Future of Better Medications and Treatments May Lie in Our Genes

NEW YORK CITY, Oct. 31- Genetic variety influences not only our distinct physical appearances, but also our varied responses to prescription medications. A drug that helps one patient may cause serious side effects in another or elicit no response at all. That can be problematic, since doctors must prescribe medications using a trial-and-error approach, sometimes at the expense of patients' health.

Now that the entire human genome is nearly mapped, however, genetically tailored drugs that promise less patient risk and improved effectiveness are on the horizon. An October conference at The New York Academy of Medicine explored this exciting field of "pharmacogenetics" and its potential for enhancing disease treatment and prevention. Scientists from some of the world's major universities and premier pharmaceutical firms discussed their efforts to develop better medicines that target specific human genes that control drug reactions.

"The emergence of pharmacogenetics marks a new era in medicine, with the prospect of safer and more effective drugs," said Dr. Alan R. Fleischman, Senior Vice President for Academic and Medical Affairs at the Academy, which sponsored the conference. "Pharmacogenetically tailored drugs will be commonplace within the next few years."

Pharmacogenetics involves the collection of information about specific proteins and genes in order to improve drug design and effectiveness. Researchers are already using the genome -- the DNA blueprint to our unique selves -- to pursue more sophisticated drug discovery. Eli Lilly & Co., for example, is testing new medications by monitoring large portions of the genome after administering a certain test-drug, and tracking which genes are expressed. By studying the drug's broader mode of action, rather than its usefulness at treating one specific disease, researchers have rapidly discovered that certain drugs can tackle multiple medical problems, said Lawrence Gilbert, Ph.D., a research scientist with Lilly who spoke at the two-day pharmacogenetics conference. Lilly's drug "rhAPC" is a prime example: it was developed as an anticoagulant to treat Sepsis, but has since been found to induce anti-inflammatory genes, anti-apoptotic genes and cell-survival genes. "We identified approximately 110 genes whose expression changed in response to one treatment (with rhAPC)," said Gelbert, Lilly's Group Leader of Functional Genomics.

Customized drugs will soon be developed for distinct population segments based upon people's different drug-metabolizing abilities, said Dr. Mihael Polymeropoulos, Vice President and Head of Pharmacogenetics at Novartis Pharmaceuticals Corp. These metabolic distinctions are embodied in each person's "genotype." As clinical acceptance and understanding of pharmacogenetics evolves, Polymeropoulos said, physicians may be more apt to perform genetic tests on patients to help select the best medication. Drug labels of the future may carry warnings like, People with Genotype X shouldn't take this, because it could cause the following side effects, he explained. Similarly, a patient may be advised to choose one drug over another because it is four times more effective for his genotype. "It's just going to be another way to finesse a drug and make sure it benefits people," Polymeropoulos said. "This may aid the physician in the care of patients. If we treat patients with a bit more care and individual response, we may actually save a lot of money in the system."

Much of the pharmacogenetic research to date has focused on genes that are essential for drug metabolism, many of which belong to the Cytochrome P-450 (CYP450) family. People in different population groups - such as Caucasian, African American or Asian - can vary widely in their ability to metabolize a certain medication. For example, a 2001 study from Holland showed that wildly different doses of the cholesterol-lowering drug Zocor were needed by people with different genotypes of CYP2D6 (a member of the CYP450 family). Daily dose needs ranged from 25mg to 500 mg, said David Flockhart, M.D., Ph.D., Director of Clinical Pharmacology at the Indiana University School of Medicine. Doctors may be able to avert serious patient illness or even death if they're aware of such metabolic variations before commencing treatment, Flockhart said. Doctors may also be able to quickly reject certain drugs for certain genotypes. Breakthroughs in this area are already occurring, Flockhart explained. His preliminary research has demonstrated that people with certain CYP2D6 genotypes are less efficient at metabolizing tamoxifen, the breast cancer drug. "The challenge for us is to ensure a genetic test is predictive through this mess," Flockhart said.

There is a striking amount of genotype variability across ethnic groups. Defects in the CYP2C9 gene appear in 17.3 percent of Caucasians, 2.5 percent of African Americans, and in no one of Chinese or Japanese descent, said Alastair J.J. Wood, M.D., Assistant Vice Chancellor for Research at Vanderbilt University, in his keynote speech at the conference. That is critical information, since CYP2C9 metabolizes important drugs. With some of those drugs, like the anticoagulant Warfarin, there is precious little room for error. "That's the opportunity we have with genotyping," Wood said. "It's the ability to prevent that error in dose, and develop a genotype strategy that would allow us to use drugs more safely."

Doctors will use genotype information as a tool to better predict drug toxicity, specify optimal dosing, identify drug responders and prevent adverse responses, Wood said. This tool could also speed up drug development, he said. A pharmaceutical company typically spends 10 or more years in the development phase. But clinical trials could be smaller and of shorter duration if a drug is being tested only on individuals with the genotype for which the drug was designed, Wood said.

There is a glaring need for improved drug efficacy. Though prescription drugs have helped untold numbers of people live longer and healthier lives, the performance record of widespread drug therapies is underwhelming. Only 25% of those being treated for various cancers respond to medication; for Alzheimer's, only 30% respond; for osteoporosis, 48%; for diabetes, 57%; and for asthma, 60%. "We've got a lot of wiggle room there for which we could be improving response," Wood said. Not only that, but deaths due to prescription drugs are on the rise, while deaths from rail, motor vehicle, water, and air accidents are all flat or declining, Indiana's Flockhart said.

Naturally, the hope is that pharmacogenetics may lead to treatments for society's most vexing medical conditions. As the identity and location of genes associated with diseases like cancer, diabetes and mental illness continue to be pinpointed, the development of precision-targeted medications should follow, researchers say. Several hundred genetic tests are now in clinical use to detect genetic mutations and many more are under development, according to the U.S. Department of Energy's Human Genome Project. An important treatment boon should result from health care providers' ability to create personalized medicine profiles for patients based on their genetic makeup, experts at the meeting said.

Despite great hope for pharmacogenetics, prescribing-by-genotype certainly won't solve every problem, noted Flockhart, a practicing physician who said he hates "pharmacogenetics hype." "The idea that you put a person's entire genetic sequence on a credit card - we all know that's nuts, but the public doesn't," he said. Nor will prescribing-by-genotype happen overnight, several speakers noted. Doctors don't routinely use this new tool yet, and labs don't routinely offer the necessary genetic screening, Polymeropoulos said. Some doctors shy away from pharmacogenetics because they have a fear of not understanding the science, Flockhart added, and there is a lack of clinician education on this new approach to treatment. Steep costs also pose a problem: genetic testing can run about $500 per test, Flockhart said. "There are real barriers to widespread clinical use of pharmacogenomics," he said.

Whether tailor-made drugs will be too financially risky, is an important question that remains unanswered, Wood said. Will it be difficult to market a drug that works only for a specific genotype? Will the lesser financial benefits of a drug designed for a smaller audience, dissuade pharmaceutical companies from pursuing development? No one is certain, but as any television viewer knows, drugs with high marketing potential are regularly hawked in TV ads that help manufacturers to build a customer base and recoup their steep R&D costs.

"Wall Street likes to talk about the blockbuster drugs," Wood acknowledged. Today's non-genetic approach to prescribing, leaves doctors sometimes prescribing one drug and then another before finding the patient's ideal treatment. "There's a lot of money to be made out of giving drugs to the 60 percent of people who don't respond to them," Wood concluded.

The conference was sponsored by the Academy with support from the Pharmacogenetics Working Group, consisting of 19 pharmaceutical companies engaged in pharmacogenetics research.

Posted on October 31, 2002

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