On the Road to Personalized Medicine The use of biomarkers in clinical drug development will usher in the age of personalized medicine, allowing developers to predict a patient’s response to a compound. The result will be not only better treatment for patients, but also an improvement in how companies make portfolio decisions. By Denise Myshko The future of healthcare will enter an exciting age over the next five to 10 years with the promise of newer and better drugs to treat life-threatening illnesses as technologies such as proteomics, pharmacogenomics, imaging, and assay development mature. The use of biomarkers to diagnose disease and assess therapeutic outcome is not an entirely new concept. Biological and surrogate markers have been used for decades in clinical-care settings and in drug development. Blood pressure, for example, has long been a marker for stroke and heart attack. But as technology that allows for the identification and validation of new biological and genomic markers evolves, there will be more ways to measure and assess disease, as well as a compound’s impact on patients. There is hope that physicians will be able to measure the effects of some diseases, such as Alzheimer’s, Parkinson’s, and many cancers in which the disease has progressed significantly before clinical signs appear, early enough to pursue much more promising treatment options. The use of such biomarkers also is expected to expand beyond that of disease diagnosis. In pharmaceutical development, biomarkers are valuable tools for stratifying patients in clinical trials into groups that are most likely to respond to a therapeutic regimen and identifying patients who will have an adverse event. The benefits of pinpointing such outcomes are that they can save failed products by identifying patients who will benefit from a compound, and they allow developers to make go/no go decisions earlier in the development process. Biomarkers also can lead to the development of companion diagnostic tests for the drug under development. Many industry leaders think of this evolution as the beginning of personalized medicine, and there is much interest in the discovery of new biomarkers and how to use of them. The Food and Drug Administration and other regulatory agencies, the National Institutes of Health, pharmaceutical companies, and suppliers of genomic and biomarker technologies and services are evaluating the opportunities and hurdles. “Biomarkers have been thought of as a diagnostic,” says William Moffitt, president and CEO of Nanosphere Inc. “But a rapidly emerging use of biomarkers comes from the pharmaceutical industry. Pharmaceutical companies are using biomarkers in ways that span the entire drug development and marketing process.” Technologies have evolved to a state where they are now providing practical solutions for medical care, says J. Fred Pritchard, Ph.D., VP of drug development programs at MDS Pharma Services. “If we can apply those advances in a very practical setting, either in the research world or diagnostic world, we’ll have made an advancement in medicine,” he says. Other industry leaders predict even further evolution in this field. “New diagnostic platforms will allow us to answer different and broader questions in the clinic with respect to patients than those we’ve been able to answer to date,” says Thomas Metcalfe, head of the biomarker program at Roche. “Specifically, there will likely be an evolution around testing multiple parameters at once and looking at multiple analogues in a sample. We call this multiplexing.” Additionally, he says, researchers will be able to get a much broader understanding of pharmacogenomics. “We’ll have the ability to deal with pharmacogenomics in the clinical setting through the use of clinical tools such as DNA chips,” Mr. Metcalfe says. “This will mean that in the clinic there will be broader acceptance of personalized medicine approaches, which will likely lead to more use of personalized medicine approaches by the industry.” Industry incentives A biomarker, or biological marker, is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention, according to the NIH’s Biomarkers Definitions Working Group. Biomarkers may have the greatest value in early efficacy and safety evaluations, such as in vitro studies in tissue samples, in vivo studies in animal models, and early phase clinical studies to establish proof of concept. One use of biomarkers is for the development of companion diagnostics. Perhaps the best-known example of this application is with Genentech’s Herceptin, which is the first humanized antibody approved for the treatment of HER2 positive metastatic breast cancer. But the product would not have reached the market without an accompanying diagnostic test that helps physicians identify patients whose cancer cells express the protein HER2, a Cambridge Healthtech Advisors’ report notes. Pharmaceutical companies are expected to embrace the use of biomarkers more and more. According to researchers at Life Science Insights, some of the key drivers of this include: competitive industry trends; the need to implement past investments; and a growing awareness that toxicity markers may be a regulatory requirement for future filings. These researchers suggest that drug companies will continue to increase their investments in biomarker development primarily focused on the early discovery stages through Phase I/IIa clinical trials. There is widespread recognition of the need to develop more effective tools to improve health outcomes. In April 2005, the NIH announced a program to provide resources to validate candidate biomarkers for well-defined human diseases of liver, kidney, urological tract, digestive and hematologic systems, endocrine and metabolic disorders, diabetes and its complications, and obesity, for which there are no or very few biomarkers or for which standard biomarkers are currently invasive or prohibitively expensive. Officials with the FDA have indicated they may consider developing guidelines as part of the Critical Path Initiative. This would include refining a regulatory framework, as well as considering individual projects on biomarker and surrogate endpoint development. FDA officials say biomarkers can be used in early drug development to evaluate activity and safety in animal models, bridge animal and human pharmacology via proof-of-mechanism or other observation, and evaluate human safety early in development. In later development, biomarkers can be used to evaluate dose-response and optimal regimen for desired pharmacological effect, determine dose-response for toxicity, and determine the role of differences in metabolism. Within industry, there is much interest as well. Pfizer and Roche have both made commitments to biomarker research. “We believe that to make better and more competitive medicines — medicines that are clearly differentiated from competitive products — we have to understand biology better and we have to find better intervention points,” Mr. Metcalfe says. “First, we have to identify projects that attack those intervention points, and second, we have to collect data that show we’ve been effective in making a difference in that disease.” He says one of the biggest changes the company has made recently is requiring development teams to have a biomarker plan along with a toxicity strategy when evaluating whether to move medicines into man. “We think about the overall value equation,” Mr. Metcalfe says. “With this requirement, we believe we have the potential for systematic learning as a consequence.” Other organizations also are entering this area in a big way. In June 2005, MDS Pharma Services teamed up with several other companies to form The Biomarker Alliance. The alliance provides a wide range of biomarker discovery and development programs and is made up of biomarker service providers Caprion Pharmaceuticals, Gentris Corp., Massachusetts General Hospital Department of Radiology, and MDS Pharma Services. Challenges and Hurdles While there is a great deal of potential for the use of biomarkers in drug development, there is still much uncertainty, especially with regard to how regulators will use and interpret such data. Frost & Sullivan Industry Analyst Philip Webster says one of the sticking points on the regulatory side concerns the validation of a biomarker and surrogate endpoint in a clinical trial. “A physiological measurement, such as body temperature, can be used as an endpoint, but it is more complicated to validate a molecular biomarker as an endpoint to determine whether a particular drug is safe or effective,” he says. “There is some confusion about the validation of biomarker endpoints because, at the moment, no one is 100% sure what an endpoint must be or how to define it.” One industry concern is that regulators may not have the appropriate context to interpret biomarker and genomic data, says Donna Mendrick, Ph.D., scientific fellow and VP of toxicogenomics at Gene Logic Inc. “A pharmaceutical company may have data from 100 compounds, but when the company goes to the FDA, it may be submitting data on one compound,” she says. “Because the FDA doesn’t have access to all of the data, there are questions as to how regulators will use the data and in what context. This is why the FDA has been encouraging voluntary data submission. Regulators want to get experience in analyzing and interpreting the information.” Within the development process, there is a question as to whether the use of biomarkers will change the type of studies that companies need to conduct for regulatory approval, says Bruce E. Seligmann, Ph.D., founder, chairman, and chief scientific officer of High Throughput Genomics (HTG). “There are two applications; first developers have to identify biomarkers that can be measured in the study design and validate how the biomarker results correlate to the actual outcome in a hard and fast way,” Dr. Seligmann says. “There is a need to generate the data and, ultimately, convince the FDA that the biomarker results are as reliable and as valid as the actual outcome. It may be possible to modify clinical trials to rely more heavily, possibly entirely, on biomarker studies. The second application is in the selection of subsets of patients for clinical trials. In this case, the same test needs to be available as a diagnostic so the appropriate selection of patients can continue to be made in the clinical setting.” Cost issues Initially, discovering and validating a marker could add cost and complexity to drug development, Mr. Webster says. “As more biomarkers become available for different disease indications, then ultimately the cost of drug development can be reduced; however, this will take time,” he says. “At the start, the investment should be made in the most cost-effective way possible.” Dr. Pritchard says, however, there is the potential to save money by using biomarkers in the development of a new product. Additionally, he says some drugs that might be pulled from the market because of safety concerns could potentially be saved because patients who exhibit adverse events could be identified. The Way Forward As the pharmaceutical industry continues to examine ways to address the cost and complexity of using biomarkers in drug development, the Pharmaceutical Research and Manufacturers of America (PhRMA) has formed a biomarker consortium to share some of the costs of biomarker development and validation, says Stephen Williams, M.D., Ph.D., worldwide head of clinical technology at Pfizer Global Research and Development. “There are a few biomarkers that are small enough and cheap enough so they can be validated within an individual drug company within one drug program,” Dr. Williams says. “But the biggest benefits of biomarkers are in the big disease markets, such as Alzheimer’s, atherosclerosis, osteoarthritis, and so forth. In these areas, biomarkers are too expensive and would need to be validated against different drug programs. And even if one company could afford it, there might not be a positive return on investment because there is a limit to the number of times one company would use a particular biomarker.” Dr. Williams is on the consortium’s science committee and is helping to bring the effort forward. He says the business arrangement for the consortium will be finalized this year, and he expects to start work on projects next year, adding that subcommittees are now forming to define where the research gaps are. Industry experts explain that new technologies can now be applied to test for biomarkers as a way to diagnose diseases. One example, they say, is the early detection of neurodegenerative diseases, such as Alzheimer’s disease. In February 2005, scientists at Northwestern University announced that in using bionanotechnology, they were able to detect in human cerebrospinal fluid (CSF) miniscule amounts of a toxic protein — amyloid ß-derived diffusible ligands (ADDL) — that is associated with Alzheimer’s disease. In the end, the goal of pharmacogenomics is better health outcomes, Dr. Pritchard says. “New biomarkers can lead to early detection and tracking, which leads to early treatments, which leads to better outcomes for patients and their families,” he says. PharmaVOICE welcomes comments about this article. E-mail us at [email protected]. There have been recent examples of compounds that were determined to be not as efficacious as originally considered. But when researchers examine the data more closely using biomarkers, they may find that some patient populations respond very well to the drug. There is going to be more incentive to subpopulate studies. PharmaVOICE October 2005 Dr. Donna Mendrick The economic model for expensive surrogate endpoint development is flawed. Government sponsorship focuses on new biomarker discovery. So there is a gap. The PhRMA consortium project, as well as improving FDA involvement, will hopefully help bridge some of that economic gap. Dr. Stephen Williams Biomarkers will allow us to establish new diagnostic platform Markers, which will enable us to answer different and broader questions in the clinic with respect to patients than those we’ve been able to answer to date. Thomas Metcalfe Biomarker benefits Current Biomarker Areas of Focus Efficacy reflects beneficial result of treatment Mechanism reports the downstream effect of drug Disease relates to clinical outcome or measure of disease Toxicity reports toxicological effect of drug on in vitro and in vivo systems Staging distinguishes between different stages of disease Source: Life Science Insights, Framingham, Mass. For more information, visit lifescience-insights.com. Mechanism Disease Efficacy Toxicity Staging 22% 22% 28% 8% 20% Key Biomarker Trends: 2004 to 2010 Influences on Biomarker Use in Clinical Trials F Escalating costs and time-scales in drug development demand greater productivity. F Genomic and proteomic techniques are becoming more commonplace in the postgenomic era. F Regulatory agencies have no stance on the use of biomarkers in clinical trials currently, although this is set to change. F Leading drug companies are responding by investing in biomarker discovery programs in this very early market stage. Market drivers High cost of clinical trial failure. Duration of clinical trials needs to be reduced. Increased prevalence of terminal diseases, such as heart disease, in the aging baby-boomer generation require an accelerated drug pipeline. Increasing s ze of drug discovery is likely to drive demand for improved clinical-trial efficacy further into the future. Market restraints Initial costs of biomarker discovery are high. Regulatory climate does not favor the validation of biomarkers as clinical endpoints. Using biomarkers makes clinical trials more complicated. There are concerns about misdiagnosis and safety issues. Source: Frost & Sullivan, San Antonio. For more information, visit frost.com. As technology has evolved, there are more and more ways to measure disease conveniently. If we can apply these learnings in a very practical setting, either in the research or diagnostic arenas, we will make significant advancements in medicine. F Dr. Bruce Seligmann There are initial start-up costs for biomarker-based programs, but thereafter companies will be able to discontinue failing programs earlier or select candidates with improved odds of success, saving time, money, and opportunity costs. In the long term, costs could be drastically lowered by increasing the success rate of drug discovery. Dr. J. Fred Pritchard At the moment, one of the sticking points on the regulatory side concerns the validation of a biomarker and its surrogate endpoint in a clinical trial. No one is 100% sure what an endpoint must be or how to define it. F Philip Webster Experts on this topic Donna Mendrick, Ph.D. Scientific Fellow and VP of Toxicogenomics, Gene Logic Inc., Gaithersburg, Md.; Gene Logic develops genomics technologies, bioinformatics systems, and information products and services that increase the productivity and efficiency of pharmaceutical and biotechnology drug discovery and development. For more information, visit genelogic.com. Thomas Metcalfe. Head of Biomarker Program, Roche, Nutley, N.J.; Roche is a research-oriented healthcare company with core businesses in pharmaceuticals and diagnostics. For more information, visit rocheusa.com. William Moffitt. President and CEO, Nanosphere Inc., Northbrook, Ill.; Nanosphere is a nanotechnology-based life-sciences company that is using the application of proprietary nanotechnology to create new standards in medical care and public safety. For more information, visit nanosphere-inc.com. J. Fred Pritchard, Ph.D. VP, Drug Development Programs, MDS Pharma Services, Montreal, Quebec; MDS Pharma Services offers a full spectrum of resources to meet the drug discovery and development needs of the pharmaceutical and biotechnology industries. For more information, visit mdsps.com. Bruce E. Seligmann, Ph.D. Founder and Chairman, High Throughput Genomics, Tucson, Ariz.; High Throughput Genomics discovers and develops molecular biology-based processes that improve the efficiency and productivity of drug discovery and enable new diagnostics. For more information, visit htgenomics.com. Philip Webster. Industry Analyst, Frost & Sullivan, San Antonio; Frost & Sullivan publishes world-class market consulting information and intelligence on emerging high-technology and industrial markets. For more information, visit healthcare.frost.com. Stephen Williams, M.D., Ph.D. Worldwide Head of Clinical Technology, Pfizer Global Research and Development, New York; Pfizer discovers, develops, manufactures, and markets leading prescription medicines for humans and animals and many consumer brands. For more information, visit pfizer.com.

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