Genetics emerging new frontier for drug trials
Targeted therapy still in early stages
When the general public pictures genetic research, they think of new screening tests to detect rare diseases, or they think of cutting-edge gene therapy experiments that have the potential to completely reverse a previously fatal condition.
However, the real promise of genetic knowledge, say many experts, is in the potential to target drug therapy for common diseases, such as heart disease and cancer, that affect huge numbers of people.
"A lot of the efforts now are looking at common complex diseases, cancer, diabetes, or doing cardiac risk assessment," notes Dawn Allain, MS, CGC, president of the National Society of Genetic Counselors. "The idea is that if we can identify those individuals who are at increased risk for developing these diseases from a genetic perspective, then are there medical interventions, preventive treatments and lifestyle changes that we can do to prevent the onset of disease."
In the last few years, genetics has revolutionized research into cancer therapy as investigators have discovered links between certain genes and tumor grown and patient response to therapy.
For example, the drug Herceptin (trastuzumab) targets the overexpression of the human epidermal growth factor receptor 2 (HER2) that occurs in approximately 25% of women with breast cancer. Researchers working on the drug discovered that such over expression facilitated tumor metastases. For HER2-positive patients, combination treatment with Herceptin and paclitaxel can slow the cancers’ progress.
In April, researchers at the National Cancer Institute discovered that lung cancer patients whose tumors featured a certain mutation in an epidermal growth factor receptor gene were more likely to show a favorable response to the drug gefitinib (Iressa).
Such discoveries may be just a drop in the bucket in terms of the potential for genetic information to direct therapy for different conditions, experts say.
One day, physicians may be able to determine which patients will do better from early initiation of drug therapy and which will benefit more from lifestyle alterations. Obviously, genetics can play a role in determining which patients will respond better to specific treatments. But, genetics may also point out which patients are more likely to suffer serious side effects from a particular drug, allowing doctors to use new drugs only in patients likely to benefit without undue risk.
"Heart disease, in my opinion, is not one disease, but many, many different diseases with similar characteristics," says Janice Kurth, MD, PhD, a geneticist and current vice president of life sciences for Visualize Inc., a software development company in San Diego. "The same is true of cancer. It is not one single disease, but many separate ones with separate causes. There are people who are very thin, who have very healthy lifestyles, who do everything right, and they still end up with heart disease. That is a patient who has a very large genetic component. There is also the couch potato, who weighs 300 pounds, doesn’t exercise, and eats potato chips and watches TV all day and they don’t get heart disease. Then, there is your average overweight, sedentary smoker who has the risk factors and gets it. We don’t know whether they would get it without these risk factors or not."
Pinpointing risk factors
The ultimate goal for researchers is to discover which genetic risk factors cause disease and how that disease differs from the disease caused primarily by environmental or lifestyle factors.
"When it comes to therapy, obviously, it would be really nice to know which groups of patients are going to respond to which therapies best. That really thin person that exercises and eats right but still has a cholesterol level of 250-260. They need early aggressive therapy. If we had a way to pick those people out, maybe we would start treating them in their teens or even childhood," Kurth says. "The next-door neighbor who really doesn’t have the added risk, but needs to get out and run a bit and eat more vegetables, you might focus more on the lifestyle issues. The question is, can we get to a point where we can prevent — not only heart disease, but cancers and Alzheimer’s disease — and also be able to treat patients early and treat them appropriately. That is the goal of what we would like to see in the long run."
Future: Targeted therapies
With all of the hype surrounding the completion of the mapping of the human genome in the early 1990s, many assumed that such targeted approaches were right around the corner. Reality has shown, however, that much more research will be needed before medical science can reach that point, she says.
In order to determine which gene mutations are linked to disease, and which are linked to drug response (pro or con), large-scale studies that collect genetic information from patients with these diseases are needed.
At this point, the funding mechanisms and research structures are not optimized to allow such research to proceed, Kurth contends.
Pharmaceutical companies, which sponsor most of the drug research in this country, are reluctant to fund studies that might place limits on the potential market for their compounds.
"The big pharmaceutical companies would really like to continue to develop big blockbuster drugs that will work in everyone," Kurth explains. "In designing clinical trials, they are really trying to show that [the particular compound] works. If they get a really good response in a smaller group of patients, then that is good, but they really don’t want a label on it that is going to limit how it works."
Drug companies also are going to be very reluctant to fund studies that compare their drug with comparable drugs from other manufacturers to determine which patients might do better with their drug and which might do better with a competitor’s — research which also is necessary if the science is going to advance as needed, she points out.
Not only is such research problematic for the companies from a market standpoint, but it is very expensive, Kurth notes. "Currently, we don’t have the funding mechanisms in place that would support head-to-head research on the large scale that is necessary."
Sketchy subject compliance with treatment recommendations also complicates the ability of researchers to reliably determine which responses are due to genetic factors and which responses are the results of better or worse compliance with treatment, she continues.
"The largest contributor to the variance in how patients respond is compliance. Many people don’t do what they are supposed to do, whether it is lifestyle or pharmacotherapy. And where we are looking for very, very subtle differences in response rates based on genetics, this may be a big obstacle," Kurth says. "I think, in many cases, we are going to find that it is not one single gene and one single thing we can point to, but a combination of things that cumulatively lead to variances in response. To be able to dissect the genetic component out from the rest is going to be very difficult."
At this point, many, many large-scale clinical studies are collecting DNA for genetic analysis, but research sponsors are largely taking a wait-and-see approach before pursuing actual genetic approach.
"They are collecting DNA samples from all of the patients in all of their trials. But to date, that is not being done actually as a part of the development process," Kurth notes. "In other words, they are storing that information. And their idea is really not let it interfere with the approval process now then later go back and do some work."
Herceptin was a rare example of a drug that actually used genetic information as a basis for drug development and as the key focus of their application for approval from the FDA, she says.
Kurth contends, however, that the future of drug development is in developing genetically targeted therapies for smaller populations. The big, blockbuster drugs have already been discovered. Yet, there is vast potential for discovering new therapies that work extremely well in certain subsets of patients.
"In theory, drug company A, B, C, or D would love to have something that is good for everybody. But I think we are well beyond that. The markets are already so fragmented, just because there are so many competing compounds out there," she says. "We are fooling ourselves if we pretend it is not."
Second chance for bad’ drugs?
The reluctance of companies to pursue genetic studies also means that many patients who could be helped by certain, high-risk drugs are not, Kurth notes.
Certain compounds have been pulled from the market or abandoned late in development that held great promise for a large number of patients, but also were found to carry the risk of devastating side effects for some patients.
"I have known of some drugs taken out of development somewhere in Phase 3 because some very, very rare events came up which were quite bad," Kurth says. "There have even been situations where drugs have been taken off the market because of really rare, but very serious, even fatal, adverse events. It is very difficult to pinpoint why, partly because they are so rare, why those things happened to those patients."
If researchers were able to pinpoint a factor influencing which patients were likely to suffer these rare adverse events, it would allow clinicians to prescribe the compounds for patients who badly needed the treatment and who did Snot risk the adverse side effects.
"If we could completely avoid treating those patients, the vast majority of patients could then safely take various compounds, which have been very helpful," she says.
In some ways, the positive coverage that genetic research received in the early 1990s when the Human Genome Project was completed has hurt the progress of gene research now, Kurth adds.
Patients and some medical professionals believed that gene therapies and targeted treatments were right around the corner when, realistically, that was not the case, Kurth says.
"We have a long ways to go before we can even get to that idealistic place," she says. "One of the ways the genetics community has probably erred in recent years is we somehow misled the public into believing we were going to be able to solve a bunch of complicated problems much quicker than we really can. All of these technologies have great promise. But because we are dealing with human lives, it takes a lot of work and a lot of time to do put it into practice ethically and properly. I think the public has expected more immediate rewards partly because of the hype that we in the community have put out there."
The science of genetics holds great promise for clinical research; however, Kurth emphasizes, just on a longer timetable than previously thought. "The potential is not gone, people I think are a disillusioned that we overpromised too early," she says. "We are not giving up and neither should our funding agencies and political support.
When the general public pictures genetic research, they think of new screening tests to detect rare diseases, or they think of cutting-edge gene therapy experiments that have the potential to completely reverse a previously fatal condition. However, the real promise of genetic knowledge, say many experts, is in the potential to target drug therapy for common diseases, such as heart disease and cancer, that affect huge numbers of people.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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