AstraZeneca Early-Risk Research Strategy On Trial

Courtesy of AstraZeneca The purple profit machine driven by AstraZeneca's $6 billion flagship medication, Prilosec, finally wound down last year. Once the world's largest selling prescription drug, the patents have expired, and the bright purple pill is now pink and sells over the counter at cut-rate pricing alongside Tums and Pepto-Bismol. Shares of the company sank with Prilosec's fortunes, and some analysts questioned whether AstraZeneca, the world's fifth-largest drug maker, would rebound. "The going it likely to get worse before it gets better," the company's CEO, Tom McKillop, told investors in 2001.1 Years before Prilosec was relegated to drugstore shelves, however, company scientists were deep into new technology and re-search collaborations, building what independent analysts now say is one of the best early-drug pipelines in the industry. SWELL TO SURVIVE Following the 1998 merger of Sweden's Astra and Britain's Zeneca, a merger many analysts say was driven out of desperation to ride out the Prilosec shortfall, top management made discovery research a priority. With few new drugs in the wings, the managers had little choice. SPREADING RESEARCH WINGS AstraZeneca has set up six specialist units that work globally, bringing expertise in new technologies to support its research centers. High-throughput screening centers in Wilmington, Del., Alderley Park and Charnwood in the United Kingdom, and Mölndal, Sweden, support researchers throughout the company by rapidly testing large numbers of compounds. Pharmaceutical Research Institute--AstraZeneca R&D at Griffith University in Brisbane, Australia, studies plants and marine organisms collected from Australia's rainforests and oceans. Bioinformatics Center--Based in Boston, the center develops computer and mathematical techniques for collecting and analyzing information about the sequences, structures, and functions of genes and proteins. Transgenic Center--Based in Mölndal, the center investigates genes that are most significant in disease processes and singles them out for further study. The center also provides accurate models to allow testing of new substances that may become therapeutic drugs. Biotech Laboratory--In addition to potential therapeutic agents, Astra-Zeneca researchers are looking for drugs that restore normal function to disease genes. Based in Södertälje, Sweden, this lab uses genetics technology to select proteins produced by disease genes. Imaging Center--Using magnetic resonance imaging, nuclear medicine, ultrasound, and computed tomography, scientists can track how well agents are working against chronic diseases that progress slowly. Based in Alderley Park, UK, and Mölndal, the center also collaborates with academic centers. Structural Chemistry Laboratory--Based in Mölndal, this center uses technology, including X-ray crystallography and nuclear magnetic resonance, to determine the structures and functions of molecules, which can then be refined to produce better drugs. Today, AstraZeneca has 12,000 researchers concentrated at nine sites in Sweden, England, India, Canada, and the United States. Last year, it opened a new research facility outside Boston to focus on infectious disease and cancer. The company has a research budget of more than $3 billion a year, with 20% of it designated for early discovery. In addition, it has 700 outside collaborations with biotech firms, technology companies, and academics. "They have one of the fullest and deepest pipelines in the pharmaceutical industry." says Mara Goldstein, a drug analyst with CIBC World Markets, Toronto. All large drug makers remain under pressure to turn promise into real treatments for patients. "Their in-house research and development is not as successful as it was in the 70s and 80s," says Leland J. Gershell, a New York City pharmaceutical consultant and CEO of Charger Pharmaceuticals, Piscataway, NJ. "They've invested in technology but they have not really had success in the sense that they have not increased their pipelines in any relation to the money they have spent." New technologies and the mapping of the human genome have failed to result in an explosion of new drugs as quickly as once hoped. Too often exciting leads generated through genomics have become meaningless in the development process, during which the realities of solubility, dosing, and toxicity put an end to so many potential drugs. Often the bad news comes only after extensive and expensive preclinical and clinical testing. "In the early days we have gained time in some parts of the program, but you lose it at the other end if it is not all integrated," says Martin Nicklasson, executive vice president of global drug development at AstraZeneca. "The genomic revolution has not paid off yet, because it is more complicated than us finding a number of genes that upregulate or downregulate a protein. The body is smarter than that. If you try to suppress one gene, another compensates," he says. TECH TRICKS It's not the technology, but how you use it. Astra-Zeneca has embarked on a research strategy to integrate all steps in the discovery and development process to improve the company's productivity. The strategy is built on four main themes: humanizing discovery, front-loading risk, develop- ing high-quality compounds, and working globally. Humanizing discovery puts more emphasis on early integration of patient and preclinical information. For example, the company is increasingly looking for targets from human tissue, better translational models, and more predictive response markers, and it is testing for appropriate patient populations during discovery research. "You can do your experiments in test tubes and animals but how the heck do you know if a rat is schizophrenic or not?" Nicklasson says. "Before we dig deeper into too much animal or preclinical work, we need to know if we are on the right track." By front-loading risk, the company is asking project teams to evaluate risk and find ways to test for fatal flaws in a compound early on. Christof Angst, vice president of central nervous system discovery at AstraZeneca's research labs in Wilmington, Del., says scientists are challenged to identify high risks such as potential side effects as early as possible in a drug discovery project and to address those risks early on. Serendipity, he says, counts for only so much. "In development, risk analysis is accepted. In discovery, risk analysis is not part of the traditional mindset, given the many uncertainties. I would say you can manage risk." But there are tools to help make decisions about risk along the project continuum. AstraZeneca has deployed a range of new technologies to help it sift through the dizzying number of leads, Gershell says. He points to partnerships with firms that help AstraZeneca with structural biology, high-throughput screening, information management, and robotics. "In my opinion they are spending wisely," Gershell says. "Among the big pharmas, they stand out." Richard Keith, a global project manager at the Wilmington facility, says the new tools are becoming a way of life, not a novelty. "My experience is that in the past there has been a lot of talk about technology," he says. "Since the merger, there has been a real sense of commitment to the technology" Navid Malik, an analyst with Williams de Broe in London, says one of Astra-Zeneca's most interesting collaborations is with a British company, Astex Technology. Astex is developing fragment-based drug discovery using high-throughput X-ray crystallography to identify novel, small molecule therapeutics. Malik says Astex has crystallized a key liver enzyme that may help drug developers to work around problems in metabolism or toxicity. EARLY RESEARCH: AstraZeneca looks to regain profits once brought in by Prilosec Angst says AstraZeneca is using Astex to screen a cocktail of compounds to identify those that bind with an enzyme crystal structure, including those with minimum affinities. The technology allows the visualization of binding sites for drug fragments within the enzyme crystal, which can then be linked together to produce potent leading compounds. "The advantage is you can start with simple compounds," Angst says. "Usually when medicinal chemists optimize a drug, they do it by adding to the size of that molecule. Too often a useful drug is not discovered because the molecule is too big and may not be well-absorbed into the body, may not enter the brain, or may interact with a metabolic enzyme. Here we can start with the absolute minimum size." Starting small requires a change in thinking among researchers, Angst says. "In the past, nobody wanted to lose a compound because it didn't work. You always went to the highest possible dose which is where you started to begin to see side effects." QUALITY COURSE Reducing potential side effects ties into the third leg of the company's research strategy, developing better-quality drugs. Angst says he believes that new rules for drug discovery are beginning to emerge in the postgenomic era. He noted that of 30,000 protein-encoding genes, only 3,000 to 5,000 may be potential drug targets, and of those, only about 500 targets may result in a therapeutically important agent. Through the 1990s, he says, a prevailing philosophy aimed to identify novel targets, obtain strong patent protection, and become the first to exploit the targets. Now, he says, that philosophy is changing. Companies should put a greater emphasis on validating the best possible targets and employing the most advanced technologies for drug discovery. Better quality testing makes for better business decisions, says Nicklasson. "It creates more options for the business to select the real winners based on quality in our data, not just speculation on findings in animals or in vitro." After the merger, AstraZeneca suddenly became a major global player. Its researchers could draw on resources at existing labs, as well as the company's three Enabling Science and Technology Centers in Boston, the United Kingdom, and Sweden. The company's labs throughout the company use the cutting-edge technologies concentrated at these centers. Beyond the company's own labs, it has collaborations with 700 other research organizations, 200 of them new in the last year. Some of AstraZeneca's partners include Cellomics in Pittsburgh, Pa.; Cyclacel in Dundee, UK; Celltech in Berkshire, UK; Orchid BioSciences in Princeton, NJ; Gene Logic in Gaithersburg, Md.; and Amersham Biosciences in Piscataway, NJ. The company's links to academia and independent research organizations include the University of Pennsylvania, Washington University in St. Louis, Oxford University, and the Curie Institute in Paris. Collaborations with outside researchers are vital to the company's global working strategy. Its new cholesterol- lowering drug, Crestor, was licensed from Japanese drug maker Shionogi in 1998. "AstraZeneca is distinct among the big pharma companies in having a lot of interest in doing outside collaborations with smaller companies that are focused on more minute aspects of the drug discovery process," says Gershell. Courtesy of AstraZeneca AstraZeneca R&D, Boston Angst says AstraZeneca is overcoming long-time industry reluctance to consider seriously any compounds not developed entirely in-house. "If you have a project that has already been validated by others, then there's no reason not to take advantage of that knowledge and expertise, and continue to collaborate to develop a product that adds an important therapeutic advantage," says Angst. Historically, he says, collaborations between big drug companies and small biotech firms have not always been successful. Collaborations usually concentrated on performance of technologies and a handoff between the two partners. In the past, Biotech did not understand that it eventually had to deliver viable drugs, and Big Pharma didn't understand the technology. Drug firms also were overly concerned about espionage. "They said to the biotech, 'You do this up to that stage and we will take over,'" says Angst. "They were very concerned the biotech would share too much information. It was not a true collaboration." Now, Angst says, most collaborations are structured with clear milestones and incentives that reward both companies if they are successful. He says collaborations are managed jointly and foster interaction of scientists and managers from both companies in all facets of the program. "Through true collaboration, we challenge each other, but it's a kind of friendly competition," he adds. Keith says he recalls the days in which research was a lonely, isolated job. Now he says he is amazed to find himself collaborating with AstraZeneca colleagues around the world and with researchers outside the firm. He has learned to schedule Japanese conferences so his colleagues can make the last train out of Tokyo. "To get 12,000 people to point their noses in the same direction, you have to embrace a lot of communication and discussion," Nicklasson observes. The company's strategy is reflected in its choice of staff. AstraZeneca is looking for chemists, including people with specialties in safety assessment and toxicology. "We are also looking for very experienced medical people in clinical science for this type of front-loading activity," he says. "These people are not always easy to find." Keith says the company's drive to do "more, better, faster" appears to be working. He remembers the days, more than 20 years ago, when he would work on six or seven projects over seven to eight years and come up with two compounds. AstraZeneca says its new strategy is producing one candidate drug each month, ready to enter preclinical testing, which reflects an increase of 20% over the past three years. Still, for all its emphasis on front-loading and early decision-making, Gershell says, it is too soon to know if AstraZeneca's strategy is really working. "We don't know yet if all this will pan out," he explains. "It's still going to be three or four years before we know for sure." Susan Warner (swarner@the-scientist.com) is a freelance writer in Philadelphia. 1. M. Slud, "Astra eyes slower growth," CNN, Feb. 8, 2001, available online at cnn.com/2001/BUSINESS/02/08/astrazeneca function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

AstraZeneca Early-Risk Research Strategy On Trial

Interested in reading more?

Become a Member of