Putting personalized medicine to the test

By Matt Windsor | UAB Mix Blog
Long before scientists sequenced the human genome, or even understood the inner workings of DNA, clinicians were practicing personalized medicine. As Francis Collins, M.D., Ph.D., and Harold Varmus, M.D., pointed out in February in the New England Journal of Medicine, doctors have been testing patients’ blood types for more than 100 years, and they’ve taken height and weight into account in drug-dosing for even longer. “But the prospect of applying this concept broadly,” Collins and Varmus wrote, “has been dramatically improved by the recent development of large-scale biologic databases (such as the human-genome sequence), powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays and even mobile health technology) and computational tools for analyzing large sets of data.”

“Personalized medicine involves using a patient’s genome and their own unique characteristics to target their management and therapy,” said Selwyn Vickers, M.D., dean of the UAB School of Medicine. It is also the future of medicine, he notes, encompassing everything from basic science to routine clinical care and everything in between. This past summer, UAB announced three interrelated initiatives, all housed in the medical school: the UAB-HudsonAlpha Center for Genomic Medicine, the Hugh Kaul Personalized Medicine Institute and the Informatics Institute. “UAB will proceed in this endeavor in partnership with HudsonAlpha as we build our programs around both rare diseases and chronic illnesses,” Vickers said.

Broadly speaking, the UAB-HudsonAlpha Center for Genomic Medicine, co-directed by Bruce Korf, M.D., Ph.D., chair of the Department of Genetics at UAB, and Richard Myers, Ph.D., president and director of the HudsonAlpha Institute of Biotechnology, investigates the genetic underpinnings of the onset and progression of diseases. Its research will enter the clinical realm in the form of new therapies to treat genetic changes that lead to disease. The Kaul Personalized Medicine Institute, led by interim director Nita Limdi, Pharm.D., Ph.D., MSPH, professor in the UAB Department of Neurology, focuses on the interaction between genes and drug response. In an oft-cited phrase associated with personalized medicine, it seeks to identify the right drug, at the right dose, for each patient — and then implement those findings in actual practice at UAB. Meanwhile, the Informatics Institute, under James Cimino, M.D., a renowned leader in informatics who was most recently chief of the Laboratory for Informatics Development at the National Institutes of Health, will collect and analyze the massive amounts of data created in genetics and genomics research, and develop new ways to deliver the results to clinicians and researchers.

Dose and Consequences

Limdi is an expert on the effects of anticoagulant drugs such as warfarin. In 2012, 33 million Americans received a prescription for this old but highly effective medication, which has been used to treat and prevent blood clots for 60 years. It’s a powerful therapy, but not one to be taken lightly. If patients receive too little, they remain at high risk for heart attacks and strokes — the very reason they are put on warfarin in the first place. But too much of the drug can lead to serious, even life-threatening, bleeding. Warfarin causes one-third of U.S. hospital visits related to drug side-effects in patients ages 65 and older.

That’s why doctors start patients slowly — typically at a 5-milligram dose — and then adjust dosages until they find the right balance between efficacy and bleeding risk in each patient. The “right” dose of warfarin varies 20-fold between patients, and there is a pronounced racial effect; variability in dose differs among people of European and African descent, for example.

In a study published in The Lancet in 2013, co-led by Limdi, scientists at UAB and other institutions found one reason: African-American participants were more likely to have a genetic variation — known as rs12777823 — that was associated with a 20 percent reduction in warfarin dosing. In other words, the normal warfarin dose would be too high for these patients, putting them at risk for bleeding complications.

Gene-Drug Interaction

This is just one example of the growing awareness of the effect of genes on drug response. Many studies have shown that genetic variations affect how a patient responds to antidepressants, cholesterol medications, cancer therapies, pain drugs and more.

More than 130 FDA-approved drugs have pharmacogenomic information in their labeling, Limdi notes. To enable clinicians to integrate genetics in treatment decisions, the Clinical Pharmacogenetics Implementation Consortium develops freely available, peer-reviewed, updatable and detailed guidelines. “There are more than 25 such gene-drug-pair guidelines currently available to guide choice and dosing of medications,” Limdi said. President Barack Obama’s Precision Medicine Initiative, a $215 million program announced in January, aims to discover many more.

Those discoveries have the potential to reshape clinical practice, Limdi says, enabling personalized treatment, improving effectiveness and reducing side-effects. “Forty percent of the African-American patients we see in clinic at UAB have that [warfarin] marker,” Limdi said. “Possession of one copy of the marker lowers warfarin dose by 7 milligrams per week, while possessing two copies reduces the dose by 9 milligrams per week.” But identifying genetic markers is just the first step, she notes. “Next you have to come to the clinical realm to see, ‘if I put this into practice, will it make a difference, will it improve outcomes?’”

The Kaul Personalized Medicine Institute will particularly “focus on treatment of diseases that are more prevalent in the Southeast, where we have large populations that are racially diverse,” Limdi said. “For example, if you look at heart-failure admissions in the past couple of years, 38 to 40 percent of our patients at UAB were African-American. More than 50 percent of patients who receive a kidney transplant at UAB are African-American, which is far higher than the national average.” Finding better ways to treat these understudied populations — identifying the best drug or dosage, for example — is a tremendous opportunity, Limdi adds. “Few other places in the country have this degree of racial diversity to be able to look at differences in medication response by race.”

Discovery to Implementation

The institute has two key initiatives, Limdi says. “One is facilitating discovery through research; the other is implementation of these findings in the clinical setting. Lots of people do the discovery part at UAB, and they are all over campus — researchers in cancer, in hypertension, in obesity and in psychiatry, for example, are all doing work in human samples, and there’s an even bigger group working with animals.”


Nita Limdi

The institute aims to implement this research in clinical studies at UAB Hospital, which is the third-largest public hospital in the United States. UAB is in a position to answer the difficult questions that will help move personalized medicine out of research labs and into everyday life, says Limdi. How can you incorporate genetic tests into routine clinical patient care? How do you add the results into a patient’s medical record and make sure that they are presented to the doctor at an appropriate time? How much will these extra procedures add to health care costs, and will they ultimately provide value and be cost-effective?

Plavix in Practice

In January, the institute began its first large-scale study. Each year, somewhere around 1,000 patients receive stents at UAB. All patients are put on two antiplatelet medications; 70 percent of patients at UAB, Limdi says, receive prescriptions for the combination of aspirin and clopidogrel (Plavix). “There is evidence that genes affect how effective clopidogrel is, and there is an FDA-approved test that enables us to look at the gene that activates clopidogrel and tell a physician what to give the patient based on his or her genetic makeup,” Limdi said.

Clopidogrel needs to be converted to its active form by an enzyme known as CYP2C19, Limdi explains. People with variants in the CYP2C19 gene do not activate the clopidogrel in adequate quantities, “so their platelets are more likely to stick to each other.”

Patients who receive a stent at UAB — and consent to take part — will provide a cheek swab, which will then be tested in the UAB Hospital Molecular Diagnostic Laboratory for one of three genetic variants that are associated with response to clopidogrel. Results will be available within an hour and will be placed in the patients’ electronic medical records, Limdi said. “Then, when a physician clicks to prescribe clopidogrel, a warning will appear asking whether the patient has just had a stent and possesses the genetic variant.” If the physician checks yes, the system will suggest that he or she prescribe an alternative drug for patients who possess variants that are associated with lower activation of clopidogrel.

Whether the patient receives a different prescription or not, the researchers will follow his or her progress for one year, looking for differences in 30-day re-admission rates, strokes, stent thrombosis, bleeding complications and other outcomes.

“People have shown in different studies that this gene is important; we are taking that newly discovered information, putting it into practice and seeing if it changes outcomes,” Limdi said. The data will start to answer the question, “If you implemented this systemwide, would it be effective?” she added. In addition to outcomes analysis, researchers will be analyzing cost-effectiveness as well, Limdi says.

Early Warning System

Later this year, Limdi hopes to launch an even more ambitious study: a single test that will screen for several genetic markers that have been implicated in drug-dosing.

One option is to collect the sample during a routine clinical visit such as an annual physical examination. The genotype results for actionable gene-drug pairs can then be added to a patient’s medical record, Limdi explains. “That way, if you need a clopidogrel prescription five years from now, that information is there. Or if you are diagnosed with depression, your doctor will have a better idea of which medications to prescribe.”

Implementing personalized medicine approaches, especially in a major academic medical center such as UAB, will rely heavily on informatics and genomics, Limdi points out. “Personalized medicine will require an investment and a critical mass of clinicians willing to learn and systematically incorporate patient-specific genetics and genomics into treatment decisions,” Limdi said. “But if we can do this, we will help patients at UAB, Alabama and potentially around the world. It will be worth it.”

Reposted with permission from UAB Mix Blog