Transforming AstraZeneca's R&D productivity
概述
在2010年对澳门葡京赌博游戏的研发战略进行了重大审查之后, 澳门葡京赌博游戏创建了一个新的5R框架来指导澳门葡京赌博游戏如何发现和开发新的候选药物. Looking at our productivity 和 success rates over the past 5 years we can now see a transformation in our productivity – enabling us to discover more innovative therapies for patients than ever before.
In a new report published in Nature Reviews Drug Discovery, Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D和其他科学家解释了澳门葡京赌博游戏的5R框架(正确的目标)是如何实现的, right patient, right tissue, right safety, 正确的商业潜力)已帮助指导成功, efficient drug discovery 和 development. In just five years, we have achieved a five-fold improvement in the proportion of our pipeline molecules that have advanced from preclinical investigation to completion of Phase III clinical trials – from 4% to 19%. This improvement moves AstraZeneca well above the average success rates of 6% for small molecules in the 2013-2015 timeframe (Data sourced from CMR International’s 2016 Global R&D Performance Metrics Programme).
这种转变的核心是澳门葡京赌博游戏文化的重大演变. We have established an open, collaborative 和 ‘truth seeking’ culture where science thrives. Within this environment, 澳门葡京赌博游戏从不害怕提出“致命问题”或严格检验澳门葡京赌博游戏的假设. This has enabled us to improve the quality of the drug c和idates we take forward into pre-clinical studies 和 subsequently into clinical trials.
Our success reflects an evolving approach in which we are integrating state-of-the-art technologies to identify new targets 和 the latest translational science to confirm proof-of-mechanism of our novel therapeutic modalities at safe therapeutic doses which can be taken into human studies.
We continually look to the future, 让澳门葡京赌博游戏的科学家有时间保持好奇心和原创思维, enabling them to follow the science, further improve our R&提高成功率，为患者提供变革性治疗.
Focusing on quality
支撑5R框架成功的是澳门葡京赌博游戏开展研究方式的改变, which have enabled us to improve the quality of the c和idate drugs we take forward in our pipeline. 在澳门葡京赌博游戏的研究文化中，澳门葡京赌博游戏的科学家被鼓励提出“致命问题”, we rigorously test our hypotheses, build confidence in promising targets 和 dismiss unfavourable ones much earlier in the discovery process.
Selecting the right target remains the most important decision we make in the drug discovery process. 澳门葡京赌博游戏的目标是在澳门葡京赌博游戏的主要治疗领域:肿瘤学中确定疾病的分子驱动因素, cardiovascular, renal 和 新陈代谢, 和 respiratory 和 immunology, via our company-wide genomics initiative, launched in April 2016.
“A selective high-quality molecule will never become a medicine if it is modulating the wrong target. 这就是为什么目标选择是澳门葡京赌博游戏在研究中做出的最重要的决定.” Mene Pangalos，澳门葡京赌博游戏R的执行副总裁&D
基于澳门葡京赌博游戏不断增长的疾病生物学知识, we have exp和ed the classes of drug targets we investigate 和 we increasingly aim to identify compounds with novel mechanisms of action. Broadening our target class composition, significant investments in genomic data, 下一代测序和CRISPR基因编辑使澳门葡京赌博游戏能够识别, 以一种以前不可能的方式询问和验证目标. This has translated to the increase in success rates from finding an active compound to an optimised molecule (‘hit to lead’) from 23 to 48%.
Integrating pre-clinical ‘absorption, distribution, 新陈代谢, excretion’ (ADME) 和 safety data into our predictions of how drugs will act in patients is improving the quality of our drug c和idates. We are advancing the best practice, predictive 和 translational science needed to show target engagement 和 proof of mechanism at safe, 可以用于人体研究的治疗剂量. As a result, we are delivering better quality c和idates that are less likely to fail due to safety or other issues at later development stages.
提高澳门葡京赌博游戏的能力，为合适的病人配上合适的药物, we plan for biomarker-guided patient stratification at an early stage of our drug discovery projects. By establishing searchable, 可供科学家使用的人体组织生物库, we are supporting translation of biology from the clinic to the laboratory 和 this has contributed to improved screening assays 和 novel biomarkers. Consequently, approximately 80% of our 2012–2016 portfolio from Lead Optimisation onwards has a patient selection strategy compared to less than 50% in 2005-2010. 今天，在澳门葡京赌博游戏的治疗领域，这个数字超过了90%.
Our focus on defining the ‘right patient’ has enabled us to launch nine companion diagnostics tests in 2012–2016, compared with just one in 2005–2010. 澳门葡京赌博游戏已经引入了基于生物标志物的EGFR诊断测试, 表皮生长因子受体T790M, BRCA 和 PD-L1 to identify patients most likely to benefit from our targeted treatments for non-small cell lung cancer, ovarian cancer 和 bladder cancer. We also pioneered new tests using circulating tumour DNA as the biological sample type to broaden patient access.
通过调整和重新设计澳门葡京赌博游戏的临床前和早期临床试验, we are setting rigorous st和ards so we rapidly 和 efficiently select only the best c和idates for further development. 通过澳门葡京赌博游戏的5R框架的不断发展和应用, we are converting our preclinical data into knowledge to be used to improve clinical study decision making, thereby narrowing the data-to-knowledge gap. 澳门葡京网赌游戏已经被公认为在应用方面处于领先地位 人工智能(AI)进入早期临床试验 through the iDecide research programme – an innovative five year collaboration between AstraZeneca, 曼彻斯特大学癌症科学研究所, 癌症生物标志物科学中心和克里斯蒂NHS基金会信托基金(digitalECMT). As a result, we can make rigorous, quantitative decisions about the drug c和idates we progress to the later stages of development.
“The Manchester collaboration is a tremendous opportunity for industry 和 academia to work h和 in h和 with patients. It brings together the AstraZeneca team, clinicians at Europe’s largest cancer hospital, 曼彻斯特大学的科学家和英国癌症研究中心. 澳门葡京赌博游戏可以一起在临床试验和人工智能应用方面进行创新.” 曼彻斯特实验癌症医学临床负责人安德鲁·休斯教授说.
Uncovering new biology
At the core of our strategy to follow the science is a determination to advance our fundamental underst和ing of disease biology to uncover novel drivers for the diseases we want to treat, 防止, modify or even cure. We believe our approach is unique. We don’t just collaborate with world- experts, we have established joint laboratories with academic centres of excellence where our scientists work side-by-side with academic scientists. Our teams are committed to discovering how changes in cell biology lead to diseases such as cancer, 肺部和免疫系统疾病，心脏和代谢疾病. We are also committed to sharing our research assets such as screening collections 和 clinical compounds to enable academic research under our Open Innovation initiative.
As a result of these collaborations, we have published novel biological findings in several high impact journals together with our partners. 仅在过去的18个月里，这一数字就包括了 Nature Medicine, Science Translational Medicine, Circulation 和 Science Advances. In oncology, through a highly successful collaboration with the Medical 研究 Council’s Laboratory of Molecular Biology, 澳门葡京赌博游戏使用了最先进的低温电子显微镜(cryoEM), to describe, for the first time, the structure 和 activation mechanism of human ataxia-telangiectasia mutated (ATM) protein. This protein is a key trigger in the DNA damage response (DDR) 和 this collaborative work has resulted in insights that will help us uncover novel binding sites for future drug targeting.
With our respiratory 和 immunology research, we have identified the sub-set of dendritic cells, called cDC2 cells, 这对启动免疫反应对抗入侵者至关重要. Identifying how 和 where cDC2 cells fit into the complex process of immunity enables us to examine new targets in diseases driven by inappropriate antibody responses such as asthma, 慢性阻塞性肺疾病和自身免疫.
In cardiovascular, renal 和 metabolic diseases, our extensive programme of cardiac regeneration research is identifying new targets 和 pathways that may play a role in repairing damaged heart muscle in people with heart failure. In recent studies with Professor Bin Zhou at the University of Chinese Academy of Sciences in Shanghai, we highlighted the importance of paracrine factors in cardiac regeneration.
With our scientists at the AstraZeneca Integrated Cardio Metabolic Centre (AZ-ICMC) at the Karolinska Institute, 澳门葡京赌博游戏为了解糖尿病贡献了两项开创性的研究. By identifying a new role for insulin-like growth factor 1 (IGF1) in driving the formation of harmful epicardial fat tissue in the heart we have opened up fresh opportunities for tackling the growing burden of heart disease 和 obesity. In addition, 通过阐明胰岛细胞亚群的功能, 澳门葡京赌博游戏已经提高了对它们在糖尿病中的重要性的认识.
In neuroscience, our scientists at the AstraZeneca-Tufts Neuroscience Laboratory at Tufts University are bringing new insights into control mechanisms for nerve excitation in the brain, including increasingly detailed knowledge of the essential role of neuronal potassium-chloride transporter protein (KCC2). We are collaborating with researchers at the University of 剑桥 to study the cellular processes for degrading unwanted proteins, with the aim of activating these mechanisms to degrade misfolded proteins such as huntingtin in Huntington’s disease.
“澳门葡京赌博游戏对有好奇心的合作伙伴感兴趣, 谁相信理解科学将缩短通往临床的道路. Our partnership with AstraZeneca is a natural fit because AstraZeneca is truly focused on the science 和 on ‘blue-sky’ thinking that’s informed by current state-of-the-art knowledge.” Professor Iain McInnes, 导演, Institute of Infection, Immunity 和 Inflammation, University of Glasgow
As we apply our knowledge of disease biology, we are diversifying our chemical toolbox to develop new therapies against an array of drug target classes. 澳门葡京赌博游戏不再只关注小分子，现在澳门葡京赌博游戏的项目中有30%左右是小分子 exploring new modalities 和 drug delivery devices 这是澳门葡京赌博游戏努力让每个目标都能被麻醉的一部分.
澳门葡京赌博游戏对CRISPR/ cas9的日常使用和发展提供了快速, 精确的, efficient gene editing to help us discover new drug targets 和 create more relevant cell lines 和 animal models. 通过世界领先的合作伙伴关系和澳门葡京赌博游戏的内部专家团队, 澳门葡京赌博游戏不断推动技术，以提高筛选和效率. In two recent high impact publications, we showed how it is possible to barcode guide-RNA to improve screening 和 develop novel hybrid DNA:RNA guides to improve binding efficiency.
Speeding up the automated testing of thous和s of potential new molecules is NiCoLA-B – the world’s most advanced drug discovery robot. NiCoLA-B uses sound waves to move tiny droplets of potential drugs from storage tubes into miniature ‘wells’ on assay plates – billionths of a litre at a time.
Our investment in multimodal molecular imaging is enabling us to uncover new insights into our drug targets, 和 to see the impact of our drug c和idates on molecular 和 cellular pathways in ways that were previously impossible. With mass spectrometry, we have created detailed images of the deposition of asthma drugs in multiple structures of the lung over time. We have also mapped drug 和 metabolite distribution for combinations of targeted cancer therapies to evaluate their impact on the tumour microenvironment.
为了进一步提高澳门葡京赌博游戏预测候选药物对人类的影响的能力, 澳门葡京赌博游戏正在与世界领先的“芯片上器官”设计专家合作, 开发微生理系统的技术和生物学.
Rapid progress with our genomics initiative 和 next-generation sequencing (NGS) are enabling us to identify novel targets 和 pathways within large patient populations. 事实上, we have already analysed more than 200,到2026年，澳门葡京赌博游戏计划探索200万个基因组中的000个, including 500,000 from our own clinical trials. This is supported by on our recent partnership with UK Biobank 和 Regeneron to sequence the genomes of 500,000 UK Biobank samples, 加速最大的广泛可用的“大数据”人类测序资源.
AI is already helping us address our biggest challenges in chemistry 和 AI-based informatics are starting to convert ‘big data’ into valuable knowledge. The development of novel AI techniques are currently being applied in ongoing clinical trials to improve the identification 和 prediction of safety 和 tolerability signals. 观察家, is an AI-driven system that notifies clinicians 和 study teams involved in clinical trials of potential safety issues. The system can ‘reason’ over clinical trial data to assess the risk of specific clinical events enabling the team to take appropriate action early.
“观察家 is a decision support system being developed to continuously monitor specific patient risk 和 alert the study team early. Our aim is that Watcher will ultimately identify those patients at potential risk before they materialize 和 ameliorate this same risk.” says Dr Dónal L和ers, OncTMU早期临床发展主任-决定项目, CRUK Manchester Institute
在R&D we will never be complacent; we will continually look beyond the way we develop drug c和idates today 和 explore how we can best use emerging technologies to accelerate the design 和 testing of tomorrow’s medicines. With our novel drug discovery platforms, we are moving towards multiple classes of medicines that target the biology of disease in totally new ways. 用明天的创新取代今天的传统, we are turning science fiction into science fact.
