Delivering our pipeline through scientific leadership

Innovative Medicines & Early Development Biotech Unit 2016 – A year in review

Delivering our pipeline through scientific leadership 1 Introduction Contents

Introduction 02 The next wave of scientific innovation: An introduction from Mene Pangalos 04 IMED Biotech Unit 2016 in numbers Therapy area progress area Therapy

Therapy area progress 06 Oncology 16 Respiratory, Inflammation and Autoimmunity 26 Cardiovascular and Metabolic Diseases 36 Neuroscience

IMED functions IMED functions 44 IMED Asia 54 Case Study: NiCoLA-B 56 Discovery Sciences 62 Case Study: Single Molecule Detection 64 Drug Safety and Metabolism 72 Early Clinical Development 82 Pharmaceutical Sciences 90 Case Study: Nucleotide platforms 92 Personalised Healthcare and Biomarkers 102 Case Study: Harnessing the code of life to develop new treatments science innovation science for Collaborating

Collaborating for science innovation 106 Case Study: Max Planck Institute and AstraZeneca 108 Enterprise leadership through collaboration 112 Collaborating and sharing data to redefine the future of 116 Open Innovation 118 Innovation without boundaries 120 Case Study: Foundation Medicine and AstraZeneca where science thrives science where environment An An environment where science thrives 122 Inspiring great scientists 126 Our strategic science centres 128 Building our future 132 Our reputation for scientific leadership 136 High impact publications in 2016 140 Preparing for the future with our IMED Futures teams

2 IMED Annual Review 2016 Delivering our pipeline through scientific leadership 01 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

ene Pangalos , Executive Director Pascal Soriot, Executive Director and Chief Executive Officer 2016 was an important year2016 AstraZenecafor in which furthermade we significant theprogress delivery of on our science-led strategy. innovative the most of Some research and development being undertaken at the is taking in our place moment including IMED Unit, Biotech transformative new platforms, such as oligonucleotides, modified and nanoparticles RNA technologies and new in our work advance to personalised healthcare, genomics and genome editing. propelled This is being work culture entrepreneurial the by that IMED has fostered, collaborations that have established withbeen world- leading partners and by the outstanding people who work here at AstraZeneca, whose is helping science for passion the and deliver discover us to next generation of medicines to transform patients of the lives around the world.” M Executive Vice President President Vice Executive Unit and Global IMED Biotech Business Development

Delivering our pipeline through scientific leadership 03

I am also immensely proud of our scientific leadership and our abilityto follow the science. the At beginning of knew we the it year, would be tough outperformto our number of high impactand high quality publications didn’t We justfrom beat 2015. the target from last year smashed- we it. delivered we In 2016, 40 high impact high qualityand publications, 311 and a total of 552 publications overalll. This is truly phenomenal progress that not only reflects the quality of the research conducted in our laboratories and with our partners, but also the strength and depth of our science across the IMED Biotech Unit. Whilst it is impossible capture to all of the achievements from across our teams in the past I hope year, the IMED Annual gives you a feelReview 2016 for the outstanding calibre of our science and our scientists and strive how we push to the boundaries of science deliver to life- changing medicines for patients around the world. Pangalos Mene Executive Vice President IMED Biotech Unit and Global Development Business

AZD1419, our inhaled TLR9 agonist,AZD1419, the firstever study designedto investigate whether asthma patients can be kept in remission rather than simply treating their symptoms. In cardiovascular disease, AZD8601 - the firstworld’s modified RNA forVEGF-A from our Moderna partnership - received positive regulatory approvals enter to Phase I clinical development. VEGF-A is a proteinkey in new blood vessel formation and cardiomyocyte proliferation. AZD8601 is being investigated as a regenerative treatment option for patients with heart failure, in diabetic wound healing and other vascular diseases. Finally, AZD3293, inhibitor our BACE1 in co-development with Lilly for Alzheimer’s disease transitioned into Phase III. We now two have late stage trials running simultaneously and are poised be to one of the firstto launch a disease-modifying treatment for Alzheimer’s. One personal of my highlights was of 2016 the announcement of our new genomics initiative and I was particularly delighted Professor David Goldstein joined our team in September. Professor Goldstein will play role a key in ensuring have we our launch to people and skills right the dedicated Centre for Genomics Research, as well as providing strategic guidance integrateto our genomics initiative into our research and development pipeline and into work with our partners. I would also call like to out the outstanding entrepreneurial our achievements ScientificPartnering and Alliances (SP&A) team creating made in 2016, over million in$150 value for AstraZeneca in externalisation revenue. Working closely with groups across the IMED, SP&A team partnershipsstrengthened global our with leading scientists from academia, biotech and pharma. The breadth and depth of pipeline progress made the by IMED Biotech canUnit be highlighted in 2016 by examples from across all therapy areas. In Oncology supported we the transition of five molecules into pre-clinical development, of which three – inhibitors Bcl2/xL and CDK9-of MCL1, are all targeting pro-survival proteins in support of our goal build to an industry-leading ‘tumour cell death’ portfolio. Resistance cellto death is one of the hallmarks of cancer. These programmes drive cancer cells apoptosis to and look particularly exciting for research in haematological malignancies, combination in including with acalabrutinib, our best-in-class BTK inhibitor. In Respiratory, Inflammation and Autoimmunity refocused we our efforts on lung epithelium, lung immunity and lung regeneration allow to us better to define novel disease drivers and treatment options for patients with respiratory diseases. Within lung immunity, we initiated a landmark Phase II trial with

Pancreatic beta cells at different Pancreatic stages of regeneration As I reflect on the past sixyears leading Innovative Medicines & Early Development (IMED), I am immensely proud of our transformational achievements. Every year met have we orsince exceeded 2010, our pipeline goals across all of our therapy areas - testament the to calibre of our passion and dedication their scientists, for science and our culture challenge to thinking. conventional a view of ourTaking pipeline delivery against industry benchmarks, continue we maketo remarkable improvements in cycle times and success rates. When we compare our productivity from 2005-2010 can we thatto see of today, that have we improved our success rates from first time in man and successful completion of Phase III from three and a half per cent per cent over 15 to - a clear improvement over the current industry average of four per cent. Even more importantly, this is translating into the delivery of olaparib, drugs like medicines, with new osimertinib and CAZ having AVI graduated a successfulto launch.

n introduction from

scientific innovation Introduction of next The wave

Mene Pangalos A 02 IMED Annual Review2016 In 2016 we set we ourselves In 2016 targetsambitious ensure to remain we fully to on-track bold our company’s deliver the improve – to ambition 200 of lives million patients and be a $45 company billion is clear2023. from ourby It new flourishing a pipeline that AstraZeneca is emerging. Introduction Introduction IMED Biotech Unit 2016 in numbers

>95% progress area Therapy 115 of IMED projects with post docs a personalised ~2,300 healthcare approach people in IMED

23 IMED functions Phase I and II starts (New 69 $13.5M Molecular generated clinical project Entities) from Open 6 combinations Innovation diagnostics in oncology launched science innovation science for Collaborating

552 peer reviewed publications ~1,000 31 40 current clinical projects high impact 3 collaborations (New Molecular publications Phase III Entities)

investment thrives science where environment An 125 decisions new hires

04 IMED Annual Review 2016 Delivering our pipeline through scientific leadership 05 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 07 Delivering our pipeline through scientific leadership 07

“2016 has been an impressive year for IMED Oncology with Oncology IMED for year impressive an has been “2016 of III progression Phase - from all areas in developments significant to the the of Phase II trials, multitude of five nomination savolitinib increased have We portfolio. discovery strong drugs and a candidate and supporting the portfolio collaborations of external the number response, damage DNA areas: key expansion of our driven have immuno- small molecule and resistance and tumour drivers the delivery position to continue in a great are we Overall, oncology. and beyond.” 2017 through to patients medicines of new IMED Oncology Susan Galbraith, VP

Oncology tumour drivers – cell surfaceOncology tumour drivers and lipid bilayer with receptor Therapy area progress Oncology 06 IMED Annual Review 2016 06 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives . The Melanie Frigault Frigault Melanie Melanie Frigault is a Principal Oncology, in Scientist Translational currently on secondment working the leading and acalabrutinib on at group science translational Acerta. Melanie is also a leader on savolitinib, where she delivered biomarker rules to automate patient inclusion/exclusion in future clinical trials of savolitinib in patients with ‘MET-driven’ papillary renal cell carcinoma (PRCC). This may be the first trial to use biomarker selection in renal cell. Melanie also led research from the patient to the bench resulting in discovery of novel biomarkers, leading to a new patent filing. Alex Hird Alex Hird led chemistry the MCL1 and early project teams to deliver the candidate drug AZD5991 in Alex2016. co-authored three peer reviewed publications in 2016, including a high impact paper in Nature Chemical Biology paper resulted from an alternative innovative approach to covalently target a lysine residue on MCL1, carried out within the AstraZeneca post-doc programme. In addition, Alex is Leader a Team in the chemistry department in Boston.

Delivering our pipeline through scientific leadership 09 Paul Secrist Paul Paul Secrist is Director of Oncology Bioscience and had a significant impact on the pre-clinical portfolio this year - serving as the biology lead for two successful candidate drug investment decisions (CDIDs) for AZD5991 and AZD0466 (MCL1) (Bcl2/xL). Paul was the major driver of the overall cell death strategy research multiple led has and prominent with collaborations this in laboratories academic exciting area of drug discovery. In addition, Paul co-leads the immuno-oncology molecule small strategy within AstraZeneca and has been instrumental in building both the pre-clinical portfolio and the rapidly expanding repertoire of within capabilities immunological Oncology. IMED Simon BarrySimon Simon Barry is a Senior Principal Bioscience, Oncology in Scientist who was awarded Senior Scientist of the at the Year IMED Science Awards for his 2016 depth and breadth of scientific achievement across the oncology portfolio. He has worked on a number of small and large molecule drug projects, from target selection through Phase III development. He has had a specific focus on the role the tumour microenvironment playsin tumour progression and within both working resistance, AstraZeneca and with external collaborators. He is currently the lead bioscientist on AZD5069 (CXCR2 inhibitor), AZD8186 (PI3Kb inhibitor) and cediranib (VEGFR inhibitor). Simon co-leads the small molecule in strategy immuno-oncology together working and AstraZeneca with Paul Secrist is driving the pre- clinical portfolio and capabilities to opportunities therapeutic develop in this exciting area. webinar and was invited by Mark O’Connor Mark Mark O’Connor is Chief Scientist in Oncology, heading up the DDR biology area. Mark has provided scientific leadership on olaparib and was instrumental in the in- licensing of the inhibitor Wee1 MoreAZD1775. recently, Mark has overseen the growth of DDR within AstraZeneca to an industry leading portfolio containing seven DDR agents, and played a keyrole in this year’s high level DDR strategy investment that led to significant additional investment in the area. MarkIn 2016, published several international peer reviewed papers including a high impact trapping PARP on publication Science in published was that Translational Medicine, he gave a Science American Association for Cancer Research (AACR) to give a keynote presentation at their DDR meeting, the only non-academic faculty member at the four-day event, thus leading industry our demonstrating position in the area. Cross section of cells from tumour of cells from section Cross stained to The cells are biopsy. receptors of target confirm presence for AstraZeneca and MedImmune therapeutic molecules People spotlight This year madehave we a number of important new hires, bringing expertise and experience substantial our consolidating and teams our to scientific leadership key in areas; these include Wenlin Shao, Viia Valge-Archer, Charles Sinclair, Deanna Mele, Laura Prickett, Juliann Chmielecki and Kris Sachsenmeier. also have We successfully transitioned the majority of our UK group Cambridge to sites, including the establishment of a new group within the Hodgkin building in Great Chesterford.

to driveto our fast-developing portfolio for haematological malignancies. The Acerta Research and Early Development group will spearhead development of acalabrutinib combinations with our development portfolio and will also take forward novel agents, such programmed the targeting those as cell death mechanisms, which a have primary line-of-sight into haematological malignancies. The high uptake of the plasma-based circulating tumour DNA (ctDNA) test for osimertinib highlights the critical value of developing minimally invasive diagnostic testing and the importance of aggressive evaluation of mechanisms of clinical resistance. With the acquisition of a majority stake in Acerta Pharma, acalabrutinib now provides a cornerstone asset

germ-line BRCA patients be to identified and has led the to initiation of a number novel Phase of II studies.

ATR inhibitorATR AZD6738 progressed to Phase II, in combination with olaparib, as part of our DNA damage response (DDR) franchise, whichsaw new investments projects. andfor ATM the Wee1 Phase II trials also started inhibitor with STAT3 AZD9150 and inhibitor CXCR2 AZD5069 combination with in administered (both our anti-PD-L1 antibody durvalumab). The A2aR antagonist AZD4635 achieved its firstPhase I dose whilst five new candidate drugs were nominated. The practical delivery of personalised medicine remains critically important in driving clinical benefit and the great majority of our current projects are developing prospective patient selection strategies. For olaparib, significant investment in next-generation sequencing (NGS) is allowing non Therapy area progress Oncology

08 IMED Annual Review 2016 EGFR mutant non-small cell lung cancer (NSCLC). EGFR mutant non-small combination shows great promise in cMet amplified in cMet amplified promise great shows combination cell carcinoma (PRCC), whilst the savolitinib/osimertinib whilst the savolitinib/osimertinib (PRCC), cell carcinoma III investment decision for savolitinib in papillary renal in papillary renal savolitinib for decision III investment leadership was delivered that led to achieving a Phase to achieving that led delivered was leadership across our cancer treatment pipeline. Key data and data Key pipeline. treatment our cancer across Through 2016, IMED Oncology has seen strong progress progress has seen strong IMED Oncology 2016, Through Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives ation

ing and ressor cells ressor y the everse with encouraging early clinical data radiation are also progressing well, also progressing radiation are suggesting that the effects of both these therapies can be enhanced in defined patient populations. In addition to the work on optimising dose/schedule and driving forward combinations with olaparib, combinations with immunotherapy and ionising Delivering our pipeline through scientific leadership 11 We developed a portfolio of small molecule inhibitors which have the potential to dramatically to dramatically small molecule inhibitors which have the potential developed a portfolio of We inhibitors such as durvalumab; despite the progress effectiveness of checkpoint increase major challenges in targeting remain immune checkpoints there seen with inhibitors of the more able to make the local tumour micro-environment cells are tumour mechanisms whereby immune-suppressive. Ionis Pharmaceuticals) that prevents oligonucleotide (licensed in from AZD9150 is an antisense which started Phase activator of transcription 3 (STAT3), of signal transducer and expression AZD9150 has shown promising with durvalumab. Previously II trials this year in combination B cell lymphoma. with diffuse large in a small number of patients responses Phase II this year in combination antagonist that also entered AZD5069 is a selective CXCR2 supp inhibits the migration of CXCR2+ myeloid-derived with durvalumab. AZD5069 our as well as showcasing achieved 20 high impact and 83 high quality publications We and ENA, a symposium hosted b industry-leading pipeline at AACR, ASCO, ESMO the National Cancer Cancer (EORTC), of and Treatment for Research Organisation European Institute (NCI) and AACR. our collaboration with A key highlight was our publication in Cancer Cell, which came from of CXCR2 demonstrating the therapeutic potential the Beatson Institute for Cancer Research, cancer for the first time. inhibition in pancreatic invitations; various high profile recognised externally through Our scientific leadership was also for the annual AACR meet Susan Galbraith was a member of the scientific committee expert panel to discuss the implement was also asked to join the AACR genomics initiative of genomics to advance personalised medicine. to tumour microenvironments and may enhance immune-mediated tumour killing. and to tumour microenvironments (A2aR) antagonist that started its Phase I monotherapy AZD4635 is an adenosine 2a receptor in a range combination dosing with durvalumab dose-escalation this year and will explore AZD4635 has been shown to r of solid tumours. Blockade of A2aR signalling with , as well as reduce tumour burden and enhance tumour burden ex vivo, as well as reduce adenosine-mediated immunosuppression mouse models. anti-tumour immunity in pre-clinical We delivered We BRCAm breast cancers. In addition,BRCAm breast our partnership with Foundationthrough Medicine, we have developed a gene patientpanel test which will allow broader selection for both olaparib monotherapy and combination trials. A key highlight this year has been the made with olaparib we have progression compoundscombinations, with three now being clinically evaluated with inhibitor; AZD1775 (Wee1 this PARP inhibitor), inhibitor), AZD6738 (ATR inhibitor). Underpinning AZD0156 (ATM these combinations is our developing understanding of how the higher levels of that occur in cancer cells stress replication and ATM ATR, can be exploited: Wee1, all activated and play complementaryare Olaparib enhances in this response. roles onto by trapping PARP stress replication forks leadingDNA and stalling replication in the generation of DNAto an increase double-strand breaks.

We set out to We Build capability in developing capability in developing Build within small molecules (IO) immuno-oncology leadership scientific Demonstrate Capitalising on our DNA damage response (DDR) strategy (DDR) response damage Capitalising on our DNA Targeting DDR deficiencies to Targeting cells, while kill cancer preferentially minimising the impact on normal cells, has the potential to be transformational range of cancers. Our portfolioin a broad over in this area has seen rapid growth the last few years, with one approved medicine and four candidate drugs now in clinical development. This pipeline the and targets is highly differentiated key molecular pathways, providing significant opportunities for innovative combinations. Ongoing work to optimise combination scheduling and increase our understanding of patient selection biomarkers is ongoing and has seen additional investment in 2016. olaparib was At the beginning of the year, therapy designation granted breakthrough gene by the US FDA for BRCA1/2 or ATM mutated metastatic castration resistant also Phase III studies are cancer. prostate pancreatic underway in gastric cancer, cancer and adjuvant and metastatic utinib. regression in regression ith cytotoxics. -day event. educing tumour size and We progressed three molecules toward the clinic following promising pre-clinical data: pre-clinical the clinic following promising molecules toward three progressed We which demonstrates tumour AZD5991 is a highly potent and selective MCL1 inhibitor We presented data from the BLOOM study at the 2016 American Society of Clinical Oncology Society of Clinical the BLOOM study at the 2016 American data from presented We is effective in r (ASCO) meeting, which demonstrates that osimertinib lymphoma multiple disease models in vivo, including acute myeloid leukaemia (AML), non-hodgkin AZD5991 has collaboration, with the ‘Beat AML’ (NHL) and multiple myeloma (MM). Working has to BCL2 and BCLxL inhibitors and compared profile demonstrated a highly differentiated in a range of myeloid and lymphoid malignancies. potential broad short-term target PK to enable AZD4573 is a selective CDK9 inhibitor with the appropriate studies have shown significant anti-cancer activity across engagement. Recent pre-clinical lymphocytic leukaemia (CLL), haematological malignancies, including AML, NHL, chronic different for combination use with acalabr and MM based on exciting clinical data, plus potential activity in a range of haematological pre-clinical AZD0466 is a dual BCL2/xL inhibitor with broad it has been intravenously, as a nanomedicine formulation administered malignancies. Delivered agents which has prevented the therapeutic window for thrombocytopenia, designed to improve delivering their full potential previously. of this profile with other mechanisms, of the BCL2 family in combination proteins these pro-survival Targeting agents were killed. All three the fraction of tumour cells that are offers the potential to increase meeting in American Society of Haematology (ASH) highlighted to investigators at the recent being developed in combination between AstraZeneca and Acerta. San Diego and are We accelerated the clinical development programme for savoliitnib, a potent and highly selective for savoliitnib, a potent and highly development programme accelerated the clinical We with kinase, by extending our collaboration tyrosine the c-Met receptor small molecule inhibitor of Savolitinib achieved a positive Phase Phase II results. promising Hutchison MediPharma following cell renal 2016. The global Phase III trial of savolitinib in papillary III investment decision in August select pivotal study to employ NGS methodology to prospectively (PRCC) will be the first carcinoma disease. patients with c-Met-driven with a of savolitinib in other c-Met-driven cancer types continues In addition, the development amplified EGFR mutant NSCLC. The Phase II expansion of the ongoingparticular focus on c-Met is with osimertinib whilst another trial in China trial is evaluating savolitinib in combination TATTON and in a similar patient population. exploring the use of savolitinib form of disease, a devastating function in patients with leptomeningeal neurological improving of property the blood-brain-barrier is a key NSCLC. The ability to access the brain by crossing a number of other EGFR inhibitors. it from osimertinib which differentiates At the same time, the combination of olaparib and AZD6738 (ATR inhibitor) has started Phase inhibitor) At the same time, the combination of olaparib and AZD6738 (ATR completing its Phase I is currently ATM inhibitor, II efficacy studies, whilst AZD0156, a selective dose-escalation study in combination with olaparib. inhibitor we to an ATM of glioblastoma patients who could be responsive a population target To AZD1390, which has been optimised to deliver inhibitor, have also nominated a second ATM blood-brain-barrier penetration and much higher drug concentrations to the brain by improving optimising drug transporter activity. multiple publications, as well as significant Our scientific leadership was demonstrated through Society for Medical Oncology (ESMO) at the 2016 AACR, ASCO and the European presence at to give a keynote presentation In addition, Mark O’Connor was invited by AACR congress. their DDR meeting, the only non-academic faculty member at the four Significant investment has been made in this area in 2016, both in monotherapy and in Significant investment has been made in this area patient populations data demonstrates the potential to both broaden combination. Our pre-clinical In addition, combinations with to monotherapy. compared and deepen the level of responses between with the potential to exploit the synergy being prioritised immuno-oncology agents are in key tumours. responses durable the mechanisms and drive much more inhibitor) is being investigated in a number of Phase Olaparib in combination with AZD1775 (Wee1 II trials in parallel with evaluation of AZD1775 in monotherapy and in combination w We delivered We We set out to We Demonstrate leadership in DNA in DNA leadership Demonstrate (DDR) response damage Build our portfolio of cell death our portfolio Build agents Demonstrate the potential of the potential Demonstrate current osimertinib beyond indications Progress savolitinib through its through savolitinib Progress decision Phase III investment first Highlights Therapy area progress Oncology 10 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Phase III / LCM Pre-clinical Phase I Phase II not including MedImmune programmes. Pipeline correct as of Q4 2016, as of Q4 2016, Pipeline correct olaparib / PARP osimertinib / EGFR acalabrutinib / BTK selumetinib / MEK / ER antagonist AZD0156 / ATM AZD4635 / A2aR / AURN AZD2811 AZD8186 / PI3Kβ AZD9496/ SERD savolitinib / MET AZD1775 / Wee1 AZD6738 / ATR AZD9150 / STAT3 AZD5069 / CXCR2 vistusertib / mTOR1/2 AZD5363 / AKT AZD4547 / FGFR AZD3759 / EGFR-BBB Oncology pipeline AZD4573 / CDK9 AZD5991 / MCL1 AZD0466 / Bcl2/xL AZD1390 / ATM-BBB AZD4785 / KRAS AZD4205 / JAK1 AZD0364 / ERK AZD5153 / BRD4 Delivering our pipeline through scientific leadership 13 Early clinical data suggests that theEarly clinical data suggests of acalabrutinib selectivity profile improved potential to ibrutinib) has the (compared benefit for clinical to translate into greater mechanism. Thesethis critically important an excellent make acalabrutinib properties acrosscandidate for combinations as with third-partyour portfolio as well novel combinations are compounds. Two in 2017 exploitingmoving into the clinic inhibitors,PI3K/AKT/mTOR pathway B-cell diffuse large such as vistusertib in lymphoma (DLBCL) and DDR inhibitors, have such as AZD6738 in CLL. We also held discussions with a number of to and clinical centres collaborative groups start planning molecularly-stratified signal or studies (so called ‘umbrella’ searching ‘basket’ trials) in diseases such as AML, (DLBCL) and mantle cell lymphoma.

i.v.

In December we nominated AZD0466In December we nominated inhibitor withwhich is a dual Bcl2/xL activity in a range of pre-clinical broad Bcl2 is ahaematologic malignancies. with venetoclax clinically validated target by the FDA in 2016being approved lymphocyticfor sub-types of chronic our dataleukaemia (CLL). However continuous oral suggests that venetoclax’s maximising cell killdosing is not ideal in often do survive are whilst those cells that survivalparallel a as Bcl2/xL exploit to able mechanism. Consequently AZD0466 has the potential to be a best-in-class agent in this field with a highly-optimised nanomedicine formulation with a broader attempts to Previous Bcl2/xL profile. seriously were develop this dual profile toxicities such by on-target compromised as thrombocytopenia. This exciting portfolio of cell death agents withand its supporting data was shared key haematological investigators at the Society of Hematology American recent (ASH) meeting. The portfolio will be developed in collaboration with Acerta working closely with AstraZeneca as critical elements of theone of the three haematological disease strategy. A second key element is the development of the cornerstone asset acalabrutinib, a highly selective inhibitor of Bruton’s (BTK) which is in a range kinase tyrosine willof pivotal studies. The final component be to maximise the value of our immuno- oncology agents, including molecules inhibitor), in such as AZD9150 (STAT3 these diseases. The practical delivery of remainspersonalised medicine driving in important critically clinical and benefit the great our current of projects majority are developing prospective strategies.” selection patient

Antibody that blocks inhibitory signals from the Antibody that blocks inhibitory signals from tumour to cells of the immune system resulting in enhanced anti-tumour immunity The second candidate is AZD4573,The second candidate with thea selective CDK9 inhibitor PK to enable short-termappropriate inhibition engagement. Transient target genes such targets of CDK9 preferentially transcriptionalas MCL1 and MYC through alternative offering an inhibition thereby inhibition. Givenmechanism of MCL1 as a protein the importance of MCL1 signal, this complementarypro-survival death the cell mechanism strengthens show that studies portfolio, while recent and indirect between direct differences inhibition of MCL1 may be exploitable in clinical studies. Our goal is to deliver a best-in-classOur goal is to deliver the most portfolio of drugs targeting together proteins, important pro-survival strategy thatwith a molecular stratification tumour with of each allows the treatment we have madethe right drug. This year with the nomination significant progress which novel candidate drugs of three in haematologicalwill advance initially is a potentmalignancies. AZD5991 that induces rapidand selective MCL1 dependent tumourapoptosis in MCL1- have demonstrated tumour cells. We in multiple disease models in regression vivo, including acute myeloid leukaemia (AML), non-Hodgkin lymphoma and multiple myeloma. Building an industry leading cell death portfolio leading an industry Building Therapy area progress Oncology The evasion of programmed cell death is The evasion of programmed the balance of As one hallmark of cancer. to is key - and anti-apoptotic proteins pro fate, one mechanismdetermining cellular to overcome able are by which cancer cells one of upregulation apoptosis is through BCL2 members of the pro-survival or more family of proteins.(B-cell lymphoma-2) of these pro-survival targeting Transient or BclxL) (such as MCL1, Bcl2 proteins inhibitors blockswith small molecule lead to signalling and will pro-survival cancer cell death. Pre-clinical increased with other anti- data shows that synergy andcancer mechanisms can be profound the class has enormous potential in both monotherapy and in combination. 12 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Author Pearson A, Smyth E, Babina I, Herrera-Abreu Pearson A, Smyth E, Babina I, Herrera-Abreu E, Smith N, Peckitt C, Kilgour Tarazona MT, NR, Geh C, Rooney C, Cutts R, Campbell J, G, Chua S, Ning J, Fenwick K, Swain A, Brown Thomas A, Johnston SRD, Ajaz M, Sumpter D, Chau I, Popat S, K, Gillbanks A, Watkins NC Cunningham D, Turner Ashton S, Song YH, Nolan J, Cadogan E, Murray Low S, Taylor J, Odedra R, Foster J, Hall PA, Ellston R, Polanska UM, Wilson J, Howes C, P, Smith A, Goodwin RJ, Swales JG, Strittmatter D, Trueman P, Z, Nilsson A, Andren N, Takáts D, De G, Parsons M, Reimer CL, Troiano Walker M, Hrkach J, Zale S, Jewsbury Witt D, Ashford PJ, Barry ST Rodrik-Outmezguine V S, Okaniwa O, Yao Z, O, Yao V S, Okaniwa Rodrik-Outmezguine H, McWhirter C, Banaji A, Won Novotny C, E, Barratt DG, M, de Stanchina Berger W, Wong N, Shokat KM Rosen Klinowska T, Cosulich S, B, Johnson J,Carr TH, McEwen R, Dougherty N, Cruzalegui F, Dry J, Lai Z, Ghazoui Z, Laing Hodgson D, Hollingsworth S JC, Barrett D, Knoppers BM,Siu L, Lawler M, Haussler Banks I, Barrett F, DJ, Liao R, Andre Lewin J, Vis R, Mao M, AA, Fitzgerald JC, Caldas C, Camargo TB, Tean Sullivan P, Sellers W, Mattison J, Pao W, E JC, Sawyers C, Voest R, ZenKlusen Ward Batra W, Bruna A, Rueda OM, Greenwood K, AS, Callari M, Batra RN, Pogrebniak Tufegdzic-Vidakovic Sandoval J, Cassidy JW, E, A, Sammut S-J, Jones L, Provenzano Hadfield J, Eldridge, M, P, R, Eirew Baird A, Lightfoot A, Barthorpe MCLaren-Douglas H, O'Connor MJ, Gray J, Cortes J, Baselga AL, Aparicio S, Serra J, Marangoni E, Welm Garnett C MJ, Caldas V, Mlecnik B, Bindea G, Angell HK, Maby SE, D, Church Angelova M, Tougeron P, Sasso T, Lafontaine L, Fischer M, Fredriksen M, Bilocq AM, Kirilovsky A, Obenauf AC, JJ, Teuch A, Bruneval P, Hamieh M, Berger Mauillon J, Rafii Sabourin JC, Le Pessot F, Speicher MR, Trajanoski P, A, Laurent-Puig Pagès F, T, Sesboüe R, Frebourg Z, Michel P, JB Galon J Latouche V, Valge-Archer Karim SA, Leach JDG, Bailey P, Steele CW, M, Bryson S, R, Rishi L, Foth Upstill-Goddard McDaid K, Wilson Z, Eberlein C, Candido JB, Clarke M, Nixon C, Connelly J, Jamieson N, Chang DK, Evans TRJ, Carter CR, Balkwill F, Nibbs RJB, Barry ST, Strathdee D, Biankin AV, Sansom OJ, Morton KS, Alden RS, Lawrance GE, Thress Oxnard JC, Barrett Cantarini M, Yang R, Paweletz CP, JC, Jänne PA Mlecnik B, Bindea G, Kirilovsky A, Angell HK, SE, Maby P, M, Church Obenauf AC, Tosolini Mauger T, A, Angelova M, Fredriksen Vasaturo A, Speicher MR, Pagès F, M, Berger S, Waldner Galon J V, Valge-Archer S, Storm M, Puri Ashford J, Lammers T, Hare G, Barry S Delivering our pipeline through scientific leadership 15 Title High-level clonal FGFR amplification and responseHigh-level clonal FGFR amplification and to FGFR inhibition in a translational clinical trial kinase inhibitor nanoparticles target Aurora tumors with favorable therapeutic index in vivo Overcoming mTOR resistance mutations with a mutations with a resistance mTOR Overcoming mTOR inhibitor new generation for Oncology Defining Actionable Mutations Therapeutic Development and effective of responsible Facilitating a culture data sharing of cancer genome Cancer Explants with A Biobank of Breast to Screen Intra-tumor Heterogeneity Preserved Anticancer Compounds cancer show Integrative analyses of colorectal of patient predictor is a stronger Immunoscore instability survival than microsatellite suppresses CXCR2 inhibition profoundly in immunotherapy metastases and improves ductal adenocarcinoma pancreatic Association between plasma genotyping with osimertinib and outcomes of treatment (AZD9291) in advanced non-small-cell lung cancer The tumor microenvironment and Immunoscore and Immunoscore The tumor microenvironment critical determinants of dissemination to are distant metastasis Challenges and strategies in anti-cancer nanomedicine development: an industry perspective Publication Nature Cancer Discovery Science Translational Medicine Nature Reviews Cancer Reviews Nature Medicine Nature Cell Immunity Cancer Cell Oncology of Clinical Journal Science Translational Science Translational Medicine Drug Delivery Advanced Reviews Key publications in 2016 in publications Key 4 9 and is an example of our and is an example of our 10. Memorial Sloan Kettering, US Our collaboration with the Memorial Sloan to Kettering to study models of resistance mTOR kinase inhibitors has led to new scientific in joint publication insights, a high profile the journal Nature commitment to supporting and communicating innovative science. 8. UK Research, The Institute of Cancer Institute of Cancer A collaboration with the a analysed biological samples from Research clinical study of the FGFR proof-of-concept in patients with FGFR1 kinase inhibitor AZD4547 Clinically we and FGFR2 amplified tumors. to FGFR response observed that single agent in high-level FGFR inhibition was only seen collaboration pre-clinical amplified cancers. The a mechanistic understanding for the provided and led to a high pattern observed of response publication in the journal joint Cancer profile, Discovery in 2016. 9. Hutchison Medi Pharma, China jointly With Hutchison Medi Pharma we are developing the highly potent and selective c-Met kinase inhibitor savolitinib in multiple diseases including c-Met amplified mutant EFGR non- small cell lung cancer (NSCLC) and papillary (PRCC). In 2016 we made cell carcinoma renal the investment decision to accelerate the PRCC a global into clinical development program Phase III trial using next generation sequencing patients with select technology to prospectively c-MET driven tumors.

7 8 6 5 evaluation of MCL1 and CDK9 inhibition inevaluation of MCL1 and mouse models of human genetically engineered leukaemia haslymphoma and acute myeloid key information to help inform future provided in cell death. projects 6. The Beatson Institute for Cancer Research, Scotland collaborating with the Beatson Institute are We to test the impact of therapeutics in genetically genetic subsets models of defined engineered cancer to identify and pancreatic of colorectal diseases. these potential new ways to treat joint In 2016 the work led to a high profile, publication in the journal Cancer Cell. 7. France Institut Gustave Roussy, established a collaboration with the We Institut Gustave Roussy to implement the immunostaining assay and develop Immunoscore of the tumor complete understanding a more and the dynamics of the microenvironment cancers. in multiple human immune response In 2016 our collaboration led to two jointly in the journals publications published, high profile . Medicine Immunity and in Science Translational and in vivo in vitro A collaboration to perform 5. UK University of Manchester, University of Our collaboration with the the sensitivity of small Manchester to determine tumour models to PARP cell lung cancer (SCLC) pre-clinical inhibitors has provided and Wee1 data supporting the initiation of new clinical trials inhibitor AZD1775 and our testing our Wee1 inhibitor olaparib. PARP 4. Australia Centre, Peter MacCallum Cancer 10 3 1 2 Therapy area progress Oncology 14 IMED Annual Review2016 A selection of key collaborations in 2016 in collaborations of key A selection We established a collaboration with the Dana- We Farber to evaluate and identify EGFR mutations and establish ctDNA in NSCLC patient plasma from patient-derived xenograft lung cancer models from in patients prior to enrolment tumour biopsies from this from the AZD9291 AURA trial. In 2016 results joint publication incollaboration led to a high profile the Journal of Clinical Oncology. 3. Dana-Farber Cancer Institute, US 2. Hutchinson Cancer Research Fred US Centre, Hutchinson Our collaboration with the Fred multiple Center to evaluate Cancer Research monitoring mass spectrometry reaction data of Mechanism (MRMMS) to deliver Proof for AstraZeneca portfolio assets has provided us with data to identify new methods by which we can evaluate the mechanistic activity of our compounds in clinical studies. 1. US Centre, MD Anderson Cancer with established a multi-year collaboration We to conduct clinical MD Anderson Cancer Center gynecological studies in ovarian and other Inhibition Wee1 cancers. A Pilot Study of Surgery Reductive Induction Prior to Tumour initiated as part in Ovarian Cancer has been with the clinical of this collaboration, along Pharmacodynamics and trial, Matched Paired in Combination Feasibility Study of durvalumab Ovarian Cancer with Chemotherapy in Frontline Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership17 Delivering our pipeline through scientific leadership 17

“2016 has been the start of a transition in our scientific in the has been “2016 start of a transition symptom from shifted has emphasis where strategy, disease drivers respiratory and understanding control achieve to paradigms treatment novel to identifying with patients cure potentially and modification disease diseases” respiratory Autoimmunity Inflammation and VP Respiratory, Sethi, Tariq Unit, Early Clinical Development Medicine Translational Inflammation Respiratory, Biology, VP Translational Outi Vaarala, and Autoimmunity

Cilia in the lung

and Autoimmunity Therapy area progress Inflammation Respiratory, 16 IMED Annual Review 2016 16 IMED16 Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Lung regeneration Lung By understanding the drivers key of pathogenesis in the lungaim we establishto hypotheses for driving lung regeneration. are We investing in novel pre-clinical models and new technologies that will enable us to explore new biological pathways with the aim of understanding can how we restore or regenerate lung tissue to prevent, reverse and one day cure disease. respiratory 300 million people worldwide suffer from asthma. Delivering our pipeline through scientific leadership 19 Lung immunityLung Building on our established expertise inimmunology and inflammation aimwe alter to disease course by resetting immunological dysfunction in respiratory disease. aim We to identify molecules which modify disease normalising by immune homeostasis in target systems. In addition to clinical endpoints of asthma the study includes an extensivecontrol, which aims tobiomarker programme, understand the immunological changes associated with the loss of asthma control of immune balanceand the restoration The outcome of thein this patient group. November 2018) will notstudy (results only determine next steps for AZD1419, studies to prevent but will also guide future asthma exacerbations. of this landmark very proud are We which we believe has the potential study, the way people thinkto revolutionise about asthma management. It also demonstrates how AstraZeneca is leading in this field, delivering our ambition to disease with modifying respiratory re-think or even cure reverse therapies to prevent, these devastating conditions. realise our ambition of disease modification and cure in respiratory disease, we are renewing our research focus in IMED RIA on Lung Immunity, Lung Lung Lung Immunity, RIA on focus in IMED research our renewing are disease, we respiratory in and cure modification of disease our ambition realise Lung epithelium Lung Disruption of the lungepithelium is driver a key lung of diseases and autoimmunity. Our goal is to identify therapies that can restore normal tissue architecture and lung epithelial integrity thereby improving patient outcome. Our refreshed respiratory strategy strategy respiratory Our refreshed To respiratory in capabilities world-class and establish innovation breakthrough focus will foster scientific This renewed Regeneration. and Lung Epithelium leaders in this field. IMED RIA as scientific disease to enable An estimated 300 million people asthma withworldwide suffer from and despite increasing prevalence of asthma datingdocumented awareness back to ancient civilisations, treatments to symptom control. limited currently are AZD1419 is an oligonucleotide toll-like a TLR9 agonist originating from receptor collaboration with Dynavax. By stimulating through 1 immune responses Type an opportunityTLR9, AZD1419 provides balance in patients immune to restore 2 inflammation an excessive Type where underlies the disease pathology to bring periods. patients disease free and pre-clinical Following promising Phase I studies we worked with the Institute to develop, for the firstKarolinska study in asthma time, a ground-breaking designed to keep patients in remission exacerbations. Therather than reduce INCONTROL, was initiated study, resulting at the end of 2016. Asthma disease modification - first patient enrolled patient enrolled Asthma - first disease modification in landmark study In our journey towards disease modification and curewe are also utilising novel drug platforms beyond target molecules small to traditional protein-protein interactions and modulate protein expression. highlight A key this year has been our exciting new collaboration with Bicycle Therapeutics exploreto the potential of bicyclic peptides treat to respiratory diseases. Our robust portfolio of early targets has the potential transform to the treatment of respiratory disease. believe We our strong biology capabilities, our deep experience coupled inhalation in capabilities and with a leading scientific strategy will put us at the forefront of delivering disease modifying medicines in the future. our inhaled inhibitor PI3Kγδ that targets asthma driven mixed by phenotype T-cell has shown promising pre-clinical results Asthis part year. of the programme, we are working with Ubiopred identify to understand and to signatures gene optimise patient response. Our third focus is lung regeneration where are we investing in fundamental understand mechanismsresearch the to involved, including the role of epigenetic mutations germline modifications, and somatic mutations. Much of this through conducted being research is academic collaborations with our institutions including the University of Southampton, Institut national de la santé et de la recherche médicale (INSERM), and the Wallenberg Centre for Molecular and Translational University. Gothenburg Medicine,

Within lung epithelial health a key highlight has been AZD5634, our inhaled sodium channel (ENaC) inhibitor, which progressed this year through first time in man and into patients. Pre-clinical data has demonstrated the potential for AZD5634 mechanistically improve to lung function and reduce risk for - with patients in triggered exacerbations cystic fibrosis. Within respiratory immunity, have we initiated a landmark Phase II trial of aninhaled toll-like receptorAZD1419, (TLR) 9 agonist, which aims restore to immune homeostasis in the airway of patients with T2 dominant asthma. This is the firstever study designedkeepto asthma patients in remission rather than has AZD1419 and exacerbations reduce the potential be to the first true disease- modifying asthma treatment. In addition,

and Autoimmunity (RIA) Therapy area progress Inflammation Respiratory, 18 IMED Annual Review 2016

devastating conditions. devastating medicines that prevent, reverse or even cure these cure or even reverse medicines that prevent, us to achieve our vision to deliver disease modifying disease modifying our vision to deliver us to achieve the basis of our drug discovery programme and enables and enables programme the our drug discovery basis of Increasing our understanding of disease drivers forms forms of disease drivers our understanding Increasing with therapies limited to treating or avoiding symptoms. symptoms. or avoiding to treating limited with therapies obstructive pulmonary disease (COPD) around the world, the world, around disease (COPD) pulmonary obstructive 600 million people living with asthma and chronic with asthma and chronic living 600 million people . There are over over are . There lung regeneration lung immunity and with a focus on three core themes: lung epithelium, core on three with a focus This year we have refreshed our respiratory strategy strategy our respiratory refreshed have we This year Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives . Danen Cunoosamy Principal Cunoosamy, Danen Biology Translational Scientist, became one of our new IMED RIA team leaders, with a team focused on the interaction of alveolar cells epithelial and macrophages in chronic obstructive pulmonary disease (COPD). This year Danen’s team has shown that alveolar macrophages in COPD show phenotype the and plasticity of macrophages could thus be modulated by inhaled therapeutics. Furthermore, Danen, together with IMED colleagues, has crosstalk the that demonstrated and macrophages between B-cells seem to contribute to the emphysematic changes in COPD. This work has generated key of Journal American in publications Medicine Care Critical Respiratory Delivering our pipeline through scientific leadership 21 Elin Boger Elin In realising our need to be world leading in predicting the local effects of inhaled drugs through based physiologically applying pharmacokinetic (PBPK) modelling, Elin Boger joined IMED RIA as Scientist, Principal Associate DMPK following completion of her PhD training at the University of Warwick. With several high quality publications and her Lung-Targeted titled thesis Receptor Occupancy by Drug Inhalation; an Experimental and Elin Evaluation, Computational embodies the scientist who is both an expert on the subject area and a mathematical modeler. With such a combination of skills Elin has taken on the task to conduct computational evaluation of inhaled drug candidates and to non-small for opportunitiesidentify molecule inhaled therapeutics. Recently Elin´s model was recognised by industry peers as non-commercial published, first the inhalation PBPK model, for which she was also awarded Breakthrough Scientist of the Year at the IMED Science Awards 2016.

. Journal of Organic Chemistry Stefan Schiesser Stefan Synthetic chemistry is key to our ability to discover novel, highly designed molecules that eventually may turn into clinical candidates. Over recent years, there has been a remarkable development of synthetic methodology that significantly changes the way molecules are synthesised. The recruitment of Stefan Schiesser Scientist, Research Senior as Chemistry, ensures that RIA chemistry continues to be at the forefront in the adoption and application of the most recent developments in the science of chemistry. synthetic Stefan has a Ph.D. degree in synthetic chemistry from the Ludwig-Maximilians-University of Munich followed by post- doctoral studies with Professor Movassaghi’s group at MIT in Boston. His research has included the synthesis of innovative anti- helped that compounds cancer to unravel the regulated NPM1 translesion DNA synthesis via interaction with the catalytic core of DNA polymerase-η. The quality of Stefan’s research is underpinned by several publications in chemistryjournals prominent such as Journal of the American Angewandte Society, Chemical Biology Chemical Nature Chemie, and Lung bronchioles Lung bronchioles People spotlight on hma cells, es to be used as ), and inhaled SGRM/ oids in pre-clinical models oids in pre-clinical onchodilation in comparison inhibitor in pre-clinical development for patients with severe development for patients with severe inhibitor in pre-clinical compounds in different classes of proteins to understand the biological effects, thus enabling the classes of proteins compounds in different functional selective targets. design of more by bringing together academic and industry experts AstraZeneca takes an active leadership role to showcase the rapid by hosting the first ever HDX-MS conference the world around from discovery. highlighting its potential as a valuable tool in drug advancement of this technology, will take place 15-17 May 2017 at the AstraZeneca site in Gothenburg. The conference We delivered literature-unprecedented inhalation PK/PD modelling to facilitate rapid decision inhalation PK/PD modelling to facilitate rapid literature-unprecedented delivered We of AZD8871, a dual-muscarinic making and highlight possibilities of best-in-class bronchodilation of mechanism was demonstrated with antagonist/β2 agonist (MABA) for COPD patients. Proof lung PK and clinical FEV1) and we used pre-clinical (through single dose lung function results repeat doses. human lung PK and efficacy after single and plasma PK to predict in the lung is crucial and their pharmacological target Understanding whether inhaled drugs reach emission receptor occupancy using positron we quantified lung for the first time ever, this year, specific PET muscarinic receptor developed a tomography (PET) imaging following inhalation. We in non- (ipratropium) by inhaled bronchodilator occupancy tracer to demonstrate the receptor human primates. This exciting development raises the possibility for PET measur for clinical efficacy in the future. a surrogate and has shown encouraging results in our asthma Phase IIa trial. and has shown encouraging results agonist (LABA), is efficacious at a potent, selective long-acting beta2-adrenoceptor Abediterol, 24 hour br ultra-low doses and has shown fast onset with sustained to other LABAs in asthma and COPD. agonist (MABA), has demonstrated fast onset and AZD8871, an M3 antagonist-beta2-adrenergic monotherapy agents. to the respective in patients relative sustained 24 hour bronchodilation excited to be working together we are where began a new collaboration with Bicycle Therapeutics, We bicyclic diseases. Highly constrained respiratory to identify and develop bicyclic peptides to treat specificity and stability coupled with rapid affinity, peptides offer an exciting novel modality with high size, these peptides can to their larger routes of administration. Due tissue penetration and flexible undruggable by traditional deemed targets interactions, allowing us to screen protein-protein target small molecule approaches. (MS) using cutting edge hydrogen-deuterium pushed the boundaries of mass spectrometry We dynamics in solution down to individual amino acid exchange (HDX) as a tool to visualise protein single residues. upon ligand binding is key to understanding the desired dynamics Detailed knowledge of protein pharmacological effects for drug compounds. its value in the identification of allosteric binding sites, detailed HDX-MS has proved understanding of the mode of action for novel ligands, studying the impact of binding We demontsrated potential for once daily steroid-like anti-inflammatory and superior anti-inflammatory demontsrated potential for once daily steroid-like We novel inhaled of in our development programme safety activity with improved bronchodilator combinations. bronchodilator greater modulator (SGRM) has shown AZD7594, an inhaled selective glucocorticoid receptor inhaled corticoster potency and selectivity than and other We saw solid progression across all phases of development in 2016: all phases across saw solid progression We in man; AZD5634 (ENaC), AZD0284 (RORγ candidates achieved first time Three Fixed Dose Combination. abediterol (oral SGRM), and AZD7986 (oral DPP1). of mechanism; AZD9567 candidates demonstrated proof Two (LABA) and AZD1419 (TLR9). into Phase II; Abediterol candidates progressed Two pMDI of Principle and our PT010 triple asthma demonstrated Proof AZD7594 (inhaled SGRM) Phase III investment decision. Phase IIa data enabling a delivered candidates. Our to many of our pipeline approach took a personalised healthcare We leukotriene driven inflammation and cysteine inhibitor targets leukotriene C4 synthase (LTC4S) could be used An activated cysteine leukotriene cascade in asthma patients. bronchoconstriction to therapy in the future. to identify patients most likely to respond also have an inhaled PI3Kγδ We data pre-clinical have promising phenotype. We asthma with a mixed T-cell uncontrolled on mixed T2/1/17 biology in ast demonstrating the effects of our lead asset AZD8154 such as inhibition of T2/1/17 cytokine release, Type 2 innate lymphoid cells (ILC2s), eosinophil 2 innate Type such as inhibition of T2/1/17 cytokine release, identifying gene we are our collaboration with Ubiopred, . Through activation in vitro and neutrophil approach. a personalised healthcare through to optimise treatment signatures setting with limited access to diagnostics. in a primary care treated patients are Most respiratory diagnostic, using blood biomarkers to respiratory point of care In 2016 we developed our first AgPlus. identify eosinophilic disease, with our diagnostic partner We delivered We

We set out to We Advance modelling and prediction modelling and prediction Advance (PD) pharmacodynamic of inhaled and efficacy in protein dynamics dynamics in protein Utilise cutting edge capabilities Utilise cutting edge Expand inhaled drug opportunities Expand inhaled small molecules beyond Demonstrate potential of inhaled of inhaled potential Demonstrate candidates bronchodilator Deliver on our ambition to lead on our ambition to lead Deliver precision with innovative an medicine approach Build and progress the clinical and progress Build portfolio Highlights and Autoimmunityand Therapy area progress Inflammation Respiratory, 20 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Author Leek H, Thunberg L, Jonson AC, Öhlén K, L, Jonson AC, Öhlén K, Leek H, Thunberg M Klarqvist J, Wikell C, Clifton S, Shearer P, Gardiner Benjamin A, Peters S P, Bäckström E, Lundqvist A, Boger E, Svanberg Hammarlund-Udenaes M, Fridén M Ewing P, Over B, Matsson P, Tyrchan C, Artursson P, P, C, Artursson Tyrchan P, Over B, Matsson SE, MA, Hilgendorf C, Johnston Doak BC, Foley Muncipinto G, P, RJ, McCarren Lee MD, Lewis J Kihlberg Perry MWD, Duvall JR, Norinder U, C, Pekkanen J, Böcking Schober Y, Brick T, JC, Riedler J,Genuneit J, Loss G, Dalphin O, Renz H, Vaarala Lauener R, Nockher WA, Mutius E, Johannes EgeBraun-Fahrländer C, von study group PASTURE M, Pfefferle PI, B, Loza MJ, Peffer N,Lefaudeux D, De Meulder R, Sousa Lutter Bansal AT, Rowe A, Baribaud F, Bakke PS, CarusoAR, Corfield J, Pandis I, Fleming LJ, Fowler Dahlén SE, M, Chanez P, Sanak M, P, SJ, Horvath I, Krug N, Montuschi Sterk PJ, F, Shaw DE, Singer T, Sandstrom Roberts G, Adcock IM, Djukanovic R, Auffray C, and the U-BIOPRED Study Group Chung KF, M, Glader P, Rehnberg Swedin L, Saarne T, Catley M Niedzielska M, Johansson G, Hazon P, O'Byrne PM, Metev H, Puu M, Richter K, Keen M, Nair P C, Uddin M, Larsson B, Cullberg M, M, Soderberg Liljevald M, Rehnberg D, Krutrok M, Borjesson J, Luciani Ramnegard N, Branden L, Johansson C, Xu X, Bjursell M, J, Keeling D, Andersson A, Hornberg Sjogren U, Jirholt J Castaño-Betancourt MC, Evans DS, Ramos den YFM, Boer CG, Metrustry S, Liu Y, MS, van Rooij J, Kraus VB, Yau Hollander W, Mitchell BD, Muir K, Hofman A, Doherty M, Kraaij R, Rivadeneira F, Doherty S, Zhang W, N, Arden E, Maciewicz RA, Barrett-Connor JM, M, Jordan Nelissen RGHH, Kloppenburg Hart DJ, Lafeber Nevitt MC, Slagboom EP, Styrkarsdottir U, Zeggini E, Evangelou F, E, Spector TD, Uitterlinden AG, Lane NE, AM, van Meurs JBJ Meulenbelt I, Valdes Delivering our pipeline through scientific leadership 23 Title Strategy for Large-Scale Isolation of Enantiomers in Strategy for Large-Scale Drug Discovery maturation rate determines the impact Neutrophil of dipeptidyl peptidase 1 inhibition on neutrophil activity serine protease Development of a novel lung slice methodology of inhaled compounds for profiling Structural and conformational determinants of of conformational determinants Structural and cell permeability macrocycle to the asthma- ω-3 fatty acids contribute milk cow’s effect of unprocessed protective asthma clusters linkedU-BIOPRED clinical adult to a subset of sputum omics Patient stratification and the unmet need in asthma Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, trial placebo-controlled γ (RORγ) adult orphan receptor Retinoid-related induced knockout mice develop lymphoblastic lymphoma for Cartilage Thickness Novel Genetic Variants and Hip Osteoarthritis Publication Nature Chemical Biology Chemical Nature Drug Discovery Today Drug Discovery of British Journal Pharmacology Pharmaceutical of Journal Sciencese Journal of Allergy and of Allergy Journal Clinical Immunology and of Allergy Journal Clinical Immunology and Pharmacology Therapeutics The Lancet Respiratory Medicine Reviews Autoimmunity PLoS Key publications in 2016 in publications Key Cystic fibrosis (CF)Cystic is fibrosis a devastating disorder genetic lung extensive that causes eventually, and damage respiratory failure. While there has been progress in treating this disease, there is still no cure and life expectancy is still under 40.”

Building on our expertise in inhalationBuilding on our expertise be given in a singlescience, AZD5634 will powder inhaler (DPI)dose disposable dry minimising risk fordevice: a device choice , a well-knowndelivery related for chronic with inhalation devices problem treatment. of the significant progress proud are We successfully we have made this year, time in man singlecompleting our first with promisingascending dose study tolerability and pharmacokinetics. safety, Our next step is to initiate a Phase Ib study to assess AZD5634 in CF patients and that AZD5634 will deliver a hopeful we are for option in the future valuable treatment patients suffering with this lethal disease.

with cystic fibrosis with cystic Potentially life-changing treatment for patients patients for treatment life-changing Potentially and Autoimmunityand Therapy area progress Inflammation Respiratory, Cystic fibrosis (CF) is a devastating genetic (CF) is a devastating Cystic fibrosis lung that causes extensive disorder failure. respiratory damage and eventually, in treating has been progress While there and life is still no cure this disease, there 40. expectancy is still under sodium channelAZD5634 is an inhaled blocks the sodium(ENaC) inhibitor that cells. AZD5634channel in airway epithelial defence fundamental host is addressing insufficient clearancedefects in CF lungs – of inhaled pathogens and particles caused by dehydration of the lung epithelium, and poor mucous viscoelastic properties caused by low airway pH, leading to infections and inflammation recurrent lung damage. This conceptand chronic value in COPDcould also be of great who have bronchitis patients with chronic dehydrated airways, poor mucociliary exacerbations. clearance and recurrent 22 IMED Annual Review2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Pre-clinical development Phase I Phase II Phase III / LCM Pipeline correct as of Q4 2016, as of Q4 2016, Pipeline correct not including MedImmune programmes. RIA pipeline RIA AZD9898 / LTC4s AZD8154 / PI3Kγδ AZD7986 / DPP1 AZD9567 / oSGRM AZD5634 / ENaC AZD0284 / RORγ AZD8871 / MABA AZD7594 / iSGRM AZD9412 / IFNβ AZD1419 / TLR9 abediterol / LABA MDI PT010 / Triple Delivering our pipeline through scientific leadership 25 10. Japan University, Tohoku drug metabolizing In human lungs, several but at low levels expressed enzymes are Satoshi with Dr. Working to the liver. compared Yamada Mitsuhiro Fujino, Dr. Naoya Kamata, Dr. Masakazu Ichinose at the Tohoku and Prof. Japan, mRNA University School of Medicine, enzymes of interest levels and activity of key being and diseased lungs are healthy from with primary human quantified and compared us to better hepatocytes. This will enable benefits and risks of inhaled drug the predict administration.

7. at Birmingham, US University of Alabama Steven Rowe, Prof. In a new collaboration with Birmingham, we are University of Alabama at by of rehydration investigating the importance to mucociliary ENaC inhibition with regards By means of airway transport and clearance. mucociliary transport surface liquid height and ) (in vitro ALI cultures rates in cystic fibrosis good efficacy and we have demonstrated on top of other cystic augmented clearance rates mechanisms and other target treatments fibrosis in our portfolio. 8. Australia, Australia University of Western have been collaborating with Professor We study in the MAVRIC group Le Souëf’s Infection Respiratory (Mechanisms of Acute Viral the effect of which aims to study in Children), rhinoviruses on the developing immune system with and to the hospital in infants presenting currently Learningswithout pre-asthma. are being applied to molecular changes in nasal epithelial cells. 9. Institutet, Karolinska to approach ChAMP is an integrated Project disease understanding and the development and models in asthma, allergies of predictive COPD. The goal of this collaboration with Sven-Erik Dahlén at Karolinska Professor Institutet is to identify sub-phenotypes of the use of a asthma and allied diseases through to model findings on systems biology approach metabolites. gene to molecular all levels from 10 8 epigenetic respiratory research, particularly into particularly into research, epigenetic respiratory combines resources asthma and COPD. This and clinical and expertise in drug discovery access to research development, funding and to enable early networks and patient groups into to be translated research stage scientific diseases. for respiratory potential new therapies 5. UK GLAZgo Discovery Centre, collaboration with our year, Now in its third University of GLAZgo Discovery Centre, strength from to grow Glasgow has continued delivering decision-making are We to strength. as translational medicine data for drug projects well as defining new concepts, for example in immunological tolerance and cell function. It is and next training for our current also providing generation of scientists in essential scientific techniques whilst embedding concepts of to academic ‘what-if’ and industrial ‘robustness’ deliver innovation. 6. University of Southampton, UK In April 2016 AstraZeneca signed a new research scientists collaboration with leading respiratory at the University of Southampton to conduct the pathways that will reveal pioneering research progression affecting disease modification and in COPD patients. Our focus will be on how smoking-induced somatic mutations in the lung can drive the of COPD, as well development and progression as on epigenetic drivers of anti-viral responses. This strategic partnership could help us areas in future potentially identify novel targets of development for the IMED RIA. 1 9 3 4 6 2 5 straZeneca, Asthma UK, British Lung straZeneca, Asthma UK, British Lung 4. Asthma UK/British Lung Foundation/ Council Technology Medical Research (MRCT), UK A have joined Foundation and MRC Technology to to fund drug discovery collaborations forces respiratory in the field of accelerate research for epigenetics and develop new treatments collaboration is asthma and COPD. The severe to submit novel calling on academic researchers to accelerate proposals epigenetic target associated with biologics, are advantageous in advantageous in are associated with biologics, to enable rapid tissue a small molecule format of administration. routes penetration and flexible 3. santé et de la Institut national de la médicale (INSERM), France recherche will evaluate Our collaboration with INSERM in cytokine profile the leukocyte subsets and disease (ILD) in cells COPD and interstitial lung peripheral blood, BAL and lung derived from is to define the tissue. The primary objective cells subsets of Treg phenotype and function COPD and ILD (natural or induced) isolated from of tissue and localisation of the defined subset cells in the lung tissue from Treg tissue resident patients. The secondary objective is to define the phenotype and function of other immune cell DC, alveolar macrophage, B, NK, subsets (T, ILCs) and to determine their interaction with Treg cell subsets by analysing the immunological phenotype of COPD and ILD patients by flow cytometry and immune chemistry.

) ® 7 In December 2016 we signed a multi- with Bicycle agreement collaboration target Therapeutics, aimed at the identification and development of bicyclic peptides to treat metabolic and cardiovascular respiratory, diseases. (Bicycle bicyclic peptide The proprietary 2. Bicycle Therapeutics, UK In 2016 we established the Wallenberg Centre Centre the Wallenberg In 2016 we established Medicine for Molecular and Translational in of Gothenburg, (WCMTM) at the University and Alice Wallenberg collaboration with Knut Götaland and Foundation, Region Västra is to Our goal the University of Gothenburg. in the field of enhance scientific collaboration and inflammatory diseases in the respiratory its world-leading and regain region Gothenburg This is done research. position within medical to the of top young scientists via recruitment they will be where University of Gothenburg able to evolve their full potential as leading independent scientists in a flourishing academic to hospital with unique connections environment in Gothenburg. and AstraZeneca infrastructures 1. for Molecular and Centre Wallenberg Medicine, Sweden Translational A selection of key collaborations in 2016 in collaborations of key A selection platform provides the opportunity to screen a a the opportunity to screen platform provides vast number of highly constrained macrocyclic respiratory disease-relevant peptides to address difficult deemed currently Targets targets. traditional small molecule using to target interactions e.g. protein-protein approaches, and shallow binding pockets, based on large affinity and become accessible due to improved These attributes, usually specificity. target and Autoimmunityand Therapy area progress Inflammation Respiratory, 24 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives c leadership 27 Delivering our pipeline through scientific leadership 27 Delivering our pipeline through scientifi “In the last 12 months we have made excellent progress in our pipeline excellent made “In have the we last months 12 progressed the first We milestones. our key many of and achieved modifiedever programme RNA Cardiovascularin Metabolic and Diseases, RNA messenger VEGF-A (mRNA), clinical into development. threeOur consists of clinical drugsheart now for pipeline failure/ coronary artery the microRNA nonalcoholic disease programme plus for (NASH)/diabetesI/IIa Phase to progressed into which steatohepatitis in ourstep and a major achievement Thisthis is a tremendous year. journeyleadership.” scientific to and Metabolic Diseases VP IMED Cardiovascular Schindler, Marcus

Chronic Kidney Disease - selective crystal structure crystal structure Kidney Disease - selective Chronic the body it from traps potassium and removes

MetabolicDiseases Therapy area progress and Cardiovascular 26 IMED Annual Review 2016 26 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Delivering our pipeline through scientific leadership 29 Cardiac regeneration Cardiac We strengthened our work with the University of Gothenburg by establishing new collaborative our work with the University of Gothenburg strengthened We Jenny Nyström joined IMED CVMD as Chief Scientist, CVMD scientist Daniel Professor projects. Head of IMED CVMD, was Schindler, and Marcus Linden was appointed Associate Professor, in Pharmacology. appointed Adjunct Professor We successfully progressed candidates in both our small molecule and new modalities pipelines and candidates in both our small molecule and successfully progressed We inhibitor) and AZD5718 (FLAP inhibitor). We we saw two candidates enter Phase I: AZD4831 (MPO in diabetic patients with non-alcoholic fatty liverinitiated a Phase I/IIa trial of AZD4076 (miR103/107) (VEGF-A) AZD8601 for our modified RNA programme, also gained full approval disease (NAFLD). We into clinical development. to progress from representation with collaborative projects identified multiple new pipeline entries through We our strategic collaborations also achieved several publications within We areas. disease all three Karolinska published in collaboration with the were including several high impact publications. Two and in Circulation (ICMC), which featured Centre our Integrated CardioMetabolic Institute, through Cell Metabolism. Pernille Professor B. Kidney Disease (CKD), a new Head of Bioscience Chronic recruited We to stop progression Hansen, to drive our early science strategy and deliver new targets Laerkegaard and journals, high quality of which 50 were achieved 99 new publications in major peer-reviewed We nine high impact. together with our collaborative partners andThe Medicinal Chemistry department in IMED CVMD, of chemical science with at the forefront are colleagues in IMED RIA and DSM, demonstrated they four high impact publications during 2016. advancement of our discovery and clinicalreflecting the impressive results In addition, significant Society of in 2016 including European at key conferences presented were stage programmes Association Dialysis and Transplant Renal Association – European (ESC), European Cardiology Association for the Study of Diabetes (EASD), American Diabetes European (ERA-EDTA), Congress Association (ADA), American Chemical Society (ACS), American Heart Association (AHA) and (ASN). American Society of Nephrology of CKD. We strengthened the science by progressing several projects aimed at CKD in our early aimed at CKD several projects the science by progressing strengthened of CKD. We we continued to invest in our collaborations with Evotec, the ICMC and theportfolio. Furthermore, University of Michigan. We delivered We

muscle cells Cardiac regenerating regenerating Cardiac We set out to We Enhance our scientific exchange Enhance our scientific exchange with universities local Strengthen and progress our and progress Strengthen pipeline clinical stage on our scientific Deliver collaborations within the field progression Drive disease kidney of chronic reputation Enhance our scientific scientific and demonstrate leadership Highlights studies and characterised strong by human target validation. believe We our drive for innovation and advancing targeted drug delivery will bring life- with patients medicineschanging to cardiovascular and metabolic diseases.

A major milestone of IMED CVMD in supporting our ambition in heart failure was the progression of AZD8601, the firstever modified RNA programme in throughCVMD, regulatory approvals and further into Phase I in early AZD8601 is a VEGF-AJanuary 2017. mRNA developed in collaboration with Moderna Therapeutics. It marks the first of hopefully many programmes enterto development through our broad partnership with Moderna in cardiovascular and metabolic diseases as well as cancer. In metabolism, our anti-microRNA (miR AZD4076 represents103/107) a new approach in the potential treatment of diabetic patients with non-alcoholic steatohepatitis (NASH), with the first diabetic patient with non-alcoholic fatty liver disease (NAFLD) being dosed keep pushingin To August the 2016. boundaries of science, our early pipeline was further strengthened with in 2016 projects based on human genetics

While previous years saw us build knowledge and invest technologies in key developto both our pipeline and our level of scientificexpertise, we are now strengthening a patient-centric approach the understanding better at aimed interplay and potential causal relationship between these diseases, which often present in the same patient. This is unprecedented opportunities up opening for novel treatment paradigms and will enrich our pipeline with further differentiated drugs. saw we significantIn 2016, progress in the discovery and clinical phases. During the saw we two programmesyear, achieve first time in man; AZD4831 (MPO inhibitor) (FLAPand AZD5718 inhibitor). Both of these small molecule projects were invented and developed AstraZeneca by scientists and the have potential help to patients with heart failure with preserved ejection fraction (HFpEF) or coronary artery disease (CAD) respectively.

MetabolicDiseases Therapy area progress and Cardiovascular 28 IMED Annual Review 2016

and chronic kidney disease (CKD). kidney and chronic the treatment of heart failure, diabetes diabetes of heart failure, the treatment to defining the new standard of care for care of to defining standard new the Diseases (CVMD), we are committed committed are (CVMD), we Diseases In IMED Cardiovascular and Metabolic and Metabolic Cardiovascular In IMED Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Author Menzies RI, Tam FW, Unwin RJ, Bailey MA Unwin FW, Menzies RI, Tam AI, Knerr L, Drury WJ 3rd, Gopalakrishnan R, Frolov E Valeur A, Ericson E, L, Nordqvist Paunovic AI, Drowley G, Kvist AJ, Mouchet E, Jonebring A, Grönberg MR, Gedda K, Goumans M-J,Engkvist O, Brown Plowright AT QW, Wang F, SM, Reyazee SU, Moro Lauschke VM, Vorrink R, Bell CC, Sison-Young Å, Hendriks DF, Nordling Park BK, Goldring CE, Ellis E, Johansson I, Mkrtchian M S, Andersson TB, Ingelman-Sundberg Lind M C, Olsson M, Schnecke V, Skrtic S, Cabrera Raedle M, Friedemann J, Heinrich R, Shulhevich Y, William-Olsson L, Pill J, Schock-Kusch D Segerstolpe Å, Palasantza A, Eliasson P, Andersson Palasantza A, Eliasson P, Segerstolpe Å, A, AC, Sun X, Picelli S, Sabirsh EM, Andréasson M, MK, Smith DM, Kasper Clausen M, Bjursell R Ämmälä C, Sandberg Ma Q, Sultana N, Hadas LY, Zangi L, Oliveira MS, Ye Chepurko E, Später D, Zhou B, Chew WL, Ebina Y, Chien KR Q-D, Pu WT, Abrial M, Wang W, J Doak BC, Over B, Kihlberg Matsson P, J, Lundstedt A, JornerPapadakis R, Li H, Bergman A, Zietz B, R, Haldar S, Jahn B, Denisova K, Ayub Leifer K, Ottosson H H, Lindh R, Sanyal B, Grennberg L, Capdevila M, Casani L, Varela Gutierrez G, Vilahur Carlsson L, Hidalgo A, F, A, Pons-Lladó G, Carreras Badimon L Said Stålsmeden A, Johansson, JR, Beke-Somfai T, Kann N Doak BC, C, Artursson P, Tyrchan Over B, Matsson P, Foley MA, Hilgendorf C, Johnston S, Lee MD, Lewis Muncipinto G, Perry M, Duvall JR, P, RJ, McCarren J Kihlberg Marx U, Andersson TB, Bahinski A, Beilmann M, Beken S, Cassee FR, Cirit M, Daneshian M, O, Gaertner C, Giese C, GriffithFitzpatrick S, Frey J, de Jong WH, Heringa MB, Hoeng L, Hartung T, Kojima H, Kuehnl J, Leist M, Luch A, Maschmeyer Tagle T, D, Sips AJ, Steger-Hartmann I, Sakharov S, van de Stolpe A, Tsyb T, A, Tralau DA, Tonevitsky J, Wiest J, Rodenburg Wang P, R, Vulto Vandebriel M, Roth A G, Diczfalusy U, Hayes MA, Li XQ, Gronberg Andersson TB Boucher J, Softic S, El Ouaamari A, Krumpoch MT, Kahn CR Kleinridders A, Kulkarni RN, O'Neill BT, Delivering our pipeline through scientific leadership 31

Title Purinergic signaling in kidney disease Purinergic ChemicalTherapeutic Potential of Foldamers: From Drug Candidates? To Biology Tools Regeneration for Cardiac Phenotypic Screen Activity in HumanIdentifies Molecules with Differential Fibroblasts Cells versus Cardiac Epicardium-Derived of cellular microRNA Massive rearrangements drivers of hepatocyte key are signatures dedifferentiation HbA1c variablesContemporary risk estimates of three following diagnosis of type 2 to heart failure in relation diabetes kinetic model for the transcutaneousImproved of glomerular filtration rate inmeasurement experimental animals Single-Cell Transcriptome Profiling of Human Profiling Single-Cell Transcriptome 2 Diabetes and Type Islets in Health Pancreatic Drives EpicardialAn IGF1R-Dependent Pathway Injury After Myocardial Adipose Tissue Formation rule of 5 Cell permeability beyond the photochemical silylations and transferMetal-free and of benzenoid hydrocarbons hydrogenations graphene Injury on Myocardial Effects of Protective After Infarction Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications Structural and conformational determinants of cell permeability macrocycle system microphysiological Biology-inspired dilemma of to solve the prediction approaches substance testing ofCYP3A specifically catalyzes 1β-hydroxylation deoxycholic acid: Characterization and enzymatic synthesis of a potential novel urinary biomarker for CYP3A activity Roles of Insulin and IGF-1 ReceptorsDifferential in Adipose Tissue Development and Function Publication Cell Metabolism Kidney International Kidney Medicinal of Journal Chemistry Chemical Biology ACS Hepatology Heart International Kidney Circulation Drug Delivery Advanced Reviews Communications Nature Circulation Chemical Reviews Chemical Biology Nature ALTEX Drug Metabolism and Disposition Diabetes Key publications in 2016 in publications Key . Journal of Clinical Clinical of Journal Messenger RNA Professor Pernille B. Lærkagaard Lærkagaard B. Pernille Professor Hansen Professor Pernille B. Lærkagaard Hansen joined AstraZeneca in 2016 as Head of Bioscience Chronic Kidney Disease (CKD) IMED CVMD, where she is responsible for driving the early science strategy for delivering new targets to stop progression of CKD and lead the She discipline. kidney bioscience was recruited from her position as Professor and Deputy Department Head of Cardiovascular and Renal Research at the University of Denmark. Southern Professor Hansen brings over 20 years ofexperience in studying the kidney and has worked in cardiovascular- translational, the renal area for almost ten years prioritising use of human material, kidney and blood vessels in experimental settings. She holds a PhD in physiology from the University of Southern Denmark and has previously held positions as post doc at the National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), USA and Associate Professor at the University of Southern Denmark. Her scientific reputation includes over peer-reviewed 75 publications including Investigation, Proceedings of the National Academy of Sciences and ResearchCirculation Professor Hansen’s expertise is a crucial part of the research for IMED CVMD as her capability completes the three-pronged disease area focus of IMED CVMD; heart failure, diabetes and chronic kidney disease. Furthermore her interest and focus on cardiovascular and renal diseases as well as vascular and renal effects during diabetes underlines the value she brings to IMED CVMD. This recruitment has been a major focusin 2016. Recruiting and retaining world- class talent is fundamental to the dedication creativity, innovation, and execution-focus that will enable CVMD to become industry leaders. People spotlight

We have also have We achieved several our through entries pipeline new Pharmaceuticals Ionis with collaboration whichprovides uswithcomplementary a toolbox of antisense oligonucleotides addressto targets unsuitable for small molecule drugdiscovery. These results exemplify our model of collaboration and externalisation and reflect our ability chooseto and partner successfully with worldleaders access to and create value from novel technology. Therapy area progress and Cardiovascular Diseases Metabolic In IMED successfully have we CVMD, built on our small molecule pipeline withthrough targets2016 pursued using new modalities of modified mRNA and oligonucleotides. antisense One of our promising candidates is AZD8601, our modified VEGF-A mRNA, which is designed provide to a unique regenerative treatment option for patients with heart failure or after a heart attack, as well as for diabetic wound healing and other ischaemic vascular diseases. presentedWe exciting data at the American Heart Association (AHA) Scientific Sessions demonstrating2016, that at one week post Myocardial Infarction (MI) a single occasion injection of AZD8601 markedly improves cardiac function in a validate large animal model, suggesting feasibility of partially reversing cardiac dysfunction in patients post MI. This year gained we approval progressto AZD8601 into clinical trials. Progressing the clinical building pipeline and Progressing science modalities new for evidence 30 IMED Annual Review 2016 Introduction Therapy area progress Cardiovascular and We are now strengthening Metabolic Diseases a patient-centric approach aimed at better understanding the interplay and potential causal relationship between these diseases.” Strengthening presence and commitment to fight chronic kidney disease Therapy area progress area Therapy CVMD pipeline

Pre-clinical

AZD8233 / undisclosed

million people globally are fighting chronic 200kidney disease. Phase I AZD5718 / FLAP AZD4831 / MPO AZD8601 / VEGF-A MEDI8111 / rhFII IMED functions

Phase II

AZD4076 / miR 103/107

Phase III / LCM

Stem cell-derived kidney ticagrelor / P2Y12 organoid stained with kidney markers WT1 dapagliflozin / SGLT2 and NPHS1 saxagliptin / DPP4

This year has been an exciting year of Collaborating for success role in the initiation and progression of We are committed to the fight against exenatide / GLP1 progress and transformation for our glomerular disease and may be a novel heart failure, diabetes and CKD and ZS-9 / Potassium exchanger In parallel with our strong in-house

early CKD research. An important treatment target for drug development. excited by the progression we have innovation science for Collaborating science, we expanded our collaboration roxadustat / HIF milestone was the recruitment of the made in 2016. Our emerging portfolio with the University of Michigan by Building our capabilities with Head of Bioscience CKD, Professor is being enhanced with novel targets epanova /omega-3-carboxylic acids joining the Renal Pre-Competitive cutting edge science Pernille B. Lærkagaard Hansen - the leveraging our small molecule as well Consortium (RPC2), giving us access to experience, expertise and enthusiasm The development of physiologically as new modalities approaches. We Pipeline correct as of Q4 2016, a world-leading clinical and molecular that Professor Hansen brings to the relevant cellular models look forward to seeing our current not including MedImmune programmes. database of CKD patients. RPC2 is a department has helped establish a new with translatability to human programmes progress and hope to unique industry-academia collaboration path forward to enable delivery of the pathophysiology is critical for the see our vision realised to halt, slow or focusing on the use of patient-derived medicines for tomorrow. identification and validation of novel reverse the progression of disease in data to understand molecular pathways, therapeutic targets. Working closely patients in the future. Every member CKD is a critical global healthcare issue targets and networks in CKD with with our colleagues in Discovery of IMED CVMD can be proud of our with increasing prevalence, affecting diabetes complications; integrate clinical Sciences, we have pushed the achievements in particular where more than 200 million people worldwide. and histopathological data with large boundaries of science to establish a we lead the way venturing into new There are currently no treatments to stop scale genomic data; and to openly share kidney organoid model system utilising scientific areas. or reverse deterioration without kidney data with other consortium partners. CRISPR/Cas9 in induced pluripotent transplantation, and so CKD represents thrives science where environment An We believe that the knowledge stem cells (iPSCs). These organoids a large and growing unmet medical generated in the consortium will lead show expression of key markers of need. In IMED CVMD we are focusing to the strengthening of the level of kidney biology, including renal cortical on the drugs of tomorrow aimed to slow human target validation in our portfolio, structures with microvilli, tight junctions the disease progression and further our with potential targets already identified and podocyte foot processes. This progress towards the drugs of the future for our early CVMD pipeline. The first development of human nephron-like where we aim to stop or even reverse deliverable from the consortium was structures in vitro fills a major gap the disease. Key to realising these goals presented at the American Society for in assessing effectiveness of CKD- will be Professor Hansen, her team and Nephrology (ASN) Kidney Week 2016, treatments as well as the possibility the strong collaboration between our and showed the identification of an of clinical translations. Details of the core functions to deliver the innovation, intrarenal transcriptomics biosignature model were presented at ASN Kidney patient insight and technology required. for mesangial cells, which play a critical Week 2016.

32 IMED Annual Review 2016 Delivering our pipeline through scientific leadership 33 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

10. University of Oslo, Norway a five-year entered The University of Oslo has AstraZeneca in the area with agreement research of the agreement, of type 2 diabetes. As part at the university will work from four researchers laboratories in Sweden on joint AstraZeneca’s in adipose biology. topics of interest Delivering our pipeline through scientific leadership 35

8 A collaboration with Prof. Winston Shim onA collaboration with Prof. stem cell–Derivedhuman induced pluripotent for disease modeling with thecardiomyocytes in that play a role aim to characterize mutations Ejection Fraction. with preserved Heart Failure modalities we will use different Additionally, to reverseincluding CRISPR methodologies “patient-in-a-dish” model. deficits in this innovative 8. Singapore National Heart Center, 9. Institutet, Sweden Karolinska Professor Berggrens’s group at the Karolinska at the Karolinska group Berggrens’s Professor Institutet (KI) has established an in vivo translational validation platform in which mouse transplanted into islets are or human pancreatic the anterior chamber of the eye of mice, where they become vascularized and innervated, and Diabetes blood glucose. IMED CVMD control has started a 3 year collaboration with Professor to discover and validate novel islet Berggren this platform. using targets 7. santé et de la Institut national de la médicale (INSERM), France recherche collaboration initiated in 2015. year A three is to advance The aim of the collaboration 2 diabetes and CKD understanding of Type based on this and develop new treatments with Professor knowledge. The collaboration better understanding Fréderic Jaisser aims at corticoid receptor the complexities of mineral for CKD. The activity as a potential treatment to further research collaboration is pursuing pathways leading evaluate the MR mediated with damage. The collaboration to organ explores Dominique Langin currently Professor adipose tissue pharmacological ways to prevent to normalise of lipid into the circulation, release sensitivity in insulin fat deposition and increase with collaboration peripheral tissues. The third Dr Raphael Scharfmann is working to develop models of human β-cells which have lost their insulin, to better and release ability to produce it understand the biology of this effect and how treatment. through can be corrected 9 2

1 10 7 of cardiovascular, metabolic and renal diseases diseases metabolic and renal of cardiovascular, in the alliance first project The as well as cancer. clinical development. A Phase has entered tolerability and pharmacodynamic I safety, patients in Europe enrolling study is currently mRNA-based for AZD8601, an investigational by AstraZeneca that therapy being developed encodes for VEGF-A. 5. Moderna US Therapeutics, to discover and An alliance initiated in 2013 for the treatment develop mRNA therapeutics 6. University of Michigan, US Kretzler Matthias A collaboration with Professor that will tackle the validation of novel therapeutic identification the CKD, of treatment the for targets of biomarkers to guide clinical development and the selection of translational animal models for this collaboration Through research. pre-clinical AstraZeneca has access to a world-leading data and animal transcriptomic patient intrarenal models which allows us to better correlate with molecular drivers of CKD that our targets could ultimately lead to potential new therapies. validation data package Deliveries: human target decisions on supporting for all portfolio projects, and animal models selection. progression project 5 3 6 1 1 4. IONIS Pharmaceuticals, US A strategic collaboration to discover and develop antisense oligonucleotide (ASO) therapies for diseases. renal metabolic and cardiovascular, AstraZeneca and IONIS also continue their delivery collaboration to discover new targeted disease relevant to access more approaches tissues for oligonucleotide therapeutics. 3. US Stem Cell Institute, Harvard Doug Melton’s A collaboration with Professor the novel finding that progress to group functional human beta cells can be generated better aiming at are stem cells. We from understanding how the function of beta cells regenerative declines in diabetes, and to find drugs using inducible pluripotent stem cells. The focus is mainly on three strategic The focus is mainly on three and metabolism themes: heart failure, research Christer Betsholtz, a world CKD. Professor outstanding scientific leading scientist with an appointed as the new has been track record, IMED and Chief Scientist, the centre for director a position at the CVMD, while maintaining University of Uppsala. 4

Therapy area progress and Cardiovascular Diseases Metabolic 2. (ICMC), Metabolic Centre Integrated Cardio Sweden Institute,In 2013 AstraZeneca with Karolinska Stockholm, Sweden established a unique joint and metabolic on cardiovascular for research centre diseases. The uniqueness of this collaboration Institute are Karolinska is that the scientists from working side-by-side with AstraZeneca scientists within to identify and validate novel targets and metabolic diseases.cardiovascular In 2016, AstraZeneca joined a two-year a two-year In 2016, AstraZeneca joined Pre-Competitive collaboration with the Renal a personalised Consortium (RPC2) to foster this in CKD. Through medicine approach has access to collaboration AstraZeneca 1. Consortium Renal Pre-Competitive Eli Lilly and (University of Michigan, US and Denmark Novo Nordisk), of patient intrarenal a world-leading source the transcriptomic data to advance drivers of CKD understanding of molecular Deliveries: targets. and identify novel therapeutic with first-in class potential; novel targets and for patient stratification novel approach personalised medicine. A selection of key collaborations in 2016 in collaborations of key A selection 34 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Delivering our pipeline through scientific leadership 37 Delivering our pipeline through scientific leadership 37 science, with a number of high impact and high impact of high withscience, a number to continue was in 2016 Our challenge papers. quality reduction withto do this a significant change, amidst of IMED and integration and resources in overall unit. development into a single teams MedImmune to this therapy approach our innovative However, and portfolio together with a competitive area, that has meant neuroscience talent, world-class to thrive.” continues Iain Chessell, VP IMED Neuroscience Iain Chessell, VP IMED

“2016 has been both challenging and rewarding – both has been “2016 and rewarding challenging with our progress great made have we of our progression seeing significant pipeline, with pain therapies, and neurodegeneration anti-amyloid our studies for of patient completion of our beta progress continued Aß42 antibody, in compound (BACE) enzyme cleaving secretase and theand Company, with Eli Lilly collaboration in our Phase I study from data of first emergence top-class of delivery also continued have pain. We

Neurons in the brain Neurons Therapy area progress Neuroscience 36 IMED Annual Review 2016 36 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Phase II Phase III / LCM Pre-clinical Phase I Pipeline correct as of Q4 2016. as of Q4 2016. Pipeline correct AZD3293 / BACE Neuroscience pipeline MEDI1341 / α-synuclein MEDI0168 / PAR2 Aβ42 MEDI1814 / MEDI7352 / NGF / TNF AZD3241 / MPO Brain scan Delivering our pipeline through scientific leadership 39

exciting opportunity to test the amyloid hypothesis in a whole new way. Our Phase I study completed in 2016 and findings demonstrate preliminary promising with botha compelling safety profile intravenous (IV) and subcutaneous of administration being well(SC) routes was linear and predictable tolerated. There serum pharmacokinetics and clear evidence of dose-dependent central target engagement as well as selectivity for Aβ42 fluid (CSF). vs Aβ40 in cerebrospinal of this best enable the progression To pleased to haveexciting candidate, we are with Lilly a worldwide agreement entered to co-develop MEDI1814. This extends our collaboration on BACE productive already which combines the expertise of our two passion tocompanies but also our shared bring new medicines to patients suffering debilitating illness. this from Alzheimer’s disease is a devastating, Alzheimer’s that affects more condition progressive than 44 million people and their families the globe and, despite continuing around no disease modifying are efforts, there available. therapies currently disease is characterised Alzheimer’s by amyloid plaques found in the brain made up of amyloid beta (Aβ) which are peptides; Aβ40 is the most abundant, toxic. The leading but Aβ42 is more hypothesis in the field is that cognitive bydriven is disease Alzheimer’s in decline of Aβ42- seeded oligomers the presence in the brain. MEDI1814 is a high affinity monoclonal Aβ42 antibody that specifically targets in the brain without affecting Aβ40. This with selectivity is unique compared antibodies that have other Aβ targeted an been studied to date and represents Aß42 specific antibody in development for development in Aß42 specific antibody Alzheimer’s disease Promising Phase I data for MEDI1814, the MEDI1814, only for Phase I data Promising The consistent high quality of our science has led a strong to portfolio with some assets. desirable and valuable highly These the have potential provide to the next of revenue wave generation for AstraZeneca as well as transform to the lives of patients living with devastating chronicdiseases, neurodegenerative pain and psychiatric conditions.

Our business model thrives on being dynamic and partly externalised, with a laser-like focus driving science within our areas key of interest. Early, flexible partnering with the brightest and best in the world allows us combine to clinical progress and knowledge development as well as share the high with associated costs high and risks neuroscience research. An example is our ongoing collaboration with Eli Lilly and Company (Lilly) which led a Phase to III investment decision for AZD3293, our oral potent small molecule beta secretase clearing enzymes (BACE) inhibitor. As a result, two have we Phase III trials running simultaneously and are we poised potentially to be one of the firstto launch a disease modifying treatment for Alzheimer’s disease in the future.

Many of the team are now based at our Cambridge site and includes a concentrated organisation of world class scientists. Our approach is to build on this in the coming years by hand-picking high quality scientists jointo our unique working environment we where US, both inthe the UK and retain a smaller footprint. It is an exciting time be to working progress more with neuroscience, in mechanism research disease basic in in the years last 10 than the previous 50. Being a small, focused group allows us behave to in an agile reacting way: breakingto science as it happens. As an example, as data accumulated linking alpha-synuclein spreading to Parkinson’s disease were we able to react in real-time, initiating a programme developto a monoclonal antibody targeting the protein. Therapy area progress Neuroscience 38 IMED Annual Review 2016

to deliver firstmedicines. in class deliver to within the IMED Biotech Unit which makes us well placed makes placed uswithin well which Unit the IMED Biotech MedImmune Neuroscience into a single, focused function focused a single, into MedImmune Neuroscience year we have restructured our organisation to incorporate incorporate restructured to have we year organisation our diseases, chronic pain and psychiatric conditions. This pain conditions. chronic psychiatric and diseases, changing medicines to patients with neurodegenerative with neurodegenerative patients to changing medicines neuroscience with ongoing investment to deliver life- deliver to investment with ongoing neuroscience AstraZeneca has made a long-term commitment to to commitment AstraZeneca a long-term has made Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Fraser Welsh Fraser Fraser Welsh is a Project Director in IMED Neuroscience and is currently leading on the MEDI7352 Phase I clinical study. Fraser has been at Cambridge Antibody MedImmune (CAT), Technology and AstraZeneca years, for 16 initially in antibody engineering and latterly in research project head was he where management of the Cambridge RPM group for two years. He has significant and research the in experience pre-clinical phases of drug development projects and in portfolio management having worked in each of the therapeutic areas over the course of his career. As part of IMED Neuroscience, Fraser’s role is primarily project contributes also he but leadership to the IMED Neuroscience leadership team and provides project and portfolio management needed. supportwhere Prior to joining in July CAT 2000 Fraser obtained a BSc in Chemistry from the University of St Andrews and a PhD in Chemistry from the University of Edinburgh. He had a brief spell as a postdoc with a Biotech company in Leeds before moving yet further south to join CAT. People spotlight

Delivering our pipeline through scientific leadership 41 million people affected by chronic pain across Europe 100 Pre-clinical studies using MEDI7352 Pre-clinical between a synergy have demonstrated in resulting NGF and TNF sequestration effect in modelsa significant analgesic and neuropathic of both inflammatory This of NGF. pain at <20% sequestration means low level sequestration synergistic interfere adversely doesn’t MEDI7352 that and may have awith other NGF actions profile, tolerability and safety different profile as efficacy as well as a different a result. such potential toAs a candidate with impact the millions of people suffering we were pain in the future, with chronic very excited to see MEDI7352 enter the clinic in a Phase I trial at the beginning of 2016.

Neurons in the brain Neurons MEDI7352 brings new hope for chronic pain sufferers chronic for hope brings new MEDI7352 an estimated pain affects Chronic and Europe 100 million people across by thedespite substantial investment over severalpharmaceutical industry progress has been little decades, there and safe efficacious in developing new, analgesic treatments. a key factor (NGF) is Nerve growth and several of inflammatory pain regulator antibody therapiesanti-NGF monoclonal shown promisingin development have levels. at >90% suppression results has been However clinical progression by cases of rapidly progressing hampered beto appears which (RPOA) osteo-arthritis and exacerbated bydose-related anti-inflammatory drugnon-steroid (NSAID) co-administration. MEDI7352 is a first in class, dual action (bispecific) antibody exploiting synergy factorbetween NGF and tumour necrosis alpha (TNF alpha). By binding two different pain, it has the involved in chronic targets potential to work in inflammatory pain, such as in arthritis, but also neuropathic where pain, such as diabetic neuropathy available. currently treatment is no there

s psychiatric research, s psychiatric research, The consistently high quality high The consistently of a strong has to led our science highlywith portfolio some valuable anddesirable assets.” Nature in Nature achieved many high impact and high quality publications including one published We In gene for schizophrenia. the identification of the enzyme AS3MT as a risk Medicine providing protein neuropathogenic known as CCT restricts protein addition, a paper on how the chaperone Communications. via autophagy was published in Nature aggregation We progressed two distinct targets/neural circuits, not regulated by current addiction medicines, by current not regulated circuits, two distinct targets/neural progressed We which is one of relapse prevent of nicotine and critically properties both the rewarding to address the biggest goals of addiction research. is the focus of IMED’ Substance abuse, in particular addiction to nicotine (NIH) and highly successful partnerships with the National Institutes of Health carried out through National Institute of Drug Abuse (NIDA). Clinical data on one of the mechanisms (mGluR2) is expected in early 2017. and academic collaborations, closely aligned and continue to build world-class commercial We and key to our success. of interest focused on our areas in Boston is focused around University Department of Neuroscience Our collaboration with Tufts led by Professor Neuroscience, laboratory for Basic and Translational the AstraZeneca-Tufts to delivering our early portfolio. The contributing of scientists are a group Stephen Moss, where are plasticity and subsequent brain processes we believe neuronal where lab works on projects emphasis. and epilepsies being a current Diseases (MND) disturbed with Motor Neuron Professor also enjoy a close collaboration with the University of Cambridge, working with We to our Maria Spillantini looking at novel mechanisms related David Rubenstein and Professor disease. and Parkinson’s in particular Huntington’s in neurodegeneration, programmes We commenced Phase I trials with our first in class dual action (bispecific) antibody, MEDI7352, dual action (bispecific) antibody, commenced Phase I trials with our first in class We pain. neuropathic which has potential to work in inflammatory and in our work understanding neuro-immune In addition, we have seen significant progression in the right place focusing on accessing the right target interactions and transcriptional regulation clinical development. toward with exciting molecules progressing We began a second Phase III study of AZD3293, our oral potent small molecule BACE inhibitor, in BACE inhibitor, III study of AZD3293, our oral potent small molecule began a second Phase We disease and dementia (DAYBREAK-ALZ). collaboration with Lilly in patients with mild Alzheimer’s FDA fast track designation this year to expedite the development andAZD3293 was also awarded potential therapy. this promising of review Aβ42 specific monoclonal our Phase I study of MEDI1814, our from saw exciting early results We disease patients. In of Alzheimer’s of Aβ42 in the CSF demonstrating selective reduction antibody, with Lilly for this asset that complements we announced a co-development agreement December, our collaboration on AZD3293. alpha-synuclein for toward with our antibody directed making good progress we are Equally, disease, with clinical studies set to start in 2017. Parkinson’s focused on specific disease mechanisms which should provide Earlier in the portfolio we have projects years. disease (MND) in future neuron and motor Parkinson’s opportunities for Alzheimer’s, We delivered We We set out to We Demonstrate our scientific Demonstrate leadership Nurture our collaborations and our collaborations Nurture partnerships Deliver on our commitment Deliver to addiction Progress our chronic pain pipeline our chronic Progress Progress our neurodegenerative our neurodegenerative Progress diseases pipeline Highlights Therapy area progress Neuroscience 40 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Our world-class commercial collaborations academic and aligned and focusedare closely and are our interest areason of key to our success.” Author Li M, Tao R, Jaffe A, Shin J, Wang Y, Chen Q, Li Wang R, Jaffe A, Shin J, Li M, Tao B, Straub R, Brandon N, Maher Ohi T, C, Jia Y, McKay R, H, Hyde T, A, Chenoweth J, Wei Cross D Kleinman J, Weinberger Rannals MD, Merfield Y, Saito A, Taniguchi Sedlak EB, Ballinger MD, Koga M, Ohtani Y, BJ, A, Moss SJ, Brandon NJ Maher Cross TW, Kamiya A M, Thom G, CI, Hatcher J, Burrell Webster I, Chessell IP Gurrell Thornton P, R, Offiah I, Didangelos A, Dawes J, Cartwright Bradbury EJ, O’Sullivan S, Williams Khullar V, Pallas K, Graham G, O’Reilly D, Chessell IP, BA, McMahon SB Delivering our pipeline through scientific leadership 43 Title A human-specific isoform of AS3MT isoform of AS3MT isoform A human-specific isoform factors in the molecular risk and BORCS7 are locus 10q24.32 schizophrenia-associated modulation Early postnatal GABAA receptor maturation in deficits in neuronal reverses model of a conditional neurodevelopmental DISC1 antagonist Enhanced delivery of IL-1 receptor to the central nervous system (CNS) as a novel neuropathic anti-TfR-IL-1RA fusion reverses mechanical hypersensitivity mediators in of inflammatory The expression bladder pain syndrome Publication Nature Medicine Nature Molecular Psychiatry Molecular Pain Urology European Key publications in 2016 publications Key 6. UK UK Dementia Platform, of the AstraZeneca is a key member intent is to further UKDP platform, whose (AD) and Disease understanding of Alzheimer’s experimental other dementias by prosecuting One research. medicine and translational is the industry lead, example, for which AZ phenotyping (DFP) is the deep and frequent of studying the transition we are platform. Here, to mild/ the prodromal Disease from Alzheimer’s biomarkers, moderate stage using biochemical imaging (PET and MRI) as behavioural readouts, which measures well as a range of exploratory will help us understand not only a ‘biomarker fingerprint’ for AD, but may also define endpoints which can be used in progression interventional studies. 7. Eolas Therapeutics and National Institute of Health, US have an exciting collaboration with Eolas We Therapeutics, a biotech start-up which came out of The Scripps Institute in Florida, supported by the NIH Blueprint Neurotherapeutics Network, with the aim to develop medicines for smoking cessation and other indications. The collaboration embraces the externalized and flexible model championed by the AstraZeneca The team have diligently group. Neuroscience identified and characterized a range of and are years chemotypes in the past three now focussing on a lead molecule to bring into clinical development.

7 6 5 2 4 electrophysiological approaches to understand to understand approaches electrophysiological interact with neurones proteins how aggregating to disrupt synaptic communication. These data support candidate investment decisions than standard objective with data that is more cognition models in rodents 5. College, UK King’s Stephen Our collaboration with Prof McMahon at Kings College, aims understanding of the role to increase of inflammatory mediators like nerve growth in pathways factor factor and tumour necrosis The work pain states. contributing to chronic will investigate the potential for additive of interactions as a result effects or synergistic between these and other mediators. These studies will help elucidate the mechanism of existing clinical candidates and potentially to the portfolio. contribute new targets 4. College Dublin and Brigham and Trinity US and Hospital, Ireland Women’s with Trinity Our ongoing collaboration and Women’s College Dublin and Brigham is focussed on Hospital, Cambridge MA, understanding toxic species of aggregating Disease brain in Alzheimer’s present proteins and in vivo using biochemical are samples. We selective for amyloid-beta 42 (Aβ42), which is 42 (Aβ42), which is selective for amyloid-beta in Phase I trials as a potential disease- currently disease. This for Alzheimer’s modifying treatment builds on the existing collaboration agreement AZD3293, a BACE inhibitor in two to related pivotal Phase III trials. 4 1 3

In 2016 we announced a collaboration with Lilly In 2016 we announced a collaboration with Lilly to co-develop MEDI1814, an antibody 3. Eli Lilly & Company (Lilly), US Building on an existing strategic partnership Building on an existing strategic partnership between AstraZeneca, MedImmune and the University of Cambridge in the UK, in late 2014 with leading year collaboration we began a three scientists to advance our understanding and such disorders of neurodegenerative treatment and Huntington’s Alzheimer’s as Parkinson’s, investigators with prominent diseases. Working the collaboration has two key aims: to drive and biomarker identification selection target mediators in the detailed study of key through focussing in on potential the autophagy pathway, understanding starts; to build a greater project synuclein, of alpha of the pathological spread working with our candidate antibody. 2. University of Cambridge, UK 1. US University, Tufts University Our collaboration with Tufts is a true academia- Department of Neuroscience in late industry hybrid. Formed A selection of key collaborations in 2016 in collaborations of key A selection biotech lab to conduct 2013 we established a to drive our early stage portfolio, research and deliver excellent publish high quality data consisted of science. By 2016 our collaboration conducting research 10 postdoctoral scientists – neurodegeneration, areas main in three a with and disorders psychiatric disorders to synaptic plasticity pathology related prevalent such as epilepsy. Therapy area progress Neuroscience 42 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Sustainable growth through innovation 87 Delivering our pipeline through scientific leadership 45 Delivering our pipeline through scientific leadership 45

“We have advanced our portfolio advanced have “We significantlyAZD3759, in 2016. the firstout drug investigational IMEDof Asia, well is progressing trials. BLOOM global in ongoing AZD3759 also gained China category Drug New (IND)1 Investigational approval, a major milestone for us. Our high impact publication Translationalin Science Medicine further enhanced our scientific reputation externally.” IMED Asia Xiaolin Zhang, VP

Cells under a microscope IMED functions IMED Asia 44 IMED Annual Review 2016 44 IMED Annual Review 2016 86 AstraZeneca Annual Review Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Kan Chen Kan Kan Chen joined AstraZeneca as in 2010 part of the DMPK function in Asia. Kan applied his knowledge fromthe CNS Oncology AZD3759 programme to support compound screening and candidate selection ofCNS penetrable candidates for the AZD1390 programme. AZD1390 was approved and progressed to clinical development stage Kanin 2016. established innovative assays to find the candidates to cross the CNS barrier efficiently. more Delivering our pipeline through scientific leadership 47 and +image 2 In collaboration with IMED Oncology we delivered a new candidate AZD1390, as well as four a new candidate In collaboration with IMED Oncology we delivered to our BBB penetrant compounds including one published in Sciencepublications relating Medicine. Translational data on our BBB penetrant molecule AZD3759 was selected for oral For the second year in a row, the invited us to present at ASCO, following which the Society for Neuro-Oncology presentation data at their annual meeting in November. In Oncology, we delivered preliminary data from BLOOM, our Phase I study of AZD3759, showing BLOOM, our Phase I study of data from preliminary we delivered In Oncology, typical of the activity with a tolerability profile encouraging intracranial and extracranial anti-tumour a new candidate AZD1390. also delivered We class of treatment. taking significant steps towards a of our CKD programme, In CVMD we continued progression potential candidate drug. Inflammation and Autoimmunity (RIA), we achieved a high quality publication In Respiratory, ongoing collaboration with the Respiratory Division of Zhongshan Hospital, Shanghai our through demonstrates that IL-13+ type 2 innateInstitute of Respiratory Disease. Our publication in the response. status and treatment with asthma control lymphoid cells correlate Our study data supported the NDA submission of osimertinib and CTP filing of durvalumab testing rates nationwide through T790M and BRCA also significantly increased to CFDA. We In addition, we contributed to biomarker studies in educational programme. a comprehensive osimertinib, AZD3759, olaparib and savolitinib clinical trials, as well as boosting patient access to Asia. gefitinib across We delivered We Li Zheng As one of the kidney disease project bioscience leads, Li Zheng effectively guides vitro in in vivo bio scientists, making a significant contribution to project progression. The team successfully delivered the lead compound’s dose-dependent efficacy for buildingPK- up coverage-efficacy relationship, verified the effect in animals at different disease severities, confirmed target engagement by Ca analysis on insitu podocytes of glomeruli, and finally understood the compound’s working mechanism and differentiation from currently used drug steroid. Li also leads the bioscience team in Asia, collaboratively working with Oncology to successfully deliver the primary pharmacology data package for AZD1390 CDID.

Strengthen our scientific leadership leadership our scientific Strengthen penetrant (BBB) in blood-brain-barrier compounds China Support AstraZeneca with our expertise We set out to We pipeline across the project Progress areas main therapy our three Highlights Renhong Tang Renhong As the project leader of the respiratory virus team, Renhong made Tang a key contribution to the smooth transfer of the project from Infection to the Asiateam. Renhong set up our virology capability from scratch within two months and helped establish our differentiation strategy for AstraZeneca’s replication inhibitors from inhibitors with other modes of action. This was achieved with minimal additional headcount and investment. People spotlight People

Cancer cell We have further have We enhanced our scientific reputation through collaboration with globally, institutions leading inespecially China.” In addition, our Chronic Kidney Disease (CKD) programme, within the Cardiovascular and Metabolic Disease (CVMD) therapy area, has progressed well this year with significant steps towards a potential candidate drug achieved the by project team. an to out-licensed been has *AZD3759 clinical global further party for external development

AZD1390, as well as high impact publications and congress activities. Currently in Phase I clinical trials, inhibitorAZD1390 is an ATM designed to patients glioblastoma of population a treat through optimised delivery of drug to the brain. Another highlight key was the promising data from BLOOM studies for whichAZD3759*, was selected for oral presentation at the American Society of Clinical Oncology (ASCO) as well as the Society for Neuro-Oncology (SNO) annual meeting. AZD3759 was discovered by IMED Asia and is a novel epidermal growth factor receptor (EGFR) mutation positive inhibitor treat to non-small cell lung cancer (NSCLC) with central nervous system metastases. These preliminary findings showed encouraging intracranial and extracranial anti-tumour activity with a tolerability profile typical of the class treatment. of

in China. in This year seen have we significant across progression pipeline AstraZeneca’s three main therapy areas. In Oncology, continued have we strengthento our scientific leadership in blood-brain-barrier (BBB) penetrant compounds with a new candidate

We have supported have We our business in China deliveringby data support to New Drug Application (NDA) and Clinical Trials Permission (CTP) submissions the to China as (CFDA), well FDA as biomarker across trials support clinical to studies the portfolio. also have We continued to work with centres across Asia drive to testing uptake and thus increase patients’ access novel to therapies. In addition, further have we enhanced our scientific with collaboration through reputation especially globally, institutions leading prevalent in this part theprevalent world. of drugs for the treatment of diseases that are diseases most of the treatment drugs for with global teams to actively explore new potential new explore actively teams to with global During 2016, we have continued to work closely closely work to continued have we During 2016, to innovative medicines across China Asia. and across medicines innovative to The aim of IMED Asia is to accelerate patient access patient The aim IMED of accelerate Asia to is IMED functions IMED Asia 46 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Molecular structure trainees from China, Hong Kong, Korea and Vietnam market teams 600 Delivering our pipeline through scientific leadership 49 AZD3759 has been out-licensed to an external party for further global clinical development All patients were treated with AZD3759 treated All patients were in escalating dose cohorts and the pharmacokinetic analysis demonstrated excellent encouraging central nervous system (CNS) penetration, with a ratio of fluid (CSF) and 1:1 between cerebrospinal tolerabilityThe concentrations. plasma free consistent with EGFR TKI class was profile effects (primarily skin rash and diarrhoea) CNS adverse eventsand no drug-related reported. were Encouraging intracranial and extracranial anti-tumour activity was observed with The BLOOM studyAZD3759 treatment. of BM and LMhas completed enrolment patients for AZD3759 and the majority still ongoing with medianof patients are than six months.follow up time greater *

tyrosine-kinase inhibitor (TKI) and tyrosine-kinase This first time chemotherapy. in man study aims to determine the maximal tolerated dose and/or Phase II dose as well recommended efficacy. as preliminary AZD3759* is the first investigational drug by IMED Asia. It is a blood- discovered brain-barrier (BBB) penetrant EGFR ofinhibitor evaluated for the treatment NSCLC with brain metastasis (BM) and leptomeningeal metastasis (LM) which has shown anti-tumour activity in pre-clinical BM and LM models. excited to present This year we were BLOOM, data from preliminary promising at ASCO and our ongoing Phase I study, subsequently at the SNO annual meeting the Society forfollowing an invitation from Neuro-Oncology. BLOOM is an open label, multi-centre study to assess safety and tolerability of AZD3759 in patients with EGFRm+ with EGFR NSCLC who progressed Promising preliminary AZD3759 presented for results American andat Clinical Society (ASCO) of Oncology Neuro-Oncology (SNO) Society for We contributed to the to contributed We T790M of uptake accelerated testing across and BRCA China technical providing by training workshops, seminar education and lab evaluation willwhich patient increase osimertinib to access and olaparib in China.” Our leading scientific reputation hasreputation Our leading scientific by 13 high qualitybeen demonstrated one in including publications this year, which Medicine Science Translational and early clinicaldescribes the discovery also continue We development of AZD3759. with leadingto establish collaborations of our PhD expansion institutions through well as two as and graduate programme being appointed asof our senior scientists University at the Tongji adjunct Professors School of Medicine. also supported CTP filing to the CFDA foralso supported CTP NSCLC bydurvalumab in 1L/3L/adjuvant study ofprevalence completing a PD-L1 NSCLC patients in China. uptake contributed to the accelerated We China testing across of T790M and BRCA workshops, technical training by providing lab evaluationseminar education and to patient access which will increase in China. We osimertinib and olaparib for 30 training sessions also provided EGFR mutation testing, involving over 600 China, Hong Kong, Korea trainees from over the last seven years. Thisand Vietnam EGFRmcontinuous effort has increased 0% to 60% and hadtesting rates from a significant impact for NSCLC patients’ access to gefitinib. Supporting business growth in China and across Asia across in China and Supporting growth business Our science unit in China is closelyOur science unit in China study teams, theengaged with global Company, AstraZeneca China Marketing and GlobalGlobal Medical Affairs to supportMedicines Development Asia. Our in China and business growth scientific/technical is to provide remit science datasupport and translational AstraZeneca’s packages to advance in China and Asia.pipeline and portfolio to the the team contributed This year, successful NDA filing submission of osimertinib to the China Food and Drug Administration (CFDA) in August 2016 by leading a study evaluating T790M tumour DNA (ctDNA) testing ascirculating We a potential patient selection biomarker. IMED functions AsiaIMED 48 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 51 Phospholipid particles We also continue to establish to also continue We collaborations with leading institutions through expansion our PhD and graduate of programme as well as two being scientists our senior of Professors as adjunct appointed School University the Tongji at of Medicine.”

9. ZhongshanRespiratory Division of of RespiratoryHospital, Shanghai Institute Disease, China with the RespiratoryOur ongoing collaboration InstituteShanghai Hospital, Zhongshan of Division IL-13+ typeof Respiratory Disease demonstrates with asthma 2 innate lymphoid cells correlate which response, and treatment status control American Journalhas been published in the of Biology. Respiratory Cell and Molecular 10. China Hospital, Sichuan West China University, China Hospital, Our collaboration with West Sichuan University began in June 2014, and investigates the distribution of both somatic and germline BRCA1 and BRCA2 variants in Chinese cancer patients. breast 4 9 3 6. China Chongqing Medical University, formed a collaboration with the Children’s We University to hospital of Chongqing Medical of otherwise study the clinical characteristics old) naturally infected healthy infants (0-2 years virus. by a respiratory 7. College Peking Union Medical Hospital, China have been working together with Peking We Hospital to explore Union Medical College molecular mechanism of central nervous system (CNS) metastasis, including leptomeningeal metastasis and brain metastasis, in EGFR mutation positive NSCLC patients by whole exosome sequencing. 8. Shandong Cancer Hospital, China isHospital Cancer Shandong with collaboration Our withto study the effect of EGFR TKI in combination radiation on lung cancer and/or lung cancer brain mechanism. the potential metastasis and explore 5 7 2 6 8 1 10

5. Institute Pasteur of Shanghai, Chinese Academy of Sciences, China collaborated to characterise the anti-viral We effect of small molecule compound in animal virus. models infected with a respiratory novel compound can significantly AstraZeneca’s thus its viral load in infected mice, reduce the first in vivo efficacy data for this provided virus research. working mechanism in respiratory Our collaboration with the Shanghai Chest Shanghai Chest Our collaboration with the 2013 and investigates Hospital began in May mutations in Chinese plasma testing of EGFR highly sensitive NSCLC patients using the PCR. digital droplet 4. China Zhejiang Cancer Hospital, have been working together to explore We of leptomeningeal the underlying mechanisms paper, joint A patients. NSCLC in (LM) metastasis ‘Exploration of the underlying mechanisms of leptomeningeal metastasis in NSCLC patients (NGS) of next generation sequencing through World at the was presented fluid’, cerebrospinal on Lung Cancer 2016. Conference 3. China Shanghai Chest Hospital, IMED functions AsiaIMED We have been working with the Shanghai have been working with the Shanghai We Lung hospital since May 2013 to investigate: plasma testing of EGFR mutations in Chinese of first mechanisms NSCLC patients, resistance generation EGFR-TKI therapy and resistance generation mechanisms to osimertinib (third EGFR-TKI). 2. Shanghai Lung hospital, China Since November 2010, IMED Asia has beenSince November 2010, IMED University onworking together with Peking including: applying a number of key projects to study calciumadvanced imaging technologies in normal and disease dynamics and their role exploring the molecular pathophysiology, transporters and theirmechanisms of phosphate insulin an diseases and targeting in human roles with neutralising antibody for signalling regulator sensitivity. insulin reverse 1. Medicine, PekingInstitute of Molecular China University, A selection of key collaborations in 2016 in collaborations of key A selection 50 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Sun L, Qing Y, Yang Z, Ding J, Tan L, He L, L, He L, Tan Z, Ding J, Yang Sun L, Qing Y, C Wan Sun Y, M, Zhong W, Chen X, Xu Y, Zhao J, Ye M Wang Z, Zhu G, Gu Y, Yang Yang Z, Kim DW, Yang JW, Yates P, Ballard A, Hickey JC, Cantarini M, Pickup K, Jordan K, Varnäs M, Grist M, Box M, Johnström P, D Cross PA, KS, Jänne Malmquist J, Thress Zhang L, Chen K, Y, Z, Guo Q, Wang Yang S, Jiang Rabbie X, Bai Y, Yin Cheng Z, Xu Y, JC, Zhang X H, Ahn M, Kim D, Yang J, Hammar N, Zhang L, Wei Gao W, Dong Y, Qiao Q X, C, Wu Cabrera J Chen M, Wei Chen Y, Ji Y, K, Feuers R, Hong H J, Tang H, Wei Ye Author Delivering our pipeline through scientific leadership 53 profiling of extended major major of extended profiling Gene expression (xMHC) region histocompatability complex candidate genes in schizophrenia nine reveals fluid in cerebrospinal EGFR mutation status patients who of non-small cell lung cancer system metastases developed central nervous after EGFR-TKI treatment with Comparison of Osimertinib Pre-clinical Other EGFR-TKIs in EGFR-Mutant non-small cell lung cancer Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. AZD3759, a blood-brain-barrier-penetrating of EGFR EGFR inhibitor for the treatment mutant non-small cell lung cancer with central nervous system metastases metabolic to Patient characteristics related complications in type 2 and chronic disorders diabetes mellitus patients hospitalized at the Qingdao Endocrine and Diabetes Hospital from 2006 to 2012 in China the isoforms across Analysis of cancer-specific cancer genome atlas tumor types: potential disease linkages network through Drug repositioning pharmacology Title Publication Journal of Clinical Journal Psychiatry Cancer Chemotherapy Cancer Chemotherapy and Pharmacology Clinical Cancer Research Science Translational Medicine and Vascular Diabetes Disease Research of Translational Journal Science Medicinal in Topics Current Chemistry Zhong X, Dong Z, Dong H, Li J, Peng Z, Deng Zhong X, Dong Z, Dong H, Li J, Peng Z, Deng Su X, Zhang L, Lu X, Shen F, L, Zhu X, Sun Y, Zheng H Gu Y, Aoki D, Jinno H, Nomura H, Kataoka F, H, C, Wombwell Womack Sato Y, Kitagawa Y, X C, Yin Hodgson D, O'Connor M, Harbron J, Gao W Wei Chen Y, Fang X, Zhu X, Bai C, Zhu L, Jin M, Jia Y, R, Chen Z X, Hu M, Tang Wang Peng Z, Wei J, Lv X, Zheng H, Zhong X, Gao J, Lv X, Zheng H, Zhong X, Gao Peng Z, Wei Jing J Chen Y, W, J Liu Q, Wei Y, H, Zhang X, Chen Ye J, Lv X, Zheng H, Zhong X, Gao Peng Z, Wei Jing J Chen Y, W, Z J, Wen Wei Ouyang W, Gao W, Li X, Chen Y, Hu N, Li K, Wang Z, Tang W Z, Tang Hu N, Li K, Wang Z Huang L, Wang Y, Z, Sun X, Bai H, Wang X, Zhuo M, Ye Yang J M, Wang Duan J, Wu Zhao J, An T, J, Liu Q Ma Q, Wei Y, Chen Zhang W, Sun Y, Chen M, Zhu F, Wang Xu D, Zhang M, Xie Y, J KQ, Wei Ni JY, Wang MZ, Sun Y, X, Zhang Zheng D, Ye L, Zhang L, Luo J, Zhang J, Tang J, Zhang HP, Xu JF Su B, Chen G, Zhu G, Gu Y, X, Gavine PR, Phillips J, Wang Chen H, Tucker Steinbacher S, P, C, Augustin MA, Schreiner M, Ogg D Preston Author Prevalence and Prognostic Role of and Prognostic Prevalence in Unselected Chinese Breast BRCA1/2Variants Cancer Patients of potential biomarkers associated Expression in repair with homologous recombination patients with ovarian or triple-negative breast cancer Clinical characteristics and antimicrobial patterns in complicated intra-abdominal infections: a 6-year epidemiological study in southern China Cells Correlate 2 Innate Lymphoid IL-13+ Type Status And Treatment With Asthma Control Response Differences in diagnosis, treatment patterns in diagnosis, treatment and Differences outcomes between rural and urban patients 2005 to 2009 diagnosed from Ranking novel cancer driving synthetic lethal gene pairs using The Cancer Genome Atlas (TCGA) data and survival patterns of female Treatment cancer Chinese patients diagnosed with breast between 2005 and 2009 in Southwest China Epidemiology and Outcomes of Complicated Skin and Soft Tissue Infections among 2008 to 2013 Inpatients in Southern China from DTMiner: Identification of potential disease DTMiner: Identification of potential disease mining biomedical literature through targets tumour DNA Plasma EGFR T790M circulating (ctDNA) status is associated with clinical outcome in advanced non-small cell lung EGFR-TKI cancer patients with acquired resistance Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical site kinase hinge ATP-binding Synthesis of chiral 1, 4- Benzodioxanes and Benzodioxanes and Synthesis of chiral 1, 4- by enantioselective palladium - chromans reactions catalyzed alkene Aryloxyarylation Rhodium-Catalyzed Highly Enantioselective to Simple Aryl Addition of Arylboroxines of Escitalopram Ketones: Efficient Synthesis alleles in circulating Quantification of mutant survival in lung cancer tumor DNA can predict related Identifying anti-cancer drug response genes using an integrative analysis of transcriptomic and genomic variations with cell line-based drug perturbations Title Publication Angewandte Chemie Chemie Angewandte Edition International American Journal of American Journal Cell and Respiratory Biology Molecular International Journal Of Journal International Agents Antimicrobial Cancer Biomarkers PLoS One PLoS One Medicine Oncotarget Oncotarget Acta Crystallographica Crystallographica Acta Section D Scientific Reports Scientific Bioinformatics Oncotarget Oncotarget Angewandte Chemie Chemie Angewandte Edition International Key publications in 2016 publications Key IMED functions AsiaIMED 52 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

ultivating a porous scientific culture NiCoLA-B will be deployed into our ground- breaking collaborative laboratory, the UK Centre for Lead Discovery, based in our new research facility in Cambridge. areWe making NiCoLA-B available our to research partners through Open Innovation – our pioneering initiative for sharing compounds, technology and expertise with academic and industry collaborators. The first research partners work to with NiCoLA-B are Cancer Research UK and the Medical Research Council. By combining our expertise, we Enabling drug discovery of the future NiCoLA-B generates and processes large amounts of data, performing science on a scale, timeframe, complexity, precision and consistency not possible before. Each year the combined group of robots will test around 40 million chemicals, investigating 40 50 to diseases and ultimately identifying the best potential molecules as starting points for future development. medicine Drug discovery is changing, using more disease more and models disease complex relevant cell assays – the modularity and flexibility of NiCoLA-B allows to us align and evolve this to work. C are accelerating medicines research for the treatment of diseases with substantial needs. unmet Historically, assays were were assays Historically, the to what robot moulded with NiCoLA-B do. Now, could the to configure it is possible the what match to technology the science wants researcher drug to do; helping make and faster, smarter, discovery to work cheaper. Designed quickly times more three drug discovery than previous is also more NiCoLA-B robots, and flexible scientist-friendly, responsive. .” DeliveringDelivering our our pipeline pipeline through through scientific scientific leadershipleadership 55 55

, Biosolutions HighRes NiCoLA-B delivers a new way a new delivers NiCoLA-B of working, reduing costs and transforming our ability to that could molecules identify new become medicines of the future Paul Harper, Associate Principal Scientist - Screening Sciences, IMED Biotech Unit out-of-hours operation. out-of-hours AstraZeneca is entering a is entering AstraZeneca of drug discovery era new theby most advanced unveiling in the world. robots screening on drew Our scientists working decades of experience robots with first-generation partnership and, through with a bespoke co-developed to the delicate suited system and human manoeuvres needed in drug interactions discovery. profile Technology The main robot system is called ”CoLAB” (for collaborative laboratory) and the plug-in component carts are called “CoLAB Flex” (for collaborative and flexible deployment). The system can operate as a whole perform to highly complex biological experiments, or be separated perform to simpler experiments. This mitigates the issue with older systems where running a simple experiment on a complex robot would leave much of the equipment redundant. The modules are also mobile, allowing them be to relocated to specialised labs for certain experiments required. as Previously robots had be to isolated but NiCoLA-B is a collaborative robot, interacting with and learning from scientists in the same space. It can also be controlled remotely via a “Cellario called smartphone/tabletapplication Connect” allowing scientists interact to with NiCoLA-B at any time; from labs, offices, homes, or even the other side of the world. In addition developing to the robot, there has been significant investment in the enhancement of the controlling schedulesoftware. This includes autonomous decision making for error recovery, and experimental progress; essentially automating some of the simpler decisions scientists would make free to their time for scientific innovation andto permit reliable

– The intelligent – The automation is modular – For certain experiments the Modular and mobile so it can be easily shared across researchers’ needs Mobile to relocated be can robots mobile people protect either to specialised labs from the biology, or the biology from people the correctionIntelligent robot is able detect to errors and make science no that ensure to corrections lost is – The robots and their – Three times faster than previous Key facts Fast technology, analysing 300,000 samples a day removed have – We barriers Removing all physical barriers so scientists can directly interact with their experiment that is being performed at an industrial scale Configurable controlling software are easily and quickly configurableto the requirements of the science

Case Study robot in the world the in robot advanced drug discovery discovery drug advanced NiCoLA-B: The most 54 IMED Annual Review 2016 54 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives ship 57 Delivering our pipeline through scientific leader Delivering our pipeline through scientific leadership 57

, saw in vivo and in vitro our first Cryo-EMprotein structures and witnessed the finaldevelopment of the stages of our acoustically enabled high throughput mass spectrometry cap machine. To delivery thetook year we off, high new our revolutionary of throughput screening (HTS) that willrobots future-proof both our own finding hit ouractivities and those of collaborators, who will share thembuilding in our new in Cambridge.” To support projects, we projects, support To advanced our knowledge and gene-editinguse of techniques both Mike Snowden, VP Discovery Sciences

“2016 was another great year great was another “2016 discovery AstraZeneca. at for substantial saw growthWe inthe Sciences Discovery both internal through pipeline and external Open Innovation projects and saw exciting withadvances a number technology our developing of platforms. supported We providing internal by projects hit series, tissues,more and models, cellular/animal thanassays before, ever and grew the IMED early phase Open Innovation than more to portfolio 40 forging by projects screening partnerships with world- renowned institutions.

CRISPR (clustered regularly regularly CRISPR (clustered repeats) interspaced palindromic gene editing tool IMED functions Discovery Sciences 56 IMED Annual Review 2016 56 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives CRISPR/Cas9 actions. Within six weeks, CRISPR/Cas9 actions. Within six weeks, all mice developed human-like lung our knowledge, To adenocarcinomas. this technology is the most advanced to date for the ultra-fast generation of in vivo tumour models human relevant now intend to develop and in mice. We apply similar technologies employing our unique Cas9 inducible mice model validation in to enable ultra-fast target and other AstraZeneca therapy areas develop novel in vivo disease models. Emanuela Cuomo Emanuela Emanuela joined AstraZeneca from in 2015 the Cancer Institute, University College London, as an Associate Principal Scientist in the UK Cell Reagentteam. Since joining, Emanuela has taken a leading role in development of our internal CRISPR cell line capability and driving innovative approaches using this technology. This includes the generation of novel CRISPR- based cellular models of clinically relevant mutations for targets such as EGFR and further driving our understanding of drug resistance by mutagenesis saturation leading and initiating based CRISPR approaches to prediction of drug resistance. Emanuela was also instrumental in the organisation of the first AstraZeneca-Sanger CRISPR conference in 2016.

Delivering our pipeline through scientific leadership 59 The first major application of this innovative Cas9 inducible mouse has the speed for been in revolutionising engineering mouse models of human lung cancers to test and validate and AstraZeneca anti-cancer targets test and optimise new drugs. Cas9 nuclease is induced and the animals’ lungs infected with adeno-associated to delete the engineered virus (AAV), the and target p53 tumour suppressor cancer driving K-RasG12 mutation via Paul Harper Harper Paul High Scientist, Principal Associate is Paul Throughput Screening. He joined AstraZeneca in 1999 to the newly formed Charnwood screening centre after specialisingin high throughput screening with GlaxoSmithKline and Pfizer. With a background in the design and development of technology to fulfil scientific gaps, he has been pivotal in the evolution ofAstraZeneca’s automated science for Hit Identification. Moving to Discovery Sciences he currentlyin 2011, leads the development of the next generation of automated screening HighRes partnership with through technologies Biosolutions. Paul works closely with the HighRes team, to co-develop the world’s most advanced screening robotics which will be deployed into a ground-breaking new laboratory as part of the UK Centre for Lead Discovery. Cancer cell lipid bilayer

AstraZeneca was one of the first adopters of CRISPR in the industry and we continue to drive an industry- leading position, including working best in collaboration with the world’s the Sanger Institute, MIT scientists from use Whitehead, UC Berkeley and IGI. We CRISPR/Cas9 technology to empower our drug discovery activities across by delivering our main therapy areas and in vivo models sophisticated in vitro into human translatable directly which are disease, enabling us to bring meaningful lead compounds into the pipeline. It our use of animals also helps us reduce by developing animal models, which step in drug a necessary regulatory are Previously, quickly. much more discovery, several generations of mice had to be over 12-18 months to arrive at the bred in the offspring, whereas gene of interest to four months. three now it takes around A significant achievement this year was the generation of a transgenic mouse inducible a tightly controlled, expressing with no detectable basal Cas9 protein activity of the non-induced transgene. This unique and novel mouse model will in impact on future have widespread and in vivo applications of genome vitro engineering, as it allows us to avoid any potential Cas9 toxicity issues and focus to on the adult phenotypes most relevant This means that human disease biology. in vivo mouse human disease modelling experiments which once took years to complete can now be achieved in weeks. Taiana Maia De Oliveira Oliveira De Maia Taiana Taiana is Senior Scientist, Structural Biology and joined AstraZeneca in April from 2016 the EMBL (European Molecular Biology Laboratory) in Grenoble, to establish our capability in Cryo- Electron Microscopy, a fast breaking technique with the possibility of transforming the field of structural biology. She has made an immediate impact within the Discovery Sciences function, establishing our infrastructure and delivering the first internal AstraZeneca protein structures by this technique. Originally from Brazil and having studied for her PhD in Norway, Taiana has joined the Structure and Biophysics group in Cambridgewhere she is using a number ofintegrated structural biology techniques to further our understanding of key molecular disease. driving mechanisms People spotlight People Accelerating our drug discovery with CRISPR (clustered regularly interspaced interspaced regularly with CRISPR (clustered our drug discovery Accelerating repeats) palindromic

Acoustic mass specrometry Acoustic mass specrometry It was a record year for year for was a record It both internal discovery startsproject growth and for in our Open Innovation discovery efforts.”

editing (PGE) and phenotypic based screening. Our CRISPR genome editing platform delivered new reagents, and lines cell new complex including animal models for target validation and disease modelling. published have We this work widely in high impact journals. In addition advances to in target identificationtechnologies we made significant progress withtechnologies aimed at either finding or optimising the molecules of the future. took We delivery of state-of-the-art HTS robotics and saw the development of platforms that enable us study to the properties of in resulting biomolecules isolated single new instances some in or data, better data types. Of these, Cryo-Electron Microscopy (CRYO-EM) and Total Internal Reflection Fluorescence (TIRF) microscopy promise be to important techniques for the discovery scientist of the future.

This year sought we provide to outstanding project support the to growing pipeline of IMED Discovery Science projects and continue to develop to a number of technology platforms to key our future success. It was a record year for both internal discovery project starts and for growth in our Open Innovation discovery efforts collaborations with include now which the very best non-pharma discovery institutes including University of California, San Francisco (UCSF), Institut recherche la de et santé la de national médicale (INSERM), the Medical Research Council (MRC) and Cancer Research UK (CRUK). The programme has a very exciting pipeline of early projects and are we looking forward to translating innovative ideas into scientific breakthroughs in the future. saw excellentWe progress with a number of target identification/validation platforms including precise genome IMED functions Discovery Sciences

58 IMED Annual Review 2016 to therapeutic areas within IMED. therapeutic to finding and compound optimisation expertiseoptimisation findingcompound and extensive target identification/validation, hit into five core scientific disciplines we provide provide we disciplines scientific core five into areas and other teams across IMED. Divided IMED. Divided teams across areas other and support and platform technologies to therapy therapy to technologies platform and support Discovery Sciences (DS) provides pre-clinical (DS) provides Sciences Discovery Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives , an important Oncology target and to , an important Oncology target Author Segerstolpe A, Palasantza A, Eliasson P, Segerstolpe A, Palasantza A, Eliasson P, A, Sabirsh A, Clausen Andersson E, Andreasson M, Bjursell M, Smith D, Ammala C, Sandberg Z, Rodrik-Outmezguine V S, Okaniwa O, Yao H, Novotny C, McWhirter C, Banaji A, Won M, de Stanchina E, Barratt DG, Berger W, Wong Rosen N, Shokat KM Cosulich S, klinowska T, Akcay G, Grimster N, Aquila B, Belmonte A, Lamb L, Rawlins P, M, Chuaqui C, Hird S, Su Q Tentarelli G, Bobby M, Chen H, Rabow A, Walker Waring R, Boiko S, Bradbury H, Callis R, Dale I, Daniels Kikhney A, D, Flavell L, Holdgate G, Jowitt T, McAlister M, Ogg D, Patel J, Robb G, Robers Whittaker D W, D, Wang M, Stratton N, Svergun Exell J, Thompson M, Finger L, Abbott M, J, McWhirter C, Jones. C, Nissink Debreczeni S, Grasby J Durant T, Ward W, Segerstolpe A, Palasantza A, Eliasson P, A, Sabirsh A, Clausen Andersson E, Andreasson M, Bjursell M, Smith D, Ammala C, Sandberg Delivering our pipeline through scientific leadership 61 models for assessing efficacy and safety efficacy and safety and in vivo models for assessing sophisticated in vitro developed of We generated an example, we In a recent biological matter. and novel chemical and novel targets of mouse will accelerate the development inducible Cas9 mouse that exquisitely controllable of this mouse has The first major application months to weeks. disease from models of human To cancer. p53 KO, K-RasG12 mutation driven model of lung mediated been to develop a AAV is the most advanced to date for the ultra-fast generation of humanour knowledge, this model is potentially game changing for the Oncology field. in vivo tumour models in mice, and relevant kinetic and structural studies at the single technology platforms that enable three delivered We response individual molecules using cryo-EM for a DNA damage visualised molecule level. We kinetics of Cas9 binding to DNA using a platform successfully followed the We project. with optical tweezers to help us understand the propertiesthat combines confocal imaging component. In addition, we have employed total genome editing of this important precise projects. to a number of (TIRF) single molecule microscopy fluorescence internal reflection and with action information with a fraction of the reagent detailed mode of This has delivered such prevented whose properties compounds project data quality for key unprecedented analysis previously. and enabled mass spectrometer achieved a world first HTS using our unique acoustically We to molecule binding sites in proteins developed industry-leading techniques to map small Exchange (HDX) mass using Hydrogen-Deuterium amino acid residue almost a single residue times faster than any current Our HTS acoustic MS system can sample 60 spectrometry. enabling us to deploy the technology for diversity based HTS, saving time and technology, we have with our collaborators at the LMB and assay development. Together money in screening α used HDX to investigate tool compound binding to PI3K for autoimmunity. a target MALT1, in the world to AstraZeneca robots two of the most sophisticated screening delivered We faster than any times three are collaboration with HighRes Biosolutions. Both robots our through such as autonomous decision in Pharma and have advanced features robot other screening tablets and through application control and experimental progress, recovery making for error systems. The availability of these systems hashighly advanced touch and visual recognition for Lead in the Centre assets and will be core accelerated our Open Innovation discovery pipeline with the MRC and CRUK.Discovery AstraZeneca will share (CETSA) developed by Pelago to support enabled multiple forms of the thermal shift assay We specificity of their compounds in or target engagement to confirm cellular target needing projects cellular binding affinities for antagonists developed a system to measure complex systems. We Receptor and showed, for the first time, that the technology platform could beof the Androgen (e.g. KCC2). but also for multi-pass transmembrane proteins used for not only soluble proteins, We delivered We Title Single-cell transcriptome profiling of human of human Single-cell transcriptome profiling islets in health and type 2 diabetes pancreatic mutations with a mTOR resistance Overcoming new generation mTOR inhibitor Modification of a Non- Inhibition of Mcl-1 Through Side Chain Catalytic Lysine Potent and selective bivalent inhibitors of BET bromodomains Humanof Inhibitors N-Hydroxyurea Active Cellular Flap Endonuclease 1 Co-crystalise in the Active Reaction by and Prevent Site of Human Protein Blocking Substrate Double Nucleotide Unpairing of human Single-cell transcriptome profiling islets in health and type 2 diabetes pancreatic We set out to We precise and develop to use Continue as a tool techniques editing genome science pre-clinical for of methodologies a suite Advance kinetic us to study allow that would of single properties and structural molecules Push the mass boundaries of analyte rapid (MS) for spectrometry mapping small and for detection on proteins binding sites molecule of high generation a new Develop (HTS) robotics screening throughput compound collection proof to future the next for AstraZeneca at screening 10 years Expand our use of cellular thermal drug to confirm shift assays in cells engagement target discovery Publication Cell Metabolism Nature Chemical Biology Nature Chemical Biology Nature Chemical Biology Nature Cell Metabolism Highlights Key publications in 2016 publications Key

8 3 6 8. (KTH), Royal Institute of Technology Sweden collaboration The objective of the Secretome all human secreted and screen is to produce to unravel new biology leading to proteins discovery. target biological hypothesis and all proteins will produce During 2016-2018, KTH which will then be in the extracellular space in cell-based phenotypic assays at screened KTH has already AstraZeneca. During 2016, which have the first 700 proteins delivered Hits have in five cellular assays. been screened cell assays and T-regulatory been confirmed in assays. proliferation cardiac 9. of London, UK University Royal Holloway, AstraZeneca and Royal Holloway have partnered with the EU funded collaboration ExCAPE, an initiative to transform the way machine-learning discovery to applied within drug algorithms are and harness vast resources utilize supercomputing This partnership data. amounts of heterogeneous allows us to take the lead in and support us in our transformative efforts to automate chemistry and hit finding. 9 7 5 1

7. Cambridge Pharmaceutical CryoEM Consortium, UK Joining with 4 Pharma partners, the leading technology company FEI, the MRC, and the University of Cambridge, AstraZeneca have established a ‘state of the art’ Cryo-Electron University’s facility housed in the Microscopy Nanosciences department. 4. Hospital, US Massachusetts General to collaboration with Keith Joung A research activities assess off target develop technologies to of genome editing techniques. 5. Council Technology Medical Research (MRCT), UK epigenetic collaboration to identify new A research diseases for respiratory targets/compounds 6. Imperial/Lumicks, Netherlands to investigate the collaboration A research combined use of optical tweezers and confocal interacting for the study of DNA microscopy (initially CRISPR Cas9). proteins 4

2

1

1 2 IMED functions Sciences Discovery Research collaboration focused on the on the collaboration focused Research ‘CETSA’ application and extension of Pelago’s to engagement technology, cellular target in vivo cellular and tissue target measure directly engagement by small molecules. 3. Pelago Bioscience, Sweden to other Pharma. the first acoustic This collaboration to deliver individual from dispensing (Labcyte) direct the first and sample storage tubes (Brooks) generation of acoustic workflow for the entirely miniaturised, plates. The compound screening high-speed workflow will enable any compound an will provide and to be supplied to any screen data unparalleled level of quality in the screening biological assays. our from produced 2. US Brooks/Labcyte, A Research and Development collaboration and Development collaboration A Research a world first focused on developing Once spectrometer. acoustically enabled mass AstraZeneca Waters) (through commercialised on sales and royalties hardware will receive 1. Acoustic Labcyte/Waters/AstraZenca A selection of key collaborations in 2016 in collaborations of key A selection US/UK collaboration, mass spectrometry 60 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives ip 63

aving access to this technology is a major cientist perspective cientist H “ evolution of our team in Discovery Sciences and being based in Cambridge, at the heart of the recent advances, really helps keep the in edge AstraZeneca leading the at industry. CryoEM still has some way to go become models resolution atomic before routine, but to be part of an organisation best the early with collaborating investing external groups in the world, and positioning it for the first time within the drug discovery exciting.” really setting is classical strong crystallographic our With quality high produce ability to and capabilities proteins, Discovery Sciences is perfectly technology. this of advantage take to placed In our first year, we have already exceeded structures novel two delivering by expectations DNA the for systems molecular complex of Oncology. IMED in responsedamage initiative important to drug discovery, such as integral large multicomponent or membrane proteins become now macromolecular machines, accessible for study for the first time. homogenous highly requires that technique The protein solutions are frozen (in liquid ethane) ice. vitreous of layer thick molecule single a in (~100,000) molecules individual of number A Through microscope. the observed then in are a series of image analysis algorithms a 3D the structure molecular of the reconstruction of target protein is derived. S Delivering our pipeline through scientific leadersh Delivering our pipeline through scientific leadership 63 ryo-Electron Microscopy (CyroEM): (CyroEM): Microscopy ryo-Electron AstraZeneca, have we developed next-generation a virtual reality molecular viewer, Molecular will allow focused progress for compounds modulating DNA-protein protein-protein or interactions important in disease states and highlight new directions in drug discovery.” Imperial College with collaboration in 2016, In already been has technology this Lumicks, and characteristics binding novel uncover to used of a strategically important DNA interacting characterising binding the Fully protein. and modulation better allow will capabilities target. value high this activity of the of control C Expanding the impact of structural biology Structural biology plays a significant role in Techniques medicines. new of discovery the that allow us to model and visualise, at atomic protein the structures of the resolution, our which and disease, drive which molecules drugs bind to and modulate, have allowed the osimertinib. as such medicines new of design structures protein currently these However, are only really accessible by crystallography and we are unable to crystallise many of the proteins we are interested in. cryo-electron molecule Single is microscopy few last The structural the world. changing years have seen technical advances that have capability of the in change step enabled a an now are there and electron microscopy impressive number of high resolution protein structures that have been determined by this structural this the biologist For technique. is transformational, as many target proteins At Rift, which creates a virtual reality environment steered with hand movements. Traditional 3D visualisers ‘just’ show molecules on a screenin front of you; with Molecular Rift a drug designer can enter a protein-ligand complex. Metaphorically speaking remove we the digital screen and let the user step into molecules, such as a protein-ligand complex, look to around. The system uses the Oculus Rift headset with a Leap Motion Sensor, which was recently released offering a higher resolution and accuracy for gesture recognition. In addition,by using the Leap Motion infrared camera, have we achieved an augmented reality. This means that the user can still visualise their surroundings through the Oculus Rift, allowing them see to other people, and is one step towards a more collaborative virtual reality. Although, date, to Molecular Rift may be seen as a specialised tool in development, are we confident that this way of interacting with molecules will impact the way future design will be performed. Molecular Rift: a hands-on experience for the single molecule molecule single the for experience hands-on a Rift: Molecular

he ability to physically see single protein cientist perspective cientist T “ Optical Tweezers: determining mode mode determining Tweezers: Optical level single-molecule a at action of with combined Tweezers Correlative the allow (CTFM) Microscopy Fluorescence wide a on information detailed of collection sub-pico mechanisms with molecular range of sub-nanometer and resolution force Newton position resolution. Lasers are used to and capture that beads magnetic control hold molecules of interest such as a DNA. and manipulated be then can molecules The measured. forces resultant changes in the In addition, real-time fluorescence imaging characterisation of and visualisation allows small as such interactions, binding ligand DNA. to binding proteins or molecule transcription, as processes such DNA replication, repair and modification can each of kinetics the track to modelled be resolution high with real-time in component determine to single-molecule level the at This compounds. of action of mode the resolution high unique and visualisation elucidation of mechanisms of action for protein- protein or DNA-protein interactions is not traditional methods. currently by accessible S molecules interact with DNA is very exciting. very exciting. is DNA with interact molecules believeWe this technology will have a big impact on our pre-clinical work as the identification and characterisation of novel mechanisms interaction and action of modes ‘State of the art’ of ‘State FEI Titan Krios cryo-electron withmicroscope 2/3 and GatanFalcon K2 cameras enables single molecule imaging proteins of disease to key processes.”

is year have we gained a lot of experience Typically run we biochemical cellular assays Scientist perspective Scientist with the platform in early stage drug discovery where have we demonstrated ligand receptor selectivity, profiled the interaction of nuclear receptors with cofactors and measured kinetic binding data for unstable targets. Looking the to future, are we excited explore to the enormous potential of TIRF microscopy in late stage discovery programmes, in particular with Th regard biomarker to detection. “ that require a high concentration of molecules or cells get to the read-out forthe assays. With this technology can we watch a single molecule in action, following its binding a to receptor or monitor to its catalytic properties. This means it is possible observe to the action of a single molecule rather than an ensemble of molecules. Combining the resulting data with the read-outs of multiple molecule scans can we find information thatwould have been lostby measuring a collection of molecules alone.”

Case Study This year our Discovery Sciences team, along with key external with along key Sciences team, our Discovery This year that enable platforms world-class three pioneered have partners, level. the molecule studies at single kinetic and structural In the past, we have always had to study the average of our the average had to study always have In the past, we at can look Science means that we Molecule Single reagents. and therefore averages rather than specific molecules individual, We can also begin to quality data. better significantly get interesting very which can provide sub-sets of molecules study space. insights in the discovery Total Internal Reflection Fluorescence (TIRF) microscope molecule single the Microscopy: InternalTotal Reflection Fluorescence (TIRF) microscopy is a technique image to fluorescently tagged molecules in real time. Using a special lens, a laser illuminates the bottom of a glass coverslip at an angle where it is totally internally reflected. This causes an oscillating electric field - an evanescent penetrate - to wave the interface but only a depth to of about 200nm before it decays. This allows for selective excitation of surface-bound fluorophores, while non-bound molecules are not excited. At AstraZeneca have we a unique TIRF developed primarily platform, microscopy in-house and our team is leading the field when it comes applying to this technology to drug discovery. The technique has ultra-high sensitivity that has allowed us track to molecules at concentrations a thousand-fold lower than previous assays as well as detect very weak interactions. Our work in this area has already resulted in three papers in high quality journals as well as several invitations speak to on the topic at various conferences. Impacting projects today Single Molecule Detection with technology of tomorrow 62 IMED Annual Review 2016 62 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives ip 65 Sustainable growth through innovation 87 Delivering our pipeline through scientific leadersh Delivering our pipeline through scientific leadership 65 Stefan Platz, VP Global Drug Safety and Metabolism pharmacodynamic (PK/pharmacodynamic betterdata, to predict PD) risk in humans. Embedding the of characteristics disease is critical, population patient for example, haemodynamic measures in healthy animalsyoung be not may measures of representative in elderly patients. In addition, there has been significant progress in optimising drug delivery that can improve an risk unacceptable benefit by increasing drugprofile the target at uptake tissue.” organoid in vivo data and vivo in and system to compare species species compare to system sensitivities, toxicokinetic toxicodynamic and risk organ of modelling cross-species incorporating in vitro integrated pharmacokinetic/ “Our Drug Safety and Metabolism journey is about inus all leading aspects of pre-clinical safety in addition drugto metabolism and pharmacokinetics (DMPK). made have we In 2016 progress towards excellent this Our vision. is in focus three areas: species cross key comparison of toxicity such as using an in vitro

Cells under a microscope IMED functions Drug Safety and Metabolism 64 IMED Annual Review 2016 6486 AstraZeneca IMED Annual Annual Review 2016 Review Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

cut- potency such as in porcine aortic Delivering our pipeline through scientific leadership 67 KDR margins. off for selectivity in lead series of compounds. The modelling work gave the project team information to not only effectively prioritise compounds but also to know which subseries were sufficiently de-risked and could therefore select molecules based on otherkey criteria than Jay MettetalJay Jay Mettetal is the Leader of the Safety metabolism distribution, absorption, and and excretion (ADME) modelling function in DSM and is responsible for application of quantitative approaches to translating drug safety from discovery to the clinic. Jay earned his PhD in Physics at MIT on an NSF Graduate Fellowship. He has publications over 15 in the fields of Systems Biology and Quantitative Pharmacology. A key impact for the Safety and ADME Modelling function was the in 2016 delivery of translational PK/PDmodelling of KDR-induced BP risk for the programme. KITm In order to differentiate from competitor compounds the project KITm team needed to avoid hypertension caused by KDR (VEGFR2) inhibition, which is seen with several cancer drugs in the clinic. The DSM safety team sought to provide the team with guidance on how KDR inhibition translated into blood pressure (BP) elevation and incidence of hypertension. The approach used PK/PD models extracted from literature reports of BP changes and comparing this to PK/PD models of in house in vivo rat telemetry data. By correcting for vitro in endothelial (PAE) assay and considering different PK drivers we were able to give an vitro in

in vitro-in vivo translation hepatocyte differentiation. in vitroin Lyn Rosenbrier Ribeiro Ribeiro Rosenbrier Lyn Rosenbrier-RibeiroLyn leads the Secondary Pharmacology group in Discovery Safety. gainedLyn her PhD at the University of molecular the investigating Manchester mechanisms of drug metabolism regulation during The dual PI3Kγδ inhibitor program in RIA was identified to have potent off-target ENT1 inhibitor activity. In asthmatic patients, adenosine challenge leads to increased dyspnoea and bronchoconstriction. ENT1 inhibition can lead to increased local concentrations of adenosine and known ENT1 inhibitors have been linked to a higher incidence of these safety effects. the Understanding of ENT1 inhibition and ability of this compound to sensitise the airways was essential to assess the risk of progressing their lead molecule. performedLyn a semi-quantitative translational safety analysis using a set of marketed drugs with ENT1 activity to demonstrate the level of pharmacological coverage of ENT1 required to drive these detrimental effects. Bronchospasm was found to be a risk for respiratory patients only, and based on the current estimated human exposure values and the expected low incidence rate, a safety margin of 30-300 fold was deemed acceptable for the lead molecule. This is a great example of patient centric risk assessment and the work was recently published in . This year expanded we our organisation with the formation of dedicated Modalities, New teams for Systems Microphysiological Translational and (MPS) Biomarkers and Bioanalysis.” People spotlight

: Modelling informed : Modelling supported identification : Modelling the set criteria for Microphysiological systems Microphysiological - biochip with cellular matter Tm DK9 ZD2014 + Palbo of dosing schedule with an acceptable safety profileto advance. KI candidate drug target profile and confidence in safety profile to select and advance lead molecules. A significant support across the portfolio and has been critical decision to making in three projects: key C selection of next clinical schedule incorporating seven day holiday. enhanced have We our quantitative risk assessment capabilities by models sophisticated together bringing and mathematical algorithms allow to us predict to safe doses for humans more precisely and help achieve maximum therapeutic effect with minimal safety risks. a MPS Centre of Excellence can we increaseour focus on the development and delivery of MPS models that will be research organisation across the adopted as drug discovery platforms, as well as advancing our understanding of disease pathways. The Translational Biomarkers and Bioanalysis group has been formed to expand ouranalytical expertiseto support two critical areas of DSM research. Firstly, developto novel safety biomarkers for use in translational prediction target of organ safety risk from pre-clinical the to clinic, and secondly support to safety, andPK assessment PKPD of modRNA, ASOs and CRISPR modalities. Quantitative risk assessment has been an area of outstanding achievement in particularly2016, the exceptional work simulation, and modelling in progress and which is becoming increasingly integral ourto approach. The group has delivered

his year expanded we our organisation T with the formation of dedicated teams for New Modalities, Microphysiological Systems (MPS) and Translational Biomarkers and Bioanalysis. align with ourTo strategic investments and oligonucleotides antisense in modified RNA, the New Modalities Group will focus on safety considerations associated with novel therapeutic approaches and their delivery. MPS are miniaturised models that combine engineering and biology to generate organ function in vitro to emulate human biology at the smallest acceptable scale. MPS models enable scientists link to organs together and discover factors key involved in organ cross-talk that drive particular disease phenotypes – generating data with a high likelihood of clinical translation and offering a real alternativeto the use of animals in drug discovery. By developing

pipeline progression across our main therapy areas. main our therapy across progression pipeline to support project decision-making and enable enable and decision-making project support to deliver fully comprehensive, tailored safety packages safety tailored packages fully comprehensive, deliver We utilise our vast range of expertise and of design utilise range vast to our We to bring better, safer medicines to patients sooner. sooner. patients to medicines safer better, bring to nine functions with driving the purpose of science Drug Safety into (DSM) Metabolism and split is IMED functions Drug Safety and Metabolism 66 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Delivering our pipeline through scientific leadership 69 Sophisticated modelling to betterSophisticated modelling Damage toxicity of the DNA predict Response portfolio OncologyThe clinical utility of combining limited by is frequently treatments tolerability issues. additive or synergistic and schedule inOptimisation of dose often and costly, the clinic can be slow of combinations.leading to abandonment humanisedDevelopment of predictive that key data models will provide in vitro prioritisation ofcan be used to guide clinical dosing schedules and combination partners. Those with most favourable therapeutic index can be prioritised for in vivo studiesevaluation in pre-clinical and in the clinic. for toxicity with organ A key target This Oncology agents is bone marrow. year we have seen initiation of the development and the validation of a bone in which we can build a MPS, marrow of the time course understanding greater and mechanism underlying bone marrow is also the potential to There toxicity. druguse fluid handling tools to control in this model to enable in vivo exposure like evaluation of PK/PD relationships. example of how this type of A recent is illustrated can impact projects approach by the development of a model for seen inthe dose-limiting neutropenia, the clinic when one of our Oncology compounds was given in combination with another compound. The model was built using clinical PK/PD data and mechanistic data on the effects of the bone the in vitro combination derived from models. The model has helpedmarrow the team to identify dosing schedules that and willwill likely alleviate the neutropenia now be tested in the clinic.

Innovative approaches to quantitative risk assessement to quantitative approaches Innovative risk Building our quantitative is extremelyassessment capabilities allows us to predictimportant because it precisely more safe doses for humans maximumand accurately achieve with minimal safetytherapeutic effect, seen manyrisks. This year we have to significantlyelements come together and accuracy the precision improve These innovativeof our assessments. the have impacted across approaches byIMED portfolio, as demonstrated these examples. Using 3D MiniGut models to measure intestinal toxicity pre-clinically encounterOncology drugs frequently intestinal toxicity as a dose-limiting with partnered adverse event. We inventors of the MiniGut intestinal Hans Clevers’ lab at the organoids, Institute, to enhance our abilityHubrecht to investigate and understand intestinal One of our Oncology toxicity pre-clinically. dose limiting encountered programmes studies. Inintestinal toxicity in pre-clinical to this we developed multipleresponse MiniGut models using stem cells from species and demonstrated thatdifferent significantlyhuman intestinal cells are to the drug-mediated resilient more intestinal toxicity than those species studies. This dataused in pre-clinical of the contributed to the progression it previously where clinical programme may have been terminated. Modelling and simulation to optimise dosing schedules Quantitative risk assessment in CDK9 showed hematological toxicityprojects studies with very narrow in pre-clinical therapeutic index, and the team looked to open the window by selecting an optimal dosing schedule. A modelling and was performed forsimulation approach both efficacy and safety with endpoints of effects and tumour survival toneutrophil identify the optimal schedule. The model therapeuticsuggested that a reasonable obtained by going to a could be margin clinical schedule that split each dose into two separate doses - specifically going one day on/13 days off, to two daysfrom on/12 days off. and TRPC6. We also work with IMED and TRPC6. We γδ , and MSI helped to compare the distribution of NP-formulated drug the distribution , and MSI helped to compare ® We introduced a new hepatic cell line based spheroid model in Q2 2016. It is one of the first model in Q2 2016. a new hepatic cell line based spheroid introduced We based hepatic safety assays. It is cost effective and significantly increases human organoid models. to previous compared sensitivity by 30 per cent and specificity by 20 per cent demonstrated, together with our partners at TissUse, a physiological glucose homeostasis We islet connected in the same system to human pancreatic are when human liver spheroids on a chip model using human bone marrow also characterised a bone marrow We spheroids. niche. Excitingly which mimics the bone marrow microenvironment, stem cells in a bioengineered into haematopoietic lineages. Our successful collaboration with Emulate (athese cells mature to enhance an active Oncology project spin-off) has enabled us to test compounds from Harvard our human risk assessment, following detection of hepatotoxicity in vivo. have further defined our algorithms in the chemical toxicity space in 2016, to enhance the We of impact on the portfolio Examples quality of the chemical substrate in the discovery process. of the chemical structure include the early integrated assessment, which includes a review pharmacology of hit series. This enables deselection of as well as off-target and properties chemical series with intrinsic safety concerns starting material. and focus on the most promising exploiting the highly innovative Conformal increasingly computational tools are Our predictive In scientists with statistical confidence in the predictions. framework, which provides Prediction pharmacology safety analysis influences chemical design addition, our structural and off-target such as, SYKB, SERD-BC, PI3K during LO programs We applied in-house MSI technologies in a clinical setting. AZD2811 is an Aurora B kinase in a clinical setting. AZD2811 is an Aurora applied in-house MSI technologies We myeloid leukaemia (AML) patients but was in acute results inhibitor that showed promising (NP) The drug was encapsulated into a novel polymeric nanoparticle limited by therapeutic index. formulation, ACCURINS (VEGF-A),AZD8601 for package data safety pre-clinical the of submission successful achieved We for patients option regenerative treatment a unique designed to provide a modified RNA therapy, diabetic wound healing and other ischemic vascular diseases. Significantwith heart failure, in man in January 2017 and with AZD8601 was made in 2016 to enable the first time progress with Modernamarks an exciting milestone in our ongoing collaboration Therapeutics. objective of demonstrating stretch also achieved the aspirational IMED subcutaneous We enabling 10-fold therapeutic window and therefore a tolerable formulation with a predicted in 2017. of CVMD modified RNA projects progression which combines models, IPP-HOP, developed and validated two new novel lung function We pattern data as well as resistance respiratory and telemetry to provide plethysmography measures model that assesses the sensory nerve irritationand compliance, and a novel electrophysiology liability of these inhaled agents. based on known clinical agents approach The validation of these models has used a translational have been incorporated in to the new inhaledand their effects in patient populations; both models risk a thorough development, to provide pre-clinical being used on projects, in vivo strategy, system. assessment of the respiratory We delivered We project medicinal chemists as part of a chemical toxicology network to promote good practice and to promote medicinal chemists as part of a chemical toxicology network project understand needs. animals. Results confirmed NP- them simultaneously in the same animals. Results confirmed with deuterated drug by dosing in tumour periphery. drug distribution to be predominantly delivered AZD2811, one patient developed a rashDuring of NP-delivered a subsequent dose escalation study used desorption sample for the first time using in-house MSI facilities. We and we analysed a clinical able to localise the layers of skin and were visualise different ionisation (DESI) MSI to electrospray with no other drug formulation constituents being detected. drug within the papillary dermis Enhance the prediction in theEnhance the prediction space chemical toxicity Advance our microphysiological our microphysiological Advance (MPS) models systems Implement a new target liver strategy liver target a new Implement Develop novel lung function models novel Develop Develop messenger RNA and New and New RNA messenger Develop Modalities with our partner Moderna We set out to We Utilise the expanded Mass platform Imaging (MSI) Spectrometry distribution target to assess drug within organs Highlights IMED functions Drug Safety and Metabolism 68 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Sjogren E, Eriksson J, Vedin C, Breitholtz K, C, Breitholtz E, Eriksson J, Vedin Sjogren Hilgendorf C S, Randall K, Henderson, N, Reens, J, Eckersley, G, Nyström, A, South, M, Balendran, C, Böttcher, Hughes, G, Price, S Zamora I, Winiwarter S Rolf MG, Stewart J, Duffy P T, Mitchard Hall AP, K, L, Bower D, Cross A, Belke E, Amberg Ahlberg Gompel J, K, Van Custer L, Dobo K, Ford Harvey J, Masamitsu Honma M, Jolly R, Joossen E, Kemper R, Kenyon M, Kruhlak N, Kuhnke L, Neilan C, Naven R, Quigley D, Shuey Leavitte P, et al. D, Sprikl HP, Foster J, Goodwin RJ, Swales JG, Strittmatter N RJ, Swales JG, Strittmatter Foster J, Goodwin E, A, Spreckley Alamshah A, McGavigan H, I, O’Hara Tough Kinsey-Jones J, Amin A, G, R, Hyberg Moolla A, Banks K, France Bloom S, Lehmann A, Norton M, Cheong W, Cox H, Murphy K S, Strittmatter N, Nilsson A, Mohammadreza Zhang X, Alvarsson A, Kallback P, Goodwin R, Svenningsson P, T, Vallianatou P Andren Johann E, Lauschke V, R, Sison-Young H, Gerets E, Antherieu S, Aerts Alexandre H, Labbe G, Schofield C, Stahl S, Lovatt C, Holder J, Richert L, Kitteringham N, Jones Ingelman- R, Hewitt P, R, Elmasry M, Weaver Goldring C, Park K M, Sundberg J, Wikell C, Clifton S, Shearer P, Gardiner Benjamin A, Peters S Pinto M, Khunweeraphong N, Montanari F, Boyer S, Chiba Wlcek K, Sohail MI, Noeske T, Stieger B, Kuchler K, Ecker GF P, C, Abrahamsson A, Hultman I, Vedin Winiwarter S, Darnell M A, Cross S, Pointon A, Williams Ravenscroft M, Sidaway J L, Gooderham N, Saleh A, Fellows M, Ying Priestley C Author Delivering our pipeline through scientific leadership 71 Excised segments of rat small intestine in Ussing chamber studies: A comparison of native and stripped tissue viability and permeability to drugs levels in ulcerative colitis Claudin-2 expression development and validation of an in-situ hybridisation assay for therapeutic studies Polypeptide Anion Transporting Modelling Organic inhibition to elucidate interaction 1B1 (OATP1B1) risks in early drug design plate dysplasia and fracture Femoral head growth anti- in juvenile rabbits induced by off-target angiogenic treatment Extending Quantitative structure–activity (Q)SAR, to incorporate proprietary relationship, purposes: A case study knowledge for regulatory amine mutagenicity using aromatic Aurora kinase inhibitor nanoparticles target nanoparticles target kinase inhibitor Aurora index in favourable therapeutic tumours with vivo and hormone release gut promotes L-Arginine food intake in rodents reduces multipleSimultaneous imaging of substances and neuroactive neurotransmitters ionization electrospray in the brain by desorption mass spectrometry A Multi-Center Assessment of Single Cell of Cell Measures Models Aligned to Standard of Acute Hepatotoxicity Health for Prediction the Maturation Rate Determines Neutrophil Impact of Dipeptidyl Peptidase 1 Inhibition on Activity Serine Protease Neutrophil Flagging drugs that inhibit the bile salt export pump system for Use of HμREL® human co-culture and metabolite of intrinsic clearance prediction formation for slowly metabolized compounds enhanced non-myocyte cells show Cardiac pharmacological function suggestive of contractile maturity in stem cell derived cardiomyocyte microtissues The lack of mutagenic potential of a guanine-rich triplex forming oligonucleotide in physiological conditions Title Publication Science Translational Translational Science Medicine International Journal of Journal International Pharmaceutics PLoS One Pharmaceutical of Journal Sciences Pathology Toxicologic and Toxicology Regulatory Pharmacology Diabetes, Obesity Diabetes, and Metabolism NeuroImage of Toxicology Archives of British Journal Pharmacology Pharmaceutics Molecular Pharmaceutics Molecular Sciences Toxicological Sciences Toxicological Key publications in 2016 in publications Key 9 7 9. a Institute, Sweden Karolinsk evaluation of advanced A collaboration to test the model with immune 3D airway epithilial/fibroblast testing with Dr Mattias component for toxicity Svensson. 10. Quantitative Systems Translational IMI-2 consortium, Belgium Toxicology, and academic In collaboration with industry we have initiated Europe, collaborators across to develop project a €10 million, five year quantitative and translational systems improved toxicology models. The ultimate aim for is to develop novel approaches this project quantitative and translational that improve toxicology understanding and therapeutic liver, in cardiovascular, predictions margin systems. and kidney organ gastrointestinal Led by Jay Mettetal, AstraZeneca will lead the computational modelling elements of this collaboration bringing our expertise to bear in safety and absorption distribution metabolism (ADME) modelling. and excretion 10 2 3

5 8 6 7. University of Nijmegen, The Netherlands Martijn Wilmer our collaboration with Dr Through investigating a kidney cell model for we are clearance, of human renal prediction improved drug-drug interactions. 8. University of Cambridge, UK collaborating with the University are We of Cambridge on a GSK funded two-year post-doctorate investigating Drug Induced in the Context of Hypoxia. Mitochondrial Toxicity A collaboration to develop quantitative quantitative A collaboration to develop of cardiac translational understanding systems, house in vitro contractility between in contractility in of in vivo telemetry and measures pharmacology models. the clinic using systems 5. UK University of Edinburgh, Jamie Professor collaborating with are We as an in vitro Davies to evaluate mini-kidneys nephrotoxicity. model for investigating 6. University of Cambridge, UK identifying Along with LHASA and GSK we are to structural adverse outcome pathways related cardiotoxicity. 4. US University of Florida, 1 4 IMED functions Drug Safety and Metabolism We are currently investigating cell-autonomous investigating cell-autonomous currently are We of regulation mechanisms for circadian membrane excitability and contractility in with Dr John O’Neil. cardiomyocytes 3. Council (MRC), LaboratoryMedical Research of Molecular Biology (LMB), UK 2. UK Cancer Research, £20 million as principal have been awarded We UK Cancer Research investigators in a winning The consortium Grand Challenge consortium. including collaborations builds on existing strong the Beatson the National Physical Laboratory, Institute and , as well will focus on new ones. The research as forges using MSI technologies to generate “A Complete Cartography of Cancer”. 1. US University, Harvard Sciences andIn collaboration with Discovery novel investigating Keith Joung we are Professor of ‘off-target’ technologies for the determination technology in in vitro effects of the CRISPR/Cas9 and in vivo systems. A selection of key collaborations in 2016 in collaborations of key A selection 70 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives hip 73 Delivering our pipeline through scientific leaders Delivering our pipeline through scientific leadership 73 Anthony Johnson, VP Early Clinical Anthony Johnson, Development clinical science. We continue continue clinical We science. all aspects improve to of reflected delivery, operational in study cycle industry-leading times andsaving more than through person per 50 hours simplification. Inaddition we significant a developed have strategic partnership with make to our ClinicalCovance efficient.” more even Operations

“In 2016, three years since “In 2016, the Early of the launch Clinical Development (ECD) organisation, we establishedhave our three strategic pillars of innovation integrating trials, clinical in and knowledge to data target human earlier achieving validation. ECD continues class talent attractto world our capabilityacross areas and are increasingly our scientists published in high impact journals, reflect which both of the industryat our position forefront of translational

Immune cells IMED functions Early ClinicalDevelopment 72 IMED Annual Review 2016 72 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives 50 Key to the collection of data is our Real- time Analytics for Clinical Trials (REACT) tool, which is now being applied to over 50 clinical trials across the portfolio

Delivering our pipeline through scientific leadership 75 In addition thisto are we very proud pioneered have to and successfully implemented several novel study endpoints, reducing sample sizes promote to trials shortening and clinical progression through agile development. developed We CompEx fora Phase II study in asthma, which relevant clinically incorporates deteriorations as well as traditional exacerbations. CompEx allowed us halveto the sample size and is now being used as an exploratory endpoint inongoing clinical studies. also We completed Phase IIa study in COPD within three months using ExDo, a novel design that was enriched for outcome. hadIf we used COPD exacerbations, the traditional primary endpoint, the study would taken have four times as long and required a significantly larger population. patient

Eosinophil prior to apoptosis A key highlightA key this year in the delivery of innovative clinicalstudies has been to pioneering approach continued our innovative molecularly stratified multi- drug studies, known as ‘umbrella’ or ‘basket’ trials. In an ‘umbrella’ trial, patients with a single disease are treated with different treatments specific to their through indicated mechanism as disease biomarkers. For example, this year we initiatedhave a Phase BISCAY, Ib study, evaluateto four different immunotherapy therapies targeted molecule small and inpatients with metastatic muscle- invasive bladder cancer. Patients are assigned the to appropriate study module based upon the specific gene mutations in their tumour. We design and deliver innovative clinical studies clinical innovative deliver design and We By moving quickly, identifying opportunities initiating and where appropriate while also no it’s when work stopping thing do, the right to longer realise to been able have we significant time quality, and efficiencies.” cost inhaled p38 MAP kinase inhibitor failed to show any benefit in patients with COPD, so the study was terminated as soon as possible. By moving quickly, identifying opportunitiesand initiating where work stopping also while appropriate when no it’s longer the right thing do, to been have we able realise to significant quality, time and cost efficiencies. By pioneering new innovations such as our clinical trial software tools: REACT, are we and helpingPROACT Watcher, our team ensure that IMED and AstraZeneca are at the forefront of a revolution in the thatway early phase clinical trials are carried out. are We making them smarter, faster and more cost-effective, so that more patients can benefit from advances in medical science as quickly and safely as possible. An exciting example of our commitment collaborationto is a pan-European Paediatric Basket Study using a number of our Oncology assets, which began in By working2016. with other organisations across Europe hope we bring to the right patients paediatric right the to medicine even faster.

Our role in ECD is all about testingif the research taking place across the IMED Biotech Unit can transform patients’ lives – it is the place where science meets the patient. Our talented people lead this important work designing by and delivering innovative clinical studies, integrating data, informing research and development and accelerating human target validation. In the months last really have 12 we seen the results of embedding our leadershipkey behaviours - being collaborative, being entrepreneurial and agile and being pioneering follow to the science. Being agile has enabled the team leverageto adaptive trial design in the BEECH study (AZD5363 with paclitaxel for advanced breast cancer), targeting AKT1 inhibitor and the ATM programme where delivering real- enabled pharmacokinetic data time faster decision making. also have We demonstrated agility through our flexible resourcing of several programmes agonist TLR9 the acalabrutinib, including Glucocorticoid Selective oral and Receptor Modulator (SGRM) improve to quality and efficiency. In a Chronic Obstructive Pulmonary Disease (COPD) an isoform AZD7624, study, specific

packages based on innovative modelling techniques. modelling innovative on based packages for example simplification of our clinicalof pharmacology simplification example for high impact publications and in and clinical trial publications efficiencies, impact high translational clinical scientists, reflected in several of ourof several in reflected clinicaltranslational scientists, months we have demonstrated our strength our as skilled demonstrated have we months for Early Clinical Development (ECD). In the last 12 (ECD). Clinical Early Development for 2016 has been a year of great progress and delivery and progress great has of a year been 2016 IMED functions Early ClinicalDevelopment 74 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives . Steve Rennard Rennard Steve StephenIn 2016 Rennard became Head of the Clinical Discovery Unit for RIA and CVMD and a member of the ECD leadership team. Steve has helped lead a team effort to advance human target validation and patient segmentation. He has also contributed to the leadership of the NOVELTY study in collaboration with Global Medical Affairs and to the Targeted Genome Editing project in collaboration with DS. Working with RIA, he has been a leading contributor to the development of discovery a research programme focussing on COPD and regenerative medicine. Steve has authored over 700 publications, of which 24 were his in 2016, H-index is 88 and he has over 34,800 citations. This year Steve was also elected as a Professorial Fellow at Homerton College, University of Cambridge and was published in the New England Journal of Medicine Delivering our pipeline through scientific leadership 77 and another in Communications Nature Allan Vaag Vaag Allan AllanVaag is an endocrinologist specialising in diabetes research with an emphasis on the pathophysiology 2 diabetes. of Type Allan has published 340 peer-reviewed articles with one in Nature Hisin 2016. H-index is 68 and has more than 20,000 citations. Allan is head of the ECD CVMD Therapeutic Medical Unit and is a member of the ECD leadership team. He serves on the CVMD Research Board, is a member of the internal advisory board for the Dapa mechanistic studies and has co-organised collaborative cross functional teams across IMED, as well as ECD clinical project challenge and journal club meetings. Allan is involved in developing several explorative studies accelerating human target validation in CVMD.

Immune response to cancer - white Immune response cell blood cells attacking a cancerous Melinda Merchant Melinda Melinda Merchant is a Senior Medical Science Director who serves as lead for the Boston Oncology Therapeutic Medical Unit and represents ECD on the Site LeadershipTeam. Apediatric oncologist with a PhD in Immunology, her prior expertise in immunotherapy has been valuable in the early clinical development of AZD4635 (A2aR) and implementation of the Phase I First-Time-in-Human trial this Her year. collaborative efforts with IMED and Acerta are reflected in the successful Candidate Drugs AZD5991 AZD0466 (MCL1), (Bcl2/xL), and AZD1390 (ATM-BBB). People spotlight People

such as CompEx saving time, money and influencing regulators, as well as gaining approval as well as gaining approval regulators, such as CompEx saving time, money and influencing the requirement for leaner Clinical Pharmacology packages which use modelling to reduce for additional trials. AstraZeneca and Being collaborative – this forms part of everything we do, both across with external partners. A particular highlight this year has been our collaboration with the glomerular and tubular Institute heralding generation of transcriptomes from Karolinska and healthy kidneys and a publication in Science relating diabetic nephropathy tissues from risk. to cardiometabolic We delivered data to accelerate the human target validation of our VEGF-A programme in heart validation of our VEGF-A programme data to accelerate the human target delivered We plasma associated with decreased significantly genotypes are found that the different We failure. reserve. These flow ejection fraction and coronary concentrations, reduced VEGF-A protein for VEGF-A in patients. validation findings have accelerated human target between plasma the team established the quantitative relationship In the FLAP SMAD study, will be used to guide dose This assessment and the plasma biomarker LTB4. AZD5718 exposure on plasma also using an in-house database, based are for the planned Phase IIa in patients. We Ejection Fraction with preserved Heart Failure for samples, to identify potential new targets (HFpEF). optimised the way we work by focusing on key behaviours aligned to our AstraZeneca We Values: our adaptive trial design agile – as demonstrated this year through and Being entrepreneurial for AZD7594, our inhaled SGRM. Also in the early termination of our AZD7624 trial in COPD following conclusive efficacy data generated using our novel ExDo endpoint in half the time, using half the patients. and Being pioneering to follow the science – we constantly drive innovative approaches reduced technologies such as our pioneering modelling techniques that have significantly have also developed new endpoints the cost of our clinical pharmacology packages. We We achieved 96 publications – seven of which were High Impact and 41 High Quality. These 41 High Quality. High Impact and 96 publications – seven of which were achieved We RIA, CVMD, early clinical development science in Oncology, demonstrated world-class (QCP), Biometrics and Study Operations. Quantitative Clinical Pharmacology milestones including first-dose all of our main therapy areas, across led clinical progression We (MPO) and Phase I first time in man including AZD4831 our portfolio. This included seven across IIa starts including five NMEs such as AZD1419 (TLR9) for treatment AZD5634 (ENaC), 12 Phase and cancer, in combination with olaparib for patients with gastric of asthma and AZD6738 (ATR) including savolitinib + osimertinib in lung cancer patients. Phase IIb starts for non-NMEs three paediatric cancer trial, BISCAY, the E-SMART studies including basket and umbrella pioneered We in Oncology and our PI3 kinase study in Oncology. innovative endpoints such as CompEx and ExDo in RIA that successfully reduced delivered We sample size, trial length and saved significant cost. tumour DNA (ctDNA) tests to identify by incorporating circulating boosted trial recruitment We genotype in an early phase Oncology trial.patients with a rare by a inhibitor, the cost of the clinical pharmacology package for AZD1775, our Wee1 reduced We of $11 million using innovative trial design. estimated reinvestment with an third 2 diabetes patients and used this for modelling over 4,894 Type data from integrated renal We renal outcome the confidence in the investment decision to progress time. The analysis increased like empagliflozin. the kidney evidence dapagliflozin is expected to protect study by providing (REACT) tool, our Real-time Analytics for Clinical Trials through continued to deliver innovation We also used data generated We in real-time. which this year allowed us to adjust our savolitinib trial ATM to conduct sophisticated modelling, which significantly accelerated our REACT through inhibitor (AZD0156) programme. our and PK modelling using data collected throughout completed advanced ADME We At the End-of-Phase II meeting with the FDA, this data was deemedsavolitinib Phase II program. proposed. This is to a variety of studies normally an sufficiently informative to stand as surrogate our industry leading position in this area. by the FDA and reflects approach unprecedented We delivered We

Nurture values and leadership and leadership values Nurture with our culture consistent behaviours Accelerate human target validation target human Accelerate Integrate data to inform research research to inform data Integrate and development Implement innovative study designs study innovative Implement areas therapeutic the core across We set out to We the pipeline across progression Drive portfolio IMED functions Early Development Clinical Highlights 76 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 79 Phase IIa in patients. are We also using in-house integrated clinical databases (RECIPE, PROFLOW), which now have been made open access internally, to provide HTV data for ongoing clinical projects as well MPO and VEGF, FLAP, as identify to potential new targets for cardiometabolic research area with focus on heart failure and high risk coronary arterydisease. TLR9 endosome and receptor We accelerate human target validation target human accelerate We This year accelerated have we human target validation(HTV) for VEGF-A in patients Infarction post-Myocardial as part of our ongoing collaboration with Moderna Therapeutics. did We this identifying by genotypes that are significantly associated with decreased concentrations, protein VEGF-A plasma reduced ejection fraction and coronary flow reserve. This will help inform patient forward. moving segmentation Our scientific leadership in this areawas further demonstratedour by pioneering approach In HTV. the to FLAP SAD/ MAD the study, team established the quantitative relationship between plasma exposureAZD5718 and the plasma biomarker This assessment LTB4. will be used guide to dose for the planned studies across programmes25 across the portfolio. 110 Key to the collection of data is data our of the collection to Key Realtime Analytics Clinical for Trials (REACT) is which tool, 110 around to applied being now 25studies programmes across the portfolio.” across Watcher is an early form of Artificial Intelligence focused initially on liver function. This software confirms whether a patient has abnormal liver function and provides an initial assessment as the to possible cause. A Watcher collaboration with the savolitinib team has delivered a pilot based on a full retrospective analysis of current Phase II study data in REACT and the system will now be deployed in the forthcoming Phase III study in papillary renal cell carcinoma (PRCC). This current implementation of Watcher applies clinical heuristics support to the interpretation of Liver Function in Tests order ensure to that any Drug Induced Liver Injury (DILI) or potential Law Hy’s event is quickly identified and notified theto clinical study team. The system is designed reason to over the REACT data continuously and in real-time. Watcher is planned be to deployed in the BISCAY soon. study

us focus to the clinical trial on the patients. right Dapagliflozin inhibitoris our SGLT2 that improves glycaemic control in adults 2 diabetes.with Type The team wanted dapagliflozin whether determine to confers renal protection similar the to recent positive empagliflozin outcome trial. Renal data (eGFR) from 4,894 Type 2 diabetes patients in eight Phase II and III trials was integrated andused for modelling over time. The model demonstrated an overall renal protection potential for all levels of eGFR baseline versus placebo. The beneficial effect was dose dependent. This finding investment underpinnedAstraZeneca’s outcome renal the progress to decision study providing by evidence that dapagliflozin will protect the kidney like empagliflozin. the to collectionKey of data is our REACT tool, which is now being studiesapplied across around to 110 programmes25 across the portfolio. This allows us work to in an agile way makingby adjustments while the trial is ongoing. For example during this year, a savolitinib trial, real-time visualisation of tumour response and biomarker data highlighted that therapy was most effective patients in MET+ allowing IMED functions Early Development Clinical 78 IMED Annual Review 2016 We integrate data to inform research and development research to inform data integrate We Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Martinez F, Mannino D, Leidy NK, Malley Mannino D, Leidy NK, Malley Martinez F, Han ML, KG, Bacci ED, Barr RG, Bowler RP, SI, Make B, Meldrum CA, Rennard Houfek JF, BP J, Yawn Thomashow B, Walsh Woodruff PG, Barr RG, Bleecker E, Christenson PG, Barr RG, Bleecker Woodruff HanselD, Curtis JL, Gouskova NA, SA, Couper E, Lazarus EA, Kanner RE, Kleerup NN, Hoffman DP, S, Tashkin Rennard SC, Martinez FJ, Paine R, Han MK A et al Horikoshi M, Vaag A, Di Narzo A, AkersFranzen O, Ermel R, Cohain H, Giambartolomei H, Foroughi-Asl N, Talukdar J, Sukhavasi K, Köks S, Gan LM,C, Fullard C, Kovacic J, Betsholtz C, Losic B,Gianarelli Skogsber J, Hao K, Roussos P, Michoel T, J Björkegren Ruusalepp A, Schadt E, Carter L, Rothwell DG, Mesquita B, Snowton C, Leong HS, Fernandez-Gutierrez F, CJ, Burt DJ, Antonello J, Morrow Li Y, Hodgkinson CL, Morris K, Priest L, Carter Dive C, M, Miller C, Hughes A, Blackhall F, Brady G Sharma RA, Plummer R, Stock JK, Greenhalgh Ataman O, Kelly S, Clay R, Adams RA, TA, SR, Buckland RD, Billingham L, Brown Baird S, Bulbeck H, Chalmers AJ, Clack G, Cranston AN, Damstrup L, Ferraldeschi R, Forster MD, Golec J, Hagan RM, Hall E, Hanauske A-R, Hawkins MA, Illidge Harrington KJ, Haswell T, Melcher AS, McDonald F, Jones H, Kennedy T, JR, Saunders MP, Pollard O'Connor JPB, T, J, Staffurth D, Smitt M, Sebag-Montefiore SJ IJ, Wedge Stratford Metev H, Keen Richter K, Puu M, O’Byrne P, M Uddin M, Larsson B, Cullberg C, Nair P, Hardin Hobbs BD, Parker MM, Chen H, Lao T, Yim M, Qiao D, Hawrylkiewicz I, Sliwinski P, JJ, Kim WJ, Kim DK, Castaldi PJ, Hersh CP, J, Celli BR, Pinto-Plata VM, Criner Morrow N, Bueno R, Agusti A, Make BJ, GJ, Marchetti Lomas Crapo JD, Calverley PM, Donner CF, J, Paré PD, Levy RD, Vestbo EF, DA, Wouters NM, Lin X, Beaty SI, Zhou X, Laird Rennard TH, Silverman EK, Cho MH Author Martinez FJ, Rabe K, Anzueto A, Sethi S, Pizzichini E, McIvor A, Siddiqui S, Rekeda L, Zetterstrand S, SI Miller C, Reisner C, Rennard Alagappan V, K, Ranjit K, Rabinovich1 RA, Miller BE, Wrobel LD, Lomas DA, E, Edwards Williams MC, Drost J, Wouters R, Vestbo SI Agusti A, Tal-Singer Rennard Bolton JT, EFM, John M, van Beek EJR, Murchison CE, MacNee W and Huang JTH Delivering our pipeline through scientific leadership 81 A new approach for identifying patients with A new approach obstructive pulmonary undiagnosed chronic disease Effect of Roflumilast and Inhaled Corticosteroid/Long- Obstructive Pulmonary Acting β2-Agonist on Chronic Disease Exacerbations (RE2SPOND). A Randomized Clinical Trial desmosine levels do not predict Circulating associated with but are emphysema progression obstructive risk and mortality in chronic cardiovascular pulmonary disease (COPD) Clinical significance of symptoms in smokers in smokers of symptoms Clinical significance spirometry with preserved for birth weight and Genome-wide associations with adult disease correlations Cis downstream risk loci share Cardiometabolic tissues and diseases genes across and Trans tumor Molecular analysis of circulating cells identifies distinct copy-number and in patients with chemosensitive profiles cancer small-cell lung chemorefractory Clinical development of new drug–radiotherapy combinations Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, trial placebo-controlled Exome array analysis identifies a common variant in IL27 associated with chronic obstructive pulmonary disease Title We have built a strategic We partnership to simplify Clinical working are Operations. We with almost 50 employees from saved Covance and have already both money and time for science. The partnership has also improved governance, developed new sample tracking solutions and standardised processes. 7. Medicines Agency European (EMA), UK The EMA has asked AstraZeneca input to guidance on to provide genomics in clinical trials. Cath CSBS was the ECD Mela from the AstraZeneca in representative contributor group cross-functional feedback on two which provided guidance documents in May/ June 2016. The final document is scheduled for 2017. 8. Covance Laboratory Strategic Partnership Publication New England Journal Journal England New of Medicine American Journal of American Journal and Critical Respiratory Medicine Care of American Journal and Critical Respiratory Medicine Care Respiratory European Journal Nature Science Medicine Nature Clinical Reviews Nature Oncology The Lancet Respiratory Medicine of American Journal and Critical Respiratory Medicine Care Key publications in 2016 in publications Key

3

2 8 We are collaborating as part of AcSé-eSMART, collaborating as part of AcSé-eSMART, are We Paediatric Basket Study a pan-European using a number of our Oncology assets. This collaborative paediatric cancer study aims to double in two years the number of new drugs that based on the molecular to children will be offered of their tumour. profile ECD has established a collaboration to develop ECD has established a collaboration to develop and implement iDecide, our cutting edge clinical informatics R&D framework. This facilitates accelerates early of results, rapid interpretation identification of safety and efficacy signals, the patient understanding of and improves in collaborating with leaders are experience. We information technology and artificial intelligence (AI) to fundamentally change the way clinical trials performed. are 10. National Cancer Institute and The French France Gustave Roussy, 7. Agency (EMA), UK Medicines European 8. Strategic Partnership,Covance Laboratory Global simplify have built a strategic partnership to We Bioanalysis Clinical Sampling Operations, and Speciality Laboratory contracting and from working with 50 full-time employees are this alliance. dedicated to Covance who are 9. Institute, Manchester Cancer Research The Christie and the University of UK Manchester, This has provided improved governance improved This has provided both money and time and saved procedures procedures. standardised for science through The EMA has asked AstraZeneca to provide to provide The EMA has asked AstraZeneca in clinical trials. input to guidance on genomics Clinical Sample and Bioanalytical Cath Mela from ECD representative Sciences (CSBS) was the contributor in the AstraZeneca cross-functional guidance feedback on two provided which group 2016. The final documents in May/ June for 2017. document is scheduled 10 9 7 1 relating to Cardiometabolic risk loci. Cardiometabolic to relating Science particular highlight this year has been particular highlight this 5. University of British Columbia (UBC), Canada with the partnering AstraZeneca and UBC are (PROOF) Centre Failure of Organ Prevention of Death, on the Canadian Study of Prediction Events Dialysis and Interim Cardiovascular (CanPREDDICT) – a study designed to improve the understanding of determinants of renal in (CV) disease progression and cardiovascular kidney disease. patients with chronic 6. Canada University of Toronto, Cherney David AstraZeneca and Professor submitted an ESCR to (University of Toronto) investigate effects of dapagliflozin on albuminuria CKD patients. function in non-diabetic and renal Gilbert (University of Toronto), Richard Professor potential impact of was consulted regarding (as SGLT1 selectivity towards having reduced seen with canagliflozin). 4. Institute (SCRI), US Sarah Canon Research Collaboration between Global Medicines Development (GMD) /ECD and SCRI. Successful face to face transition meeting in July in Nashville to transfer AZD1775 to GMD, with the support and SCRI. input from A Institute (KI) collaboration with the Karolinska transcriptomes from heralding generation of diabetic from glomerular and tubular tissues publication a and kidneys healthy and nephropathy in Through the ECD-initiated collaboration with Dr Through the KaRen cohort withLars Lund at KI, based on integrated clinical dataset, IMED a comprehensive Heart for identifying new targets scientists are (HFpEF), Ejection Fraction preserved with Failure recently. presented with one first target 3. and Gothenburg Institute Karolinska Sweden University, 6 8

4 5 IMED functions Early Development Clinical A collaboration to characterise human kidney A collaboration to characterise human kidney tissue was successfully initiated and the first transfers of kidney material between the parties has now been completed. The tissue will be used to gain knowledge about kidney biology and and function to inform new ways of treating kidney disease. preventing 2. University Hospital, Sweden Sahlgrenska ECD supports the Experimental Medicine InitiativeECD supports the Experimental of Cambridge School of(EMI) with the University this collaboration we Clinical Medicine. Through funding a PhD student modelling currently are a second PhD student toxicology, cardiovascular and aninvestigating Apelin endocrinology working in nephrology. Academic Clinical Lecturer and clinical PhD students three EMI aims to recruit over the next three six Academic Clinical Lecturers years. inaugural meeting ofAstraZeneca hosted the attracted over 60the EMI in Cambridge which Ian Wilkinson to hear Professors researchers the goals of the and Tim Eisen (ECD) introduce initiative. This strategic collaboration is supported by the University of Cambridge in partnership with the Cambridge University Hospitals, NIHR Centre, Cambridge Biomedical Research AstraZeneca and GSK. collaboration ECD, has a direct Johnson VP Tony Reader Kevin O’Shaughnessy, with Professor in Clinical Pharmacology at the University of Cambridge and Honorary Consultant Physician at the Cambridge University Hospitals NHS The collaboration currently Foundation Trust. entails a post-doc working on cardiovascular/renal science and targets. ECD Biometrics has an affiliation with the Medical Hub with a Council Biostats Methodology Research funded by ECD. and post-doc engaged in this area A selection of key collaborations in 2016 in collaborations of key A selection 1. Cambridge, UK University of 80 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives DeliveringDelivering our our pipeline pipeline through through scientific scientific leadershipleadership 83 83 Anders Holmén, VP PharmaceuticalAnders Holmén, VP Sciences contributed to changes in to contributed that projects direction early of the smooth facilitate could clinical through progression in the future. development than less being a yearDespite already seen have we old, some really exciting science, both internallyand through our collaborations with companies, specialised biotech driving and progression molecules.” future enabling “By establishing“By PharmaceuticalSciences asfunction a within the are we IMED Unit, Biotech givingIMED teams across our cutting to access edge andscience unique skillset inearlier the drug discovery Already are we journey. the having rewards of reaping pharmaceuticalscience clearly IMED on project represented teams where we contribute with solving a problem to future potential view to large This hasscale production.

Microfluidiser making nanoparticles Microfluidiser

Sciences IMED functions Pharmaceutical 8282 IMED IMED Annual Annual Review Review 2016 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Large scale lab - rotating flask boiling scale lab - rotating Large the drug product off solvent to produce Delivering our pipeline through scientific leadership 85 We successfully delivered the regulatory clinical trial application (CTA), the validated methods clinical trial application (CTA), the regulatory successfully delivered We first clinical trial utilising modRNA as a therapeutic agent in for the world’s and the product collaboration with Moderna Therapeutics. performed (CMC) activities were Manufacturing and Control Chemistry, related All drug product in-house by implementing novel technologies and new ways of working. The complexity of the drug substances demanded that new analytical methods for modRNA, based on electrophoresis be set up and validated to Good (HPLC) had to and High Performance Liquid Chromatography Manufacturing Practice (GMP) level. The generated internal knowledge, capabilities and innovations will pave the way for future modRNA and other new modality projects. the scientific built new strategic alliances with academic institutions to strengthen We delivery of new medicines to our major sites and further drive innovative ecosystems around companies and key also building new strategic alliances with biotechnology are patients. We science and technology. academics to access frontline high impact publications since joining IMED in 2016. In 19 high quality and three delivered We including the Swedishcongresses, 19 invitations to speak at various addition, we have received Annual Meeting 2016. Society of Toxicology We delivered We Gothenburg our Boston, Cambridge, established a dedicated team of 180 people across We externaland sites which, along with several partners, truly makes us a global needs of of talent and skills to meet the breadth developed a function with the function. We diverse and complex portfolio. an increasingly expertise in compounds using the team’s prepare and efficient ways to developed reliable We of MEDI4276, production The synthetic development and analytical chemistry. chemical process with high potency intermediates makingan anti-HER2 antibody drug conjugate, took 36 steps unusually challenging. By utilising a high containment facility andscaling up production exceeded expectations with a innovative approach of synthesis, the team’s modifying the route yield, contributing to the compound achieving first time in man in product in significant increase 2016. The team has also established efficient manufacturing techniques such as continuous different example, we ran three or “flow chemistry” within early development. For processing of one of our compounds; two chemical stages as in the production continuous processes singe isomer starting material using to the desired well as the conversion of a racemic mixture simulated moving bed chromatography.

Develop clinical trial materials for the for clinical trial materials Develop RNA modified scale large ever first clinical trial in humans and collaborations partnerships Build leadership scientific Demonstrate We set out to We function establish new Successfully within IMED chemical in early Innovate bringing together by development a unique mix of specialities Highlights

we ®

and Autoimmunity (RIA) team, are we focused on developing new to ways evaluate inhaled compounds in the pre-clinical phase, using our inhalation including platforms technology nebulisation, dry powder and pressurised metered dose inhalation devices. This year met we an important milestone where took we AstraZeneca’s first modalities. new successfully encapsulated our targeted intoAurora a B kinase inhibitor, AZD2811, novel polymeric nanoparticle formulation. the how highlights manuscript The team developed the first nanoparticle pre-clinical candidate, through careful characterisation of efficacy, safety, in distribution and pharmacokinetics pre-clinicalmodels. With the Respiratory, Inflammation II Phase into inhaled oligonucleotide and going forward are we broadening the scope towards inhaled proteins and Through our co-exclusive license with Pfizer for accessto the BIND Therapeutics ACCURINS in 2016. where our remit

Advanced drug delivery drug Advanced is deliver to cutting-edge technology enableto effective molecules of the future. By focusing on cellular targeting, improving cellular uptake and enhancing drug delivery, aim we improve to target efficacy and delivery of both small such modalities molecules new and as microRNA, messenger RNA and therapies. oligonucleotide antisense already have we In seen 2016 significant benefits of bringing our unique set of skills project to teams across the IMED Biotech Unit. highlight A key has been our work with the Cardiovascular and Metabolic Diseases (CVMD) team manufacturing the first world’s modified RNA therapeutic product as part of our collaboration with Moderna Therapeutics. also have We been working on some really exciting science using nanoparticle technology in drug targeting with the Oncology team, which was published in Medicine Translational Science

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Our work is focused in three areas: key where development chemical Early we a highlyhave innovative team providing a powerful resource across the IMED Biotech Unit. Our unique approach of bringing those designing synthetic molecules into the same team as those producing them has already reaped rewards, including many high impact publications in 2016. wh productEarly development utilisewe our specificexpertise in the formulation of products based on established technologies for candidates including clinical testing, into going device strategies for inhalation and parenteral drugs in early development. within science specialised this to Access the IMED Biotech Unit has resulted in developing innovative new ways of working, increasing efficiency and costs.reducing ever-expanding drug platforms and modalities. and drug platforms ever-expanding cutting-edge drug delivery systems to support our support cutting-edge to drug systems delivery analytical expertise as as our well chemistry, in design, solid state chemistry, biopharmaceutics and biopharmaceutics chemistry, state solid design, access to excellence in organic synthesis, route route synthesis, in organic excellence to access molecules. Our unique approach gives IMED gives teams Our unique approach molecules. established as part of the IMED Biotech Unit in 2016 in 2016 asestablished part Unit the IMED of Biotech newof design the influence to cutting-edge science The Pharmaceutical Sciences function was Sciences The Pharmaceutical bringing specialist team skillsare and a dedicated complex portfolio across our main therapy areas. We We areas. main our therapy across portfolio complex to meet the needs of an increasingly diverse and diverse an increasingly of the needs meet to

Sciences IMED functions Pharmaceutical 84 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Large scale lab - vessel in Large reactor a continuous flow Jeremy Parker Parker Jeremy Jeremy Parker is AstraZeneca’s Principal Scientist for New Modalities and Tissue Targeting, leading the chemistry activities on the development and commercialisation of a range of newtherapeutic modalities including antibody drug conjugates, dendrimer drug conjugates and polymer drug conjugates. His interests include contemporary synthetic methodology, route selection, linker chemistry and the synthesis of a wide range of New Modalities. Therapeutic Delivering our pipeline through scientific leadership 87 mechanistic modelling modelling mechanistic Ulrika Tehler Tehler Ulrika UlrikaSince Associate Tehler, 2011 Principal Scientist, RIA Early Product Development, has focused on drug delivery to the lungs. She has been a major contributor to the development of an internal silico in tool for inhaled drug delivery and pioneered the inhaled dissolution area within AstraZeneca. Ulrika is an interdisciplinary scientist renowned for building relationships across departments and delivering results and innovative solutions to projects.

Annette Bak The recruitment of Annette Bak, Senior Director,Advanced Drug Delivery, strengthens (CMC) Control and Manufacturing Chemistry, our knowledge within pre-formulation, formulation development and drug delivery. Her research drug and characterisation include interests delivery of macromolecules such as peptides via injectable and alternative routes such as transdermal. and oral Annette is also active in the area of pharmaceutical cocrystal design to optimise design formulation properties, physicochemical to ensure sufficient and targeted pre-clinical and clinical exposure, and strategies to ensure effective project translation from discovery to early development. Annette has authored more than 35 publications and has been aninvited speaker/presenter at over 30 scientificvenues. People spotlight People

paper, paper, as well as the as well as the Science Large scale lab - chromatography scale Large Advanced Drug Delivery Drug Advanced gained a strong scientific reputation in the nanomedicine the space. In 2016, team achieved a high impact review in Delivery Drug Advanced Medicine Translational Science and two further high quality papers in the area, presenting at a number of key conferences and connecting with several academickey groups and labs within the drug delivery field. 2016 In the 2016, team achieved a high impact review in of key conferences and connecting with several key academic groups and labs within the drug delivery field. Translational Medicine paper, Medicine and two furtherTranslational high quality papers in the area, presenting at a number

In collaborationwith Starpharma and using their dendrimer technology, a second has nanomedicine approach been adopted. In this approach the drug is conjugated a dendrimer to resulting in both improved tolerability and solubility of a lipophilic drug. A number of targets in our Oncology portfolio are currently being evaluated with this technology. also has Sciences Pharmaceutical implemented the innovative modelling effortsto help in the design phase and built an internal capability produce to nanoparticles, prototype enabling rapid exploration in internal projects. In addition, the team has been driving across collaboration through science further to IMED, understand the elements translational and technology of nanomedicines including potential impact in combination therapy. Our approach of using nanoparticle technology as part of the discovery phase enable to new candidate drugs from challenging targets is industry- leading and our work in the area has paper ) using an ion pairing pairing ion an using ) ® IMED functions Sciences Pharmaceutical Lack of therapeutic index remains a major challenge in developing innovative cancer medicines. Nanomedicines can be used change to a candidate drug’s and tumours target to biodistribution also regulate the rate of drug release from a nanoparticle improve to safety and efficacy. Pharmaceutical Sciences championed nanomedicinehas using approaches improve to therapeutics index and enable project progression. is an AuroraAZD2811 B kinase inhibitor acute in results promising showed that myeloid leukaemia patients but was limited therapeutic by index. Through collaboration with BIND Therapeutics, whose assets were subsequently acquiredwe successfully Pfizer, by encapsulated into a novel AZD2811 nanoparticlepolymericformulation (ACCURINS Using nanomedicines to enable innovative cancer innovative enable Using nanomedicines to index therapeutic medicines with improved published in February 2016. approach. AZD2811 nanoparticles AZD2811 approach. sites tumour to biodistribution increase and provide extended release of drug in the This tumour. is currently being clinically evaluated as a treatment for and tumours solid and haematological is currently in Phase I MAD This study. is the first AstraZeneca nanomedicine project in clinical development and the first non-cytotoxic drug in clinical development in a polymeric nanoparticle. This work resulted in a high impact Medicine Translational Science 86 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives TNO gastrointestinal model 1 (TIM1) TNO gastrointestinal tract upper gastrointestinal Lammers T, Kiessling F, Ashford M, Hennink M, Hennink Ashford Kiessling F, Lammers T, G D, Strorm Crommelin W, Harburn J, Steed J, McCabe J, Berry D Corner P, Hare J, Lammers T, Ashford M, Puri S, Storm G, Ashford J, Lammers T, Hare Barry S Phillips A, Coobmes S, Kiraly P, Moutzouri P, Nilsson M, Morris G H, Andersen SM, Cruz Karlsson S, Sorensen P A, Ryberg Author Delivering our pipeline through scientific leadership 89 Cancer nanomedicine: is targeting our target? Cancer nanomedicine: is targeting Stabilisation of amorphous form of ROY by co-former interaction of a predicted presence Challenges and strategies in anti-cancer Challenges and strategies in anti-cancer nanomedicine development: an industry perspective detection and Clearing the undergrowth: quantification of low level impurities using 19F (NMR) nuclear magnetic resonance of an alkenoic An enantioselective hydrogenation acid as a key step in the synthesis of AZD2716 Title Publication Advanced Drug Delivery Drug Delivery Advanced Reviews Nature Reviews Materials Reviews Nature Chemical Communications Chemical Communications Research Process Organic and Development Key publications in 2016 publications Key 1 9 8. Munich, Ludwig-Maximilians-University Germany we are Rädler, Joachim with Professor Together scattering to study using a small angle x-ray (bulk phae) of lipid nanoparticles how the core also are We to pH changes. (LNP) respond translation using – ie studying single cell mRNA synthesis – of mRNA mRNA uptake and protein part of this collaboration the LNPs and in a third on LNP surface (using adsorption of proteins spectroscopy). correlation fluorescence 9. Perth, Australia Curtin University, Andrew In collaboration with Professors computer using Rohl and Julian Gale, we are simulation to model the physical performance of molecular crystals, aimed at building a computational methodology for the identification and quantification of crystalline slip planes and allowing for distinguishing between elastic and plastic deformations in materials. 10. University of Innsbruck, Austria of the University Bernkop-Schnürch With Andreas self-emulsifying researching of Innsbruck, we are drug delivery systems (SEDDs). SEDDs are of oils, surfactants and solvents/ mixtures isotropic co-solvents that form stable emulsions in the shown promise (GI) tract and have gastrointestinal for oral delivery of peptide drugs. The aim is to exploit the application of SEDDs optimised for oral delivery of antisense oligonucleotides. 3 8 10 6 4 2 5 Joining the Crystal Form Consortium, we are Joining the Crystal Form Consortium, we are working with leading chemists with the aim to crystal small molecule derive knowledge from The to inform solid form selection. structures Crystal Form Consortium is a collaborative chemists bringing together development venture sector leading companies in the industrial from experts database and research with software, has at the CCDC. The Consortium currently spanning major 14 member organisations businesses pharmaceutical and agrochemical the world. around 7. Dame, US University of Notre Olaf Wiest, In Collaboration with Professor we aim to develop a method that can predict enantioselectivity for given substrates and The method catalysts, with a high accuracy. has been implemented as a virtual screening with the robotic capability that is synergistic facility used by Pharmaceutical screening Science in Macclesfield UK. By selecting only expected to give high selectivity, ligands that are can be concentrated on screening the robotic the potentially improving efficiency and stability, of magnitude. capacity by 1-2 orders screening In collaboration with Professors Ian Paterson and In collaboration with Professors of Cambridge, we David Spring at the University to further understand and advance working are (ADC) Chemistry. Antibody Drug Conjugate of to progression Innovative science is key the therapeutics, where such ‘next-generation’ therapy avoids dose-limiting potential of targeted that occurs because of toxicity of chemotherapy The development of its effects on normal cells. by synthetic chemists new linkers and warheads advancement of will be crucial to the further of next generation the field and the emergence ADCs. 6. The Cambridge Crystallographic Data (CCDC), UK Centre 5. UK University of Cambridge, 7 IMED functions Sciences Pharmaceutical In collaboration with Professor Jonathan Steed Jonathan In collaboration with Professor focused on at the University of Durham, we are crystallization small molecule gels as targeted Gels, formed media for solid form discovery. web of by liquid trapped within a porous hold many technological fibres, nanometre-scale possibilities, for example as selective sorbents or uptake agents. 4. University of Durham, UK Working together with Professor Hadi Valadi Hadi Valadi together with Professor Working this collaboration studies exosomes as an mRNA delivery system. This collaboration aims to evaluate the possibility of using Lipid Nanoparticle (LNPs) to load a modified mRNA cell different into exosomes originating from types. Using LNPs, we aim to further optimise and to of exosomes the mRNA loading process evaluate transfection of mRNA loaded exosomes and in vivo. in vitro 3. Sweden University of Gothenburg, 2. UK University of Cardiff, Jones Arwyn T. In collaboration with Professor working we are at the University of Cardiff, and understand the together to characterise trafficking pathways of intracellular delivery and tumour cell mRNA delivery systems in different of how understanding lines. By gaining a greater trafficked the delivery systems enter and are how cell types, we aim to explore by different this knowledge can be applied to design and the efficient strategies for develop improved intracellular delivery of nucleic acids and other macromolecules. This collaboration is to explore the benefits ofThis collaboration is to explore dendrimer technology to improve Starpharma’s in AstraZeneca’s the therapeutic index of drugs Oncology portfolio and pipeline. 1. Starpharma, Australia A selection of key collaborations in 2016 in collaborations of key A selection 88 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Antisense oligonucleotides Antisense synthetic are Antisense oligonucleotides acids nucleic strandedsingle strings of

a generation 2.5 oligonucleotide antisense a that prevents expression of signal transducer (STAT3). transcription 3 of activator and plays that transcription factor a is STAT3 proliferation, normal cell in critical role a differentiation, and apoptosis. It has been an creates signalling STAT3 that shown tumours in environment suppressive immune which can contribute to escape from treatment. Suppression inhibitor checkpoint usingof AZD9150 STAT3 has been shown in animal models to enhance response to we year, this and, inhibitors checkpoint were excited to progress the combination of AZD9150 with durvalumab into Phase II. that bind to RNA and thereby alter or reduce expression of the target RNA. They can reduce the expression of proteins targeted transcript, the of breakdown by protein restore can they alternatively expression or modify proteins through interference pre-mRNA with splicing. Antisense drugs can potentially be created for any target including many previously considered un-druggable traditional small by technology. molecule haveWe been working in collaboration with Ionis Pharmaceuticals to discover and cancer treat to drugs antisense develop developing expertise in our combining by antisense Ionis’ anti-cancer with agents platform.technology One of the candidates in clinical development that has shown significant progression this year is AZD9150, Delivering our pipeline through scientific leadership91 Delivering our pipeline through scientific leadership 91 800 microRNAs been have identified in the human genome

new

Anti-microRNA MicroRNAs are small RNA molecules, typically 20 to nucleotides25 in length, that do not encode proteins but rather regulate gene expression. More than 800 microRNAs have been identified in the human genome, and over two-thirds of all human genes are believed beto regulated microRNAs. by A single microRNA can regulate entire networks of genes and microRNA expression, or function, has been shown be to significantly altered or dysregulated in many disease states. Developing chemically modified single stranded oligonucleotides that target microRNAs, anti-miRNAs, offers a unique approachto treating diseaseby modulating entire biological pathways. During have we worked 2016, with Regulus to discover and develop microRNA therapeutics for potential application in cardiovascular, metabolic and renal diseases, as well as cancer. As a result of this research, saw progression 2016 into the clinic for AZD4076 - a GalNAc-conjugated anti-microRNA, targeting as a treatment miR103/107 for diabetic patients with non-alcoholic steatohepatitis (NASH). Increased expressionin the liver of miR-103/107 has been associated with insulin resistance in people with NASH. Pre-clinical studies have shown AZD4076 affectto biological pathways implicated in NASH progression, as well as improved insulin sensitivity and glucose tolerance in animal models. pioneering

Case Study if not impossible, to target. to target. if not impossible, At AstraZeneca, through our collaborative approach, many candidates candidates many approach, our collaborative through AstraZeneca, At significant saw and in 2016 we modalities in our pipeline utilise new the across delivered science being thanks to thegreat progression the opportunity to design modalities provide Unit. New IMED Biotech difficult, considered to disease mechanisms previously therapeutics Advances in our understanding of molecular biology and genomics, biology of molecular in our understanding Advances acid, nucleic to synthesise and manipulate developments technological up an extremely opened have systems drug delivery as advanced as well agents. acids as therapeutic opportunity to use nucleic exciting 90 IMED Annual Review 2016 90 IMED Annual Review2016 Synthetic RNA messenger Messenger RNA Therapeutics™ is a novel drug technology that leverages the fundamental role that mRNA plays in protein synthesis, produce to human proteins inside patient cells. Synthetic messenger RNA is delivered directly tissue, to stimulating the production of intracellular and secreted therapeutic protein, without triggering an innate immune response. This unique approach opens up new treatment options for a wide range of diseases that cannot be addressed today technologies. existing using have beenWe working in close collaboration with Moderna Therapeutics™ discover, to develop and commercialise this pioneering technology for the treatment of serious cardiovascular, metabolic and renal diseases, as well as cancer. This have we year, progressed the first candidate, AZD8601,towards clinical development, resulting in the first patient being successfully dosed in January 2017. AZD8601 encodes for vascular endothelial growth factor-A (VEGF-A), a protein known for stimulating tissue repair and cardiac regeneration. AZD8601 is directed via local tissue injection and initiates a strong, local and transient surge of VEGF-A expression, which may lead the to creation of more blood vessels and improved blood supply. The compound has been shown improve to cardiac function and increase neovascularisation in animal models with heart failure and has also shown efficacy in animal models with wounds. diabetic The programme represents a new scientific and medical approach that could one day provide a unique regenerative treatment option for patients with heart failure or after a heart attack, as well as for diabetic wound healing and other ischaemic vascular diseases.

AstraZeneca’s Nucleotide platforms: modality science Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 93 Delivering our pipeline through scientific leadership 93 Ruth March, VP PersonalisedRuth March, and Biomarkers Healthcare osimertinib as a treatment also delivered We option. our first beyond diagnostic Biomedical the Nova Oncology; a point- Test, Acid Pro Uric that measures test of-care treatment. gout to response industry- our announced We leading genomics initiative, led by Professor David Goldstein, in April. This unprecedented strategy the analysis on focuses from two sequence genome of identify new to million patients targets and biomarkers linked mechanismsto disease, of our entire across integrated research and development pipeline.” “We aim use Personalised to “We Healthcare (PHC) transform to patients’ livesthrough personalising treatment. our drugMany of launches diagnostic tests on rely now and biomarkers to match AstraZeneca to medicines likely benefit. most to patients six launched we In 2016 diagnostic tests linked to our medicines, through partnerships with diagnostic particular, In companies. Food and first AstraZeneca’s Drug Administration (FDA) approved companion diagnostic tumour circulating on based cancer lung enabled DNA a unable provide to patients be offered to tissue sample

Minute pieces of circulating tumour Minute pieces of circulating DNA (ctDNA) in the bloodstream IMED functions Personalised Healthcare Biomarkers and 92 IMED Annual Review 2016 92 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives David Goldstein David Professor David Goldstein joined AstraZeneca in September to lead our integrated genomics initiative. David is the Director of the Institute for Genomic Medicine and Professor of Genetics and Development at Columbia University. Heis renowned for his research on human genetic diversity, the genetics of disease and pharmacogenetics. Professor Goldstein received his PhD in biological sciences from Stanford University and has previously held positions at University College London and Duke University, North Carolina. He has published over 250 papers in the field and is a recipient of the Royal Society Wolfson Research Merit Award. Delivering our pipeline through scientific leadership 95

50 areWe well on track to deliver around 50 drug launches by 2023 requiring a diagnostic test. Looking forward our to next of wave PHC innovation, announced we the launch of an industry-leading integrated genomics initiative focused onthe analysis of genome sequence from two million patients, aimed at validating newtargets and biomarkers linked to mechanisms of disease. welcomed We Professor David Goldstein the to team, who will lead the scientific direction of the initiative, while continuing in his full- time role at Columbia University Medical Center. During began we build to 2016, our in- house centre for Genomics Research, analysing genomic data from academic partners as well as our own clinical trials, helpto apply these potentially ground- entire our across insights breaking research and development pipeline.

EGFR Mutation Test v2’, EGFR Mutation v2’, Test ® Investigation of protein expression in a positive expression Investigation of protein (TMA) on a Tissue Microarray tissue core control slide containing non-small cell lung cancer In 2016 we worked we with ourIn 2016 expert tests diagnostic six partners launch to linked our to medicines, increasing our totalnumber diagnostics of launched Our focus15. to on scientificsince 2014 innovation has led AstraZeneca’s to first FDA approved circulating tumour DNA (ctDNA) companion diagnostic, the ‘cobas Roche expanding the option for treatment with osimertinib non-small to cell lung cancer (NSCLC) patients who are unable to provide a tissue sample. Our commitment bring to PHC to main across AstraZeneca’s patients therapy areas has resulted in our first diagnostic outsideof Oncology: the BiomedicalNova Pro Uric Acid Test, a hand held point-of-care test aligned to lesinurad, which can be used measure to a patient’s response gout to treatment. Bringing personalised Bringing personalised to patients healthcare disease with respiratory As part of our drive accelerate to delivery of personalised healthcare across our main therapy areas, developed have we an innovative prototype point-of-care diagnostic test for eosinophilic respiratory disease. The prototype combines novel electrochemistry and metallic nanoparticle traditional with signaling immunoassays, provide to sensitive and quantitative detection of soluble biomarkers. successfully have We demonstrated proof of concept in a pilot clinical study and with our partners, AgPlus Diagnostics (UK), Ltd aim we deployto the hand-held prototype test into early clinical trials. This diagnostic can be advanced help to physicians in specialty and primary care rapidly to identify the right respiratory treatment for the right patient.

drug launches with a companion diagnostic test by 2023. by test diagnostic withdrug a companion launches a PHC approach. We are well on track to deliver around 50 around deliver to track are on well We approach. a PHC and more than 80% of our clinical pipeline now following following than now clinical more and 80%our of pipeline to achieve this, with 95% of our small-molecule pipeline pipeline this, small-molecule our with of achieve 95% to invested heavily in the skills, heavily partnerships technology and invested science based approach to drug development. We have have We drug to development. approach based science Personalised Healthcare (PHC) is at the heart our (PHC) at is Healthcare of Personalised IMED functions Personalised Healthcare Biomarkers and 94 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives 500 conductedWe the largest and most comprehensive study to compare the assays analysing squamous cell carcinoma of the head and neck (SCCHN) tissue samples from 500 patients

Delivering our pipeline through scientific leadership 97

Jill Walker Jill Jill Walker is a recognised leader in the diagnostic science testing, of PD-L1 representing AstraZeneca on the cross- industry Blueprint Consortia and directing an unprecedented series of large-scale assay comparison studies that have established AstraZeneca as an industry leader. As Executive Diagnostic Director for our immuno-oncology programs, Jill uses diagnostic and clinical in background her development to drive testing and diagnostic submissions for durvalumab and the combination of durvalumab and tremelimumab in pivotal over 10 clinical studies. Jill has co-authored some of the most significant publications in the field and has extensive diagnostic international in experience regulatory interactions. Our results in NSCLC were presented at the American Association for Cancer Research (AACR ) congress in showing an2016, overall percentage agreement across of >90% the three tests. available commercially theAt European Society for Medical Oncology congress, (ESMO) 2016 we presented the comparison data for SCCHN showing high–level agreement between three assays (Dako 22C3, Dako 28-8, Ventana SP263), but clear differences Ventana with(both SP142 for tumour and immune cell staining). Results from this study are already being applied in clinical development, using diagnostic science help to interpret results from the many PD-L1 tests available. expect We that this data will lead better to use of scarce decisions clearer and resources clinical for patients.

People spotlight People PD-L1 assay and most comprehensive Largest comparison express tumours whose Patients are morePD-L1 likely benefit to from immuno-oncology therapies. set We out compare to the four commercially measure that tests diagnostic available expression;PD-L1 Dako 22C3, Dako 28-8, Ventana SP263 (developed in partnership with MedImmune) Theseand Ventana assaysSP142. beenhave developed independently and use different antibody clones, immunohistochemistryprotocols, scoring algorithms and cut-offs. conductedWe the largest and most comprehensive assay PD-L1 comparison studies in 500 tissue samples from patients with NSCLC (using Dako 22C3, Dako 28-8, Ventana SP263) and in 500 samples from patients with head and neck squamous cell carcinoma of the head and neck (SCCHN) cancer (using Dako 22C3, Dako 28-8, Ventana SP263, Ventana SP142). Alexander Kohlmann Alexander Alexander Kohlmann is a leader in innovative diagnostic science, whether using novel ctDNA testing or multi-gene panel next-generation sequencing; recently, his collaboration with the CRUK-Cambridge Institute, using a portable third generation Nanopore sequencing device, has generated exciting proof-of-principle data. Alexander has published peer-reviewed over 120 papersto date and is using experience gained in his previous role from theMunich Leukemia Laboratory to spearhead a new wave of companion diagnostictests in AstraZeneca. As franchise lead for haematology programmes in Oncology PHB’s companion diagnostic unit, he has delivered central prospective diagnostic testing for early and late stage Oncology programmes (e.g. PARP inhibitor olaparib and MET inhibitor savolitinib).

EGFR Mutation Test v2’ tissue (Japan) and plasma test (US, Japan) for selecting v2’ tissue (Japan) and plasma EGFR Mutation Test ® We launched an integrated genomics initiative to transform drug discovery and development launched an integrated genomics initiative to transform We high-profile with several and development pipeline. Together research entire our across million genome sequences. two an unprecedented collaborators, we will leverage information from AstraZeneca in September and will David Goldstein joined Renowned genomics expert Professor of the initiative. for driving the scientific progress be responsible for PHC drugs in FDA approvals is industry leading; we have achieved more Our PHC approach the last two years than any other pharmaceutical company. our companies, increasing with diagnostic have signed 10 new collaboration agreements We a number of leading academic also partnering with are investment to over $160 million. We University Columbia University, Centre, including Stratified Medicines Scotland Innovation centres, Sanger Institute. Trust Heart Institute and Wellcome of Helsinki, Montreal high impact and 36 high quality three have demonstrated our scientific leadership through We journals this year. publications in peer-reviewed We launched six diagnostic tests with our diagnostic partners, linked to three AstraZeneca tests with our diagnostic partners, linked to three launched six diagnostic We medicines: Roche ‘cobas (EU), the Uric Acid Test Pro initiated, in addition to the launch of the Nova Biomedical We with our partner patients diagnostic for respiratory development of an innovative point-of-care AgPlus Diagnostics Ltd. CVMD clinical 20,000 samples from on approximately out genomics research carrying are We studies with associated clinical endpoints. in NSCLC and squamous cell studies and most comprehensive largest the world’s delivered We PD-L1 assays. available of the head and neck (SCCHN) comparing commercially carcinoma PD-L1 antagonists in with PD-1 and supports patients treated Our industry leading approach clinical practice. to implement a highly sensitive, AKT1 used innovative BEAMing digital PCR technology We selectThe test was used to prospectively mutation ctDNA plasma test (Sysmex Inostics, Inc). patients by screening study recruitment patients for a new medicine in a clinical trial, accelerating participate. who would not otherwise have had the opportunity to EGFR T790 of concept data for a novel method (‘CAm-seq’) to identify proof delivered We MinION Nanopore sequencing technology (Oxford mutations using cutting-edge Nanopore hasand technologies sequencing current of prospects the beyond us takes assay The instrument). diagnostic ctDNA testing in the future. the potential to deliver rapid, non-invasive, portable We delivered We patients with the T790M mutation for treatment with osimertinib. for treatment patients with the T790M mutation uric acid as serum (EU), to measure (POC) Test Uric Acid point-of-care Nova Biomedical Pro including lesinurad. gout treatment, to a biomarker for patient response sequencing (NGS) FFPE Kit and Multiplicom’s BRCA 1-2 next-generation therascreen Qiagen’s CE-IVD-labelled molecular diagnostic tests, on complementary MASTR™ Plus; two BRCA Tumour with olaparib. with BRCA1 and BRCA2 mutations for treatment platforms, for selecting patients over 80% right patients to medicines in our clinical trials with committed to matching the are We of our clinical pipeline having a PHC approach.of our clinical pipeline having

Establish leading scientific reputation reputation scientific Establish leading healthcare in personalised Transform discovery and development and development discovery Transform approach genomics with an integrated Drive new technologies and novel and novel technologies new Drive diagnostic of approaching ways testing Bring the benefits of personalised Bring thepersonalised benefits of Oncology (PHC) beyond healthcare to all therapy areas to all therapy We set out to We (PHC) healthcare personalised Deliver to patients IMED functions Healthcare Personalised Biomarkers and 96 IMED Annual Review 2016 Highlights Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 99 DNA strand and red blood cells DNA strand and red bladder - 19 Entities Large molecule moxetumomab pasudotox# PLAIT CD22 HCL durvalumab# PD-L1 2L tralokinumab IL-13 severe asthma benralizumab# IL-5R severe asthma anifrolumab# IFNαR SLE

breast

Alzheimer’s

2 diabetes Type 2 diabetes Type Phase III and Life Cycle Management Phase III and Life Cycle PHC adoption across AstraZeneca pipeline across PHC adoption Small molecule hyperkalaemia PT010 LABA/LAMA/ICS COPD AZD3293# BACE Early disease acalabrutinib# BTK inhibitor B cell malignancy selumetinib MEK 2Ldiff.thyroid olaparib / BRCAm ovarian & breast osimertinib EGFR NSCLC fulvestrant ER antagonist ticagrelor P2Y12 acute coronary syndromes dapagliflozin SGLT2 saxagliptin 2 diabetes Type DPP4 exenatide GLP1 epanova omega-3-carboxylic acids hypertryglyceridaemia roxadustat# HIFPH anaemia CKD/ESRD ZS-9 potassium exchanger Applicable

treatment

# A Project with PHC Approach PHC Not RIA CMVD Oncology Other zumab# ACS

asthma/atopic dermatitis Large molecule MEDI-573# cancer IGF metastatic breast MEDI0382 GLP-1/glucagon diabetes/ obesity MEDI4166 PCSK9/GLP-1 diabetes/CV MEDI6012 LCAT AZD9412 Inhaled βIFN asthma/COPD tezepelumab# TSLP inebili CD19 neuromyelitis optica mavrilimumab# GM-CSFR rheumatoid arthritis MEDI5872# syndrome primary Sjögren’s MEDI3902¶ Psl/PcrV pseudomonas MEDI4893 staph alpha toxin SSI MEDI8852 influenza MEDI8897# RSV passive prophylaxis

6 asthma/COPD Entities Phase II - 27 New Molecular Small molecule Includes significant fixed dose combination projects, and parallel indications that are in a separate therapeutic area # Partnered; ¶ Registrational Phase II/III study miR103/107 NASH abediterol# LABA AZD1419# TLR9 asthma AZD7594 Inhaled SGRM asthma AZD3241 Atrophy MPO Multiple System MET pRCC MET vistusertib (AZD2014) 1/2 solid tumours mTOR AZD9150# & solids haems STAT3 AZD5069 CXCR2 haems & solids AZD3759 EGFR-BBB NSCLC CNS mets AZD6738 solid tumours ATR AZD407 AZD1775# solid tumours Wee1 AZD4547 FGFR solid tumours AZD5363# breast cancer AKT savolitinib# Pipeline correct as of Q4 2016. Pipeline correct

Alzheimer’s disease Large molecule MEDI0562# hOX40 solid tumours MEDI0680 PD-1 solid tumours MEDI1873 GITR solid tumours MEDI4276 HER2 solid tumours MEDI-565# GI tumours BITE CEA MEDI9197# TLR 7/8 solid tumours MEDI9447 CD73 solid tumours MEDI8111 Rh-FactorII trauma/bleeding MEDI9314 IL4R atopic dermatitis MEDI1814# amyloidβ MEDI7352 NGF/TNF osteoarthritis pain MEDI0700# BAFF/B7RP1 SLE MEDI4920 CD40L-Tn3 pSS MEDI7734 myositis ILT7

cardiovascular CAD Entities Phase I - 27 New Molecular Small molecule PHC adoption across AstraZeneca pipeline across PHC adoption AZD0284 DPP1 COPD AZD9567 ATM solid tumours solid ATM AZD2811# Aurora solid tumours AZD4635 A2aR inhibitor solid tumours AZD8186 PI3Kβ solid tumours AZD9496 SERD ER+ breast AZD4831 MPO HFpEF AZD5718 FLAP AZD8601# VEGF-A Inhaled RORγ psorisis AZD5634 Inhaled ENaC cystic fibrosis AZD7986# oral SGRM RA AZD8871# COPD MABA AZD0156 IMED functions Healthcare Personalised Biomarkers and 98 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives 10 care diagnostic test for eosinophilic respiratory respiratory diagnostic test for eosinophilic care disease available to patients via their physicians. 8. Myriad Genetics, US expanded our companion diagnostic We collaboration to seek Japanese regulatory for the BRACAnalysis CDx, to select approval patients with BRCA1/BRCA2 mutations for with olaparib. treatment 9. UK Cambridge Institute, UK Cancer Research principle proof-of This collaboration delivered third-generation cutting-edge nanopore Nanopore sequencing data using the Oxford device. MinION Technologies 10. The Institute for Molecular Medicine, Finland This collaboration studies AZ genes of interest in This collaboration studies AZ genes of interest the Finnish population, which is known to carry genetic rare of a higher than normal frequency variants. Finland‘s integrated health record system and national biobanking law facilitate volunteers carrying these the invitation to recall clinical evaluation. variants for thorough Mosko MJ, Nakorchevsky AA, Flores E, Met- E, AA, Flores Mosko MJ, Nakorchevsky Boom DJ, Sherwood zler H, Ehrich M, van den AO JL, Nygren JM, Heuckmann V, Rooney C, Geh C, Williams K, Dymond Al-Kadhimi Menon R, Schneider P, Smith PD, T, French M, Smith NR, Baker D, JC, Kilgour E Harrington EA, Barrett 9 7 Delivering our pipeline through scientific leadership 101 5

Longevity, Inc (HLI), from which HLI will sequence Inc (HLI), from Longevity, exomes or genomes. These genomic samples will include those donated by patients under optional clinical trials. informed consent in AstraZeneca’s 5. Stratified Medicine Scotland Innovation UK Centre, A collaboration to enable access to genomic of DNA samples. Through thousands from results this collaboration, partners will be able to recall patients for further genetic and clinical evaluation to gain additional insights. 6. US Columbia University Medical Center, A collaborative genomic initiative between AstraZeneca and Columbia University Medical Center to analyse and extract meaning from patients genomic datasets, including those from held in the New York with medical records Medical Center’s University Presbyterian/Columbia clinical data warehouse. 7. AgPlus Diagnostics, UK our collaboration with AgPlus, we aim to Through make a rapid and innovative handheld point-of- Ultrasensitive Detection of Multiplexed SomaticUltrasensitive Detection Assisted LaserMutations Using Matrix of Flight (MALDI-ToF) Desorption/Ionization - Time Mass Spectrometry locus in squamousCharacterisation of FGFR1 (sqNSCLC) non-small cell lung cancer amplicon and heterogeneous broad a reveals 3 6

2 8 4 1 Journal of Molecular of Molecular Journal Diagnostics PLoS ONE to share up to 500,000 DNA samples with Human to share A selection of key collaborations in 2016 collaborations of key A selection 1. Roche, US approved a regulatory Our collaboration delivered blood based diagnostic for T790M testing, which allows patients access to osimertinib in cases biopsy sample available. is no there where 2. Roche Tissue Diagnostics, US across A collaboration that supports projects of immuno- indications. In the area numerous programme, durvalumab the specifically oncology, the partnership focuses on delivering a PD-L1 diagnostic assay based on SP263 aimed at patients. decisions for optimising treatment 3. Foundation Medicine, US with Foundation Medicine enables Working genomic AstraZeneca to use comprehensive in clinical for patient stratification profiling in several being followed trials – an approach in clinical development. currently programmes 4. Human Longevity Inc, US This collaboration allows AstraZeneca Badoer C, Garrec C, Goossens D, Ellison G, C, Goossens D, Ellison G, Badoer C, Garrec H, Berwouts S, Mills J, Dzial M, El Housni Delnatte C, Favero Guevellou VG, Concolino P, S JD, Capoluongo E, Bézieau Stanforth D, Hirsch FR, McElhinny A, J, Jansson M, Kulangara K, Ranger-Moore - Hanks D, Vennapu P, Towne W, Richardson S, R, Averbuch sa B, Mistry A, Kalamegham K, McCaffery Novotny J, Rubin E, Emancipator J, Tsao J, Longshore I, Williams JA, Walker MS, Kerr KM Reck M, Hagiwara K, Han B, Tjulandin S, Morabito A, Novello S, T, C, Yokoi Grohé Arriola E, Molinier O, McCormack R, Ratcliffe M, Normanno N Murray MJ, Bell E, Raby KL, Rijlaarsdam MA, H, Destenaves Gillis AJ, Looijenga LH, Brown B, Nicholson JC, Coleman N Ratcliffe MJ, Sharpe A, Rebelatto M, Scott M, J Walker P, Barker C, Scorer Cebers G, Alexander RC, Haeberlein SB, Han Ye T, L, Olsson D, Goldwater R, Ereshefsky N, Rosen L, Russell M, Maltby J, Eketjäll S, Kugler AR H, Sharpe C, Brown Sherwood JL, Corcoran AD, Musilova M, Kohlmann, A JC, Yang Z, Kim DW, Yang JW, Yates P, Ballard Hickey M, A, Cantarini M, Pickup K, Jordan K, Malm- Varnӓs Grist M, Box M, Johnstrӧm P, D Cross KS, Jӓnne PA, quist J, Thress S, Arsenault HR, Trompet Postmus I, Warren CL, Bis JC, Chasman DI, de Keyser BJ, Avery CE, Deshmukh HA, Evans DS, Feng Q, Li X, KD, Arnold Taylor Sun F, Smit RAJ, Smith AV, AM, Barnes MR, Barratt BJ, Betteridge J, Boekholdt SM, Boerwinkle E, Buckley BM, Ida de Craen AJM, Cummings SR, Denny Chen Y, Durrington PN, Eiriksdottir G, JC, Dubé MP, I, Guo X, Harris TB, Heckbert SR, Hofman Ford Launer LJ, Liu A, Hovingh GK, Kastelein JJP, PB, McKeigue PM, Munroe Lumley T, C, Liu Y, O’Brien E, F, Neil A, Nickerson DA, Nyberg RS, Poulter N, Vasan O’Donnell CJ, Post W, Sattar N, Sever Rice K, Rich SS, Rivadeneira F, Shaw-Hawkins S, Shields DC, Slagboom PE, P, Smith NL, Smith JD, Sotoodehnia N, Stanton Uitterlin- A, Stott DJ, Stricker BH, Stürmer T, EA, RGJ, Whitsel Westendorp W, den AG, Wei Wiggins KL, Wilke RA, Ballantyne CM, Colhoun HM, Cupples LA, Franco OH, Gudnason V, Hitman G, Palmer CNA, Psaty BM, Ridker PM, Caulfield MJ, J, Tardif JM, Stein CM, Stafford Rotter JI, Krauss RM Jukema JW, Author

Comparison of Pre-clinical Activity of Osimertinib Activity Comparison of Pre-clinical with Other EGFR-TKIs in EGFR-Mutant non-small cell lung cancer (NSCLC) Brain Metastases Models, and Early Evidence of Clinical Activity in Patients with Brain Metastases Meta-analysis of genome-wide association (HDL) studies of high-density lipoprotein A pipeline to quantify serum and cerebrospinal A pipeline to quantify serum and cerebrospinal detection of for diagnosis and fluid microRNAs cell tumours in paediatric malignant germ relapse A comparative study of PD-L1 diagnostic of the head assays in squamous cell carcinoma and neck (SCCHN) AZD3293: Pharmacokinetic and pharmacody- and patients in healthy subjects namic results disease with Alzheimer’s KRAS improve methods Optimised pre-analytical tumour DNA mutation detection in circulating cell lung patients with non-small (ctDNA) from cancer (NSCLC) to statins response cholesterol Performance of Multiplicom’s BRCA MASTR BRCA Performance of Multiplicom’s BRCA1 and BRCA2Dx kit on the detection of tumor breast and ovarian frozen fresh in mutations samples (IHC) Assays forPD-L1 Immunohistochemistry Phase 1 of the Blue- Lung Cancer: Results from Project print PD-L1 IHC Assay Comparison DNA (ctDNA) Tumor-derived Free Circulating - Determination of EGFR Mutation Status in Re Patients with and Japanese al-world European Advanced non-small cell lung cancer (NSCLC): the ASSESS Study Title Publication OncoTarget OncoTarget Journal of Medical Genetics of Journal Clinical Cancer Research PLoS ONE Journal of Alzheimer’s Journal Disease Annals of Oncology British Journal of Cancer of Cancer British Journal Journal of Thoracic of Thoracic Journal Oncology Journal of Thoracic of Thoracic Journal Oncology Key publications in 2016 publications Key IMED functions Healthcare Personalised Biomarkers and 100 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Key facts areWe working with public and private partners (HLI), Longevity Inc Human including University, Helsinki Sanger Institute, The England, Genomics Montreal Heart Institute, Columbia and Scotland Medicine Stratified University Center. Medical willWe analyse sequences from up to two ~500,000 samples including genomes million from AstraZeneca’s clinical trials, donated by patients from the past and next 15 years. 10 Genomic data will be integrated with clinical data in a bespoke, integrated database of at least five petabytes (PB). Latest big data analytical techniques will be used to understand the influence of genomics on the causes of disease as well as response treatment. to pipeline entire transform our will initiative This development and discovery drug driving therapeutic areas. our all across Delivering our pipeline through scientific leadership 103 Delivering our pipeline through scientific leadership 103

Harnessing the power of the genome through generation next in technological advances bioinformatics and sequencing Until recently, DNA sequencing remained prohibitively expensive and tooslow be to than $1,000. Genomic data from this initiative will be combined with extensive clinical data, including up 500 to measurements per patient from our clinical trials. The latest big data analytical techniques will be used integrate to and mine this data, giving a unique opportunity analyse to the influence of genomics, not only on the causes of disease, but also on response treatment. to The scale of this data is needed identify to those very rare genomic differences that interact with the environment cause to disease. used routinely in drug discovery and development. The first human genomewas sequenced in 2003, a remarkable breakthrough in genomics, which years took 10 complete to and cost nearly $3 billion. Using next-generation sequencing (NGS) can we now sequence whole human genomes in only a few days, for less

Case Study and development platforms, our genomics initiative will help us deliver to novel insights into the biology of diseases, enable the identification of new targets for medicines, support selection of patients for clinical trials and allow patients beto matched with treatments more likely to benefit them. so the knowledge gained from an unprecedented two million genomes can be applied comprehensively across our entire research and pipeline. development By embedding genomics across all research

to develop new treatments treatments new develop to Harnessing the code of life life of code the Harnessing Studying genome sequences across large populations allows the development of innovative new treatments andhelps target to the right patient the to right medicine. For decades, scientists have predicted that one genomicday, studies would transform drug development and patient care. Now is a pivotal time in genomics research where can we start harnessto the power of the genome. This is why have we launched an integrated genomics initiative, advised Professor by David Goldstein, transformto drug discovery and development. The genomics initiative is centred on samples donated patients by through clinical trials. The full genome sequence from these patients will be combined with extensive clinical and drug response data from clinical studies. This insight will be combinedwith genomic information from collaborative partners in a bespoke database, 102 IMED Annual Review 2016 102 IMED Annual Review 2016 A genome is the full instructionsA genome of set make to every needed cell, tissue in and organ consists our In bodies. humans,the genome than more of three base define pairs, DNA together which billion theus in information as unique of most individuals. Although is the same between individuals, there arethe genome small can differences combine believe scientists withenvironmental that such as diseases to cause diabetes, influences asthmaor cancer. Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Stratified Medicine Scotland Medicine Stratified partnershipThe AstraZeneca between and Innovation Scotland Medicine Stratified the represents Scotland, NHS which Centre, industryScottish and Universities partners, initiative The opportunities. unique offer will will not only have access to genomic results generously samples DNA of thousands from donated for research by patients in Scotland Scotland, in healthcare system the to due but, recall patients to partners able be our also will to evaluation further clinical and for genetic insights. additional gain Access to this resource of genomics results potential records great has patient to aligned in helping us to find new drug targets and identify most patients we way the improve likely to benefit from novel therapies. 500,000 samplesgenomic with clinical data from Astrazeneca clinical trials Delivering our pipeline through scientific leadership105 Delivering our pipeline through scientific leadership 105 10,000 It would take 10,000 years listento 5 petabytes to (PB) of music

and techniques today will help us gain to new understanding of disease develop to the treatments of tomorrow, in our mission pushto the boundaries of science deliver to life-changing medicines patients. to Understanding the biology of disease today today disease of biology the Understanding to develop the treatments of tomorrow The successful treatment of many of today’s health disorders relies on uncovering the causes of disease so that can we develop new medicines. By combining our skills in drug discovery and development and our unique collection of research samples and data with leaders in industry and academia, will we maximise the potential for discovering and developing new treatments in areas of high unmet medical need. knowledge genomics latest the Harnessing

, newly identified biomarkers , our understanding and research and understanding our , , we will, we be well placed deliver to better Case Study Now is a pivotal time in is a pivotal Now we research, where genomics can start harnessto the power of the genome.” 104 IMED Annual Review 2016 104 IMED Annual Review 2016 Driving progress across our pipeline pipeline our across progress Driving This unprecedented genomics initiative will generate knowledge be to applied across our entire pipeline and will drive drug discovery and development across all our therapeutic areas. It will allow us identify to new biomarkers and targets for medicines and understand which medicines will work best for which patients. discovery In An innovative model of collaboration collaboration of model innovative An partners global with achieve thisTo ambitious initiative are we workingwith the best private and public partners, each carefully selected bring to complementary expertise and access unique to genomics databases. Our private partner, Human Longevity Inc (HLI), brings world-leading sequencing expertise and machine learning analytics. Our public partners, including The Sanger Institute, Helsinki University, Montreal Heart Institute, Genomics England, Stratified Medicine Scotland and Columbia University Medical Center bring both disease area and genomics expertise. will be transformed unlocking by hidden causes of disease, uncovering innovative drug targets linked molecular to mechanisms. development In medicines, faster, the to right patients achieve to the best medical outcome. will allow us better to select the right patients for the right clinical trials targeting the underlying genomic mechanisms of disease. launch At Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

DeliveringDelivering our our pipeline pipeline through through scientific scientific leadershipleadership 107 107 work on complex phenotypic screens using human derived material within AstraZeneca. Through this collaboration have we learnt state-of-the-art approaches for phenotypic screen evaluation and target deconvolution, which have resulted in the generation of several targets for our CVMD portfolio. Thecollaboration has also given us access new to collaborations through the Institute’s network. The skills and expertise the of Max Institute, especially Planck and peptides in chemical biology, natural complements products, thatvery well the competence in been building up have we new modalities chemistry at AstraZeneca in Gothenburg.” Eric Valeur, Associate Director, New Modalities, AstraZeneca Modalities, New Director, Associate Valeur, Eric We have alsoWe seen significant progress with our With our scientists directly our scientists directly With ofembedded within the group and working Herbert Waldmann at side with researchers side by in an open, innovative the institute are we environment, and creative kind to a different access gaining the and relaxing of knowledge academia and boundaries between the .

of chemistry and biology. The basis of the collaboration is discover to and develop new chemical modalities that will address the most demanding biological targets, both in basic science and drug discovery. New modalities are important, as classical modalities such as small molecules have limitations when addressing challenging targets. Within CVMD, new modalities such as stabilised peptides, macrocycles and molecular conjugates present a novel and innovative address way to these challenging targets and through our collaboration with the Max Planck Institute are we now in a position find to new compound classes allow to us do to this. At the satellite unit, are we specifically focused on the modulation and activation of transcription factors – important biological targets, but which today are considered undruggable. Our work has already resulted in the discovery of compounds that bind to transcription factors and are we now determining if they modulate their activity and the biology influenced them.by This would be a great achievement as, if successful, this approach could enable a whole new range of therapeutic options in many diseases. Therefore, the work being done has the potential to drive science forward and be truly ground-breaking. Max Planck Institute Institute Max Planck Joining AstraZeneca: and forces to academia and industry across approaches chemistry novel discover Metabolic and Cardiovascular in (CVMD) Disease that believe we AstraZeneca, At comes drug discovery successful in industry working about through with academia. That’s partnership of our proud incredibly we’re why with the Max Planck collaboration established Initially Institute. this successful ago, years four in 2014 extended was partnership to unit, which is linked to a satellite embedded IMED CVMD and now in the Max Planck Institute Dortmund. Our collaboration with the Max Planck Institute has provided us with an interface between the disciplines Case Study Professor Herbert Waldmann, Director, Department of Chemical Biology, Max Planck Institute Dortmund, Germany In really successful collaborations, both partners stake a scientific in have must and accept they must the project; value the weaknesses and the strengths, the limitations and the both partners. of needs In the with AstraZenecacollaboration arethese prerequisites fully met.” 10607106 IMED IMED AstraZeneca Annual Annual Review Annual Review 2016 2016 Review Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives MedImmune Focuses on biologics research and in development proteins, therapeutic antibodies monoclonal and other next-generation molecules attack to a range of diseases. Delivering our pipeline through scientific leadership 109 Biologics Biotech Unit MedImmune

and Combination Collaboration IMED Biotech Unit Biotech IMED Focuses on using state- of-the art discovery translational and platforms molecules, small in science other and oligonucleotides technologies. emerging Development Commercial Global Medicines Global Medicines

Unit Small and Early Innovative Medicines Therapies Nucleotide Development (IMED) Biotech Molecules and Global MedicinesGlobal (GMD) Development Focuses on late-stage development our of pipeline, innovative exciting transforming science into valued new ensuring and medicines world the around patients can access them.

+ savolitinib osimertinib (small molecule) (small (small molecule) (small only when combined non-small cell lung cancer Synergy in certain cancers Phase II early responses in

+ mechanisms (large molecule) (large (small molecule) (small AZD6738 (ATR) AZD6738 Synergy between Durvalumab (PDL-1) Phase I squamous cell cell squamous I Phase cancer (head and neck) + olaparib mechanisms (small molecule) (small (small molecule) (small AZD6738 (ATR) AZD6738 Synergy among two two among Synergy Phase II gastric cancer molecules same the with

Our IMED Biotech Unit applies its skills, across the technologies and capabilities company enable to the AstraZeneca R&D engine and accelerate the progress of the pipeline. Through great collaboration across our three science units are we confidentwe can deliver the next wave of innovative medicines transform to the lives of patients around the world.

through collaboration Collaborating science for innovation leadership Enterprise 108 IMED Annual Review 2016 we deliver a sustainable and innovative pipeline. and innovative sustainable a deliver we stage development organisation, we are ensuring are we organisation, development stage Global Medicines Development (GMD), our late- (GMD), Development Medicines Global with MedImmune, our global biologics arm, and arm, and with biologics our global MedImmune, driving AstraZeneca’s success. Working together together Working success. AstraZeneca’s driving The IMED Biotech Unit plays a critical role in a critical role Unit plays The IMED Biotech Despite major advances in healthcare and science, the world still faces unmet medical needs. More than eight million lives are lost each year cancer, to with one in six people developing the disease in their lifetime. IMED and MedImmune are exploring novel combinations of immunotherapies based on innovative antitumour strategies fightto a wide range of cancers. Combining expertise cancer new to advance treatments Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives IMED IMED Operations great Making science possible – working with acrossgroups enterprise the deliverto in excellence cross-functional portfolio,facility and systems management.

king medicineking Personalised Personalised Healthcare Biomarkers and Ma –personal partnering across science units commercialand teams deliver to personaliseda healthcare andapproach companion diagnostics. positive non-small cell lung positive cancer (NSCLC) have who anprogressed on EGFR TKI a tissue whom for medicine, be feasible. not may biopsy Delivering targeted therapies, as osimertinib,such the to right patients at the right time demonstrates our commitment testing andto quality companion diagnostics.” Andrew Coop, Vice President, US Medical Affairs, Oncology, AstraZeneca Delivering our pipeline through scientific leadership 111 Early Clinical Clinical Early Development science Where patient the meets conducting – to trials clinical test potential medicines in humans for the first time, plus quantitative modelling informto drug clinical for development IMED and GMD.

urning science science urning Pharmaceutical Sciences T into medicine - the developing formulations first of potential medicines to determine how they are delivered in the human body. The availability an of Food and Drug Adminstration blood-based (FDA) -approved, diagnostic is a companion forward step tremendous for with cancer in lung patients a high-quality of need test results withthat provides time. turnaround rapid a offers This development thean for important option of T790Mthe identification with in patients mutation mutation- EGFR metastatic

Drug Safety Safety Drug Metabolism Delivering a safe and effective pipeline - testing the safety of drugs how metabolise in the body. Discovery Discovery Sciences Where it begins all – seeking potential hits for new targetsdrug fuelto the AstraZeneca pipeline. Collaborating across AstraZeneca across Collaborating The osimertinib team worked seamlessly across organisational boundaries. was tell who couldn’t You – the group from which energy was electric!was It ‘all hands deck’ on and an how of example exceptional making for a shared passion a differencelives to patients’ the best inbrings out our AstraZeneca people.” VP PersonalisedRuth March, and Biomarkers Healthcare Collaborating as cross- a Collaborating functional team, together with our IMED Unit Biotech are we advancing colleagues in portfolio bothour Oncology small and biologics. molecules our the science, following By teams are united in their efforts our leveraging cancer, fight to expertisecombined progress to immuno- overarching our strategy get to oncology as patients to options treatment quickly aspossible.” David Berman, Head of Oncology Innovative Medicines unit and Senior Vice President, MedImmune in NSCLC. In addition, the IMED Biotech Unit has pioneered the use of various plasma assays monitor to for using resistance primary osimertinib both baseline and early time-point blood samples from the completed AURA trials, which demonstrated the benefits of osimertinib as second line therapy. This ground-breaking collaborative effort has established AstraZeneca as a scientific leader in the NSCLC community, which has been demonstrated through invited speakerships workshops at FDA and international conferences, as well as high numerous of publication through papers. impact

40 per centpatients of with NSCLC MEDI4276, an anti-HER2MEDI4276, antibody drug conjugate currently in Phase I, has a 36-step synthetic route the to cytotoxic agent and conjugation theto antibody and includes several high potency intermediates, which make scale-up for particularlychallenging. production This the Pharmaceutical year, Sciences team in IMED worked closely with the AntibodyDiscovery and Protein Engineering group at MedImmune bringto expertise in chemical process development and analytical chemistry addressto these challenges. By utilising a high containment facility and modifying the route of synthesis, the innovativeteam’s approach delivered the complex ADC payload with an increased product yield and reduced cost, contributing MEDI4276 to achieving first time in man 2016. in AstraZeneca as well as regulatory agencies, achieved we approval FDA of the diagnostic in September – a 2016 world first.Furthermore, colleagues in PHB and IMED Oncology worked with our commercial teams successfully to define the clinical utility and enhance market uptake, enabling NSCLC patients unsuitable for tumour biopy be to tested with a non-invasive option and providing results with a rapid turnaround time to help make osimertinib available the to eligible for treatment but unable to provide a tissue biopsy. IMED Oncology continues collaborate to with teams across AstraZeneca to evaluate the emerging mechanisms of osimertinib resistance. Working closely with been have GMD, we able fill to data gaps through the collection of paired tumour biopsies as part of the Phase III FLAURA investigating study, osimertinib as first-line treatment ~

Osimertinib

Collaborating science for innovation through leadership Enterprise collaboration Developing the next generation of Antibody Drug Conjugates (ADCs) is one of the four strategic pillars of the AstraZeneca and MedImmune Oncology strategy in advancing cancer therapies. It provides a great example of how we combine the expertise of IMED and MedImmune develop to a targeted ADC approach with the potential optimise to delivery of the cancer drug the to tumour. An ADC is a three-component system consisting of a potent cytotoxic agent known biodegradable a and linker, collectively and as the a ‘payload’, monoclonal antibody. The antibody binds specificto markers at the surface of the cancer cell and the whole ADC is then internalised within the cancer cell where the cytotoxic agent is released. ADC payloads are highly complex organic molecules with a typical synthesis of 30-40 steps which, combined with their high cytotoxicity, makes them very complicated handle. to Antibody Drug Conjugates Antibody 110 IMED Annual Review2016 Through continued have we 2016 see to osimertinib with progression impressive USfollowing Food and the Drug 2015 Adminstration (FDA) approval in non- small cell lung cancer to (NSCLC). Key delivering this success is the collaborative approach of the IMED Biotech Unit with Global Medicines Development (GMD) drive to science forward, and with our Commercial organisation to into translates science this ensure new understanding of treatment with healthcare professionals and therefore new options for patients. As an evolution the to approved which test diagnostic companion identified theEGFR-T790M mutation samples, tumour-biopsy using and Healthcare Personalised the Biomarkers (PHB) team in partnership with Roche drove the development of blood-based circulating innovative an tumour DNA (ctDNA) diagnostic test. By working closely with teams across Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Delivering our pipeline through scientific leadership 113 fibrosis bronchiectasis, by inhibiting DPP1 by inhibiting bronchiectasis, fibrosis of NSPs. and its activation across collaboration Our multi-target and Metabolic and Cardiovascular Respiratory Bicycle Therapeutics,Diseases (CVMD) with development of for the identification and a medicine callednovel class of small molecule has allowed usbicyclic peptides (Bicycles®), many the possibilities of overcoming to explore drug modalities.of the limitations for existing our partnerships in bolstered also We collaborationCVMD with our worldwide Our investigationwith APT Therapeutics. apyrase therapy, of an innovative human disease, is of thrombotic for the treatment FDA-approved current from uniquely different drugs that can increase antithrombotic bleeding risk. Our success in existing partnerships has We also led to further scientific innovation. into a partnership with Eli Lilly &entered Company (Lilly) to co-develop MEDI1814, an antibody selective for amyloid-beta 42, which in Phase I trials as a potentialis currently for Alzheimer’s disease-modifying treatment builds on our existingdisease. This agreement to AZD3293, a BACEcollaboration related inhibitor in two pivotal Phase III trials. We partner with top scientists from across the across scientists from partner with top We our IMED teams establishedglobe. In 2016, covering 35 major collaborations around and exciting new areas our main therapy in progress set to drive technologies that are for years to come. medical science innovation to ensuring that we also committed are We advances that willcontribute to scientific our main therapybenefit patients outside Open Innovation we do this through areas; and externalisation. In 2016 alone: our from the first programme marked We collaboration with Moderna Therapeutics clinical trials when towards to progress Trial Application (CTA) we filed a Clinical Paul Ehrlich Institute for AZD8601 with the and the German Federal Ministry of Health. This significant step highlights our serious for treatment towards progress metabolic and renal cardiovascular, diseases as well as cancer. a key licensing we announced In Respiratory, with our partner Insmed for theagreement global exclusive rights to AZD7986, a novel oral inhibitor of dipeptidyl peptidase I (DPP1). the damaging effectsAZD7986 may decrease of inflammatory diseases, such as non-cystic Partnering: strengthening our focus on scientific leadership scientific on our focus strengthening Partnering: Highlights

Kumar Srinivasan, VP Scientific Partnering Alliances, IMED and Unit Biotech Partnering with academic and industry scientists AstraZeneca critical. is outside Combining our strengths and withresources the expertise our partners of and knowledge will ultimately benefit patients.”

My experience of working with working experienceMy of AstraZeneca at the scientists – both inhas been excellent desire theirterms genuine of driving to contribute to the forwardsprojects and in theterms clear and open of communication and intent.” Simon Ward, Drug Discovery Centre, University of Sussex, UK DMD lymphoblasts via autophagy. via lymphoblasts DMD the progressive disruption of excitatory and inhibitory neuronal circuits. are We also working with Miotherix on P2RX7 purinoceptor up-regulation, which has been shown be to responsible for the death of muscles in the mdx mouse model of DMD and human

In 2016, we continued we In 2016, build to our network of innovative collaborations biotech institutions, academic with our in companies pharmaceutical and main therapy areas. Our pioneering work in genomics is truly best in class, collaborationswith Human including Sanger Trust Wellcome Longevity, Institute, Stratified Medicines Scotland and the Institute for Molecular Medicine. alsoWe forged collaborations work to on rapidly-evolving technologies such as modified mRNA, epigenetic drivers, bicyclic peptides and innovations in healthcare–drivingpersonalised scientific progress across our entire portfolio. Out-licensing is another area of focus ensureto are we developing indications that will benefit patients outside our main therapy areas. This includes our work with BioHaven Pharmaceuticals on Rett syndrome (RTT), a neurological disorder caused mutation by of the X-linked MECP2 gene that results in data to redefine the future drugof discovery Collaborating science for innovation Collaborating and sharing of new medicines to patients. medicines to patients. of new medical science and speed up delivery speed up delivery medical science and ways of working with others to advance with to advance of working others ways We are always on the lookout for novel novel for on the lookout always are We beyond the usual collaboration models. the collaboration usual beyond open research environments that go that go environments open research Our teams are leading the way in creating in creating the leading way are Our teams 112 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 115 Collaborating with AstraZenecaCollaborating a completely has to led new and exciting model for academic-industry partnership. side side-by-by work We with AstraZeneca scientists connect ourto advanced computational and genomic withapproaches disease deep area and drug development expertise AstraZeneca at Emerging Innovations (AZEI) rapid thatin allows for a way new of and nimble exploration opportunities.” therapeutic Joel Dudley, Director of the Institute and Healthcare Generation Next for and Genetics of Professor Associate of School Icahn The Science, Genomic Sinai Mount at Medicine AstraZeneca has been invery making bold things from academia, to available talking their on academia to own terms, learning to from academia and gently teaching feel We us themselves. about we’re dealing with colleagues.” Research Medical Pelham, Hugh Sir Molecular Laboratory of Council UK Biology, Scientist examining a human placenta double stained using two different antibodies and a nuclear fluorescent counterstain by confocal microscopy With research facilities in a number of the world’s established and emerging scientific centres, recognise we the importance of leveraging our footprintconnect to 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 locations key across the globe. Our open innovation partnerships with academic translational drug discovery centres and government-linked agencies include leading global scientific institutions, which help facilitate our interactions with prominent scientists. Our partners include: : Cancer Research UK (CRUK) and the Medical Research Council (MRC). United States: National Institutes of Health (NIH) and the National Center for Advancing Translational Research (NIH-NCATS). NationalTaiwan: Research Program for Biopharmaceuticals (NRPB). Singapore: National Health Innovation Centre (NHIC). Australia: Universities of Queensland and Adelaide commercialisation units, UniQuest and Adelaide Research & Innovation. A global science network Collaborating science for innovation to data sharing and Collaborating redefine the future of drug discovery 114 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

AstraZeneca Open Innovation website I hope that our pioneering that our pioneering I hope approach to Open Innovation will the industry across spread and academia and become the is normal. enabling It new us to advance projects that neither our partners nor bewe would new and create alone do to able patients.” for therapies Director, Executive Wegner, Craig Scientific Innovations, Emerging Partnering Alliances, IMED & Biotech Unit Unit Biotech I appreciated the in openness I appreciated ourand discussions the data from received I and advice AstraZeneca. The process obtainingof the drug has been straightforward and I am already making plans that I project another for like discuss to would with AstraZeneca. AstraZeneca for congratulated be should their Open Innovation initiative and sharing with the academic community their compounds be would It repurposing. for pharma ifnice big the of rest AstraZeneca’s follow could in thisexample matter.” EfiKokkotou, Beth Israel Deaconess Center, Medical Harvard University, USA Harvard University, Delivering our pipeline through scientific leadership 117

At AstraZeneca,At great have we scientists doing truly ground- breaking research. in But order the the delivery of speed up to next generation of medicines, the access best also to we need are our labs. We outside science ways new for looking always or with working academic of industry researchers who share the advancing for our passion science and helping patients with unmet medical We needs. one being on ourselves pride and open porous the most of collaborators in our industry.” Vice Executive Pangalos, Mene and Unit Biotech IMED President Business Development Global ,

Since our its launch Open in 2014, Innovation programme has established a proven track record of success: Received over 400 proposalsfrom scientists countries in 28 across four continents. Formed 150 new partnerships – 90 per cent with academic scientists per and 10 cent with science companies. partners our with planned, or Initiated pre-clinicalover 150 and 30 clinical studies. We believeWe that sharing by knowledge and resources with other scientists, we collectively stand a much better chance of delivering novel effective treatments for serious diseases. One example of how we are putting Open Innovation into action is NiCoLa-B, the most world’s advanced drug discovery robot, which is capable of making drug discovery smarter, faster and cheaper. are We making NiCoLa-B available external to research partners including Cancer Research UK and the Medical Research Council help to accelerate their medicines research.

Our Open Innovation portal makes it easy for external scientists access to our full range of Open Innovation programmes and findtoways advance medical science together: A compound bank of ‘patient-ready’ active and discontinued compounds. A pharmacology toolbox of compounds with strong properties.pharmacological A collaborative effortvalidateto new targets, which may include high- screening. throughput Advanced cheminformatic capabilities exploreto therapeutic potential of new molecules. R&D challenges open anyone to willing offer to innovative solutions. An invitation to innovate An invitation

over 400 proposals since launch in 2014. proposals 400 over reached 150 partnerships and have now received received now have and 150 partnerships reached on projects, achieved great success in 2016. We in 2016. We success great achieved on projects, can more freely share their ideas and collaborate their ideas and collaborate share freely can more scientists both inside and outside AstraZeneca scientists both inside and outside AstraZeneca create a permeable research environment where where environment research a permeable create Our Open Innovation programme, designed to programme, Our Open Innovation Collaborating science for innovation Open innovation 116 IMED Annual Review 2016 Momentum for our Open Innovation programme was impressive. in 2016 Our Open Innovation portfolio now has 22 ongoing or planned clinical trials and over ongoing100 or planned pre-clinical trials. alsoWe launched two target innovation projects with the Centre in 2016 for Drug Research and Development (CDRD), development drug national Canada’s and centre, commercialisation and with medical research charity MRC Technology (MRCT) in the UK. theAt heart of our Open Innovation programme is our collaborative environment. recently We redesigned our Open Innovation portal make to it easier than ever for potential partners investigateto the compounds and tools available them to and submit proposals across a range of drug discovery and development activities. Our Open Innovation partners can now access over 250,000 compounds from our collection for screening a novel drug target. Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 119

Asia 90 Pacific Europe 180 Sweden 110 UK 340 US 380

Active collaborations in 2016

Collaborating science for innovation Innovation without boundaries well as in other key locations across the globe. across locations as in other key well academic and biotech partners around our sites as our sites around partners and biotech academic our scientific partnerships and alliances with and alliances leading partnerships our scientific to connect with the best external science, accelerating withto connect science, accelerating the best external recognise the importance of leveraging our footprint our footprint the importanceof leveraging recognise established and emerging scientific centres, we centres, scientific and emerging established With research facilities in a number of the world’s a number in facilities research With 118 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

DeliveringDelivering our our pipeline pipeline through through scientific scientific leadershipleadership 121 121 Head of Biopharma, Foundation Medicine This collaboration is special is This collaboration our shared of philosophy because the importanceon identifying of the right patients for the right and our desire targeted therapies all available the tools leverage to The make us to to that a reality. clinical and scientific thought AstraZeneca at areleaders very respected withinmuch Foundation They areMedicine. really the partners collaborate us to right for of truly on the field advancing molecularly focused medicine.” Melanie Nallicheri, Chief Business Officer and

AstraZeneca has a tremendous and diverse assets, Oncology of portfolio the most of one me, for but most or pieces exciting is therewarding pieces thought and science that and drives their application those of integration assets clinicalinto trials and clinical practice.” Vincent Miller, Chief Medical Officer, Foundation Medicine

view 2016

Case Study over the past fiveyears we have been ableto begin routinelyto characterise the DNA based underpinnings of a given patient’s tumour. This means that testing is becoming more widely used and doctors are beginning understand to it better – which ultimately patients. benefits involved in homologous DNA repair beyond and BRCA1 BRCA2 that are important in predicting which patients will respond this to class of therapeutic. In addition, havewe developed new biomarker strategies involving analysis of chromosomal copy number changes that believewe are going be to able expand to the range of patients who can be treated with several other classes of drugs in AstraZeneca’s pipeline. The future of our collaboration looks bright and BRCA1 and BRCA2BRCA1 mutations would confer susceptibility inhibitors. PARP to have alsoWe identified a whole series of genes Our partnership centres on personalised healthcare – getting right right the treatments the patients the at to right time. Foundation Medicine is one of the pioneers in developing methodologies for DNA sequencing and usingby their technology, can we comprehensively assess tumour samples from our early clinical trials understandto the biomarkers associated with a response our to drug programmes. are We then able taketo those markers and develop them into assays accelerateto patient recruitment for clinical trials and ultimately companiondiagnostics for approved drugs. Foundation Medicine can look at over 300 genes and comprehensively assess the profile of a tumour and because of this, have we been able make to discoveries, including identifying that somatic Established in 2012, our work withEstablished in 2012, our work Medicine has come a Foundation – the years in the last five way long has become deeper collaboration now and we complex and more that spans our a partnership have pipeline, starting Oncology entire Phase I trials right off in early products. to our marketed through in Oncology Oncology in Driving precision precision Driving AstraZeneca: AstraZeneca: Medicine and Foundation 120 IMED Annual Re 120 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 123 Linn Strindhagen, IMED Graduate Scientist Graduate IMED Strindhagen, Linn Thanks the IMED to programme, graduate gained experience fromI have both IMED RIA this and CVMD. has given Foremost, drug of knowledge a comprehensive me of network also a broad but development, This be very to scientists. valuable has proven with ideas.” me new provides and continuously

ur people make us stand out O and our values define us: science the follow We first patients put We win to play We thing right the do We are entrepreneurial We Development Continuous development of our people is high on our agenda and the majority of our development comes from on-the- job experience. From our Development Marketplace cross-team to secondments opportunities, our shadowing and continue we ensure programmes developing the skills and capabilities equipto our scientists be to the best they can be. Throughout saw we 2016, more than 60 IMED colleagues take up to role core their outside assignments broaden their learning and experience. welcomed we In 2016 more talented including team, our to colleagues respected scientists, accomplished academics and new graduates. They came for many reasons – the the science, great to commitment opportunity for personal development, the open culture, the inspiring values, the chance be to part of something life-changing. Whatever the reason, they joinedhave a truly great place work. to My secondment in IMED secondment My Communications opportunity a great has me given learn to new strategies, strengthen my network and push boundaries. is a part-time Andmy it because driving I love I still a job assignment, do to get clinical Oncology projects.” delivery for Manager, Information Project Drug Foulk, Melinda IMED OperationsIMED Our ‘Women as Leaders’ programme gives our female scientists a chance cometo together discuss to issues such as career progression and personal development, with a view increasingto their awareness of opportunities and the confidenceto pursue them. People that attended have the programme seen have a 30 per cent sponsors, gained and rate, promotion coaches and mentors. women have 120 now attended and the programme has been rolled out globally. Annual Summit,Our 2016 Women’s held in Gothenburg, Cambridge and Gaithersburg brought together over employees actively to participate1,100 in inclusion and diversity on conversations in the workplace.

Diversity We believeWe that great science comes from diverse teams with different backgrounds. And the vision for our workforce is that it reflects the diversity of our patient population. That’s are why we committed creatingto an inclusive environment for our people and foster to all this in 2016, of our line mangers received unconscious bias training. As part of creating a diverse workforce we are committed increasing to the number of women in senior scientific roles. Since increased have we 2015 the number of women in senior scientific rolesto 38 per cent and our aim is further to increase this going forward.

Amy Taylor, Associate Director, Strategic Planning and Operations, Operations, and Planning Strategic Director, Associate Taylor, Amy we’ve trialled blind screening of CVs to remove unconscious bias unconscious remove to trialledwe’ve CVs screening blind of all panels for our interviews. diverse alsoemploy We gender. to role.” usThis ensure the recruit we right for the helps best person ECD, Chairperson, Network of Women UK We’ve made sure we have a balanced sure have we recruitment made process, We’ve We want attract to We the brightest minds, the best talent, the boldest innovators – people who share our passion for science and belief in the possible. In return, offer we working a environment that truly reflects our ambitionto 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. Biotech Unit welcomed 125 new starters. 125 new welcomed Unit Biotech develop and inspire our people. In 2016 alone, the IMED alone, In 2016 people. our inspire and develop this commitment more evident than recruit, we in evident the way more this commitment ability to attract and retain the best scientists. Nowhere is Nowhere ability attract retain and to the scientists. best Our commitment to scientific leadership rests on ouron rests leadership scientific to Our commitment

scientists An environmentwhere science thrives Inspiring great 122 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 125 1,400 hours saved through automated technology for high- throughput screening of human adipocytes 1,600 hours saved through improved project planning, tracking and reporting through a cloud-based solution

saved through analysis saved through automated saved through improved Tony Johnson, VP Early Clinical Early VP Johnson, Tony Development Time for Science means efficiency, innovation and reduces It energising. and allows our bureaucracy – science on focus to scientists our critical success.” so for Highlights from our Time for Science include: initiative hours >6,000 and management next of generation IT, better through data sequencing robotics and automation. hours1,400 screening high-throughput for technology of human adipocytes. 1,600 hours project planning, tracking and reporting solution. cloud-based a through

Ruth March, VP Personalised Personalised VP March, Ruth Biomarkers and Healthcare In PHB, Time for Science is allIn PHB, Science Time for makingabout the impossible, Whatpossible. this means is release we do only that not also we but science, time for our ultimate to more deliver thecustomers, patients.”

scientists An environmentwhere science thrives Inspiring great 124 IMED Annual Review 2016 Time for Science for Time As scientists, our focus must remain on ensure to order in science breakthrough deliverwe life changing medicines. IMED saved over 100,000In 2016, hours free to up more Time for Science. By creating process efficiencies and time savings through better meetings, simplified procedures, improved IT and increased lab support, made have we progress. significant Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

Vibrant BioHubs and nurturethe Scandinavian life ecosystem. science Boston Our Boston site houses Gatehouse Park, which launched in September The site2015. has undergone a huge transformation in the past creating year, one of the Boston-area’s fastest growing BioHubs. In addition the to Neuroscience function, which has now moved the to hub, six research companies are in place sharing and exchanging ideas - two of which, Persomics and Morphic TX, expanded their presence in 2016. The BioHub at Alderley Park supports the creation and growth of successful life science companies, with an in the North of England. and perspectives in the same place, our vision is generate to a climate of open innovation that will help grow optimum environment for emerging businesses thrive to in the the UK. 2016 saw the second anniversary of the Alderley Park BioHub and established the site as the leading science facility Our BioHubs offer an energising cross- enabling environment ideas.fertilisation of Gothenburg Our Gothenburg BioHub continues to grow and foster life science discovery with a total of 20 companies now part of the hub, including our first MentorMate, company, international who announced their decision join to AstraZenecain 2016. is now in active collaboration with five of the Gothenburg BioHub companies, such as Antaros, a company specialising in advanced imaging techniques for use in cardio- metabolic and respiratory clinical trials. By combining differentvalues, ideas Left: IMED research Left: IMED research facility in Boston, US Right: IMED research facility in Shanghai, China Delivering our pipeline through scientific leadership 127 In Boston are we involved in a number of local academic and industry collaborations. Our partnership with UniversityTufts is a true academia- industry hybrid, where a groupour of scientists are working within Tufts’ addition, In department. Neuroscience our collaborations with Foundation Medicine, Dana-Farber Cancer Institute and Massachusetts General Hospital drive innovative pre-clinical and clinical science for discovering and developing new cancer medicines. Our small-molecule research facility in China is located at the Zhangjiang ParkHigh in the Tech Pudong area of Shanghai. Our research teams here focus on discovering potential new needs unique the meet medicines that of patients in Asia and drive forward main our across science translational therapy areas. China – Shanghai

Below: AstraZeneca’s Strategic Below: AstraZeneca’s in Gothenburg R&D Centre US – Boston Boston is home AstraZeneca’s to small molecule research in North America, with state-of-the-art laboratories, just west of the city centre. Our scientists focus on the discovery and development of new medicines for Oncology and conditions of the central nervous system, incollaboration with other functions from across IMED. Our Bostonsite is developing a clear identity and advancing the goal of a culture in which ‘everyone knows A everyone’. highlightkey for the site has been the Oncology, from teams cross-functional Pharmaceutical Sciences, Discovery Sciences, DSM and ECD delivering innovative target to ways a trio of new drug CDK9 andtargets Bcl2/xL) (MCL1, for the Oncology cell death portfolio. Sweden – Gothenburg Sweden Our strategic R&Dcentre in Gothenburg is the centre our of research for two of our maintherapy areas; CVMD and RIA. It is also home a large to number of our scientists from our early phase Discovery Sciences functionand our Drug Safety and Metabolism (DSM) team. In addition this to teams have we from IMED Operations, ScientificPartnering & Alliances, Early Clinical Development (ECD) and Personalised Healthcare and Biomarkers (PHB). During 2016 alsowe welcomed a new function, Sciences.Pharmaceutical All our sites create an environment to share ideas and aim tap to into great science. Our Gothenburg ‘Coffee Lab’ helps employees based there do just that. The Coffee Lab is the placeto meet and share ideas, and in 2016 sawwe true evidence of our culture of collaboration pushing the boundaries of science, with breakthrough modalities now in development.

“AstraZeneca has been on a transformative journey over the past few years, placing great science at the heart of our strategy. In addition to drugs targeting critical cell death pathways, the Boston site has become our centre of excellence for haematological malignancy biology, model systems and drug discovery and is driving our interactions with colleagues at Acerta as we develop the BTK inhibitor, acalabrutinib. Here on the Boston site, we also have a fantastic opportunity to create a unique research environment – a close, connected group of talented AstraZeneca scientists working alongside innovators and entrepreneurs from the BioHub, as well as Boston academia and industry – allowing us to explore collaboration and interconnectivity between teams even further.” Steve Fawell, VP Head of iScience, IMED Oncology “Here at AstraZeneca in Gothenburg we have a vision of becoming one of the best R&D sites in the world. are We 2,500 colleagues from over 50 different nationalities all working towards this goal with genuine commitment and enthusiasm. Having representation from not only all areas of the development process, from first idea to when the medicine reaches the patient, but also from several external biotech companies with whom we share expertise and infrastructure, really forms a unique basis for great science. supportTo innovation and collaboration, we have created a working environment in a class of its own and, earlier this AstraZeneca year, Gothenburg was awarded recognition as one of the best workplaces in Sweden.” Director Site Gothenburg Sundqvist, Jenny UK – Macclesfield Our Macclesfield site is an important hub for AstraZeneca and the second pharmaceuticallargest manufacturing site in the world. A centre of innovation, science and high- tech manufacturing, a place it’s where molecules are turned into medicines and is home the to Pharmaceutical Sciences team, who joined the IMED Biotech Unit With large-scalein 2016. lab facilities, the site hosts cutting-edge technology Pharmaceutical Sciences enable the to team implement to intelligent design of medicines and delivery systems. Seven miles at Alderley away Park, now owned Manchester by Science Partnerships, retain we a small number of IMED scientists until the R&D exit of the site is complete and colleagues join together in our new Cambridge facility.

In 2013, AstraZenecaIn 2013, announced plans its move to UK research activities a to new $500 million facility in the centre of Cambridge. Our new facility at the Cambridge Biomedical Campus will become AstraZeneca’s largest centre for Oncology research, as well as hosting scientists focused on cardiovascular and metabolic diseases respiratory, (CVMD); diseases autoimmune and inflammation (RIA); and conditions of the central nervous system. has seen2016 almost 2,000 employees Cambridge, to move start to the process of bringing together under one roof our research biologics and molecule small capability from both AstraZeneca and MedImmune for the first time in the UK. address registered AstraZeneca’s has now moved the to Cambridge Biomedical Campus, 1 Francis Crick Avenue, at which marks pointa key in delivering our science-led strategy. The construction of the new R&D centre and and headquarters continues corporate the growing Campus will successfully create an optimum environmentfor emerging businesses thrive. to UK – Cambridge UK – Cambridge An environmentwhere science thrives Our strategic centres science 126 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives ,

interested science

through an annual an through and programmes with with programmes and Cross section of cells from tumour section of cells from Cross stained to The cells are biopsy. receptors of target confirm presence for AstraZeneca and MedImmune therapeutic molecules The Cambridge Science Festival Science Cambridge The through outreachactivities, talks and sponsorship. staff over 70 In 2016, volunteers took part and overall the Festival attracted 60,000 visitors. College UniversityThe Technical Cambridge, challenge for 14-18 year olds.challenge for 14-18 delivering and Shaping activities local schools. people young Mentoring technology, science, pursuing in engineering and mathematics (STEM) careers through our partnership with Career Ready. 1,000 Lab blocks in the new build are more than 1,000 each metres square

Delivering our pipeline through scientific leadership 129 , on our our on , an artwork , where staff canwalk around - this is connected the to R&D 2016 Highlights on Cambridge Highlights on 2016 worked hours total million 1 construction site as of August 2016 Centre Energy the of Completion steelwork Centre a service by tunnel which is 14 metres below Francis Crick Avenueand seven tube carriages long 99.54% waste from the new site has been diverted from landfill (on and off recycling/incineration) site Virtual reality tour of the R&D Centre developed the building get to a feel for what it will be like work to at the new facility Build Progress Build We alsoWe an have active community support scheme in Cambridge focused science-based around educational events for young people. staff Over 160 members are actively involved in science outreach in the community and their supports: volunteering Pictures in Science installation displayed on the construction hoardings around our future home on the it CBC; is a collaboration with nine local schools and the imagination and creativity of over 400 local school students aged 7-17. Centre Science Cambridge The helping 50,000 children, young adults and their families discover life science.

2016 was an exciting time2016 for IMED as continuewe establish to ourselves in the Cambridge science community. 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 high throughput screening. Beyond cancer research, our R&D will focus on cardiovascular and metabolic and inflammation respiratory, diseases, autoimmune diseases and conditions of the central nervous system. choseWe be to in Cambridge because wantedwe be to at the heart of one of the best scientific centres in the world and believe we that the next generation of medicines will come from working collaboratively with healthcare, academia, research business and communities. Building onmore than years 25 presence in the Cambridge science community established MedImmune, by we seenhave our initiatives in the local community grow in both depth and range as the size of our employee grows. community anAt academic level, three have we joint schemes developed across AstraZeneca and MedImmune support to more than 80 PhD scholarships and eight clinical lectureships. This represents an annual investment million in excess once of $1.5 fully up and running. to designed are programmes Our identify, train and mentor start-up life science businesses. AstraZeneca’s volunteer mentors come from a range of roles, with expertise in areas like intellectual development, business property and innovation alliances. Establishing Scientific Leadership Leadership Scientific Establishing of scientists Inspiring the next generation Mene Pangalos, Executive Vice President IMED Biotech Unit and Global Business Development Being part of the very best science hubs in the world is an partBeing integral in the hubs very the of world best science Cambridge provides strategy. part our science-led delivering of technology andtalent, scientific of concentration a geographic indiversity thinking partnerships that will conversations, enable will to these relationships doubt lead no I have and collaborations. medical breakthroughs.” and scientific and unanticipated new arm, which has a long-standing presence inCambridge, been have we able to accelerate our scientific productivity and look forward having to both of our science units in the same building. areWe realising the value of co-locating leading with centres science strategic our academic and life science hubs, while collaboration and talent our enabling also partners deepen to their contribution to community. scientific Cambridge’s Our presence here has many facets. areWe able bring to and develop our capabilities as a scientific partner, a sustainability-focused a business, corporate citizen and a member of the community, inspiring the next generation scientists. of

CGI image of our new Global R&D 1 Francis Crick Avenue, Centre, Cambridge Biomedical Campus

Effective Cambridge since 2016, May is now the locationour of global corporate of construction headquarters.While our new home and strategic centre continues at 1 Francis Crick Avenue on the Cambridge Biomedical Campus, made have we significant progress inrealising our ambition follow to the here. science Since announcing our in move 2013 accelerated have we our transition to Cambridge ahead of the completion of our new facility, with over 2,000 of our staff now based across interim sites, all of whom are actively engaged in Cambridge’s scientific, academic, clinical and business ecosystem. By joining forces with MedImmune, our global development and research biologics An environmentwhere science thrives Building our future 128 IMED Annual Review 2016 Our new Cambridge home Cambridge Our new Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives jointly across jointly AstraZeneca, MedImmune, the LMB and the Universityof Cambridge. Medical AstraZeneca the Developed Research Council (MRC) UK Centre for Lead Discovery. the with collaboration new a Initiated Crick Institute explore to new avenues of medical research and drug discovery across a broad range of diseases. partnership Cambridge Ongoing with the through School Business Judge Accelerate programme – designed to identify, train and mentor start-up life businesses. science Established a world leading mass spectrometry capability 130 Collaborations across AstraZeneca and MedImmune in Cambridge, UK Delivering our pipeline through scientific leadership 131

to identify to with Cancer Research UK with the Laboratory of Molecular Collaborated with Microsoft to Microsoft with Collaborated develop a new cancer treatment modellingsystem. discovery drug multiple Initiated projects (CRUK), with 60 scientists based in CRUK laboratories at the Cambridge Institute. Established collaboration with a Therapeutics Bicycle and develop bicyclic peptides for the treatment of respiratory, cardiovascular and metabolic diseases. Evolved our blue skies collaboration project Biology (LMB), using CryoElectron Microscopy solve to the structures targetsof key in the DNA damage pathway. response and based our Centre for The success of Cambridge is built on a triple helix of research, industry and government. this Together creates a powerful force for change. strategicOur 130 collaborations in Cambridge are about advancing the development of life-changing medicines forpatients, working by across together bringing and organisations different areasexpertise. of the within collaborations These example Cambridge cluster unprecedented have potential: genomics integrated an Launched initiative Genomics Research in Cambridge. CGI images of our new Global R&D 1 Francis Crick Avenue, Centre, Cambridge Biomedical Campus Earning our place in the ‘Cambridge Phenomenon’ the our place in Earning ‘Cambridge basement area where the Research

Support Facility will be located, enabling employees walk to right through the site and around the perimeter, carefully moving around the construction teams so as not disrupt to the complex building process. The site has been attracting a great deal of interest both inside and outside our company. With various VIPs visiting over the course of the last few months, we also welcomed the AstraZeneca Board theto site in This November. was a great opportunity showcase to our progress and bring life to how our presence in Cambridge is making a differenceto our productivity. scientific Descent into the R&D Centre: Centre: R&D the into Descent a a large, large, a Highlights from the site visit tours include: Mock up space: a testing area designed tryto out equipmentand materials before these are commissioned. Here employees were able see to early laboratory designs and officelayouts and were given a first-hand insight into the been has that consultation and thinking going on create to their collaborative workplace. future Centre: Energy the Scale three-story building with the purpose of providing uninterrupted, clean energy to our R&D Centre across the road, via an tunnel. underground In 2016 we hosted we visitsIn 2016 for employees who will be located in the new building, providing an opportunity see to the progress are we making. Under the close guidance of the new build project team, visits covered areas key of the extensive site located across two plots of land on the Cambridge Biomedical Campus with(CBC), the aim see to progress directly and visualise future workspaces. Opening up our site to staff and visitors alike visitors to staff and up our site Opening An environmentwhere science thrives futureBuilding our 130 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Single-cell transcriptome transcriptome Single-cell human of profiling in health islets pancreatic and type 2 diabetes Cell Metabolism Impact: novel functionalityThese studies have revealed islet cell sub-types demonstrating, foracross not beta cells are instance, that insulin-producing andthe only cell type important for glucose control is a complex cell-cell signaling networkthat there underlying metabolic control. About the paper: defects in thePatients with diabetes suffer from islets of Langerhans, a functionalpancreatic that maintains blood the pancreas within centre glucose levels. Our team of scientists painstakingly islet cellsseparated over 2200 individual pancreatic islet cell sub-types and then utilised various across cutting-edge deep RNA sequencing technology at Institute Integrated Cardiometabolic the Karolinska characterise gene expression. to Centre Lead AstraZeneca authors: Carina Ämmälä, Pernilla Eliasson, Eva-Marie Andersson, David Smith ® Delivering our pipeline through scientific leadership 133 in vivo mpact: Aurora kinase inhibitor Aurora tumours target nanoparticles therapeutic with favourable index Science Translational Medicine to control release kinetics and maintain a high release to control B kinase inhibitorconcentration of an Aurora (AZD2811) at tumour sites. This facilitated prolonged resulting in superior tumourpharmacodynamic effects, in off-tissue toxicities. inhibition and a reduction growth About the paper: safety, characterisation of efficacy, careful Through pharmacokinetics and distribution in pre-clinical models, our scientists have developed the first The novel proof-of-concept. nanoparticle pre-clinical of tumourformulation was shown to extend reduction phosphorylated histone H3 levels in vivo for up to 96 hours following a single administration. In addition, efficacy was observed in multiple tumourincreased models at half the equivalent dose of AZD1152 and pathology. showed minimal impact on bone marrow Lead AstraZeneca authors: Susan Ashton I demonstrate the ability of ACCURINS The results Association between between Association and plasma genotyping outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer About the paper: Our scientists have analysed the genotype of patients entering the Phase I clinical study of osimertinib. Using highly sensitive digital PCR able to detect the relevant assays, the team were EGFR mutation (T790M) in tiny pieces of circulating shed into the patient’s tumour DNA (ctDNA) that are over 300 The data from (plasma). bloodstream patients showed that those with a plasma detectable T790M EGFR mutation have the same clinical outcomes as those patients with a T790M mutation a tumour biopsy. detected from Lead AstraZeneca authors: Cantarini, Carl Barrett Mireille Kenneth Thress, Impact: The outcomes suggest that patients can first be with a blood based test for the T790Mscreened osimertinib withoutmutation and, if positive, offered the need for a tumour biopsy. Journal of Clinical Oncology Journal Exemplar key publications in 2016 publications key Exemplar It is so important that we change the perception of industrial important is so of It that change the we perception we where that driven, one is process to from one science are recognised the as at translational working scientists are one Ourcutting-edge just Walls Publication innovation. of the quality emphasise we our research how to of of example as the well as wider to our sites on and visitors collaborators AstraZeneca community.” Mene Pangalos, Executive Vice President IMED Biotech Unit and Global Business Development High-impact publications (IF ≥15) High-quality publications (IF ≥5 ≥15) Low-impact publications 311 40 552 2016 233 29 446 2015 103 1 275 2010

Our ongoing commitment to develop a thriving science environment a thriving environment science develop to commitment Our ongoing both the IMEDinside progress significant in 2016, has generated ecosystem. and within scientific Unit the broader Biotech We are entrepreneurs in science, pushing the boundaries of what’s what’s pushing the boundaries of in science, are entrepreneurs We an cultivated have we why That’s and every day. each possible with a together collaboration, and open excellence of environment our gives Our spirit entrepreneurial publications. of track-record strong take to smart by the courage be risks discouraged scientists and not the latest abreast of keep only not to scientists our failure empower - we drive them. to and breakthroughs, but developments

scientificleadership An environmentwhere science thrives Our reputation for 132 IMED Annual Review 2016 Our IMED scientists consistently publish in peer-reviewed journals with high impact and respected influence across the scientific community,validating our innovative work and reinforcing our ability contributeto the to foundation of scientific advancement. continueWe outperform to our year-on- achievements publication strengthened we year and in 2016 our scientific reputation through an increased focus on high impact and high quality scientific publications. High impact publications with impact factor are a hallmarkratings of success ≥15 for scientists and an important help to way us recruit and retain the best scientists from around has the seen world. 2016 IMED achieve great success in this area with 552 manuscripts published, 40 high high quality.impact and 311 Our publications Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives IMED Science Awards Delivering our pipeline through scientific leadership 135

It was a great pleasure to be invited to the IMED to be invited to pleasure was a great It many and so see celebration Awards Science the future shaping our scientists science. exciting of are we really how showing innovation, Fantastic research making Your possible. the impossible, our pipeline, on impact is having a tremendous the around world.” patients and to our company Pascal Soriot, Executive Director and Chief Executive Officer

of Fame Our Publication Walls Walls Our Publication showcase the tremendousTo progress across IMED in the number and quality of publications, saw the launch 2016 of our Publication Walls of Fame on our sites in Gothenburg, Cambridge, Boston and Macclesfield. Focusing primarily on our early science success date, to our publication walls are outstanding our recognise designed to breakthrough share researchscientists, and showcase AstraZeneca’s scientific excellence with employees and visitors to our sites. It’s great to see the see different to great It’s IMED around teams interacting science, of a vast breadth such sure there willI’m be some valuable insights and important this of coming out actions scientificmeeting.” Clinical Early VP Johnson, Tony Development The 2016 IMED ScienceThe 2016 Retreats were held acrossfour IMED sites – Shanghai, Boston, Cambridge and Gothenburg, showcasing the breadth and depth of our research with over 360 posters presented. The Science Retreat is an important event in the AstraZeneca calendar, immerse to colleagues enabling themselves in the latest developments outside their own areas of expertise, share ideas and look at can how we innovate new and differentto ways drive leadership. scientific IMED Science Retreat IMED Science Publication wall of fame IMED Science Awards IMED Science IMED ScienceThe 2016 Awards celebrated some of the best science high-impact breakthrough, taking place at AstraZeneca. global 160 nominees were invited join to the IMED Leadership and members Team of the review panel at a black-tie celebratory dinner held in Cambridge. recognised outstanding awards The impact high achievement; scientific work acknowledged as game changing. Winning teams and individuals received trophies and are also rewarded with tailored opportunities support to future research and enhance their careers. At this year’s event we were delighted that Pascal Soriot, CEO AstraZeneca could join us and present some of the awards. These included the Scientist of the Year Simonto Barry, IMED Oncology, as voted IMEDby colleagues for his depth and breadth of scientific achievement across the Oncology portfolio. An environmentwhere science thrives Our reputation for scientific leadership 134 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives O’Connor MJ Hodgson D, Fielding A, Spencer S, Lowe E, Sovak M MB Ashford A, Lamb M, Su Q, Belmonte M, Aquila B, Hird S, Grimster N Rawlins PB, Su N, Tentarelli McEachern K McEachern Over B, Hilgendorf C, Lewis R, Perry M, C Tyrchan Waterton J Bergman J Vaag A De Bruin EC Andersson E, Smith Ämmälä C, Eliasson P, DM; Andréasson A, Bjursell M, Clausen M, Sabirsh A AstraZeneca and AstraZeneca MedImmune authors

Delivering our pipeline through scientific leadership 137

A Biobank of Breast Cancer Explants with Cancer Explants with A Biobank of Breast to Screen Intra-tumor Heterogeneity Preserved Anticancer Compounds Overall survival in patients with platinum- ovarian cancer serous sensitive recurrent olaparib maintenance monotherapy: receiving a randomised, an updated analysis from double-blind, phase 2 trial placebo-controlled, our target? Cancer nanomedicine: is targeting covalent Inhibition of Mcl-1 through modification of a noncatalytic lysine side chain PIM1 kinase regulates cell death, tumor cell death, tumor PIM1 kinase regulates triple-negative in response chemapy and growth cancer breast Structural and conformational determinants cell permeability of macrocycle cancer studies for Imaging biomarker roadmap and photochemical silylations Metal-free of benzenoid transfer hydrogenations and graphene hydrocarbons Genome-wide associations for birth weight and with adult disease correlations contributes glutathione biosynthesis Decreased in to EGFR T790M-driven erlotinib resistance non-small cell lung cancer of Human Profiling Single-Cell Transcriptome 2 Islets in Health and Type Pancreatic Diabetes Title Nature Medicine Nature Cell The Lancet Oncology Materials Reviews Nature Chemical Biology Nature Publication Chemical Biology Nature Clinical Reviews Nature Oncology Communications Nature Nature Cell Discovery Cell Metabolism Morrow C, Weir H, Lawson M, Goeppert A, M, Goeppert A, H, Lawson C, Weir Morrow Wilson J Mazzola AM, Smith A, Goodnow R Chen K, Guo Q, Zhang X, Bai Y, P, Yang Xu J, Yin Y, Cheng Z, Cohen-Rabbie S, Wang L, Zhang D Hughes A Johansson J Q, Spaeter D Wang Carlsson LG O’Connor MJ Chen R, Dale IL, Robb GR, Bobby R, Boiko S, Callis RJ, Clark E, Flavell L, Holdgate GA, McAlister M, Petteruti Saif S, Stratton P, N, Whittaker DTE, Wilson Y DM, Yao Raubo P Q, Plowright AT L, Wang Drowley AstraZeneca and AstraZeneca MedImmune authors

Laying a trap to kill cancer cells: PARP Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action Potent and selective bivalent inhibitors of BET bromodomains Molecular analysis of circulating tumor tumor Molecular analysis of circulating cells identifies distinct copy-number and in patients with chemosensitive profiles cancer small-cell lung chemorefractory Ruthenium-CatalyzedAZide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications An IGF1R-Dependent Pathway Drives Adipose Tissue Formation After Epicardial Injury Myocardial on Myocardial Effects of Ticagrelor Protective Injury After Infarction (ER) antagonists DNA-encoded chemistry: enabling the deeper sampling of chemical space AZD3759, a blood-brain-barrier (BBB)- of penetrating EGFR inhibitor for the treatment EGFR mutant non-small cell lung cancer with central nervous system (CNS) metastases epicardial human Long-term self-renewing Activating ESR1 mutations differentially differentially Activating ESR1 mutations receptor estrogen impact the efficacy of C–C bond-forming An iron-catalysed sustainable cascade providing spirocyclization frameworks access to new 3D heterocyclic stem cells pluripotent cells generated from conditions under defined xeno-free Title

Nature Chemical Biology Nature Science Translational Science Translational Medicine Circulation Circulation Chemical Reviews Nature Reviews Cancer Reviews Nature Nature Biomedical Nature Engineering Cancer Discovery Science Translational Medicine Nature Reviews Reviews Nature Drug Discovery Nature Chemistry Nature Publication

An environmentwhere science thrives High impact publications in 2016 136 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Angell HK, Valge-Archer V Angell HK, Valge-Archer MB, Ashton S, Jewsbury PJ, Ashford Barry ST, Cadogan E, Howes C, Murray J, Goodwin R, Polanska UM, Reimer C, Smith A, Swales JG, PJ, Wilson J Taylor Kilgour E, Smith NR, Rooney C Kilgour E, Smith NR, Rooney Reischl J AJ Brandon N, Cross C Barrett Carr H, McEwen R Over B V Angell HK, Valge-Archer AstraZeneca and AstraZeneca MedImmune authors Delivering our pipeline through scientific leadership 139 The tumor microenvironment and Immunoscore and Immunoscore The tumor microenvironment critical determinants of dissemination to are distant metastasis kinase inhibitor nanoparticles target Aurora tumors with favorable therapeutic index in vivo High-level clonal FGFR amplification and amplification and High-level clonal FGFR to FGFR inhibition in a translational response clinical trial Key factors for successful data integration in biomarker research A human-specific AS3MT isoform and BORCS7 10q24.32 molecular risk factors in the are locus schizophrenia-associated and of responsible Facilitating a culture effective sharing of cancer genome data Defining actionable mutations for Oncology therapeutic development Cell permeability beyond the rule of 5 cancer show Integrative analyses of colorectal of patient predictor is a stronger immunoscore instability survival than microsatellite Title

Science Translational Science Translational Medicine Science Translational Medicine Publication Medicine Nature Medicine Nature Cancer Reviews Nature Drug Delivery Advanced Reviews Immunity - cell Nature Medicine Nature Nature Reviews Drug Reviews Nature Discovery Cullberg M, Puu M, Richter K, Keen C, Uddin C, Uddin M, Puu M, Richter K, Keen Cullberg A MK, Larsson B, Malmgren Gan L J Debreczeni Durant S, McWhirter C, Nissink W, C, Cantarini MV K, Barrett Thress SI Rennard Barry Wilson ST, Z Clack G Cosulich SC, McWhirter Barratt C, DG, Klinowska T Hare JI, Ashford MB, Barry Puri S ST, AstraZeneca and AstraZeneca MedImmune authors

CXCR2 inhibition profoundly suppresses suppresses CXCR2 inhibition profoundly metastases and augments immunotherapy in ductal adenocarcinoma pancreatic Clinical development of new drug–radiotherapy combinations mutations with a mTOR resistance Overcoming new generation mTOR inhibitor Challenges and strategies in anti-cancer nanomedicine development: an industry perspective Cellularly active N-hydroxyurea FEN 1 inhibitors FEN 1 inhibitors Cellularly active N-hydroxyurea block substrate entry to the active site Association between plasma genotyping osimertinib with and outcomes of treatment (AZD9291) in advanced Non–Small-Cell Lung Cancer Clinical significance of symptoms in smokers pulmonary function with preserved Efficacy and safety of a CXCR2 a CXCR2 Efficacy and safety of patients with antagonist,AZD5069, in a randomised, persistent asthma: uncontrolled trial double-blind, placebo-controlled downstream risk loci share Cardiometabolic tissues across cis- and trans-gene regulation and diseases Title s in 2016 ation

Advanced Drug Delivery Drug Delivery Advanced Reviews Nature Nature Reviews Clinical Reviews Nature Oncology Cancer Cell The New England Journal England Journal The New of Medicine Journal of Clinical Oncology Journal Nature Chemical Biology Nature Science The Lancet Respiratory The Lancet Respiratory Medicine Publication An environmentwhere science thrives public impact High 138 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives

the rightdose, of the right drug the to rightpatient. Digital IMED The wealth of ‘big data’ in healthcare is revolutionising our approach to research and development. are We already seeing how the next generation of medicines are being shaped our by ability capture, to interpret and apply data. Combining insight from clinical health records with large-scale genomics data is enabling scientists better to predict disease outcomes in the clinic. Our team has been investigating the possibility connect to multiple data stacks from anywhere and of any type, from proprietary data real to world evidence, even social media platforms. This data stack would truly allow us mapto 360 degree views of patient journeys and gain understanding of the interplay between ‘nature’ (from genetic information) and ‘nurture’ (environmental data smartphone/sensor e.g. data) to and science in breakthroughs make ultimately patient care. iDecide iDecide isa clinical informatics research and development frameworkenabling early and better decision-making in clinical studies. In collaboration with the ManchesterCancer Research Centre (MCRC), iDecide is designed integrate, to maintain and assess data during an ongoing study utilising real time feedback from patients. Leveraging this patient-centric information in a timely adjustment appropriate enables manner clinicalto trial design, saving resources and time while helping us administer Delivering our pipeline through scientific leadership 141 Organs on Chip a (MPS) systems Microphysiological combine that models miniaturised are engineeringand biology generate to organ function in vitro human emulate to biology at the smallest acceptable scale.MPS models enable scientists to link organs together and discover key factors involved in organ cross-talk that drive particular disease phenotypes – generating data with a high likelihood of clinical translation and offering a real alternative the to use of animals in drug discovery. Our team is collaborating with some of theleading experts in the world at TissUse, Emulate, Harvard and Universities. Vanderbilt Pre-clinical Biosensors enhanceTo the impact of current online data monitoring, our teams been have the possibilities within the exploring rich data source provided sensor by technology and wearable devices. technology biosensor Incorporating into our pre-clinical studies will allow us change to current practice, improve translation and safety read-outs, while reducing the number of animal studies. Current technology allows measuring the body’s vital signs using health recognises the team our but patches true value for pre-clinical monitoring lies with invasive biosensor technology. In the future, developing pre-clinical exposure drug monitor sensors that and biomarkers of safety and efficacy will the have potential for clinical use – providing online biosensors for patients, and hence changing the status quo for patient care.

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polymeric ® ocused on creating a capability that nanoparticle technology and with with nanoparticleand technology Starpharma for exploring their dendrimer technology platform. Both these technologies improve therapeutic index and ability formulate to molecules. challenging Generation Lead in iLead F enables our scientists follow to the science and work on any therapeutic target mechanism irrespective of its tractability. aim make We to ‘undruggable’ targets ‘druggable’ by developing strategies that explore next molecule small to approaches generation hit identification and the application of peptides and cyclic peptides as novel therapeutic modalities. Some of approaches include new exciting the Acoustic Mass Spectrometry, where we inventedhave the ability use to acoustic technology (sound inject to waves) femtolitre volumes of sample into a mass samples smaller enable to spectrometer beto used and speed up the discovery process. Through collaboration with OpenEye developed have we the ability executeto virtual screens of high areas of chemical space. are We ableto screen this virtual chemical space in minutes search to for molecules that do not exist today and rapidly identify novel compounds with activity at target proteins. This represents a 10 Advanced Drug Delivery Drug Advanced Improved understanding the of physiological barriers efficient to 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 improve to efficacy by to capabilities targeting enhancing our allow delivery of both small molecules and oligonucleotide therapeutics – miRNA, mRNA and antisense. do this To our team is focused on cellular targeting, improving cellular uptake and enhancing drug delivery and other new modalities. In the latter case, a co-exclusive have we license with Pfizer for accessto the BIND Therapeutics ACCURINS increasein capability To since 2015. synthesise these compounds, are we investing in automated miniaturised chemistry synthesis techniques and machine learning inform to the best molecules progress to further. To complement thesenew methods for hit identificationwe are developing a fully automated cycle. The DMTA cycle of chemistry design and synthesis, followed biological by testing and data analysis currently (DMTA) takes around eight weeks. initiated have We a project involving machine learning algorithms aimed at fully automating this cycle to reduce this time five to hours.

Microphysiological systems Microphysiological - biochip with cellular matter “We see that current in vitro models often have limitations in human translatability. The humanised mini-organ models are aimed at overcoming these limitations and providing a relevant system for a range of applications, such as assessment of drug efficacy, safety and uptake. Availability of patient-derived and CRISPR-engineered human cells combined with the decellularized organ scaffolds will enable generation of highly relevant vitro in disease models. This will be pivotal for mechanistic investigations of targets that are not present in standard pre-clinical in vivo models. All together it holds tremendous potential for how we can further improve deliver of new innovative drugs to patients.” Magnus Althage, Leader, Team CVMD IMED Sciences, Translational

In focus: Humanised mini-organ models mini-organ Humanised focus: In The extracellular matrix (ECM) provides the scaffold that supports the architecture of tissues and organs. It also provides functional cues that support and guide cell differentiation, along with organ structure and functionality. Through the controlled removal of endogenous cells from rat hearts and kidneys, we have obtained fully decellularized organs with a largely preserved ECM composition and overall organ structure. are We then able to repopulate these scaffolds with human cardiac or kidney cells. Excitingly, we have observed that the exogenous cells use the ECM derived cues to differentiate, mature and form primitive functional organs. This mean we are able to use these humanised mini-organs to improve our understanding of basic biology in health and disease. And, eventually we will be able to test biological hypotheses and estimate efficacy and organ safety for our targets and molecules. and

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research to make the to make research possible. impossible, While advancing on focus we are we also today, our pipeline thinking the about future and transform to is going what the healthcare landscape in the next decade. Emerging as organs such technologies in and a chip innovation on targeted drug delivery are accelerating and changing progress scientific we how research. In the IMED Biotech the are we delivering Unit by innovation of next wave exploring potentially disruptive technologies that make our sky a reality. ideas blue Futures programme. Futures W of scientific innovation, we established our we established IMED innovation, scientific of IMED Biotech Unit remains at the remains cutting-edge at Unit IMED Biotech requires a new way of thinking. the ensure of requires way To a new Delivering the next wave of life changing medicines changing life medicines of the next wave Delivering teams with IMED our Futures An environmentwhere science thrives Preparingthe for future 140 IMED Annual Review2016

Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 143 An environmentwhere science thrives IMED Events 2016 142 IMED Annual Review 2016 Introduction Therapy area progress IMED functions Collaborating for An environment science innovation where science thrives Delivering our pipeline through scientific leadership 08 Delivering our pipeline through scientific leadership 145 144 IMED Annual Review 2016 .com