The Brave New (?) World of Personalized Medicine
 

BiDil®, a new drug labeled for the treatment of African-Americans with severe heart failure, now is widely prescribed. Its approval by the Food and Drug Administration (FDA) in June 2005 stimulated speculation that we are entering a brave new world of “personalized” medicine in which genetic tests or other “biomarkers” will be used to predict positive—or sometimes negative—responses to various therapies.

Diagnostic tests and therapeutic interventions targeted to a certain ethnic, racial, or other group is nothing new. In order to screen for a number of genetic diseases that occur predominantly in Jews of Ashkenazi, or Eastern European, extraction, a group of genetic tests called the Ashkenazi Jewish Genetic Panel (AJGP) can be performed. Sickle-cell anemia occurs (in the United States) predominantly in African-Americans; a hereditary enzyme deficiency that causes sensitivity to fava beans and certain drugs is found primarily in Africans and persons of “Mediterranean” descent; and after exposure to quinine-like drugs as many as 10% of African-American men develop a serious condition in which red blood cells lyse, resulting in severe anemia. Also, there are genetically-determined differences in sensitivity to the commonly used anticoagulant Coumadin due to variations in the molecular structure of the drug’s receptor.

Broader effects on the safety and efficacy of drugs are caused by variants of genes coding for the enzymes that metabolize chemical compounds. One genetic locus, CYP2D6, is responsible for the enzymes that degrade perhaps 20% of commonly prescribed drugs; in the population there exist a large number of alleles (variants), some of which only poorly metabolize the enzymes’ substrates. Persons who possess these alleles may be prone to toxicity if a drug is cleared more slowly than “normal” or may require higher than usual doses if the drug must be metabolized to an active form.

In addition to the genetics of patients, genetic anomalies in malignant tumors sometimes can be used to predict the effectiveness of therapies. For example, the amplification of a gene called HER2—seen in approximately 25% of breast cancers—leads to over-expression of HER2 protein, which results in increased cell division, more rapid cell growth, and a worse prognosis. It also correlates with responsiveness to a drug called Herceptin, however, which has been dubbed the first “pharmacogenetically developed drug.”

There is another group for whom a kind of personalized medicine is badly needed. Although not due to genetic differences, some of the most important variations seen in response to drugs are due to aging. Older patients are far more likely to experience adverse drug reactions because, for one thing, clearance by the kidneys and liver—the two most important routes for the elimination of drugs—is reduced; as people age, these organs receive less blood flow resulting in diminished activity of the hepatic enzymes that metabolize drugs.

Another age-related anomaly is related to the decrease in total body water and the relative increase in body fat seen in older people. These changes cause water-soluble drugs to become more concentrated in the blood, and fat-soluble drugs to have longer half-lives. Moreover, serum protein levels decrease in the elderly (especially if they are sick), which reduces the protein binding capacity of the blood, and leaves more free—that is, active—drug circulating. Yet, surprisingly few physicians routinely reduce drug dosages in older patients.

Whether or not BiDil® is a harbinger of additional personalized therapies, the unsettled question remains how widely useful the drug will be. Its approval by FDA was based largely on the results of the African-American Heart Failure Trial, which involved 1,050 self-identified African-American patients with severe heart failure who already had been treated with, but had not responded to, the best available therapy. That study was conducted because in two previous trials of BiDil® that did not demonstrate efficacy in a general population of severe heart failure patients, there was a suggestion of benefit to African-American patients.

The question has been raised whether drug companies have an incentive to search for biomarkers that better predict a drug’s efficacy, given that this targeted approach could ultimately narrow the population eligible for a given product. Although, in theory, it is desirable to test drugs of potential value widely and to ascertain the potential breadth and limitations of their use, the resources available for clinical trials are not infinite, and it is not unreasonable for companies to expend resources preferentially on testing in populations in which there is a high expectation of success.

Commentators have expressed a wide spectrum of views about the appropriateness of a therapy designated for one group, some even calling it discriminatory. Francis Collins, Director of the National Human Genome Research Institute, admonishes that “we should move without delay from blurry and potentially misleading surrogates for drug response, such as race, to the more specific causes.” Our ability to do so, however, will become increasingly more achievable with the availability of better tools such as microarrays—silicon chips designed to screen biological samples for genetic content—to identify exactly the genetic variations that predispose to disease, or to sensitivity or resistance to certain drugs.

But to paraphrase U.S. Secretary of Defense Donald Rumsfeld, you go to war against disease with the data you have, not the data you wish to have. Drug testing, approvals, and labeling must go wherever the data lead.