary disease (COPD).
Since entering China in 1993,
AstraZeneca has been committed
to continuously following the
science, focusing on innovation and
becoming one of the most trusted
healthcare partners in improving
the lives of Chinese patients.
AstraZeneca’s China headquarters
are based in Shanghai, and the
company has more than 11,000
employees throughout the country.
We’ve established manufacturing
sites in Wuxi and Taizhou, as well as
a China Distribution Centre in Wuxi.
AstraZeneca also has an Innovation
Centre in Shanghai, focused on
the discovery and development
of innovative candidate drugs
to address the unique needs of
patients in Asia.
Case study
Vanderbilt Center for Neuroscience
Drug Discovery and AstraZeneca
The focus of our collaboration with the Vanderbilt Center for
Neuroscience Drug Discovery (VCNDD) is to discover and develop
novel positive allosteric modulators of the muscarinic M4 receptor for
the treatment of psychiatric complications associated with Alzheimer’s
disease and Parkinson’s disease.
Case study
Partnering to develop new medicines for neurodegenerative diseases
In 2013, AstraZeneca IMED entered into a collaboration with the
Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). Together,
we hope to enable breakthrough discoveries and bring new medicines
to patients who are suffering from neurodegenerative diseases.
Our collaboration is breaking new ground, with a new way of targeting
this class of receptors where other efforts have been unsuccessful.
Professor Jeffrey Conn, Director, Vanderbilt Center for Neuroscience
Drug Discovery:
“This new model for advancing neuroscience drug discovery pioneered
by AstraZeneca fits perfectly with the mission of the VCNDD and makes it
an ideal partnership for having an impact on these devastating disorders.
Opposite
Neural network
Above
Professor Jeffrey Conn
This is a really special collaboration on multiple levels. First of all the
science is innovative, and a fundamentally new approach to treatment
of Alzheimer’s disease or other related neurodegenerative disorders.
In diseases like Alzheimer’s and Parkinson’s, we still have a huge unmet
medical need. There are very, very poor treatments available for patients
and especially for the psychiatric complications, which can become very
burdensome not only to the patients but also to the caregivers.
In interacting with AstraZeneca as a scientist, it’s clear that they are
there for a purpose, that they want to have an impact on patient care.
They can see the possibilities of really having a positive impact.
The thing I enjoy most about working with AstraZeneca is the
shared passion.
When we have meetings, when we talk on the phone, we can sense
that passion and it creates an atmosphere where we’re very strategic,
very focused. We get to the issues that are most important for the
programme rather than thinking about process or other issues that
could be distracting.
I’m really excited to be a part of something as innovative as the
Neuroscience iMed, discovering new treatments for neurosciencerelated disorders.
Together we are aiming to get a new compound into clinical testing.
Working together, we can explore new possibilities for treating patients
who suffer from these devastating diseases.”
“Together with
AstraZeneca we are
aiming to get a new
compound into clinical
testing. Working
together, we can explore
new possibilities for
treating patients who
suffer from these
devastating diseases.”
Professor Jeffrey Conn, Director, Vanderbilt Center
for Neuroscience Drug Discovery (VCNDD)
82 ©AstraZeneca 2016
The next wave of scientific innovation 83
Three science units with one shared goal
Leveraging the combined power of AstraZeneca science
Discovery and Early Development
Our IMED Biotech Unit works together with colleagues in our
Biologics team at MedImmune, and with Global Medicines
Development, to discover and develop medicines that meet
unmet medical needs.
Small Molecules
Innovative Medicines and Early Development (IMED) Biotech Unit
By following the science, we are confident that together we can
transform the lives of patients around the world.
Collaborations and Combinations
Late-stage Development
Introduction
AstraZeneca is a global, innovation-driven biopharmaceutical
company that spans discovery, development, manufacturing,
distribution and worldwide commercialisation. Our science
exploits our rare combination of capabilities in small molecules
and biologics, immunotherapies, protein engineering
technologies and devices.
Combining the strength of our science units
Global Medicines
Development
Market
MedImmune
Global Medicines Development
For further information please click here
For further information please click here
For further information please click here
Focuses on using state-of-theart discovery platforms and
translational science in small
molecules, oligonucleotides and
other emerging technologies.
Focuses on biologics across our
core areas and pioneers innovative
research using unparalleled expertise
in protein engineering, translational
sciences and immunology.
The science engine room that drives
late-stage development of our
innovative pipeline, transforming
exciting science into valued new
medicines and ensuring patients
around the world can access them.
Collaborating to exploit combination
therapeutic strategies
Following the science, it became evident to the IMED team that
both AZD9150 and AZD5069 inhibit signalling that tumours use
to evade the host immune system. Paul Lyne, Senior Director
and Global Project Lead for AZD9150 and AZD5069 believes
that the combination of a Tumour Microenvironment (TME)
modulator with immune checkpoint blockade offers a potential
to improve patient outcomes as seen with immune checkpoint
inhibition alone.
Carl Cook, Senior Director, Oncology TMU, IMED describes
how working across the science units was, and will continue
to be, critical to the accelerated progression of this project.
“I believe we successfully achieved the first study milestone
of this novel combination strategy as a result of a dynamic,
collaborative team focused on the science and on patients.
The IMED team really embedded themselves into the
durvalumab team in GMD, and because of this we have not
only been able to accelerate the programme, but to really drive
synergy and efficiency. By working smartly, transparently and
collaboratively, we manage a complex stakeholder network of
senior leaders across the entire organisation. We’ve been able to
create an environment where decision-making on the project is
very effective and efficient. This approach, where we collaborate
as one small team to drive communication and decision-making
across other business units, translates into rapid decisionmaking, data sharing and best practices with the goal to
accelerate the development of a potential novel combination
strategy with durvalumab – to ultimately help more patients.”
“Immune checkpoint blockade therapies are transforming
the therapeutic landscape for oncology patients, and have
validated the clinical strategy of supporting the patient’s
immune system to treat cancer. The next generation of
immuno-oncology approaches will include therapies that
combine complementary immune targeting mechanisms to
84 ©AstraZeneca 2016
The next wave of scientific innovation 85
An environment where
science thrives
This important study milestone was successfully achieved
dueto the collaborative approach, led by the AZD9150 team
together with colleagues from the IMED, Global Medicines
Development (GMD) and MedImmune organisations.
Durvalumab, our Phase III PD-L1 checkpoint inhibitor, is
currently demonstrating strong potential to combine with both
immunotherapy and small molecules. We have an extensive
development programme under way across our science units
and across multiple tumour types and stages of disease,
assessing the potential for immunotherapy to either replace
or combine with traditional chemotherapy.
increase the proportion of patients that can benefit. These
studies represent a key component of our organisation’s
strategy for immuno-oncology and will hopefully bring
increased benefit to patients”.
Collaborating for
science innovation
PD-L1 (MEDI4736)/AZD5069 and AZD9150
On 10 August 2015, the first patients were dosed on the
durvalumab (MEDI4736) oncology combination trial with the
oligonucleotide STAT3 inhibitor, AZD9150 or the small molecule
CXCR2 inhibitor, AZD5069.
IMED functions
IMED Biotech Unit
Therapy area progress
Biologics
MedImmune Biotech Unit
Collaborating and sharing data to
redefine the future of drug discovery
In 2015, our teams established around 60 major
collaborations covering key therapy areas and
exciting new technologies that are set to drive
progress in medical science innovation for years
to come.
– Working side-by-side with external scientists
to better understand disease mechanisms
– Sharing information, expertise and insight
– Making our compounds available through
Open Innovation initiatives
“We have fruitful, illuminating exchanges of ideas
and experience and expertise. We constantly
exchange with AstraZeneca our results and try to
subject them to discussion and we always receive
valuable information from other AstraZeneca
research groups. And this ecosystem makes things
efficient and progressive.”
Evgeny Imyanitov, Petrov Institute
“The experience we are gaining is unmatched,
and the contribution we can make is exciting.
Our scientists are motivated by the innovation
and the culture of sharing the best practice that
AstraZeneca promotes.”
Katherine Lee, Pharmaron
“As a collaboration partner AstraZeneca is
different from other pharma partners I have
worked with in the past. They’re more willing
to share information and we have found this
across several programmes.”
Jon Moore, Horizon
Several innovative compound-sharing agreements
underlined our commitment to open innovation and
information sharing. One of these involved a direct
exchange of 210,000 compounds with Sanofi from
our respective compound libraries.
“We’ve worked hard to enrich our compound
library in recent years and this exchange, which is
by far the largest we’ve achieved, enables us to
significantly increase its diversity. Most importantly,
it will accelerate our ability to identify unique starting
points that could become new medicines for
patients,” said Mene Pangalos.
86 ©AstraZeneca 2016
The next wave of scientific innovation 87
An environment where
science thrives
We joined a public-private consortium with
Genomics England to accelerate the development
of new diagnostics and treatments arising from the
100,000 Genomes Project. The GENE Consortium
is a unique partnership between industry, academia
and the National Health Service (NHS) Genomic
Medicine Centres, which aims to transform
treatment for patients with cancer and rare diseases,
providing faster access to the right therapy and
personalised healthcare.
– Sharing compounds to uncover novel target
opportunities
Collaborating for
science innovation
We engaged in a number of collaborations designed
to advance treatment in areas of diabetes and
chronic kidney disease, with key partners such as
the University of Michigan, the French National
Institute of Health and Medical Research (Inserm)
and Harvard Stem Cell Institute. We also kicked
off a partnership with the Montreal Heart Institute,
which is now genotyping up to 80,000 DNA samples
from our biobank, looking for genes associated
with cardiovascular diseases and diabetes, their
complications and treatment outcomes.
– In-licensing new chemical modalities and
platforms
IMED functions
We signed four research collaborations aimed at
harnessing the power of CRISPR, a pioneering
genome-editing technique, across our entire
discovery platform. Partnerships with the Wellcome
Trust Sanger Institute, the Innovative Genomics
Initiative, Thermo Fisher Scientific and Broad
Institute/Whitehead Institute complement our
in‑house CRISPR programme.
We work flexibly with our partners
in pursuit of breakthrough science
Therapy area progress
ene Pangalos, Executive Vice President,
M
IMED Biotech Unit, on exchange of 210,000
compounds with Sanofi.
Partnering: a way of life
Introduction
“We’ve worked hard to
enrich our compound
library in recent years and
this exchange, which is
by far the largest we’ve
achieved, enables us to
significantly increase its
diversity. Most importantly,
it will accelerate our ability
to identify unique starting
points that could become
new medicines for patients.”
Our teams are leading the way in creating open
research environments that go beyond the usual
collaboration models. We are always on the lookout
for novel ways of working with others to advance
medical science and speed up delivery of new
medicines to patients. In 2015, we continued to
build our network of collaborations with academic
institutions, biotech and pharmaceutical companies
in our key therapy areas as well as in rapidly
evolving technologies such as CRISPR and
antisense oligonucleotides. We are also pioneering
new approaches to open innovation, creating a
permeable research environment where scientists
both inside and outside AstraZeneca can more
freely share their ideas and collaborate on projects.
Global collaborations
A global science network
UK
300
Sweden
100
Europe
160
Introduction
US
340
Our open innovation partnerships
with academic translational drug
discovery centres and governmentlinked funding agencies includes
leading scientific institutions
globally, who help facilitate our
interactions with leading scientists.
Our partners include:
– United Kingdom: Medical
Research Council
Asia
80
Advancing the science through
Open Innovation
Our Open Innovation initiative continued to gain momentum in
2015. Our Open Innovation portfolio now has around 24 clinical,
180 preclinical and 30 target innovation projects. We also added
30,000 new compounds to our high-throughput screening
library and funded 12 R&D challenges during the year.
– Singapore: A*Star; National
Health Innovation Centre-Duke
An invitation to innovate
For further information
please click here
Our Open Innovation portal makes
it easy for external scientists to
access our full range of Open
Innovation programmes and
find ways to advance medical
science together.
– Compound bank of ‘patientready’ active and discontinued
compounds
– Pharmacology toolbox of
compounds with strong
pharmacological properties
– Collaborative effort to validate
new targets, which may include
high-throughput screening
– Advanced cheminformatic
capabilities to explore therapeutic
potential of new molecules
– R&D challenges open to anyone
willing to offer innovative solutions
88 ©AstraZeneca 2016
Open Innovation initiative
24 clinical projects
180 preclinical projects
30 target innovation projects
30,000 new compounds added to our
high-throughput screening library
12 R&D challenges funded during
the year
An environment where
science thrives
Out-licensing is another area of focus to ensure progression of
indications that fall outside our core focus areas. In 2015, we
signed deals with Millendo Therapeutics for AZD4901, an NK3
antagonist, for Polycystic Ovary Syndrome and Hot Flushes
and with Corvidia for MEDI5117 (anti-IL-6 mAb), a precision
medicine approach for Cardio-Renal Syndrome type 4.
– Taiwan: National Research
Program for Biopharmaceuticals
Collaborating for
science innovation
We also joined forces with the Wellcome Trust Sanger Institute,
the European Bioinformatic Institute, Sage Bionetworks and
the DREAM community on the AstraZeneca-Sanger Drug
Combination Prediction DREAM Challenge, an established
crowd-sourcing effort in the oncology area. Our unprecedented
release of preclinical data from over 50 of our medicines
reinforced our commitment to open innovation and our belief
that therapeutic combinations have the potential to transform
the way cancer is treated.
– Canada: NeoMed
IMED functions
With research facilities in a number of the world’s established
and emerging scientific centres, we recognise the importance
of leveraging our footprint to connect with the best external
science, accelerating our scientific partnerships and alliances
with leading academic and biotech partners around our sites
as well as in other key locations across the globe.
– United States: National Institutes
of Health/National Center
for Advancing Translational
Sciences; Academic Drug
Discovery Network
Therapy area progress
Innovation without boundaries
– Germany: Lead Discovery
Center
The next wave of scientific innovation 89
Case study
Ionis and AstraZeneca
Partnering to develop the next generation of antisense-based therapeutics
Our most recent collaboration with US-based Ionis Pharmaceuticals,
signed in August 2015, aims to discover and develop antisense therapies
for cardiovascular, metabolic and renal diseases. This builds on a broad
existing relationship and supports our strategic approach in these
therapeutic areas using novel RNA-targeted treatments.
Case study
Antisense drugs are short, chemically-modified, single-stranded nucleic
acids (antisense oligonucleotides) that have the ability to target any
gene product of interest. They offer new opportunities for therapeutic
intervention because they act inside the cell to influence protein
production by targeting RNA to either prevent the production of diseasecausing proteins, increase the production of proteins deficient in disease,
or target toxic RNAs that are unable to generate proteins.
Since our first collaboration with Ionis in 2012, we’ve continued to expand
our partnership every year and are now working together in the key
therapy areas of oncology, cardiovascular, metabolic and renal diseases.
“We greatly value our collaboration with AstraZeneca. One aspect of the
collaboration that we particularly value is the vision that AstraZeneca has
for RNA therapeutics in general. They have placed a major investment in
new platforms for drug discovery such as antisense, that go beyond the
traditional drug platforms like small molecules and antibodies.
We have been very pleased partnering with AstraZeneca over multiple
collaborations. AstraZeneca has a strong vision for applying RNA
therapeutic approaches to go after diseases that have significant unmet
needs with current therapeutics on the market.”
Brett Monia, SVP Drug Discovery, Ionis Pharmaceuticals
“This expansion of our collaboration with AstraZeneca establishes our
second strategic relationship. This new collaboration will help broaden
the application of our antisense technology to targets in cardiovascular
and metabolic disease. AstraZeneca is committed to finding novel bestin-class therapies for some of the largest, most complex and fastestgrowing disease segments in the developed world. Combining our
antisense technology with AstraZeneca’s strong knowledge, leadership
and commitment in these areas should be very valuable in fully exploiting
these opportunities and moving new therapies effectively and efficiently
toward the market.”
B. Lynne Parshall, Chief Operating Officer at Ionis Pharmaceuticals
“Antisense-based therapies are rapidly gaining momentum in the clinic
and becoming an important component of our early-stage pipeline.
Our collaborations with Ionis combine the world-class antisense
drug research capabilities of Ionis with our expertise in oncology,
cardiovascular and metabolic diseases drug discovery and development.
By working together, we aim to uncover targets and pathways that can
be manipulated using antisense drug therapy.”
Mene Pangalos, Executive Vice President, IMED Biotech Unit
Above
Ionis Pharmaceuticals,
Carlsbad, California, US
90 ©AstraZeneca 2016
“AstraZeneca is
committed to finding
novel best-in-class
therapies for some of the
largest, most complex
and fastest-growing
disease segments in the
developed world.”
B. Lynne Parshall,
Chief Operating Officer at Ionis Pharmaceuticals
The next wave of scientific innovation 91
A great place to work
Inspiring great scientists
We want to attract the brightest minds, the best young talent,
the boldest innovators – people who share our passion for
science and belief in the possible. In return, we offer a working
environment that truly reflects our ambition to push the
boundaries of science – a place where curiosity, innovation
and collaboration flourish, where drive and determination is
rewarded and where great science comes alive.
We also put continuous development of our people
across IMED high on our agenda. From dedicated People
Development Weeks to cross-team secondments and
shadowing, our programmes ensure we continue developing
the skills and capabilities to equip our scientists to be the best
they can be. In quarter four of 2015 alone, we saw over ten
IMED colleagues take up assignments outside their core role
to broaden their learning and experience.
#31 Graduate
Employer,
The Guardian UK
300, 2014/2015.
Opposite
CGI image of New
Cambridge R&D
Centre and Global HQ
Therapy area progress
In 2015, we welcomed more talented colleagues to our team,
including accomplished scientists, respected academics and
new graduates. They came for many reasons – the commitment
to great science, the opportunity for personal development,
the open culture, the inspiring values, the chance to be part of
something life-changing. Whatever the reason, they have joined
a truly great place to work.
In IMED, we’re committed to continually seeking ways to work
across industry and academia to advance great science and
address unmet patient needs. Some of our IMED colleagues
come to us with long and distinguished academic careers –
many of whom retain their academic links during their time
with us – while others complement their AstraZeneca career by
taking up teaching or research positions in the academic world.
Our post-doc programme offers motivated, talented postdoctoral scientists the opportunity to make a difference with an
academic-style position in a global pharmaceutical environment,
and our graduate programme gives high-performing graduates
the opportunity to gain experience across the research spectrum.
Introduction
Our commitment to scientific leadership rests on our ability
to attract and retain the best scientists. Nowhere is this
commitment more evident than in the way we recruit, develop
and inspire our people.
!
Bloomberg best
employer 2016 #2
IMED functions
Stephen Rennard
Tim Eisen, PhD FRCP
VP, RIA iMed
Adjunct Professor of Rheumatology
at Gothenburg University
Chief Clinical Scientist, Clinical Discovery Unit,
Early Clinical Development, AstraZeneca
Richard and Margaret Larson Professor of
Pulmonary Research, University of Nebraska
Medical Center, Omaha, US
VP Head of Clinical Discovery Unit, Early Clinical
Development & VP Interim Head of Oncology
Translational Medicine Unit, Early Clinical
Development, AstraZeneca
Professor of Medical Oncology,
University of Cambridge
92 ©AstraZeneca 2016
“My main interest as a respiratory
physician is chronic obstructive
pulmonary disease (COPD), which
despite being a major cause of death
worldwide is poorly understood
and researched. The attraction for
me in joining AstraZeneca was that
the company is making a major
commitment to respiratory disease and
to driving the science. Novel treatments
require novel approaches and
AstraZeneca’s willingness to pursue
these approaches offers the potential to
impact drug development and clinical
care. This role was an opportunity
to participate in that. AstraZeneca
has a lot of committed, hard-working
scientists and there is every reason to
believe that the drive to science in the
company will lead to major advances.”
“At AstraZeneca I am working with a
much broader range of people than I
would do in academia. The IMED is an
exciting place to work, where you can
combine very good science with an
ability to drive things forward. Things
move much more quickly in AstraZeneca
than in academia, so I can make faster
progress on research that could impact
patients in AstraZeneca than I could as
a purely clinical academic. I am hoping
to create a more productive relationship
between pharma and academia and
having experience of drug development
gives me a better feel for the way
industry works and where there are
opportunities for collaboration. We
in AstraZeneca spend an enormous
amount of time developing talent. I think
we offer young scientists a very active
and accelerated career, with the training
and opportunities to develop in industry
and academia. It is an experience and an
opportunity which I think is unique.”
The next wave of scientific innovation 93
An environment where
science thrives
“Throughout AstraZeneca, there is true
intent to follow the science. Combining
my academic and clinical work with
my AstraZeneca role puts me at the
hard face of drug development. I see
my primary job as being part of the
IMED and driving our portfolio, but
I have a live interface with patients
and academia which keeps me
awake and sharp, and which gives
me many ideas. At AstraZeneca you
can do world-class science but you
can explore your scientific talents as
well as your leadership talents. It’s a
friendly, collaborative company and
there is such a wide spread of people,
skills and experiences. AstraZeneca
offers an opportunity for curious people
to explore.”
Collaborating for
science innovation
Prof. Dr Maarten Kraan MD PhD
Björn Over
Katerina Pardali
Chief Scientist, CVMD iMed
Professor of Nephrology and Physiology
(St Peter’s Chair) at University College London
Postdoc, CVMD iMed, Medicinal Chemistry
Successfully completed the 2015 women
in leadership programme
94 ©AstraZeneca 2016
An environment where
science thrives
“I like the diversity at AstraZeneca
and the flexibility I have to develop
my skills. It’s such a pleasure to work
with so many people who are willing
to share expertise and ideas. What
has impressed me most is the way
the scientists work together. They try
to find solutions and combine their
expertise to get a better outcome.
I’m very grateful for the experience to
work in AstraZeneca, it’s been a great
journey and I’ve learned a lot. I am not
worried about my future now as I have
gained so much experience on this
programme.”
Collaborating for
science innovation
IMED Graduate Scientist
In the AstraZeneca IMED we
are committed to increasing
the number of women in senior
scientific roles. We firmly believe
that the most innovative science
is produced in diverse teams
with different backgrounds,
experiences and skills. That’s why
we consistently seek to identify
and develop the very best talent,
wherever it exists. Our ‘Women
as Leaders’ programme gives
our female scientists a chance to
come together to discuss issues
such as career progression and
personal development with a view
to increasing their awareness of
opportunities and the confidence
to pursue them. We believe that by
giving women the skills and support
to make good career choices
early, we will develop more role
models and increase the number of
women in senior roles... ultimately
broadening diversity and driving
innovation. In the 18 months the
‘Women as Leaders’ programme
has been running, we have seen
30% of the participants take up
expanded, larger roles.
IMED functions
Marta Wylot
Women as Leaders
Tim Eisen, VP Head of Clinical Discovery
Unit, Early Clinical Development & VP
Interim Head of Oncology Translational
Medicine Unit, Early Clinical Development
Therapy area progress
“Having never had any experience
of industry before, I’ve been very
impressed and excited to meet the
breadth of scientists in AstraZeneca.
My academic and clinical colleagues
are very interested, surprised and
even envious of the opportunity I
have had to be able to combine
industry and academia and bring
the two worlds together. I think the
scientific ethos at AstraZeneca is
very strong and the company has a
reputation for being very sciencedriven. I think it’s an attractive option
to consider for young scientists and
for clinical scientists in particular. It
is very hands-on, educational and
stimulating. I still see patients in my
clinic once a week and I get ideas
from them that I can bring back into
drug development programmes. I also
continue to collaborate with colleagues
in my clinical and academic roles but
I can now bring added insight into
the conversations.”
“The culture is really collaborative
here. You have experts in so many
fields, everybody is very supportive
and they help each other out. People
are curious about science; they
love what they do and are really
engaged. Without the guidance of the
AstraZeneca experts, my project would
not have been so successful. What we
do as postdocs is really appreciated.
We interact with academia and are
able to publish our results, which is
really important to our careers.”
Introduction
Robert Unwin
“The IMED is an
exciting place to
work, where you
can combine very
good science with
an ability to drive
things forward.”
The next wave of scientific innovation 95
Our strategic science centres
In 2013, AstraZeneca announced plans to move
our UK research activities to a new $500m facility
in the centre of Cambridge. Our new facility at the
Cambridge Biomedical Campus will become the
company’s largest centre for oncology research
and a centre of excellence for pre-clinical research,
medicinal chemistry and high-throughput screening.
Our strategic R&D centre in Gothenburg is the
centre of our research for two of our therapy
areas; cardiovascular & metabolic diseases and
respiratory & inflammation. It is also home to a
large number of our scientists from our early phase
Discovery Sciences unit and our Drug Safety and
Metabolism team.
During 2015, we laid the foundations for our new
home on the Cambridge Biomedical Campus,
and expanded our interim high-quality lab and office
facilities to accommodate our growing presence
in the city.
Our vibrant Gothenburg facility has seen the
BioVentureHub go from strength to strengthh
since its inception in 2014, with 14 companies
and one academic group now working in this
innovative ecosystem.
Our evolving science footprint in the North West
means a small number of IMED colleagues remain
at our Macclesfield campus, and at Alderley
Park until our R&D exit of the site is completed.
The growing Alderley Park BioHub is successfully
creating an optimum environment for emerging
businesses to thrive.
Below
AstraZeneca’s
strategic R&D centre
in Gothenburg
Launched in 2015, the Gothenburg
‘Coffee Lab’ is an AstraZeneca first –
to inspire employees to world-class
ideas development.
Opposite top left
AstraZeneca’s smallmolecule research
facility in Boston,
North America
External designers worked with a
project team of employees from
different functions across the site to
create a creative space for meetings,
socialising and relaxation.
Stimulating ‘cross-fertilisation’,
both between the hub companies
and with AstraZeneca, is key to the
success of the biohub approach in
our evolving sites.
Opposite bottom left
AstraZeneca’s smallmolecule research
facility in Shanghai,
China
Opposite
bottom right
The Gothenburg
‘Coffee Lab’ is an
AstraZeneca first –
to inspire employees
to world-class idea
development
US – Boston
The best innovative ideas often
come out of informal chats rather
than formal meetings, so the site
is creating an informal meeting
point, where colleagues can spend
time away from a desk or meeting
room boundaries.”
Jenny Sundqvist, Site Director
“AstraZeneca has been on a
transformative journey over the past
few years, placing great science at
the heart of everything we do in the
delivery of breakthrough medicines to
patients. Our ambition is to improve
the lives of 200 million people by
2025. Such an ambition would not
be possible without establishing
collaborations of all types with
academia and industry. Our biohubs
provide a fantastic opportunity to
explore collaboration even further.”
Kumar Srinivasan, Head of
AstraZeneca R&D Boston and VP
Scientific Partnering and Alliances
IMED functions
Boston is home to AstraZeneca’s smallmolecule research in North America,
with state-of-the-art laboratories in
Waltham, just west of the city centre,
and our Neuroscience team in the
heart of the city’s Technology Square.
Our Boston-based scientists focus
on the discovery and development of
new medicines for the treatment of
cancers and neurological disorders.
The site also houses the Gatehouse
Park BioHub, which is thriving with nine
research companies already in place
since launch in September.
“The idea is to stimulate new ways
of interacting with colleagues from
functions that you usually don’t meet.
Coffee Lab has built on the success
of the existing lounge, which draws
people from all over the site to get
together for meetings and exchanges
of ideas. The lounge is the place
to meet, and we want to build on
that buzz with a larger area for both
scheduled and spontaneous meetings.
A bold, new R&D initiative to foster
life sciences discovery and the
exchange of ideas between scientists,
our Gatehouse Park BioHub, along
with the BioVentureHub at the
Gothenburg site in Sweden, and
the BioHub at our Alderley Park site in
the UK, all have vibrant but distinctive
features offering an energising
environment, all about sharing ideas
and tapping into great science.
Therapy area progress
Sweden – Gothenburg
Creating vibrant Biohubs
Introduction
UK – Cambridge
Our creative area to stimulate
innovative thinking
Collaborating for
science innovation
An environment where
science thrives
China – Shanghai
Our small-molecule research facility
in China is located at the Zhangjiang
High Tech Park in the Pudong area of
Shanghai. Our research teams here
focus on discovering potential new
medicines that meet the unique needs
of patients in Asia and drive forward
translational science across our core
therapy areas.
96 ©AstraZeneca 2016
The next wave of scientific innovation 97
Building our future
Our new Cambridge site
Our new R&D Centre will become the company’s largest
centre for oncology research and a centre of excellence
for pre-clinical research, medicinal chemistry and highthroughput screening. Beyond cancer research, our R&D will
focus on cardiovascular and metabolic diseases, respiratory,
inflammation and autoimmune diseases and conditions of the
central nervous system.
In 2015, we laid the foundations for our new home on the
Cambridge Biomedical Campus. This proximity to leading
research and academic institutions is key to our culture of
open innovation and partnering. We also continue to develop
scientific partnerships and outreach programmes. While these
are supported by our local presence, they have UK-wide
and global reach.
Science in pictures
98 ©AstraZeneca 2016
Supporting the next generation
of scientists
In 2015, we began funding academic
clinical lectureships and PhD students
at the University of Cambridge, with
80 agreed across AstraZeneca and
MedImmune over the next five years.
We also support the Cambridge
Judge Business School’s “Accelerate”
programme designed to identify,
train and mentor start-up life science
businesses. AstraZeneca’s volunteer
mentors come from a range of roles,
with expertise in areas like business
development, intellectual property
and innovation alliances.
Cambridge Cancer
Science Symposium
As part of our open innovation strategy,
IMED and MedImmune brought
top scientists from academia and
industry together to share the next
generation of oncology science at the
Cambridge Cancer Science Symposium,
Churchill College.
Delegates were not only impressed by
the quality of the science, but also the
opportunity to get so many academic
and industry organisations together
under one roof, sharing different
perspectives in striving for the same
goal – to accelerate new and improved
treatment options for cancer patients.
An environment where
science thrives
In addition, our PhD programmes with
the University of Cambridge and ongoing
commitment to STEM programmes
in the local community underline our
commitment to support, develop and
inspire the next generation of Cambridge
scientists. By moving to Cambridge,
AstraZeneca is helping to build an
attractive UK life sciences destination
for investment, and deliver a magnet
for top scientific talent – underpinned
by a world-leading science base, a
vibrant and entrepreneurial environment
that drives innovation, as well as timely
patient access to innovative medicines.
Cambridge Biomedical Campus will be
an open, welcoming and vibrant centre
that will inspire our IMED team and
our partners to push the boundaries
of scientific innovation.
Science retreat
In October, we welcomed over 250
IMED scientists to our Science Retreat
at Robinson College in Cambridge.
Opened by Nobel Laureate Sir Venki
Ramakrishnan, the meeting immersed
delegates in inspiring science with
topics ranging from immunology, to our
progress in open innovation, the patient
perspective plus a futuristic look into
science and technology that may impact
IMED research over the next decade.
Collaborating for
science innovation
Our new Cambridge site will house 2,300
colleagues, with world-class capabilities
in target biology, medicinal chemistry,
protein engineering, translational
science, biopharmaceutical and
clinical development. Our presence in
Cambridge allows us to play an active
role in enabling a permeable scientific
hub, where the best ideas flow out,
as well as in.
IMED continued integration
into the Cambridge
community during 2015
IMED functions
At the end of 2015, we welcomed our
thousandth AstraZeneca employee into
Cambridge. This strong and growing
presence allows us to deepen our
scientific relationships as part of the
local life-sciences ecosystem, before
we move into our new R&D Centre
where IMED MedImmune and Global
Medicines Development will sit side by
side in an open, collaborative workplace.
The site will bring together our small
molecule and biologics R&D, as well as
all our discovery science capabilities
and late-stage development, opening
up opportunities to work collaboratively
across these areas to create the next
generation of medicines that will positively
impact the lives of millions of people.
“Science in pictures”, is an artwork
installation on the hoardings
around the construction site of our
new R&D Centre and Corporate
Headquarters on the Cambridge
Biomedical Campus. Following
workshops led by AstraZeneca
and MedImmune scientists and
local artists in the summer, 400
students at nine local schools
were invited to create a circular
picture that captures what science
means to them. These workshops
provided an insight into the science
behind new medicines and how
potential medicines are identified,
and developed. In addition to
active volunteer-led programmes
in schools, AstraZeneca and
MedImmune also sponsor outreach
initiatives through the Cambridge
Science Festival, Big Biology Day
and the Cambridge Science Centre.
This installation is an expression
of our commitment to community
outreach through science education
and will be visible to the Cambridge
Biomedical Campus community
and its visitors throughout 2016.
Therapy area progress
It’s an exciting time for IMED as we continue to establish
ourselves in the Cambridge science community, building on the
long-standing presence of our colleagues from AstraZeneca’s
global biologics research and development arm, MedImmune.
We chose to be in Cambridge because we wanted to be at the
heart of one of the best scientific centres in the world.
Introduction
In 2013, AstraZeneca announced plans to build a global Research
and Development Centre and its Corporate Headquarters on
the Cambridge Biomedical Campus. This is one of our flagship
initiatives and is part of redefining our future and aspiration to be
one of the best scientific institutions in the UK and globally.
Opposite and top left
CGI images of AstraZeneca’s
new Global R&D Centre and
Corporate Headquarters,
Cambridge, UK
The next wave of scientific innovation 99
Case study
The next wave of innovation
in DNA Damage Response
Targeted therapy
based on inhibiting
the DNA Damage
Response (DDR)
in cancers offers
the potential for a
greater therapeutic
window by tailoring
treatment to patients
There are three main aspects of the DDR that are different in cancer and
therefore provide a rationale for drug targeting:
– DDR pathway loss results in greater dependency on remaining DDR
pathways
– Increased replication stress leads to greater dependency on
ATR-CHK1-Wee1
– Increased levels of endogenous damage and genomic instability results
in greater sensitivity to exogenous DNA damage
Targeting DDR in cancer
An underlying hallmark of cancers is their genomic instability, which
is associated with a greater propensity to accumulate DNA damage.
Historical treatment of cancer by radiotherapy and DNA-damaging
chemotherapy is based on this principle, yet it is accompanied by
significant collateral damage to normal tissue and unwanted side effects.
Targeted therapy based on inhibiting the DNA Damage Response (DDR) in
cancers offers the potential for a greater therapeutic window by tailoring
treatment to patients with tumours lacking specific DDR functions.
An invited review in Molecular Cell by Mark O’Connor (Oncology iMed)
summarises the scientific data behind olaparib in the context of it being
the first approved, targeted cancer medicine for patients with a tumourspecific deficiency in their DDR biology, and it discusses the future
significance of DDR-based agents in cancer therapy.
Covering all DDR-targeted agents that either have been approved or are
in clinical development, the article demonstrates that AstraZeneca has a
world-leading pipeline of compounds that target DDR pathways in cancer.
AstraZeneca portfolio targets distinct aspects of DDR
Chosen for both their different roles in DNA repair and when in the cell cycle they play their primary role
Phase I
AZD0156
Effect is manifest
in M phase
AZD2811
Effect is manifest
in M phase
M
S
Target: ATM
Effect: Inhibits repair of
Double Strand Breaks
100 ©AstraZeneca 2016
Effect is manifest
in M phase
M
G1
G2
AZD6738
Phase III, approved
AZD1775
Olaparib
Effect is manifest
in M phase
M
G1
G2
Phase II
S
Target: AURORA B
Effect: Deregulation
of chromosome
segregation and
cytokinesis
M
G1
G2
Effect is manifest
in M phase
S
Target: ATR
Effect: inhibits S phase
replication stress
response and repair of
Double Strand Breaks
M
G1
G2
S
G1
G2
S
Target: Wee1
Effect: inhibits S phase
replication stress
response and G2/M
cell cycle checkpoint
Target: PARP
Effect: inhibits repair
of Single Strand
Breaks
The next wave of scientific innovation 101
Case study
Building a world-leading pipeline
The AstraZeneca portfolio targets distinct aspects of the DNA Damage
Response (DDR). This relates both to their different roles in DNA repair and
at what point in the cell cycle they exert their effect. AstraZeneca has a
number of DDR-targeted compounds in clinical development.
The latest updates on development of AstraZeneca’s DDRtargeted compounds are listed: all ongoing olaparib Phase
III trials (targeting PARP), AZD1775 (Wee1) Phase II trials and
AZD6738 (ATR) Phase I trials are included. AZD0156 (ATM)
has also entered clinical trials.
Olaparib – the first medicine based on DDR
The recent approval of olaparib the poly (ADP-ribose)
polymerase (PARP) inhibitor for treating tumours harbouring
BRCA1 or BRCA2 mutations, represents the first medicine
based on this principle, exploiting an underlying cause of
tumour formation that also represents an Achilles’ heel.
Strategy for the use of DDR inhibitors as anti-cancer agents
Effect is manifest
in M phase
G1
G2/M checkpoint
Allows time to repair any remaining DNA
DSBs before attempting cell division
DDR targets: CHK1, MYT1, Wee1
There are potential advantages of combining olaparib with
other DDR-targeted compounds, or with agents such as the
AstraZeneca VEGFR TKI cediranib that target other cancer
pathways; these combinations could provide broader and
more effective responses than a monotherapy approach.
M
PREVENT REPAIR
G2
DNA replication phase
G2
Gap/growth Phase II
M
Cell division phase
\
Cell cycle checkpoint
G1
S
MAXIMIZE DAMAGE
S-phase checkpoint
Delays replication process to allow time to deal
with unrepaired DNA damage or DNA damage
resulting from collapsed replication forks
DDR targets: ATR, CHK1, DNA-PK, Wee1
DNA replication stress – a promising
target for DDR-based therapies
Another hallmark of cancer linked to the DDR is DNA
replication stress, which occurs to a greater degree in cancer
cells than normal cells and is therefore a potential target for
DDR-based therapies such as AZD6738 and AZD1775, which
inhibit the DDR regulators ATR and Wee1, respectively.
DNA damage caused during the DNA replication phase
of the cell cycle (S phase) can lead to cell death if it is not
repaired before cell division (M phase): one therapeutic
strategy to maximize the amount of DNA damage is to inhibit
the checkpoints at which the cell cycle is halted until any
DNA damage has been repaired; for example, AZD1775
inhibition of Wee1, which regulates the G2/M checkpoint,
allows accumulated DNA damage to be carried into M phase,
inducing cancer cell death.
Mark O'Connor,
Senior Principal
Scientist IMED Biotech
Unit (Oncology)
Gap/growth Phase I
S
Investigation of both the cell cycle and cell death effects
resulting from treatment with the ATR and Wee1 inhibitors
in DLBCL models highlighted differences consistent with
the greater potency of the Wee1 inhibitor in these models;
an assessment of in vivo activity further supported these
findings. Results presented at the AACR-NCI-EORTC
International Conference on Molecular Targets and Cancer
Therapeutic in November on AZD1775 treatment of a larger
panel of in vivo patient-derived explant (PDX) models of
multiple tumour types demonstrated both the significant
breadth and depth of the Wee1 inhibitor single-agent activity.
There is also potential for this activity to be enhanced further
through combination with olaparib, a PARP inhibitor that
induces S-phase DNA damage. Together, these data have led
to the recent initiation of AZD1775 monotherapy as well as
AZD1775/ olaparib combination clinical trials.
G1/S checkpoint
Allows time to repair DNA damage
before starting DNA replication
DDR targets: ATM, CHK2, p53
What’s next?
The Phase III olaparib development programme also includes
two additional studies: a prostate cancer study that received
Late Storage Development Committee approval on 9
November 2015 (D081DC00007) and that has now achieved
FDA breakthrough status. In addition, there is also a study
of olaparib in combination with durvalumab (DUO study,
D081KC00002). The ATM inhibitor AZD0156 is the latest
DDR targeted agent to enter the clinic and will be used in
combination with olaparib to investigate whether this novel
DDR agent combination can extend the patient population
that can benefit from olaparib. AZD0156 also has the potential
to increase the effectiveness of chemotherapies that require
ATM function.
Pivotal to optimising the clinical use of this new therapeutic
category of anti-cancer agents will be the selection of the
most appropriate treatment combinations for DDR-targeted
therapies. Due to the strong mechanistic links between DDR
and different aspects of the immune response, this includes
the potential for combinations with immunotherapy agents.
Another key aspect for success will be the targeting of specific
patient populations whose cancers carry definable DDR gene
mutations. What is clear is that targeting DDR represents an
exciting new advance in our ability to treat cancer.
1
O’Connor MJ. Targeting the DNA damage response in cancer. Molecular Cell 2015; 60(4)
102 ©AstraZeneca 2016
The next wave of scientific innovation 103
Case study
By listing all the ongoing Phase III trials involving PARP
inhibitors, it becomes clear that the AstraZeneca olaparib
Phase III programme is far more extensive than that of any of
the four other molecules in this class from other manufacturers
that are under investigation in the clinic (niraparib, rucaparib,
talazoparib and veliparib).
Selective targeting of tumours that harbour a DDR deficiency
means that, unlike with radiotherapy or chemotherapy,
tumour cells can be killed without causing significant
side effects or damage to normal tissue. In 2015, clinical
validation was provided by regulatory approval of the PARP
inhibitor olaparib in ovarian cancer patients whose tumours
have a mutation in BRCA1 or BRCA2, which encode
proteins involved in the DDR. Olaparib activity is now being
explored in the clinic in non-BRCA DDR deficient cancers
(for example ATM-low gastric cancers in the Phase III Gold
trial in Asian patients), and additionally in prostate cancer.
Our reputation for scientific leadership
Our continued drive to develop a thriving science environment
has generated great progress during 2015, both inside IMED
and within the broader scientific ecosystem.
Our publications
We strengthened our scientific reputation through an
increased focus on high-quality scientific publications in
2015 with 455 papers published. We also saw outstanding
progress in publishing our science in high-impact, peerreviewed journals, moving from a single high-impact
publication in 2010 to 29 in 2015.
c-kit+ cells do not generate lung
epithelium during maintenance
and repair
American Journal of Respiratory
and Critical Care Medicine
Nature Communications
Nature Medicine
About the paper: The FGFR family
of kinases are key mediators of
both developmental and disease
associated blood vessel growth.
Prior work had only ever shown
FGFR1 with a key element to binding
ATP (the energy source) being folded
in ready to activate the protein. This
paper, a collaboration between IMED
and MedImmune scientists, for the
first time details the interactions and
stability associated with protein being
‘flipped’ into a non-active form.
About the paper: It has been
reported that c-kit+ progenitor cells
resident in the human lung regenerate
epithelial cells upon transplantation
into injured mouse lung. For the first
time, our scientists demonstrated
that during normal function and
regeneration conditions after injury,
c-kit+ cells adopt vascular endothelial
cell fate and not any type of lung
epithelial cells. In addition, c-kit+ cells
proliferate after injury and contribute
to new blood vessel formation within
the lung.
About the paper: Lymphoid follicles
have been associated with COPD
disease severity, with localised
overexpression of B cell-activating
factor (BAFF) demonstrated in
patients with severe COPD. This
paper, a collaboration between IMED,
MedImmune and Ghent University
Hospital has further described the role
of BAFF in COPD, demonstrating BAFF
overexpression in COPD patient lung
tissue and in a mouse model of chronic
cigarette smoke exposure. Furthermore,
it was shown that antagonising BAFF
can protect against alveolar destruction
and pulmonary inflammation.
Lead AstraZeneca authors:
Gareth Davies, Geoff Holdgate and
Chris Phillips
Lead AstraZeneca authors: Anja
Schinwald, Danen Cunoosamy,
Claudie Malanda, Alan Sabirsh, Eileen
McCall, Liz Flavell, Ronald Herbst
Impact: This study unravelled the
true fate of c-kit+ cells during lung
homeostasis and lung repair, calling
attention to the clinical application
of c-kit+ progenitor cells as lung
epithelial progenitors for the treatment
of pulmonary disease.
Lead AstraZeneca author:
Qing-Dong Wang
IMED Science Awards
The 2015 IMED Science Retreat took place in October at
Robinson College, Cambridge. The packed agenda of scientific
innovation, patient insight and technology of today and
tomorrow helped deliver a meeting of high-quality science
and inspiration, opened by Nobel-winning structural biologist
Sir Venki Ramakrishnan. The IMED Science Retreat is an
important event in the AstraZeneca science calendar, enabling
colleagues to get a view of the latest developments outside
their areas, share ideas and look at how we can apply science
in new and different ways to drive scientific leadership.
Our continued progress towards scientific leadership is down
to the collective effort of dedicated and talented individuals
striving to make a difference. The prestigious annual IMED
Science Awards aim to recognise and reward individual and
team efforts, share great achievements and inspire even more
great work from our scientists.
“What a fantastic and inspirational
event, the way our scientists are
pushing the boundaries of everything
we do make me very proud.”
Mene Pangalos, Executive Vice President, IMED Biotech Unit
104 ©AstraZeneca 2016
The next wave of scientific innovation 105
An environment where
science thrives
“This environment, buzzing with science and energy, is a great
place for learning about the research going on across IMED, and
to share our progress. I really enjoyed the patient insight sessions,
they were truly powerful and reminds us of our goal.”
Sepideh Hagvall Heydarkhan,
Associate Principal Scientist CVMD iMed
The 2015 IMED Science Awards celebrated some of the best
breakthrough, high-impact science taking place at AstraZeneca.
150 global nominees were invited to join the IMED Leadership
Team and members of the review panel at a black-tie
celebratory dinner. The awards recognised outstanding scientific
achievement; high impact work acknowledged as gamechanging. Winning teams and individuals received trophies and
certificates, and are also rewarded with tailored opportunities
to support future research and enhance their careers.
Collaborating for
science innovation
Science Retreat
IMED functions
Impact: This research has
demonstrated novel findings that
will influence future strategies in the
treatment of COPD.
Impact: This work has significance in
the design of kinase inhibitors and the
understanding of the stabilisation of the
non-active form of the target protein.
Therapy area progress
Structural and dynamic insights into
the energetics of activation loop
rearrangement in FGFR1 kinase
Introduction
Our commitment to being a science-led company doesn’t end
with our work in the lab. We believe that continued innovation
relies on us fostering a culture of scientific excellence,
empowering our scientists to not only keep abreast of the
latest developments and breakthroughs, but to drive them.
Role of B Cell–Activating
Factor in Chronic Obstructive
Pulmonary Disease
High impact publications in 2015
Title
Authors
Publication
Title
Authors
Cancer Cell
Acetyl-coA synthetase 2 promotes acetate
utilization and maintains cancer cell
Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS,
Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D,
Shanks E, Kalna G, Saunders RE, Jiang M, Howell M, Lassailly F,
Thin MZ, Spencer-Dene B, Stamp G, van den Broek NJ, Mackay G,
Bulusu V, Kamphorst JJ, Tardito S, Strachan D, Harris AL,
Aboagye EO, Critchlow SE, Wakelam MJ, Schulze A, Gottlieb E
Nature Communications
Structural and dynamic insights into the energetics
of activation loop rearrangement in FGFR1 kinase
Klein T, Vajpai N, Phillips J, Davies G, Holdgate G, Phillips C,
Tucker J, Norman R, Scott A, Higazi D, Lowe D, Breeze A
Nature Medicine
Acquired EGFR C797S mutation mediates
resistance to AZD9291 in non-small cell lung cancer
harboring EGFR T790M
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B,
Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE,
Cantarini M, Barrett JC, Jänne PA, Oxnard GR
Nature Medicine
c-kit+ cells do not generate lung epithelium during
maintenance and repair
Liu Q, Huang X, Zhang H, Tian X, He L, Yang R, Yan Y, Wang Q,
Gillich A, Zhou B
Cancer Cell
Nature Reviews Cancer
MEK1 and MEK2 inhibitors and cancer therapy: the
long and winding road
Caunt CJ, Sale MJ, Smith PD, Cook SJ
Cell Research
Genetic lineage tracing identifies in situ
kit-expressing cardiomyocytes
Zhang WJ, Cristinacce P, Bondesson E, Nordenmark L, Young SS,
Liu YZ, Singh D, Naish JH, Parker GJM
Nature Reviews
Drug Discovery
An analysis of the attrition of drug candidates from
four major pharmaceutical companies
Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S,
Owen RM, Pairaudeau G, Pennie WD, Pickett SD, Wang J,
Wallace O, Weir A
European Heart Journal
Effect of genetic variations on ticagrelor plasma
levels and clinical outcomes
Varenhorst C, Eriksson N, Johansson A, Barratt BJ, Hagström E,
Åkerblom A, Syvänen AC, Becker RC, James SK, Katus HA,
Husted S, Steg G, Siegbahn A, Voora D, Teng R, Storey RF,
Wallentin L
Nature Reviews
Drug Discovery
ESKAPEing the labyrinth of antibacterial discovery
Tommasi R, Brown D, Walkup G, Manchester J, Miller A
Randomized, double-blind Phase II trial with
prospective classification by ATM protein level to
evaluate the efficacy and tolerability of olaparib plus
paclitaxel in patients with recurrent or metastatic
gastric cancer
Bang YJ, Im SA, Lee KW, Cho JY, Song EK, Lee KH, Kim YH,
Park JO, Chun HG, Zang DY, Fielding A, Rowbottom J, Hodgson D,
O’Connor MJ, Yin X, Kim WH
Nature Reviews
Drug Discovery
Pioneering government-sponsored drug
repositioning collaborations: progress and learning
Frail DE, Brady M, Escott J, Holt A, Sanganee HJ, Pangalos MN,
Watkins C, Wegner CD
Nature Reviews
Drug Discovery
Towards a hit for every target
Rees S, Gribbon P, Birmingham K, Janzen W, Pairaudeau G
Journal of Clinical Oncology
Molecular profiling and targeted therapy for
advanced thoracic malignancies: a biomarkerderived, multiarm, multihistology phase II basket trial
Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R,
Carter CA, Guha U, Killian K, Lau CC, Abdullaev Z, Xi L, Pack S,
Meltzer PS, Corless CL, Sandler A1, Beadling C, Warrick A, Liewehr DJ,
Steinberg SM, Berman A, Doyle A, Szabo E, Wang Y, Giaccone G
Nature Reviews
Drug Discovery
Therapy area heat map for emerging markets
Gautam A, Li L, Srinivasan K
Neuron
Molecular Cell
Targeting the DNA damage response in cancer
O’Connor MJ
BrainSeq: neurogenomics to drive novel target
discovery for neuropsychiatric disorders
Schubert C, O’Donnell P, Quan J, Wendland J, Hualin S,
Domenici E, Essioux L, Kam-Thong T, Didriksen M, Matsumoto M,
Saito T, Brandon N, Cross A, Wang Q, Heon Shin J, Jaffe A, Jia Y,
Straub R,Deep-Soboslay A, Hyde T, Kleinman J, Weinberger D
Nature
Patient-centric trials for therapeutic development in
precision oncology
Biankin AV, Piantadosi S, Hollingsworth SJ
New England Journal
of Medicine
AZD9291 in EGFR inhibitor–resistant non–small-cell
lung cancer
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS,
Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH,
Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M
Nature
Precision medicine: AstraZeneca’s approach
March R
Science
A sustainable model for antibiotics
Perros M
Nature Chemical Biology
Translating slow-binding inhibition kinetics into
cellular and in vivo effects
Walkup G, You Z, Ross P, Allen E, Daryaee F, Hale M, O’Donnell
J, Ehmann D, Schuck V, Buurman E, Choy A, Hajec L, MurphyBenenata K, Marone V, A Patey S, Grosser L, Johnstone M,
Walker S,Tonge P, Fisher S
Science Advances
Structural basis of lewisb antigen binding by the
helicobacter pylori adhesin BabA
Nage N, Howard T, Phillips C, Brassington C, Overman R,
Debreczeni J, Gellert P, Stolnik G, Winkler G, Falcone F
Triaminopyrimidine is a fast-killing and long-acting
antimalarial clinical candidate
Hameed S, Solapure S, Patil V, Henrich P, Magistrado P, Bharath S,
Murugan K, Viswanath P, Puttur J, Srivastava A, Bellale E,
Panduga V, Shanbag G, Awasthy D, Landge S + et al..
Science Translational
Medicine
AZD9150, a Next-Generation Antisense
Oligonucleotide Inhibitor of STAT3, with Early Evidence
of Clinical Activity in Lymphoma and Lung Cancer
Aberrant splicing of U12-type introns is the hallmark
of ZRSR2 mutant myelodysplastic syndrome
Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A, Kohlmann A,
Sanada M, Grossmann V, Sundaresan J, Shiraishi Y, Miyano S,
Thol F, Ganser A, Yang H, Haferlach T, Ogawa S, Koeffler P
Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J,
Fowler N, Zhou T, Schmidt J, Jo M, Lee SJ, Yamashita M, Hughes SG,
Fayad L, Piha-Paul S, Nadella MVP, Mohseni M, Lawson D, Reimer C,
Blakey DC, Xiao X, Hsu J, Revenko A, Monia BP, MacLeod AR
Science Translational
Medicine
Tissue transcriptome-driven identification of
epidermal growth factor as a chronic kidney
disease biomarker
Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PX, Mariani LH,
Eichinger FH, Berthier CC, Randolph A, Lai JY, Zhou Y, Hawkins JJ,
Bitzer M, Sampson MG, Thier M, Solier C, Duran-Pacheco GC,
Duchateau-Nguyen G, Essioux L, Schott B, Formentini I,
Magnone MC, Bobadilla M, Cohen CD, Bagnasco SM, Barisoni L,
Lv J, Zhang H, Wang HY, Brosius FC, Gadegbeku CA, Kretzler M;
ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium
Journal of Clinical Oncology
Nature Communications
Nature Communications
Nature Communications
106 ©AstraZeneca 2016
Oxidation of the alarmin IL-33 regulates
ST2-dependent inflammation
Cohen S, Scott I, Majithiya J, Rapley L, Kemp B, England E,
Rees G, Overed-Sayer C, Woods J, Bond N, Seguy-Veyssier C,
Embrey K, Sims D, Snaith M, Vousden K, Strain M, Chan D, Carmen S,
Huntington C, Flavell L, Xu J, Popovic B, Brightling C, Vaughan T,
Butler R, Lowe D, Higazi D, Corkill D, May R, Sleeman M, Mustelin T
The next wave of scientific innovation 107
An environment where
science thrives
Pommier AJ, Farren M, Patel B, Wappett M, Michopoulos F,
Smith NR, Kendrew J, Frith J, Huby R, Eberlein C, Campbell H,
Womack C, Smith PD, Robertson J, Morgan S, Critchlow SE,
Barry ST
Collaborating for
science innovation
Leptin, BMI and a metabolic gene expression
signature associated with clinical outcome to VEGF
inhibition in colorectal cancer
Cell Metabolism
IMED functions
Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS,
Rodrik-Outmezguine V, Will M, Yellen P, de Stanchina E, Baselga J,
Scher HI, Barry ST, Sawyers CL, Chandarlapaty S, Rosen N
Therapy area progress
Feedback suppression of PI3Ka signalling in PTENmutated tumours is relieved by selective inhibition
of PI3Kß
Introduction
Publication
Preparing for the future with
our ‘IMED Futures’ teams
During 2015, our teams interrogated emerging technologies,
explored new approaches to drug discovery and challenged
conventional thinking in the search for new opportunities to
bring benefit to patients. Here we shine a spotlight on four of
our programmes.
Digital health
Targeted drug delivery
Current technology allows measuring the body’s vital signs
using health patches but our team recognises the true value for
pre-clinical monitoring lies with invasive biosensor technology.
In the future, developing pre-clinical sensors that monitor
drug exposure and biomarkers of safety and efficacy will have
the potential for clinical use – providing online biosensors for
patients, and hence changing the status quo for patient care.
“Today we have already seen the approval of wearable devices
to measure online glucose levels for diabetic patients. If we can
discover reliable biomarkers and couple these with sensitive
sensor technology this opens up a wealth of opportunities.”
Celina d’Cruz, Pre-clinical Futures Lead
Microphysiological systems
As we advance our understanding of biology and integrate
our knowledge of cellular behaviour and tissue function, it
is apparent that the current pre-clinical in vitro models have
limitations when predicting organ functionality. Complex
cellular microphysiological systems (MPS), consisting of
interacting organs-on-chips or tissue-engineered, 3D organ
constructs, present an opportunity to bring new tools to
biology, medicine, pharmacology, physiology, and toxicology.
By placing human or animal cells in a more ‘natural’
environment, we can start to recapitulate the dynamics of
drug-organ, drug-drug, and drug-organ-organ interactions
to allow better predictivity of clinical translation. Our team is
collaborating with some of the leading experts in the world
at TissUse, Harvard and Vanderbilt Universities.
“Connecting data stacks of
patient data is not new. What
would be cutting-edge is if we
could design them to handle
ever increasing data types.”
Hitesh Sanganee, Digital Futures Lead
108 ©AstraZeneca 2016
The next wave of scientific innovation 109
An environment where
science thrives
“With advances in cell culture and microfluidics it is now possible
to emulate human biology on a microscale. Taking this one step
further and connecting these organ units together, human-on-achip technology will allow us to advance our understanding of
the safety and efficacy earlier in drug discovery.”
Lorna Ewart, Microphysiological Systems Futures Lead
Collaborating for
science innovation
Improved understanding of the physiological barriers to
efficient drug delivery has resulted in significant advances
in delivery systems. This, coupled with novel analytical and
imaging techniques allow for even more sophisticated delivery
systems opening up new target space. Our team is looking to
improve target efficacy by enhancing our targeting capabilities
to allow delivery of both small molecules and oligonucleotide
therapeutics – miRNA, mRNA and antisense. To do this our
team has focused on three key areas: 1) cellular targeting, 2)
improving cellular uptake and 3) enhancing drug delivery. In the
latter case, we have already initiated collaborations with BIND
Therapeutics for their ACCURINS® polymeric nanoparticle
technology and with Starpharma exploring their dendrimer
technology platform. Both these technologies improve
therapeutic index and ability to formulate challenging molecules.
To enhance the impact of current online data monitoring, our
teams have been exploring the possibilities within the rich data
source provided by sensor technology and wearable devices.
Incorporating biosensor technology into our pre-clinical studies
will allow us to change current practice, improve translation and
safety read-outs, while reducing the number of animal studies.
IMED functions
“Connecting data stacks of patient data is not new. What would
be cutting-edge is if we could design them to handle ever
increasing data types, ‘stacking’ multiple layers of patient data –
making them flexible to connect with whichever data is current.”
Hitesh Sanganee, Digital Futures Lead
Pre-clinical futures
Therapy area progress
The wealth of ‘big data’ in healthcare is revolutionising
our approach to R&D. We are already seeing how the next
generation of medicines are being shaped by our ability to
capture, interpret and apply data. Combining insight from
clinical health records with large-scale genomics data is
enabling scientists to better predict disease outcomes in the
clinic. However, our team have been investigating connecting
multiple data stacks from anywhere and of any type, from
proprietary data to real world evidence, even social media
platforms. This data stack would truly allow us to map 360
degree views of patient journeys and gain understanding of
the interplay between ‘nature’ (from genetic information) and
‘nurture’ (environmental data e.g. smartphone/ sensor data) to
make breakthroughs in science and ultimately patient care. In
2016, the team hopes to begin a collaboration to create such
a complex data stacks in the oncology therapy area, aiming to
get targeted medicines to genetically matched patients faster.
“A key to advancing drug delivery in the next decade for RNA
therapeutics will be to enhance trafficking and cellular uptake,
to and by the desired tissue and cell type.”
Malin Lemurell, Targeted Drug Delivery Futures Lead
Introduction
Delivering the next wave of life-changing medicines requires a
new way of thinking. To ensure the IMED Biotech Unit remains
at the cutting-edge of scientific innovation, we established our
IMED Futures programme.
Below
Worldwide
transportation systems,
communication
networks and energy
infrastructures
CGI images of AstraZeneca’s new
Global R&D Centre and Corporate
Headquarters, Cambridge, UK
110 ©AstraZeneca 2016
astrazeneca.com