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Emerging Opportunities in Clinical Genomics: An Interview with Charles Cantor of SEQUENOM The clinical genomics environment is ripe with opportunities for all players in the field—pharmaceutical companies, biotech firms, diagnostics manufacturers, tool suppliers, and researchers. The promise of clinical genomics to improve drug development and enhance health care is enormous, and there are an increasing number of areas in which genomics is appearing in the clinic. One current area of growth is in clinical trials. There are currently hundreds of clinical trials in which some sort of genomics testing, either of DNA variation or gene expression analysis, is being incorporated. Another area of growth is in the area of pharmacogenomic testing for drug metabolizing enzymes to reduce adverse drug reactions. In this article, Charles R. Cantor, Ph.D., Chief Scientific Officer of SEQUENOM discusses major areas of opportunity in the field of clinical genomics. This interview is excerpted from the forthcoming CHA Advances MONITOR Series Report, Impact of Genomics on Clinical Trials and Medical Practice. For more information, please visit www.advancesreports.com or contact Cindy Ohlman@cohlman@advancesreports.com.
SEQUENOM is ten years old. We dominate commercial applications of mass spectroscopy for the analysis of DNA and RNA. Our patents are such that there are no other significant players. We originally developed our platform to do genetics, that is, to predominantly look at genetic variations on a relatively large scale, for the R&D market. We have since shown that the same platform, with essentially only software changes, is also capable of studying gene expression and DNA methylation, or epigenetic effects.
SEQUENOM brings to the field extremely high-quality data, which mass spectroscopy can provide at low cost, to perform experiments with high throughput, incredible sensitivity and quantification. Of course, there is significant upfront cost to buy the instrument. But if the highest sensitivity is needed to detect RNA or small amounts of DNA, SEQUENOM’s platform may be ideal. Our customers are now regularly publishing results they can achieve using our platform that cannot be realized using real-time PCR or other, even less-sensitive methods. Real-time PCR is considered by most in the field to be the most sensitive technique. We are, depending on which of our customers’ publications you look at, typically 100 times or more sensitive than real-time PCR. If a test involves answering the question of how much of an analyte is present (depending on whether it is a measure of methylation, gene expression, genetic variation, et cetera), SEQUENOM’s quantitative precision is at worst 5% and at best around 1% standard deviation. Ours is a very good platform, but it is an unfamiliar one to most people because it is mass spectrometry. Most people working with nucleic acids have not used mass spectrometry very much. It is SEQUENOM’s announced goal to carry this platform forward into clinical diagnostics using different types of tests, e.g., genetic tests, quantitative tests for abundance. It is public knowledge that we have a pilot project funded by SIEMENS. Third parties used SEQUENOM’s technology in real diagnostic settings in head-to-head competitions with currently available diagnostic platforms for nucleic acids. I cannot reveal the results of these pilot projects, but they have nearly been completed. They will be publicly announced and the results released in the not-too-distant future.
SEQUENOM has chosen to focus its internal clinical diagnostics efforts primarily on non-invasive, anti-natal prenatal diagnostics. We recently announced that we licensed the technology that was originally developed by Dennis Lo in 1997, while at the University of Oxford, for doing non-invasive, anti-natal diagnosis by looking at fetal DNA that is released into a pregnant woman’s blood circulation. By sampling maternal blood, it is possible to sample the fetus’ blood without having to touch it. This technique is potentially revolutionary for many indications. However, it requires tremendous sensitivity because there are so few molecules of fetal DNA in an accessible, appropriate volume of maternal blood. In addition, the mother’s blood contains so many other things that great specificity is also necessary. Some tests, such as that for aneuploidy, require very precise quantification. At SEQUENOM, we are very optimistic that we will be able to successfully commercialize the analysis of fetal DNA in maternal circulation for a variety of clinical tests. I think it is fair to say that we will at least initially try to partner these tests with players who already have a foothold in anti-natal diagnostics. In particular, SEQUENOM will seek partners that already have a marketing and sales force in that field because we do not. Interestingly, the license we have from Isis Innovation, which is the technology transfer company of the University of Oxford, applies to all technologies—not just mass spectroscopy. That means that anybody who wants to practice this technique of using the fetal DNA found in maternal circulation has to come to SEQUENOM, regardless of the technology platform they want to use.
I think it is tremendously important. For example, twins can be used to estimate the relative importance of genetics versus the environment, and disease causation. Basically monozygotic twins, who are genetically identical, are compared to dizygotic twins, who are only one-half genetically identical. The difference in the pattern of inheritability (i.e., if one twin has it, does the other twin have it?) between monozygotic and dizygotic twins is what estimates the relative roles of genetics and the environment. The bottom line is that everything is half genetic and half environmental, with some variance. So, genetic variations are responsible for half of everything that is disease causation (or risk). Whether or not an individual gets the disease will be modulated by the environment. For some diseases, such as infectious diseases, the environment obviously figures quite dominantly in terms of whether or not an individual gets the disease.
Genomics now allows us to begin searching for markers based on our understanding of the biology of diseases. These could be RNA or DNA or protein markers that can be used to monitor disease onset, disease severity, pathophysiology, disease progression, therapeutic response, remission, recurrence, et cetera. Much of the activity, in what is referred to as genomic or individualized medicine, tries to discover the most effective biomarkers. A biomarker is what we call any molecule that can ideally be measured non-invasively and informs us about disease processes. At SEQUENOM, we are particularly excited about DNA methylation biomarkers. We have customers who use ordinary DNA biomarkers (i.e., viral DNA for viral diseases), RNA markers, et cetera. But our current fascination is with methylation biomarkers. We recently published a paper in PNAS which reported the first results on these types of biomarkers. The reason why we are so excited about methylation is twofold. First, methylated DNA is a stable analyte, and it contains a lot of information that is relevant to gene expression. RNA, on the other hand, is a very unstable analyte. It is very difficult to work with in clinical samples. It is even difficult to work with in vivo. Methylated DNA is much more reliable. The second point is related to the first and that is, when measuring the level of RNA, which is what is done using real-time PCR, what is basically measured is a competition between the rate of synthesis (which is a biological process) and the rate of decay. The rate of decay is partially biological decay. But partially it is just an artifact; it is in vitro decay due to the fact that RNA is unstable. So the use of RNA as an analyte, while extremely informative, is compromised by the fact that it is so critically dependent on how the samples are prepared and stored. There is enormous lab-to-lab and even technician-to-technician variations that are seen when people try to rigorously measure levels of RNA.
What we are seeing is the race to discover the best technology that will work for these biomarkers and to discover the most useful biomarkers themselves. I believe the most successful commercial companies that prosper in the long run will be those that have important intellectual property, both on the markers and on the technology. That is why, at SEQUENOM, we are so happy about our current situation with our anti-natal technology: We have intellectual property on the markers and a technology which is very effective at using them.
A major hurdle is that some complex diseases involve many genes. Discovering those genes is proving to be expensive. Furthermore, optimizing the use of that information is a complex problem because the cumulative effect of many genetic variations is combinatorial complex. That does not mean that it is an unsolvable problem—it is just not as simple as looking at a single-gene, Mendelian disorder. I do not really see significant business or regulatory hurdles in the field of clinical genomics. Genomic tests have the advantage that they are inexpensive and produce very high-quality data. Genetic variations are unambiguous. There are many reasons to believe that if this information is used effectively it could decrease the cost of medical care. My personal mantra in this is if you are not decreasing the cost of medical care then you are in the wrong field. And the goal, of course, is to decrease the cost essentially without decreasing the quality and hopefully even increasing the quality. The only major hurdle I see down the road is that lots of people have patented lots of things. It might be a struggle for people to find freedom to operate. But this has occurred in other fields. If the parties come to the table and negotiate the sharing of intellectual property then these problems tend to go away.
I think it is going to be very difficult to be a therapeutic player without taking genetic variation into account. So however this plays out, there is going to have to be a merger, or synergy, between genetic diagnostics efforts and therapeutic efforts. Currently, the average efficacy of a drug on the market is around 50%. That is inexcusable. It means half of the money is wasted and patients are not being well treated. We are already seeing the beginning of very substantial investments in pharmacogenetic profiling of individuals in clinical trials. I believe the regulators will require this. Where there is knowledge about important genetic variation, regulators will ultimately require the pairing of a genetic test with the therapy. That way, the therapy is given only to those patients who will be reasonably responsive to it.
At this point, I think the field is being driven by the pharmas themselves. Like it or not, they recognize that clinical genomics is the future of medicine. The CEOs and high-ranking executives of major pharmaceutical companies are now broadly embracing personalized/individualized medicine in public talks. While they are not saying that there are going to be 1,000 different treatments for a single disease, I do think they are admitting that they can do better.
I would say that there are a few obvious pots of gold at the end of the rainbow. Non-invasive prenatal diagnostics is one thing that I believe will be achieved. Whether by SEQUENOM or somebody else, it will probably be achieved soon. There are 12 million births per year in relatively affluent world populations. In addition, there are many more births worldwide. There is no way to look at the parents to predict the possibility of Down syndrome except by invasive amniocentesis testing, so this is an enormous opportunity. Think of the potential recurring revenue. I think the other area where rapid progress will be made is early cancer detection. Again, this would entail looking at biomarkers circulating in the blood or urine (where they show up depends on the location of the cancer). I think we all understand that if cancer is detected very early, the current therapies work extremely well. The trick is that currently, cancer is usually not detected early enough. In my mind, those are the two biggest opportunities.
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