IN PERSON
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Walter Koch, PhD, is vice president and head of research at Roche Molecular Diagnostics (Pleasanton, CA). In 1998, Koch joined Roche Molecular’s human genetics department to head up development of cytochrome P450 genotyping and p53 tumor suppressor gene resequencing assays. From May 2001 to January 2005, he served as director of Roche’s pharmacogenetics department. He can be reached at walter_h.koch @roche.com. |
With the IVD industry developing new molecular technologies for genetically based disease indicators, physicians are being provided with an expanding armamentarium for more individual treatment of patients. Advances are being made by smaller companies as well as the industry giants.
Clinical trials assist in validating the potential clinical utility of new biomarkers, but they are increasingly expensive to mount. New regulatory requirements introduce other challenges for companies endeavoring to develop new molecular tests. But despite these difficulties, research continues to lead to therapeutic reality.
To find out what progress companies working on molecular diagnostics are making, IVD Technology editor Richard Park spoke with Walter H. Koch, PhD, head of research for Roche Molecular Diagnostics (Pleasanton, CA). In this interview, Koch discusses the work that Roche Molecular, its internal and external partners, and the industry generally are doing to help make the envisioned future of personalized medicine standard clinical practice. He talks about technological advances, the development of novel diagnostics and drugs in tandem, and the advantages of having both diagnostics and pharmaceutical capabilities in one company.
IVD Technology: What have been the biggest technological developments and advances in molecular diagnostics during the past few years?
Walter Koch: Because Roche Molecular Diagnostics’ business was built around polymerase chain reaction (PCR) technology, what we term molecular diagnostics are primarily assays that analyze different nucleic acids, rather than other molecular technologies and analytes such as immunohistochemistry, or fluorescence in situ hybridization (FISH). Therefore, I’ll restrict my discussion to our core technology platforms which allow us to identify the presence of a particular type of DNA or RNA of infectious agents for some diseases, and of the genetic variations that may be important for clinical decision making in other types of diseases.
In my opinion, the biggest technological developments for PCR have been the result of incremental technology improvements that have given us the ability to implement new concepts in our thinking and testing. One of these is the concept of multiplexing analytes. Many of our traditional diagnostics, and even our early molecular ones, analyzed only a single analyte, for example, a single virus, one at a time. It is now possible to routinely detect more than one analyte at the same time with one single, automated assay. At Roche Molecular Diagnostics, we have applied this concept to areas including blood screening and sexually transmitted diseases (STDs). We are also applying this approach in early oncology assays.
In blood screening, our multiplex test is in the final stages of FDA review. It allows detection of HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) in donated blood all at the same time with a single automated assay. Eight or 10 years ago, we did not have all the technology to develop robust assays of this type. The improvements in the efficiency of testing that multiplexing affords will have a significant impact on the blood screening industry.
In applying the concept to other types of diagnostics, such as STDs, the ability to simultaneously screen for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) is an improvement in testing efficiency. Also, in detecting human papillomavirus (HPV), it’s important to be able to differentiate between a multitude of different genotypes of the virus, each with different DNA sequences. Technologically, each genotype presents certain challenges and clinically, different genotypes represent different levels of a woman’s risk of developing cervical cancer.
These advances allow for two new abilities: to specifically detect different genotypes of HPV, the qualitative differences between these viruses, and to detect simultaneously most of the high-risk viruses versus low-risk viruses to help make decisions about the necessity of further follow-up and treatment.
I should also mention that for HCV, it is extremely important to recognize the genotype with which the individual is infected, because it has important ramifications on the duration of treatment and the likelihood of response with a Pegasys/Copegus regimen.
I anticipate that this same qualitative aspect of detecting genetic sequence variation is going to become very important in oncology as well. Thirty years of intense research has shown that mutations that arise in critical genes within cells, oncogenes and so-called tumor suppressor genes, lead to the cell’s aberrant growth. In many cases, these same changes have provided us with molecular targets to which we can apply therapeutics in order to better manage the disease. In other cases, they help predict response to therapy.
The second most significant technological advancement would be the increasing employment of microarray technology. PCR is very useful for looking at a relatively small number of analytes, anywhere from one to two dozen, perhaps. But if we want to ask questions for which a larger number of analytes are necessary, or if we want to sequence a gene in its entirety, we need a different platform, such as microarrays.
Roche Molecular Diagnostics’ first product to use microarray technology was the AmpliChip CYP450 test for genotyping. We now have the AmpliChip p53 resequencing array for oncology in late-stage development. Roche Molecular is also using gene expression profiling as a technology to provide clinically important information about diseases such as cancer in some of our products in the research and development pipeline.
You’ve touched on this already somewhat, but what trends do you see emerging in the molecular diagnostics area? What are companies such as Roche Molecular Diagnostics focusing on right now?
In virology, we’re focused on being able to detect and discriminate between viral genotypes that are present, because their distinctions have clinically meaningful ramifications. As I mentioned, HCV exhibits several different genotypes, some more resistant to a standard Pegasys/Copegus treatment regimen than others. Depending on the HCV genotype, in some patients only approximately 50% cure rates are achieved after one whole year of therapy. Other HCV genotypes exhibit a much higher cure rate, often within a much shorter period of treatment. Determination of the viral genotype, coupled with viral load assessments, provides the treating physician and the patient with a good idea of how long and how successful a treatment regimen may be. This is a great example of personalized healthcare, and how information from molecular diagnostics may be used to tailor individual patient therapies.
Roche Molecular Diagnostics is also working in HPV and conducting a clinical trial to support U.S. registration of our new HPV test. Our goal is to deliver a test that helps to reduce the risk of cervical cancer by allowing closer monitoring of those patients infected with high-risk viral subtypes.
Another important trend in molecular diagnostics is the further marriage of new technologies to therapeutic decision making in areas like oncology. We’re seeing a rapid proliferation of clinical trials that evaluate various biomarkers to understand patient response. In some cases, those biomarkers may be converted into diagnostic tests that can be used as a companion diagnostic. For example, Her2 overexpression is used in breast cancer cases to ascertain whether a patient is a candidate for Herceptin treatment.
Challenges to Overcome
What obstacles are IVD manufacturers that are developing molecular diagnostic technology and products encountering?
One of the biggest challenges we face, certainly as we develop new biomarkers, is access to clinical samples to help validate the potential clinical utility of those markers.
Another challenge is the expense of clinical trials. In terms of size and cost, our HPV trial is close to a pharmaceutical clinical trial. Yet, our diagnostic products don’t have the profit margins of pharmaceutical products. In other cases, increasing regulatory requirements mean additional work to launch tests in certain markets.
How do IVD manufacturers overcome such challenges? What has Roche done in those cases?
We are increasingly trying to leverage our advantage of having a very strong pharmaceutical division. Our Roche Pharmaceutical Division conducts numerous clinical trials that track to our research and product areas such as HCV treatment. In some cases, we try to leverage those clinical trials and the samples collected from them for both pharmaceutical and diagnostic development programs.
You mentioned increased regulatory requirements. FDA guidances on IVD multivariate index assays (IVDMIAs) and analyte specific reagents (ASRs) come to mind. How do you meet those challenges?
Based on the most recent FDA guidance, many of the current ASRs do not meet the agency’s requirements for ASR configurations. Many manufacturers are faced with the decision of reformulating their ASRs to meet these requirements, or filing a 510(k) application to convert them to IVD products.
ASRs are not recognized in Europe. Instead such products are considered IVDs and must meet the requirements of the IVD Directive. Low-risk products may be placed on the market through a self-declaration while higher-risk products must be approved by a third party, or notified body.
Drivers of Development
Is molecular diagnostics a field more likely to be driven by the traditional disease targets, such as STDs or infectious diseases, or to look more toward genetic mutations as a basis for disease?
There’s a mix of both. Certainly the two big drivers in molecular diagnostics now are virology/infectious disease and oncology. Another important clinical area in the near future is autoimmune diseases, but this is taking longer to develop, in part because we can’t sample the diseased tissue directly. But we’re seeing a lot of work in that area and expect to see growth there in the future.
In infectious disease, nosocomial infections in hospitals, community-acquired infections, and the problem of methicillin-resistant Staphylococcus aureus (MRSA) are significant threats to public health. Roche Molecular Diagnostics is among a number of companies developing MRSA tests to screen patients as they enter a hospital to ascertain whether there’s a risk they may transmit MRSA. It’s another example of detecting a specific genetic variance that has clinically meaningful ramifications.
In respiratory diseases, it’s often difficult to differentially diagnose pneumonia as viral or bacterial in origin. Again, molecular technologies will find a place in helping the physicians to rapidly ascertain the causative agent for that disease.
In terms of genetic mutations, I personally believe that it may take a bit longer for us to develop human genetics into meaningful clinical tests. That’s because most traits are not Mendelian where inheriting two defective copies of a gene has a very specific disease outcome.
Most human diseases are complex genetic diseases and the determinants that have been identified so far have had, by and large, relatively low risk probability associated with them. This means they are not very helpful for making clinical decisions, or even for taking preventive actions, but they are identifying some new targets for drug development.
However, genetic mutations that are somatically acquired (i.e., not inherited), particularly in cancer tissues—are incredibly informative in identifying the driver behind the aberrant growth of those cancers. For example, mutations in the K-RAS oncogene are an important prognostic determinant in the cancers where they are present. The p53 tumor suppressor gene also has very strong prognostic information embedded within it.
Aside from the prognostic value provided, these mutations also provide important information in terms of predicting a response to therapy or the potential to select patients that would be most appropriately treated with a particular therapy. For example, as presented at the American Society of Clinical Oncology and European Society of Medical Oncology meetings this year, the presence of K-RAS mutations in metastatic colorectal cancer is associated with generally poor responses to antibodies directed at the epidermal growth factor receptor (EGFR) kinase, such as cetuximab and panitumumab. In some countries, it is recommended that only those patients with the normal, or wild-type, K-RAS sequence be given the therapy, because that’s where it’s been shown to be most effective.
There were even some hints that some patients with K-RAS mutations treated with particular chemotherapy combinations together with EGFR inhibitors, not only did not benefit, but actually did worse than if they’d been given the chemotherapy alone. Recognizing the importance of
this and other markers, Roche recently signed an exclusive distribution agreement with DxS Ltd. to sell its TheraScreen K-RAS and EGFR mutation assays
Roche Pharmaceuticals is also collaborating with Plexxicon to develop an inhibitor that will target the mutant BRAF kinase. Roche Diagnostics is providing a Cobas TaqMan test to detect a single, common BRAF kinase mutation. Some cancers, including melanomas and colorectal, have this particular mutation as an oncogenic driver. If we can selectively shut down that kinase by selecting patients who have the mutation, we can optimize efficacy for patients, and minimize potential side effects.
Finally, the AmpliChip p53 is going to be employed with a novel class of compounds called Mdm2 inhibitors that are in development with Roche Pharmaceuticals. Mdm2 is a protein that targets p53 protein for degradation. This novel class of small-molecule compounds called Nutlins blocks the binding of p53 to Mdm2 and therefore lets p53 levels increase, which in turn induces apoptosis, or suicide, of the cancer cells.
This novel mechanism requires, however, that p53 be in the wild-type, or normal, state. As many as 50% of all cancers have mutations in the p53 gene, so one needs to select the patients for wild-type p53 status with a test like the AmpliChip p53 before they can be treated with this novel therapy. I think we’ll see many more examples like these, certainly in oncology.
Tailoring Therapies for the Patient
How will the continuing emergence of pharmacogenomics and personalized medicine affect the development of molecular diagnostics?
This is an area in which Roche is a pioneer. We are applying personalized healthcare and biomarker strategies to virtually every drug in development today, certainly in big areas like virology, oncology, and autoimmune diseases.
Beginning with discovery and through to early- and then late-stage clinical development, we evaluate whether biomarkers will help us to develop those therapeutics and, where appropriate, ultimately help us improve selection of patients who will benefit from those therapies. However, we know that one size doesn’t fit all and we don’t have 100% response rates.
This will most likely open up a very large area in coming years marked by the increasing marriage of molecular diagnostics with therapeutics development. The benefit for a company like Roche is that we have the organizations and the skill sets for both of these disciplines within the same company, which helps us to utilize the technologies and deliver them to the market more appropriately.
Our main role in this evolution is to help translate early-discovered biomarkers into routine, robust, commercializable diagnostics where needed. We’ve made some strategic and important acquisitions of new technologies over the past couple of years to ensure that we have the requisite breadth and depth in the entire diagnostics organization portfolio. Not every company can do that.
So it goes beyond just PCR and microarrays. It means marrying these technologies together with immunohistochemistry, with ISH, and with ELISA assays where those proteins are secreted into the blood, and so on. Perhaps, in the future, they will be increasingly sequence-based as well. It will take a village, so to speak. It’s likely that we will increasingly need multiple markers and diagnostic assays. Increasingly, we have to look to a lab in the future that can integrate a wide variety of different diagnostic information into algorithms that allow the clinicians to make the best decisions for their patients.
You mentioned working with colleagues on the pharmaceutical side of Roche. Is that a strategic approach that Roche is taking—that with every new drug development effort of Roche Pharmaceuticals, there is a concerted effort to develop a companion diagnostic?
It’s not a companion diagnostic development strategy, but a biomarker strategy, which helps to better understand how a drug is working and where it will be most successful in treating patients. Even at the earlier stages of clinical development, the biomarker strategy is evaluated.
This fairly new strategy is now institutionalized throughout Roche. In 2007, Roche Pharmaceuticals changed its organizational structure to revolve around five disease-biology areas: virology, inflammatory and autoimmune diseases, oncology, metabolic diseases, and urology. In fact, Roche has instituted additional structures to ensure optimal interaction between pharmaceuticals and molecular diagnostics. We have diagnostic liaison managers for every disease-biology area, who interface between the pharmaceutical development teams and diagnostics and ensure that the right people are connected and the right technologies and tests brought to bear on clinical development programs. The way the company is developing its therapeutics, taking advantage of having this diagnostic powerhouse under the same roof, represents a very big change.
Quite a few major pharmaceutical companies have partnered with diagnostic companies recently to strategize about personalized medicine and targeted therapies. Is Big Pharma in general, like Roche, seeing the future as, to some extent, formulating targeted therapies with a diagnostic that goes hand in hand with a particular drug?
I wouldn’t say that every drug will follow that model, as there will most likely be some new therapeutics discovered that are so broadly effective that we won’t need to stratify populations. But there’s also the recognition that, for many diseases, even though the presentation may look similar, there are different molecular etiologies.
So when breast cancer presents, the case may look similar to others under a microscope. However, we know there are at least five different subtypes defined by molecular profiles. One of those, defined by overexpression of hormonal receptors has been effectively treated with antiestrogen therapies since the mid-1970s.
Another breast cancer subtype is defined by Her2 overexpression. A decade ago, Herceptin revolutionized breast cancer treatment for patients with the subtype of the disease that is driven by Her2 overexpression, and boosted survival rates. And then there are other subtypes that we’re starting to see benefit differentially from various combinations of chemotherapy. There’s a recognition that disease heterogeneity dictates that those different subtypes of disease be treated differently. It’s a more rational way to approach some diseases.
Some pharmaceutical companies have come to discuss collaborations with Roche Diagnostics because they understand that we have the resources to translate the biomarkers that they’ve discovered into diagnostics that could be married with their drugs.
To what extent are personalized therapies a reality? Besides the technology and the business side of it, there are regulatory issues and reimbursement issues. And on the clinical side, doctors and patients have to buy in. When do you think personalized medicine will get beyond the developmental stages and become standard clinical practice?
We already have examples of personalized healthcare technologies that are growing each year. One would be K-RAS, which I mentioned earlier. For the other examples I provided of tests we have in early-stage development, we can’t predict what the success rate of the pharmaceutical will be. On average, pharmaceutical attrition from phase 1 through 2 and 3 is unfortunately still rather high. There is hope that our strategies will improve success rates in these pharmaceutical development programs.
I have no doubt that within four to five years we will have several additional examples of personalized healthcare as a reality. I think oncology is an area in which we’re expecting to see more of it, but this is an evolution of both drug development and management of patients that will continue over the next one to two decades.
Personalized healthcare is not only driven by technology, it is combining a better understanding of diseases and their treatments through diagnostics. Then tailoring a treatment based on that information.
A View of the Future
What is Roche Molecular focusing on these days in the way of projects and technologies?
Roche Molecular Diagnostics’ strong growth driver continues to be virology, which will not change. In that arena, we are making technological improvements to increase laboratory efficiency with both new instrumentation and new technology approaches to diagnostic targets we already have in the marketplace. These help the lab to perform the testing more effectively.
We have several tests under FDA review, including the HCV viral load monitoring test, the only system to offer full automation of the real-time PCR testing. I’ve already mentioned our clinical trials for HPV in the United States. And we recently launched a Cobas TaqMan CT test—the second version—this summer, which features a new dual-target design. Part of the problem with infectious agents is that they mutate, especially the RNA viruses. We have to try to stay one step ahead of those, because that variation challenges the technology of PCR to be broadly inclusive of all the different viral subtypes and variants that need to be detected.
In the blood screening arena too, we’re already moving to a next-generation multiplex assay that will be an even greater enhancement and improvement than the one we have in review right now.
Again, because our Roche Pharmaceuticals partner and Genentech are so strong in oncology, we are exploring a significant number of tests and biomarker approaches in that field for possible movement into clinical development programs and, where appropriate, companion diagnostics.
Which brings to mind Roche’s recent acquisition of Ventana. How does that play into your strategies, especially with regard to personalized medicine?
I think it was an excellent acquisition. We’re very excited about working together with Ventana (now called Roche Tissue Diagnostics outside the United States), because its technology filled a gap in our overall Diagnostics portfolio offering.
With PCR and microarrays, we can look at mutations, the presence of RNA and DNA analytes, and sequence variations, but we couldn’t look at the expression of the protein, which is ultimately the important therapeutic target. Ventana brings immunohistochemistry, which strategically complements the technology platforms we have today. In addition, its ISH probes provide highly effective ways of knowing whether multiple copies of a particular gene have been amplified, something that happens frequently with particular genes in cancer. So again, Ventana provides a complementary technology.
By corollary, of course Ventana technologies did not allow for detection of point mutations in genes such as K-RAS, BRAF, and p53 that I mentioned. So we see these as highly complementary and providing a more complete picture, a molecular portrait of disease for the oncologists, to help drive their decisions.
Roche Diagnostics’ overall ambition is to increasingly integrate information from a multitude of different inputs, including from all of our internal technology platforms, but also approaches like imaging. And then intelligent informatics systems will be required to develop algorithms to distill this down to something relatively straightforward and simple for the clinician to use.
What other trends and challenges in molecular diagnostics that we haven’t discussed do you think we can expect to see next year and further in the future?
Molecular diagnostics is a broad area. Although Roche is tackling a wide variety of disease states and applications, we clearly can’t do it all. So, I think we’ll see a lot of new products rolling out not only from companies as large as ourselves but also from smaller companies that focus on a very specific niche.
We’ve seen some interesting IVDMIA-type products launched in the past year by relatively small companies with a very narrow focus, and I think we’ll see more of that. It will be interesting to watch how those tests are taken up to help inform clinical decisions.
The other big trend is personalized healthcare. Again, there are unique advantages to having both diagnostics and therapeutics under one roof, not only for working together, but also for leveraging the synergistic value of the two.
