Pharmacogenomics: Gene maps could offer direction for treatment

Clinical opportunities abound, but the learning curve is daunting

It may sound dramatic, but there are predictions that the emerging science of pharmacogenomics will change the faces of medicine and pharmacy in the coming millennium.

Pharmacogenomics is sometimes described as personalized medicine. It has grown out of ventures along the lines of the Human Genome Project (see box, p. 99), the government-supported project to map the entire genetic makeup of human beings. Genomic research already has yielded a gold mine of information about the genetic components of disease. Researchers have begun to pinpoint the genetic flaws or miscues that cause or contribute to a given disease. "Pharmacogenomics" is an emerging field based on research involving genomic technologies and drugs, specifically on how genetic differences between individual patients might affect a drug’s effectiveness. There’s hope in the pharmaceutical industry that pharmacogenomics ultimately will be able to personalize — and thereby revolutionize — the diagnosis, treatment, and prevention of disease.

Gene chips’ that process data

Here’s how it might work: The patient is diagnosed with a virulent form of breast cancer. Her tumor is biopsied, and her genetic profile is fed into a computer. The variations and combinations are analyzed. Her profile is compared with those of other patients who already have used various medications. The doctor and the hospital pharmacist work together to pinpoint which drugs may cause severe adverse reactions and which are likely to be most effective on that particular tumor. They use a patient’s genetic profile to process and analyze millions of genetic sequences and defects, along with assays to help narrow the field of treatments. Together, they come up with a regime that knocks the cancer into remission.

Or, consider this scenario: A drop of the patient’s blood is analyzed, and her genotype is found to be strongly correlated with high-risk factors for a virulent form of breast cancer. A similar procedure is followed, only this time the doctor and the hospital pharmacist find the correct drug, and she never gets the disease at all.

Raymond J. Dingledine, PhD, chairman of pharmacology at the Rollins Research Center at Emory University, says, "You’ll go into the neurology clinic suffering from headaches, and my guess is that in, I don’t know how many years, possibly five years, maybe 10 years, they’ll be able to check off on your diagnostic sheet that they’d like the neurology gene chip assay to be run and that will return a list of genes that you have that are risk factors for various neurological disorders."

Dingledine says he envisions a time when a patient suffering from epilepsy, for example, won’t have to go through a lengthy and potentially uncomfortable trial and error procedure to determine which of two standard treatments works better.

New technologies like the gene chip won’t be the only things that bring about the revolution. The American Society of Health-System Pharmacists says other factors "include the fact that detailed collection, annotation, and storage of patient blood and tissue samples by medical centers have only recently begun to offer data sets useful for retrospective studies. Also, the informatics expertise of health care companies has now matured to the point researchers can hope to manage and compare large volumes of genetic and patient data."

The revolutionary pharmacist

There’s general agreement pharmacogenomics will have some impact on hospital and community pharmacists, but no one knows what the scope will be. Some suggest it will be profound, but right now, most pharmacists are just trying to get their arms around it.

Susan Winckler, director of policy and legislation at the American Pharmaceutical Association, says there is likely to be a quick learning curve for hospital and community pharmacists, but she isn’t sure yet whether it will be a steep learning curve as well. She does say the development of pharmacogenomics may force the issue of pharmacists playing a bigger role in prescribing medications.

"I’m not talking about a solo role. I’m talking about physicians being more willing to work with pharmacists as a team. We know that medicines today are already complex and that pharmacists sometimes have more knowledge about them than physicians do. So this may mean both physicians and pharmacists will have to think about pharmacists taking a more active role," she says.

Winckler also points out that pharmacists already have more computer skills than others in the health care industry; she reports that 99% are using computers for patient profile tracking and agrees that these skills may prove even more important if and when technologies such as gene chip diagnostics become reality.

The organization will begin looking at pharmacogenomics this fall as part of its internal policy development process. Look for positions and recommendations in the year 2000.

Redefining the cutting edge

The revolution is already well under way at major pharmaceutical companies. Firms like SmithKline Beecham, Ely Lilly & Co., Wyeth Ayerst Laboratories, Hoffmann-LaRoche, Novartis Pharma, Hoechst Marion Roussel, and Pfizer are among those hunting for therapeutic targets. They are creating partnerships with specialized genomic technology companies, but they also are developing the knowledge in-house.

Genset SA, a French genomics firm, and Abbott Laboratories announced their $42.5 million working partnership in 1997. According to an Abbott spokesperson, Genset will "develop a proprietary high-density, bi-allelic marker map of the human genome and will apply its technology platform to identify markers and genes associated with response to a pharmaceutical compound. Abbott will develop, produce, and market diagnostic systems derived from these genes and markers to clinically test patient response to specific drugs." This pairing was significant because it was the first and because the chief genomics officer at Genset, Daniel Cohen, MD, PhD, is credited with having devised the first rough physical map of the human genome in 1993.

Among the other high-profile agreements are these: Incyte and SmithKline Beecham, Affy metrix and Glaxo Wellcome, and OncorMed and Onyx. These and other companies are pursuing several different — and sometimes opposing — strategies to build strength in the field, positioning themselves to take the lead in applying cutting edge research in biology and genetics. Partnerships with drug firms are only a part of this picture, as are alliances with research organizations and managed care groups.

The American Journal of Health-System Pharmacy explains that "by discovering genetic markers that predict drug efficacy and adverse effects, genomics companies think they can help lower the cost and risk of clinical trials, redefine the markets for approved compounds, revive dead drugs, and help design more effective medications." This belief seems to have some heavy numbers behind it. The Journal of the American Medical Association estimated that adverse drug reactions accounted for more than 2 million hospitalizations and more than 100,000 deaths in 1994.

Obstacles and caveats

Does it pay to individualize pharmaceuticals? Will tailoring drugs to specific groups of people fragment the market? Pharmaceutical companies are wrestling with these and other difficult questions. Making drugs that aren’t meant to work for everyone is a new way of doing business. Some in the industry fear the expenses involved if several drugs must be developed for a disease. Critics say the pharmaceutical industry should focus on making drugs that are safe for everyone.

A leading voice of dissent regarding pharmacogenomics has been William Haseltine, chief executive of the genomics research company Human Genome Sciences. Earlier this year, he told the American Society of Health-System Pharmacists, "Pharmacogenomics . . . means producing a drug that could either kill or severely harm a substantial number of people. And the only thing that stands between your drug and that harm is a diagnostic test that has to be interpreted correctly. I think pharmacogenomics is a bad idea, a dangerous idea, and I don’t think it will happen." So far, though, Hasletine’s seems to be a lone voice.

There are other concerns, however. "It raises ethical issues as to who has access to this information," says Dingledine. "Do you want your insurance company knowing you’re at risk for stroke, for example? I think that those kinds of issues are broader than science and will have to be handled by a national debate. Nonetheless, gene chip diagnostics is going to come of age in the next half-dozen years or so."

[For additional information, contact Raymond Dingledine, Rollins School of Public Health, Emory University, Atlanta, GA. Telephone: (404) 727-5481. Or call Susan Winckler, American Pharmaceutical Association, Washington, DC. Telephone: (202) 628-4410.]