Personalized Medicine 4.0: Pharmacogenomics and Consumer Genetic Testing

 

[Article by Tapati McDaniels]

On May 26, 2011, the department of Biology at San Francisco State University hosted the fourth annual conference on biotechnology as it applies to medicine. Each year journalists, health professionals, educators, alumni and students gather to learn about the latest applications of genetic research in various aspects of health care. This year we gathered at the South San Francisco Conference Center to accommodate more participants, an appropriate venue given the role of South San Francisco in the field of biotechnology. Many leading biotech companies are located there and have an active partnership with the city as well as sponsoring the conference.

Master of Ceremonies David Ewing Duncan,  Journalist, Director of the Center of Life Science Policy, UC Berkeley, started us off by sharing the story of his own experience with having a full genetic workup done as well as being tested for pesticides and chemicals for his book Experimental Man. Duncan took all of that information and improved his fitness level and diet to reduce his chances for heart disease, offering an example of how this knowledge can empower consumers. He also invited us to view his Personalized Health Manifesto, which makes the case for a more integrated approach using cutting-edge genetic research in patient care. Like others at the conference his manifesto points to gaps between what we know and what is being offered to patients.

Pharmacogenomics was the subject of the morning presentations and has been described as “the right drug, at the right dose, for the right patient, at the right time.” As Kathy Giacomini, PH.D., Professor & Co-Chair, Department of Bioengineering & Therapeutic Sciences at UCSF explained, genetics is one of several factors that can cause a variation in how a patient responds to medication. Genetic factors play a role in the efficacy and safety of drug therapies. Dr. Giacomini illustrated these factors with two stories that clearly showed what’s at stake if these issues are not understood and applied to patient care.

Tapati McDaniels is the former publisher and editor of Uppity Women Magazine and is currently writing a memoir. Excerpts can be found at http://tapati.livejournal.com/ where you can contact her with questions or comments.

In the first case report, a mother was given codeine for pain, at a slightly reduced dosage. Her nursing baby died and the death was thought to be a case of Sudden Infant Death Syndrome. Upon autopsy it was discovered that the infant had fifty times the normal limit of morphine (which codeine metabolizes into) and the mother’s breast milk had ten times the normal limit. Further testing showed that this mother had two copies of an enzyme—CYP2D6–that metabolizes and increases the morphine level as codeine is processed by the liver. As a result, the FDA changed the warning level for codeine. Some populations have duplicates of that enzyme in their genetic code.

In the second case report, a 55 year old man with chest pain was given an angiogram to see whether there was a blockage in his coronary arteries. An area was found and a stent was placed to widen the artery. Blood flow resumed and his chest pain subsided. One week later he returned with chest pain and the stent was found to be blocked by a clot. It turned out that he had a variation of an allele that prevented Plavix from working properly. Plavix is always given after stents unless there is a contraindication. Normally it prevents clots from forming.

Other drugs that can be affected by genetic variation include Metformin (for diabetes), Warfarin (blood thinner), Tamoxifin (cancer drug), Atomoxetine (ADHD treatment), Abacavir (HIV AIDS treatment), Flucloxacillin (antibiotic used for penicillin-resistant bacteria), and Simvastatin (used to control cholesterol). Not all drugs have been researched for variations in how patients react because the genetic technology wasn’t available when original drug testing took place. New studies looking at data from previous studies and obtaining genetic samples need to be done. In the meantime, doctors are reluctant to test for these factors because there are no clear treatment guidelines and the FDA also hasn’t approved test kits in some cases.

Leonard Post, PhD., Vice President for Research & Chief Scientific Officer, BioMarin Pharmaceutical, Inc., expanded on this theme in his presentation. He explained that his company is putting the genetics into drugs from the beginning, learning how the compound will interact on the target. They look at the affinity for the receptor enzyme as well as drug metabolism. BioMarin Pharmaceutical focuses on specific genetic diseases, e.g. if a patient is lacking one enzyme they will try to replace it.

Dr. Post explains that our diagnostics lump together things that aren’t really the same—in cause—and shouldn’t be treated the same. We talk about cancer by organ and speak of breast cancer, thyroid cancer, prostate cancer. What we ought to do is look at the genetic variations of the cancerous tumors themselves. This will enable us to target the tumor and not damage healthy tissues surrounding it. One example cited by Dr. Post anticipated a breaking news story days later about Vemurafenib and how it neutralizes the BRAF gene in melanomas. BioMarin itself is working on PARP, or Poly (ADP-ribose) polymerase, which is involved in DNA repair. PARP could inhibit DNA repair for some tumors, leading to cell death and ultimately, death of the tumor.

With that in mind, the panel speakers elaborated on the clinical and commercial aspects of pharmacogenomics. Moderated by Ken Hitchner of Monogram Biosciences, the panel looked at the challenges of establishing clinical evidence and data for genetic tests. James Devlin, PhD., Senior Director of Cardiovascular Research for Celera, said it depends on what the test is for and what the risk is. Low risk tests with lots of evidence means faster approval. High risk tests are at the other end of the spectrum and take more time and research to gain approval. Dr. Devlin brought up the Plavix issue previously mentioned and stated that within six months tests could be offered to doctors who want it. Some labs offer testing even though the FDA has not yet approved them.

Other panel members, Mark Lee, M.D., Ph.D., Senior Director, Oncology Development, Genomic Health, Inc.,and Gordon Parry, Ph.D., CSO, Voyageur Bio and Independent Consultant in Personalized Medicine, joined in discussing the difficulties of getting the FDA to catch up, citing the problem that the FDA approves the research for the necessity of tests as well as approving the tests themselves and was lagging behind the research. One sensed an undercurrent of frustration with the bureaucracy and the red tape while lives are hanging in the balance. Genomic Health, Inc., markets the Oncotype DX® breast cancer test, which has been shown to be highly effective in predicting recurrence of breast cancers as well as the likelihood that chemotherapy will be of benefit to the patient.

We had a lot to think about as we enjoyed lunch. The food offered throughout the day was excellent and varied enough to suit vegetarians and omnivores alike. I was fortunate to share a table with two gentlemen from BioMarin Pharmaceuticals, Inc, and hear more about the work they are doing overseas and why working on certain genetic disorders leads them all around the world to populations more likely to have those disorders. It makes sense but I wouldn’t have thought of it myself. Of course populations of genetically similar people would be more prone to certain diseases. This is already common knowledge in medicine.

Returning from lunch with refreshments in hand we were treated to a presentation by Lars Uno Larsson, Executive Chairman of Swedish Biomimetics 3000. He was demonstrating how it is possible to manufacture and deliver drugs much more efficiently and quickly using their µLot® platform technology. I confess that the animated graphics were over my head since I have no familiarity with drug manufacture or synthesizing complex chemicals. I trust this meant much more to the professionals in the audience and it was well received.

Consumer Genetic Testing

The afternoon topic was all about consumer genetic testing and James Kovach .D., J.D., President and CEO, Athleticode, Inc., got us started by discussing the benefits of testing for athletes. He explained that APOE 4, present in about 25% of the population, and has been shown in small numbers to correlate with negative outcomes for sports players. APOE 4 is associated with Alzheimer’s Disease so there would be more concern for athletes with APOE 4 when they receive blows to the head during a sporting event or practice.

Other genes can determine one’s likelihood of being injured while running and a program can be developed for an athlete’s genotype to minimize that risk. Adult athletes can be tested and parents may opt to have their children tested in order to be proactive from the beginning of their involvement in sports. Those who are former NFL members and have already experienced brain injury can participate in the Former NFL Player Concussion Study Survey.

Joanna Mountain, Ph.D., Senior Director of Research at 23andMe, Inc., took us through a tour of a fictional consumer’s genetic profile to give us an idea of what their direct-to-consumer genetic testing is all about. Customers have a choice about whether they wish for their sample to be included in genetic studies and confidentiality and informed consent are high priorities, in accordance with federal guidelines. The Genetic Information Nondiscrimination Act (GINA) guards the privacy of genetic information and insures that it may not be used to discriminate in employment or health insurance matters.

Care is taken also to use graphics and information that help put genetic risks into perspective. A genetic predisposition is not the same as unyielding fate but, rather, a call for awareness and reducing other risk factors after consulting with one’s primary care physician. Testing starts with a saliva sample sent to their lab. When the results are ready customers log in to the encrypted site with their password and view the information. As of June 15, 2011, 100,611 users have been genotyped and 76% have agreed to participate in research.

Following this close look into genetic testing marketed directly to consumers, the topic turned to business, regulation and ethics of consumer genetics with presentations by a well qualified panel, beginning with Trisha Brown, MS., CGC and Vice President of Clinical Affairs at DNA Direct. DNA Direct started out offering some genetic tests directly to consumers but for now it is not possible to order directly from their website. She said that the company got tired of audits and changing regulations and is waiting to re-enter the direct-to-consumer market once regulations are well established. Third parties such as hospitals and insurance companies now order tests from DNA Direct for their own consumers. El Camino Hospital of Mountain View is one such customers and they utilize DNA Direct’s own educational materials on their website.

Kelly E. Ormond, MS., CGC, from Stanford University’s Genetics Department, elaborated on ethical concerns as they relate to consumers. Ormond stated that there were principles such as beneficence—do good, non-maleficence—do no harm, provide context counseling, respect for autonomy—informed decision-making, and finally, justice—access issues across socio-economic and cultural boundaries. She raised some important issues regarding consumer participation and when and what information is given to consumers. When do genetic counselors feel confident about the information they’re providing? These issues were raised again during the panel discussion.

Information is not knowledge. Knowledge is not wisdom. Wisdom is not truth. Truth is not beauty. Beauty is not love. Love is not music. Music is the best.–Frank Zappa. Thus began the presentation by Mohan S Iyer, CFO of Tethys Bioscience, to the delight of the audience. This quote captured the foundation of the ethical dilemmas mentioned previously. Iyer’s presentation cited the work of organizational theorist Russell Ackoff in a chart illustrating the relationships between data, connectedness, information, knowledge and wisdom. Data alone—information—is not knowledge or wisdom until it is put into context. Tethys Bioscience offers a diagnostic (not genetic) test that can pinpoint those at greatest risk of Type II diabetes in the near future.

The panel discussion revolved around these issues of ethics and communicating the full meaning of genetic information to both doctors and consumers in a useful way that will be truly understood. The issue of misunderstandings between genetic counselors and doctors, doctors and patients was a thorny one with no easy answers. The audience had quite a few questions for this panel as pretty much everyone had a stake in how these issues play out. Will poor people have full access to these technologies or will there be yet another huge divide, as with internet access? Also, there are not enough genetic counselors to keep pace with the increasing need as personalized medicine becomes better established. Regulation is also lagging behind as mechanisms intended for previous types of medical research do not fit the new paradigm. Many issues were raised and few definitive answers exist in such a rapidly changing field. One wonders what changes will have taken place by next year’s conference.

Henry J. Fuchs, M.D., Chief Medical Officer at BioMarin Pharmaceutical, Inc., gave the closing keynote speech on making medicine personal. This was one of the highly technical presentations that was difficult for laypeople to follow but one part I did find accessible and interesting is that the Rare Diseases Act of 2002 protects drug research for orphan diseases by offering financial incentives to do that research. Rare diseases are most often genetic. This enables companies such as Dr. Fuchs’ to work on drug therapies for people suffering from these diseases. Profit alone will not fund such work for small groups of patients. Dr. Fuchs went on to cover oncogenes (genes that have the potential to cause cancer).

In closing, Hon. Kevin Mullin, Mayor, City of South San Francisco spoke about the rapid growth of the biotech field which is well represented in his city. Assembly-member Jerry Hill was supposed to attend but the State Assembly was still in session. Attendees were invited to enjoy a networking reception.

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