Janury 22, 2007

Making It Personal
By Thomas G. Dolan
For The Record
Vol. 19 No. 2 P. 38

The science of pharmacogenomics hopes to change healthcare by helping to develop drugs designed for specific genetic makeups.

Imagine taking a pill designed specifically for yourself that is 100% effective and has no side effects. That is the promise of a new avenue of research called pharmacogenomics.

Genomics is the study of the basic constituents of DNA and RNA sequences that make up a cell nucleus while pharmacogenomics is the study of how genetic variations affect the ways in which people respond to drugs.

Emerging in the past decade, pharmacogenomics promises to revolutionize healthcare. In place of current drug therapy, in which drugs are designed for large segments of the population, pharmacogenomics offers the hope that each drug will be targeted to an individual’s genetic makeup, guaranteeing that each drug will work as intended with no side effects.

In the process, it appears pharmacogenomics would radically alter the way drug companies, doctors, pharmacists, hospitals, and others in the healthcare industry conduct their business. Although the definition and goals of pharmacogenomics are easy to understand, it turns out to be a complex subject, not only in terms of science but also how it affects social, economic, and political issues.

Most people in healthcare agree—to varying degrees—that introducing pharmacogenomics would be a positive step. But they also agree that it raises more questions than can be currently answered—and many say that some of the possible answers are not too attractive. Plus, although drug companies are pouring vast sums of money into research and discoveries are being made, just when this vision will come to fruition, especially in terms of widespread acceptance and implementation, is unclear.

The concept of a medicine designed for an individual patient is not a new idea. “Until about 150 years ago, all pharmacy was customized to the patient,” says Judy Cahill, executive director of the Academy of Managed Care Pharmacy in Alexandria, Va. “When a patient visited a doctor and needed a dose or dram, the prescribed elixir was generally mixed right on the spot.” All that would change through innovations in the German petrochemical industry so that by 1900, the mass production of pharmaceuticals according to uniform compounding became the norm. In this respect, Cahill says, we have come full circle again to customizing drugs, although in a new way.

In an article titled “Pharmacogenomics: Revolution in a Bottle?” (taken from the Web site AMA [Virtual Mentor] Genethics) Faith Lagay, PhD, writes, “The products of this ‘rational drug design’ technology would replace current drugs that are intended to serve the entire patient population. These blockbuster, one-formula-fits-all drugs typically work for only 60% of the population at best. More worrisome and costly than their ineffectiveness is the instance of serious adverse drug reactions (ADRs) that are responsible for 100,000 deaths a year in the U.S. and cost society an estimated $100 billion a year.”

Lagay provides a brief history of pharmacogenomics, which is based on a progenitor science, pharmacogenetics, which dates from the 1950s when researchers first noticed an inherited tendency in the way people react to drugs. A too rapid or too slow metabolism of a drug can cause it to be, respectively, either ineffective or toxic. Early investigators focused on broad categories such as ethnicity, geography, language, and race. “This approach revealed, for example, that 5% to 10% of people from Mediterranean and African ancestry lack the glucose-6-phosphate dehydrogenase enzyme and thus risk breakdown of red blood cells from 200 drugs,” Lagay writes.

The science of connecting drug reactions to genes took a leap forward in the late 1990s with the discovery and use of single nucleotide polymorphisms (SNPs; pronounced snips). In brief, as Lagay explains, on their way to sequencing the entire genome of 3 billion base pairs to create the runs across the double helix, scientists kept finding instances where one member of the base pair differed from the expected. Of the four bases—adenine, cytosine, guanine, and thymine—that DNA comprises, adenine generally bonds with thymine and cytosine with guanine. However, in approximately every 1,000 base pairs there is a mix-up of SNPs. What makes SNPs helpful is that by looking at the DNA of individuals who share a certain inherited condition, drug reaction, or susceptibility, researchers can sometimes identify a shared SNP. Lagay points out that this shared condition must be in at least 1% of the population tested, so the promise of drugs tailored to each individual is a slight exaggeration.

Enough DNA samples taken from enough people can have two results, says Lagay. First, genetic tests can identify those who would have serious ADRs before they receive the drug. Second, drugs can be designed to work effectively but nontoxically on those who have ADRs to the one-formula-fits-all blockbuster drugs.

Genetic testing to identify patients with ADRs has already occurred. Lagay points to a set of enzymes called CYP34 that metabolizes approximately 50% of all common drug compounds. Searching for SNPs that control these enzymes, pharmacologists at St. Jude Children’s Hospital in Memphis, Tenn., discovered two SNPs that “squash” production of active enzymes, which means people who carry either one metabolize drugs more sluggishly than others who harbor other versions of the gene. “Those in the field predict that testing for most enzyme-related drug reactions and resistance will be available within the next five years,” says Lagay.

Giora Feuerstein, MD, assistant vice president and head of discovery translational medicine research at Wyeth, reports that his company has been especially active in clinical trials of how drugs affect gene expression. “We are searching for biomarkers that predict genomic activity,” he says.

His research is moving beyond screening patients for adverse responses to certain drugs to evolving drugs that will specifically deliver a desired response without the unwanted side effects. “The main purpose of it all is safety, to spot ahead of time genes that may prove to be a negative event for any particular drug,” Feuerstein says.

Work is being done in broad areas, including cardiovascular, immune, and respiratory diseases, neurological disorders, women’s health, such as hormone therapy and skeletal deterioration, and cancer. For example, studies are being done to evolve scanning techniques to first track the undesirable protein aggregate that accumulates in a patient with Alzheimer’s and then eliminate it, and prevent the erosion of cartilage in bone disease. “We still want to alleviate painful symptoms, but now we are going beyond that to cure the underlying causes,” Feuerstein says. “In many diseases, such as cancer, the treatments such as chemotherapy and drug cocktails, may kill the bad cells, but they kill the good cells, too. Our aim is to target only the bad cells.”

When will these “rationally designed drugs” become available? Industry estimates vary greatly. Lagay says some estimate these drugs will be available in the next seven to 12 years, while some say the wait could be as long as 30 years. Others, such as Feuerstein, say a timetable can’t be predicted.

“I can see a huge benefit if these targeted drugs really improve health, but I’m not seeing anything yet; it seems way off in the future,” says George Isham, MD, MS, chief health officer at Health Partners, a healthcare and delivery and insurance organization in Minneapolis.

It’s probably fair to say screening for patients with ADRs will come sooner than the targeted drugs, “but even screening raises all kinds of issues,” Isham says. “Are you going to screen everybody, whatever the costs, and spend significant amounts of money when you don’t know the benefits?”

There’s the cost of the drugs themselves. “If you have a cure for breast cancer, that is wonderful, but there are hundreds of types of breast cancer,” Isham says. “If, instead of having a single drug for a very broad use in the population, you are going to have these targeted drugs, they are going to be very expensive. And affordability of drugs is even now a big issue.” This, in turn, affects insurance coverage. Isham says carriers will have a harder time reimbursing these drugs, so insurance premiums will climb.

Cahill, who also acknowledges the benefits that could result from these innovations, nevertheless raises the question, “What happens to the notion of a formulary based on gross assumptions for a generalized population? In such a new scenario, what happens to the buying and selling of drugs? Manufacturers set prices, in part, based on volume. If we were able to predict with precision which drugs will work for which patients, why would doctors even consider prescribing anything else? Why would patients or their health plans purchase any other drug? In such a scenario, what happens to the price of an individual pill? No longer prescribed for masses, but only for the particular patient who will benefit from it, we may expect that it will put an end to volume discounts. It will place a value on that particular product for that particular patient: a value hitherto not recognized.”

Feuerstein says it may be that the hundreds of types of cancer don’t each need a specific drug; they may be able to be grouped into subsets, each one of which is amenable to a single drug. This may alleviate the matter to some extent, but it still appears that costs would be significant.

Isham also raises the question of “who is going to be able to keep up with all that expertise?” He predicts pharmacists and physicians will be spending increasing amounts of time in front of their computers. Pharmacists may have to be broken down into various specialties. “If you’re a doctor and someone comes into your office with a specific condition, you’re going to have to turn to your computer to find out where the expert on the condition is today and be able to find reliable information immediately,” he says.

Today, the cost for a DNA test is approximately $500, although that number is expected to drop. Lagay predicts that it won’t be too long before technology emerges that will permit everyone to own a swipe card that contains complete genomic identification. But this, she adds, raises concerns about information management and privacy, which will necessitate major changes in how healthcare organizations are run.

There is also the issue of the FDA approving drugs based on pharmacogenomics. Feuerstein acknowledges that the FDA has been reluctant to approve biomarker drugs except in the few instances where they seem to universally work, such as in lowering blood pressure. But he also says, “The FDA is very interested in this new avenue of research.” Obviously, drug companies would not be investing billions of dollars into this endeavor if they thought the FDA wouldn’t eventually approve the drugs.

Feuerstein says that although the arrival date of these new drugs is unknown, what’s learned from research may be able to keep some drugs on the market by not prescribing them to patients with known ADRs and may cut a drug’s 10-year gestation period from development to market by one half. Clinical trials to bring new drugs to market can now cost upward of $250 million per drug, most of it spent on phase 3. However, this new approach may identify the ADRs in phase 1 or 2.

Why would a drug company want to make a product that may be limited to 40% of the population? “A drug guaranteed to work on the 40% for whom other drugs are ineffective or cause harmful side effects will return a steady revenue at a premium price,” says Lagay. In other words, drug companies will certainly make a lot of money in the new venture, but, as Lagay says, “the savings may not be passed on to patients.”

Still, the concept of pharmacogenomics offers great promise. But just when and how this promise will be kept is unclear.

— Thomas G. Dolan is a medical/business writer based in the Pacific Northwest.