Transforming AstraZeneca's R&D productivity
Overview
Following a major review of our research and development strategy in 2010, we created a new 5R Framework to guide how we discover and develop new drug candidates. 回顾澳门葡京赌博游戏过去5年的生产力和成功率，澳门葡京赌博游戏现在可以看到澳门葡京赌博游戏的生产力发生了转变——使澳门葡京赌博游戏能够为患者发现比以往更多的创新疗法.
In a new report published in Nature Reviews Drug Discovery, Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D and fellow scientists explain how our 5R framework (right target, right patient, right tissue, right safety, right commercial potential) has helped guide successful, efficient drug discovery and development. In just five years, 从临床前研究到完成III期临床试验，澳门葡京赌博游戏的管道分子比例提高了5倍，从4%提高到19%. 这一进步使澳门葡京网赌游戏大大超过了2013-2015年小分子药物平均成功率6%(数据来自CMR International的2016年全球R&D Performance Metrics Programme).
At the heart of this transformation has been a significant evolution of our culture. We have established an open, collaborative and ‘truth seeking’ culture where science thrives. Within this environment, we are never afraid to ask the ‘killer questions’ or to rigorously test our hypotheses. 这使澳门葡京赌博游戏能够提高澳门葡京赌博游戏进入临床前研究和随后进入临床试验的候选药物的质量.
澳门葡京赌博游戏的成功反映了一种不断发展的方法，澳门葡京赌博游戏正在整合最先进的技术来确定新的靶点和最新的转化科学，以确认澳门葡京赌博游戏的新型治疗方式在安全的治疗剂量下的机制证明，这些治疗方式可以用于人体研究.
We continually look to the future, giving our scientists time for curiosity and original thinking, enabling them to follow the science, further improve our R&D success rate and deliver transformative treatments for patients.
Focusing on quality
Underpinning the success of our 5R framework are changes in the way we conduct our research, which have enabled us to improve the quality of the candidate drugs we take forward in our pipeline. Within a research culture where our scientists are encouraged to ask the ‘killer questions’, we rigorously test our hypotheses, build confidence in promising targets and 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. We aim to identify molecular drivers of disease across our main therapy areas: oncology, cardiovascular, renal and metabolism, and respiratory and 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. This is why target selection is the most important decision we make in research.” Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D
Building on our growing knowledge of disease biology, 澳门葡京赌博游戏已经扩大了澳门葡京赌博游戏研究的药物靶点的类别，澳门葡京赌博游戏越来越多地致力于识别具有新作用机制的化合物. Broadening our target class composition, significant investments in genomic data, next generation sequencing and CRISPR gene editing are enabling us to identify, interrogate and validate targets in a way not previously possible. 这意味着从发现活性化合物到优化分子的成功率从23%提高到48%.
Integrating pre-clinical ‘absorption, distribution, metabolism, 将ADME和安全性数据用于预测药物对患者的作用，从而提高候选药物的质量. We are advancing the best practice, predictive and translational science needed to show target engagement and proof of mechanism at safe, therapeutic doses that can be taken into human studies. As a result, we are delivering better quality candidates that are less likely to fail due to safety or other issues at later development stages.
To enhance our ability to match the right medicine to the right patient, we plan for biomarker-guided patient stratification at an early stage of our drug discovery projects. By establishing searchable, accessible human tissue biobanks for our scientists, 澳门葡京赌博游戏正在支持生物学从临床到实验室的转化，这有助于改进筛选分析和新的生物标志物. Consequently, 2012-2016年，从Lead优化开始，澳门葡京赌博游戏的投资组合中约有80%具有患者选择策略，而2005-2010年这一比例不到50%. Today, this figure is greater than 90% across our therapy areas.
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. We have already introduced biomarker-based diagnostic tests for EGFR, EGFR T790M, BRCA and PD-L1 to identify patients most likely to benefit from our targeted treatments for non-small cell lung cancer, ovarian cancer and bladder cancer. We also pioneered new tests using circulating tumour DNA as the biological sample type to broaden patient access.
By adapting and redesigning our preclinical and early phase clinical trials, we are setting rigorous standards so we rapidly and efficiently select only the best candidates for further development. Through the continued evolution and application of our 5R framework, we are converting our preclinical data into knowledge to be used to improve clinical study decision making, thereby narrowing the data-to-knowledge gap. AstraZeneca is already being recognised as leading the way in the application of artificial intelligence (AI) in early clinical trials through the iDecide research programme – an innovative five year collaboration between AstraZeneca, the University of Manchester Institute of Cancer Sciences, the Centre for Cancer Biomarker Sciences and the Christie NHS Foundation Trust (digitalECMT). As a result, we can make rigorous, quantitative decisions about the drug candidates we progress to the later stages of development.
“The Manchester collaboration is a tremendous opportunity for industry and academia to work hand in hand with patients. It brings together the AstraZeneca team, clinicians at Europe’s largest cancer hospital, University of Manchester scientists and Cancer Research UK. Together we can innovate in the conduct of clinical trials and the application of AI.” says Professor Andrew Hughes, Clinical Lead for Manchester Experimental Cancer Medicine.
Uncovering new biology
澳门葡京赌博游戏遵循科学的战略核心是决心推进澳门葡京赌博游戏对疾病生物学的基本理解，以发现澳门葡京赌博游戏想要治疗的疾病的新驱动因素, prevent, modify or even cure. We believe our approach is unique. We don’t just collaborate with world- experts, 澳门葡京赌博游戏与优秀的学术中心建立了联合实验室，澳门葡京赌博游戏的科学家与学术科学家并肩工作. Our teams are committed to discovering how changes in cell biology lead to diseases such as cancer, lung and immune disorders and heart and metabolic diseases. 澳门葡京赌博游戏还致力于分享澳门葡京赌博游戏的研究资产，如筛选集合和临床化合物，以实现澳门葡京赌博游戏的开放式创新倡议下的学术研究.
As a result of these collaborations, we have published novel biological findings in several high impact journals together with our partners. In the past 18 months alone, this has included papers in Nature Medicine, Science Translational Medicine, Circulation and Science Advances. In oncology, through a highly successful collaboration with the Medical Research Council’s Laboratory of Molecular Biology, we used state-of-the-art cryo-electron microscopy (cryoEM), to describe, for the first time, the structure and activation mechanism of human ataxia-telangiectasia mutated (ATM) protein. This protein is a key trigger in the DNA damage response (DDR) and this collaborative work has resulted in insights that will help us uncover novel binding sites for future drug targeting.
With our respiratory and immunology research, we have identified the sub-set of dendritic cells, called cDC2 cells, that are essential for priming the immune response against invaders. 确定cDC2细胞如何以及在何处适应复杂的免疫过程，使澳门葡京赌博游戏能够检查由不适当的抗体反应(如哮喘)驱动的疾病中的新靶点, chronic obstructive pulmonary disease and autoimmunity.
In cardiovascular, renal and metabolic diseases, 澳门葡京赌博游戏广泛的心脏再生研究计划正在确定可能在心力衰竭患者修复受损心肌中发挥作用的新靶点和途径. 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, we have contributed two seminal pieces of research to the understanding of diabetes. 通过确定胰岛素样生长因子1 (IGF1)在驱动心脏有害心外膜脂肪组织形成中的新作用，澳门葡京赌博游戏为解决心脏病和肥胖日益增加的负担开辟了新的机会. In addition, by elucidating the functionality of sub-sets of islet cells in the pancreas, we have improved understanding of their importance in diabetes.
In neuroscience, 澳门葡京赌博游戏在塔夫茨大学澳门葡京网赌游戏-塔夫茨神经科学实验室的科学家们正在为大脑神经兴奋的控制机制带来新的见解, including increasingly detailed knowledge of the essential role of neuronal potassium-chloride transporter protein (KCC2). We are collaborating with researchers at the University of Cambridge 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.
“We are interested in partners who are curiosity based, who believe that understanding the science will shorten the route to clinic. 澳门葡京赌博游戏与澳门葡京网赌游戏的合作是天作之合，因为澳门葡京网赌游戏真正专注于科学和“蓝天”思维，这是由当前最先进的知识提供的.” Professor Iain McInnes, Director, Institute of Infection, Immunity and Inflammation, University of Glasgow
Turning science fiction into science fact
At all stages of drug discovery and development, we are seeking solutions to the ‘what if’ questions of today. By investing in the latest cutting-edge technologies, we are accelerating progress towards our goal of delivering the targeted, life changing medicines of tomorrow.
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. We no longer focus on small molecules alone, with around 30% of our programmes now exploring new modalities and drug delivery devices as part of our effort to make every target druggable.
Our everyday use and development of CRISPR/Cas 9 provides fast, precise, efficient gene editing to help us discover new drug targets and create more relevant cell lines and animal models. Through world-leading partnerships and our in-house team of experts, we continually push the technology to improve screening and efficiency. In two recent high impact publications, 澳门葡京赌博游戏展示了如何使用条形码引导RNA来改进筛选和开发新型杂交DNA:RNA引导来提高结合效率.
Speeding up the automated testing of thousands of potential new molecules is NiCoLA-B – the world’s most advanced drug discovery robot. NiCoLA-B利用声波将潜在药物的微小液滴从储存管中移动到分析板上的微型“孔”中，每次可以移动十亿分之一升.
Our investment in multimodal molecular imaging is enabling us to uncover new insights into our drug targets, and to see the impact of our drug candidates on molecular and 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. 澳门葡京赌博游戏还绘制了靶向癌症治疗组合的药物和代谢物分布，以评估其对肿瘤微环境的影响.
To further improve our ability to predict the effects of our drug candidates on humans, we are collaborating with world-leading experts in ‘organ-on-a-chip’ design, technology and biology to develop microphysiological systems (MPS).
Rapid progress with our genomics initiative and next-generation sequencing (NGS) are enabling us to identify novel targets and pathways within large patient populations. Indeed, we have already analysed more than 200,000 of the 2 million genomes we plan to explore by 2026, including 500,000 from our own clinical trials. This is supported by on our recent partnership with UK Biobank and Regeneron to sequence the genomes of 500,000 UK Biobank samples, to accelerate the largest widely-available ‘big data’ human sequencing resource.
人工智能已经在帮助澳门葡京赌博游戏解决化学领域的最大挑战，基于人工智能的信息学也开始将“大数据”转化为有价值的知识. 新型人工智能技术的开发目前正应用于正在进行的临床试验，以改进安全性和耐受性信号的识别和预测. WATCHER, is an AI-driven system that notifies clinicians and study teams involved in clinical trials of potential safety issues. 该系统可以对临床试验数据进行“推理”，以评估特定临床事件的风险，使团队能够尽早采取适当的行动.
“WATCHER is a decision support system being developed to continuously monitor specific patient risk and alert the study team early. Our aim is that Watcher will ultimately identify those patients at potential risk before they materialize and ameliorate this same risk.” says Dr Dónal Landers, Senior Director Physician OncTMU Early Clinical Development Director – iDecide Programme, CRUK Manchester Institute
Across R&D we will never be complacent; we will continually look beyond the way we develop drug candidates today and explore how we can best use emerging technologies to accelerate the design and 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. By replacing today’s conventions with tomorrow’s innovations, we are turning science fiction into science fact.
