By Kathy Ordoñez
November 15, 2003 | Despite many recent advances in the diagnosis and treatment of disease, there remain many challenges to improving the effectiveness and cutting the costs of healthcare. Medical practice today is primarily reactive. In most instances, we seek to arrest disease after the patient is symptomatic and the disease is relatively advanced. This is compounded by age, where common complex conditions such as Alzheimer's and cardiovascular disease affect a greater percentage of us as we live longer, with significant implications for quality of life and the resultant costs of treatment.
Neither is medicine consistently prescribed for the right patient at the appropriate dosage at the optimal time. The FDA's Center for Drug Evaluation and Research (CDER) estimates that approximately 2 million of the 2.8 billion prescriptions filled annually in the United States will result in adverse drug reactions, leading to about 100,000 deaths per year. Also, many people with common diseases don't respond to initial therapy, leading to a trial-and-error approach to therapy selection and dosage.
Clearly, drug research and development organizations stand to benefit from better diagnostic and treatment techniques to create more targeted therapies. But when and how will these advances occur?
The explosion of basic biological information, coupled with better genomics-enabling technologies, is fueling new discoveries. The genomic sequences of most medically important organisms — including the human genome — have been determined, and technological advances are letting us rapidly and cost-effectively gain an understanding of how human variation relates to disease.
Association studies compare genetic profiles between people with and without a specific disease through the examination of single nucleotide polymorphisms (SNPs) and/or gene-expression patterns. Historically, these studies have faced serious limitations and resulted in very few new products. Studies have taken years to progress, and many reported "discoveries" of genetic associations with diseases have not been confirmed through replication in multiple patient populations.
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But recent advances in automation and techniques to study human variation are accelerating discovery and improving the reproducibility of findings. Researchers are now performing genotyping and gene-expression association studies with thousands of case and control samples that interrogate nearly all genes — providing sufficient statistical power to correlate genetic differences among humans with disease.
A new technique called ribotyping, for example, lets researchers understand how the genetic contributions from each of our parents are affecting biology and how they contribute to disease. Using new proteomic capabilities, researchers are also able to determine how circulating and cellular proteins compare in patient populations and relate this information to disease.
New genomic and proteomic methods should help researchers understand more about common complex conditions such as rheumatoid arthritis and cardiovascular disease. These diseases probably have multiple inter-relating causal factors, representing the genetic variability among people, that are affected by both heredity and environment.
A greater understanding of the genetic basis for these diseases should expand the small universe of approximately 500 drug targets, and make the application of existing targets and therapies more effective. In the future, we may also use these tools to understand causation and metastasis in cancer, and to gain an understanding of which treatments are best for a group of patients at a specific point in the course of their disease.
Will the Market Shrink or Expand?
We have a tremendous opportunity to translate these scientific discoveries into medical realities and useful products. It's unlikely that we'll see "personalized medicine" anytime soon, at least as it's typically described (i.e., where a single genetic analysis produces a report predicting a person's medical future based on genes, or suggests how to personalize the formulation of a therapy for one individual). But research approaches that identify groups of people with common genetic profiles for selected therapies are already beginning to affect drug discovery.
This "targeted medicine" approach yields better-characterized drug targets and identifies subpopulations of patients who are most likely to benefit from the new, targeted therapies. This approach should also facilitate faster and more successful clinical trials and drugs with superior safety and efficacy profiles.
A key technology of targeted medicine is molecular diagnostics. New molecular methods may identify predisposition to certain diseases such as rheumatoid arthritis or osteoporosis. Lifestyle changes could then help patients delay or avoid disease development. Molecular tests will also let doctors monitor patients predisposed to disease, to determine the onset of the disease for earlier intervention and selection of the most effective treatment. Likewise, other molecular tests will let doctors monitor the safety and effectiveness of the therapy.
Some in the drug industry fear that targeted medicine will shrink the market or eliminate the potential for blockbusters, but just the opposite could occur. Better, targeted medicines — those that link diagnostics to select and deselect target populations for therapy supported by additional diagnostics to monitor their safety and effectiveness — should improve the value of medicines.
More efficient clinical trials incorporating pharmacogenomic studies could lead to faster drug approvals. Better patient compliance and earlier intervention through new diagnostics may further expand the use of existing therapies and sustain the market for targeted therapies.
Case in point: hormone replacement therapy (HRT). Study results from the Women's Health Initiative have shown the advantages of using HRT for protection against hip fractures and colon cancer. According to a recent article in The New England Journal of Medicine, these beneficial effects are more than offset by a 24-percent increase in the potential for cardiovascular disease, and earlier reports in the literature have linked HRT to breast cancer and other medical conditions.
What if some or all of these safety risks were concentrated in relatively small subpopulations with significant risk? Tests to identify these high-risk women who should avoid HRT would make it an easier choice for women with lower-risk profiles. Oral contraceptives are another example, where a woman's risk for thromboembolism can increase more than 20-fold if she has the Factor V mutation.
More Targeted Therapies
Patients are beginning to benefit from the first commercial examples of targeted medicine. Herceptin, for example, is already a standard of care for HER2-driven metastatic breast cancer and is currently prescribed in conjunction with a diagnostic test for HER2 protein overexpression. Additional tests may soon be available to predict risk for breast cancer metastasis, and to help patients and physicians make better-informed decisions about treatment.
As researchers continue to apply genotyping and gene-expression association to study human variation, the promise of targeted medicine will be fulfilled. Relevant discovery technology continues to improve, and significant investment continues among academic and commercial organizations to advance the field. While no one can guarantee the next breakthrough, life scientists will leverage genetic profiling of patient population groups to develop valuable new diagnostic tests and targeted therapies in the coming years. 
Kathy Ordoñez is president of Celera Diagnostics and Celera Genomics, in Alameda, Calif. She may be reached at Kathy.Ordonez@celeradiagnostics.com.
Illustration by David Wink