Dennis Chirico recently received a new heart. Now he’s working with his doctor to make sure his body doesn’t reject it. “I had three biopsies in ten days and then I was sent home,” says Chirico. His experience is typical for heart transplant patients, who undergo dozens of heart biopsies in the years following transplant as one indicator that their own immune system is not attacking, or rejecting, their new heart. Until now, heart muscle biopsy – an uncomfortable, sometimes painful and invasive procedure that detects rejection after the damage is already done – was the primary method to rule out transplant rejection.
Now, through molecular expression testing, there is a less invasive and risky way to assess the potential for organ rejection in the cardiac transplant patient. “This new approach to monitor heart transplant rejection has been received very well by patients,” says Dr. Mario Deng, Director of Cardiac Transplantation Research at Columbia University Medical Center in New York. Dr. Deng says this new approach – a blood test called AlloMap® molecular expression testing – can quickly determine the activity of genes that play a critical role in heart transplant rejection. “It’s the first step towards “tomorrow’s medicine’ – medicine that is personalized, preventive, and predictive,” says Dr. Deng.
The AlloMap test is a significant improvement for the patient since it requires only a blood sample rather than several samples of heart tissue required for biopsy. It is also less expensive for the payers. The list price for AlloMap testing is $2,950 while the endomyocardial biopsy costs insurers between $3,000 and $4,000 on average. But the main advantage of the AlloMap test is the quantitative and reproducible result which measures the early specific activation of the immune system (rejection) rather than the late consequence of the rejection process, the gradual cellular destruction of the heart muscle observed in biopsy specimens.
From the Research Laboratory to the Medical Center and the Patients
AlloMap testing, developed and commercialized by XDx, is one of the first practical applications from the Human Genome Project and has been available for over two years. However, physicians tend to be conservative in their use of new tests and technology, especially when something as vital as a heart transplant is at stake. How does revolutionary technology such as AlloMap testing finds its way into mainstream clinical use?
“Transplant cardiologists want to know that new technology such as AlloMap testing is beneficial for their patients, and that it gives them reliable information they can act on,” says Pierre Cassigneul, CEO of XDx. “They do not readily abandon tests or procedures, such as biopsy, that they’ve relied on for years.” XDx worked hand in hand with transplant physicians from the early stages of the test’s development. AlloMap testing was developed over 4 years through a multi-center study in which 8 of the leading heart transplant centers participated. During the study, over 5000 blood samples were compared to an equal number of biopsy samples from nearly 800 patients. Using the blood samples, over 7,000 genes were identified as potential candidates for identifying heart transplant rejection. The study winnowed out all but the best genes for the job, taking into consideration gene stability and other factors that increased reproducibility and performance of the test. In the end, 20 genes were selected for the AlloMap test, and a sophisticated algorithm converts the individual gene activity readings into a single score for the physician. The results of the study were published in The American Journal of Transplantation in January 2006. “New technology is often supported through articles in a peer-reviewed publication such as The American Journal of Transplantation,” says Cassigneul. “We are fortunate to have strong, supportive data by independent researchers, published in several peer-reviewed journals.”
Incorporating New Technology Into Daily Practice
Peer-reviewed journal articles are one way that physicians and other healthcare practitioners learn about new technology and the experience of others in using these new and improved approaches. Professional societies’ annual meeting and scientific meetings are another way clinicians gain insight into use of new technologies. The International Society of Heart and Lung Transplantation (ISHLT) sponsors such an annual meeting where clinical research pertaining to new and existing therapies, technologies, procedures and devices in heart and lung transplant are presented and discussed. At the 2007 ISHLT annual meeting, held in April, several presentations described the use of AlloMap testing in various medical centers. Two transplant centers in particular described research that indicated AlloMap testing may have applications in reducing immunosuppressive medications. There is great interest in maintaining patients on the lowest possible doses of immunosuppressive drugs – side effects from long-term use of these drugs include infections, bone loss, kidney disease, and malignancies. “Since the introduction of AlloMap testing, we’ve seen the attitude of physicians change from ‘What is it and what does it do?’ to ‘How can I incorporate AlloMap testing into my transplant patient protocols?’ It takes time and experience for this to be widely accepted,” says Dr. James Yee, Chief Medical Officer at XDx.
Because AlloMap molecular expression testing is one of the few gene expression tests in use and is based on cutting edge genomic technologies, many clinicians may not have had the opportunity to learn the fundamentals of how it works. In 2006, XDx supported a CME (Continuing Medical Education) web-based program to help physicians and nurses understand genomic tests in general as well as how to use AlloMap molecular expression testing in their patient management protocols. Through support of this program, many clinicians learned about this new technology while gaining educational credit. XDx has also created educational material that explains the test in easy-to-understand terminology. “Physicians and nurses are obviously well-educated, but much of this technology has become available in only the last 10 years. Naturally they want to know the science behind the test, and our material helps explain it,” says Dr. Yee.
The Role of Reimbursement in New Technology Adoption
As guardians of departmental and medical center budgets, clinicians are often reluctant to try new technology if they are unsure about obtaining reimbursement. This is a common problem faced by most new technologies, be it a blood test or a new imaging method. Like clinicians, insurance companies want to see evidence that the new technology is actually helping the patient while at the same time lowering their cost burden. Until the evidence is available, which may take years to accumulate, insurers frequently brand the new technology as “experimental” and may initially deny reimbursement. Further, it is common practice for medical center laboratories to “refer out” laboratory tests. This approach puts the medical center on the hook to obtain payment for the laboratory test. XDx, however, has the only laboratory certified to perform the AlloMap test and hence approaches the reimbursement issue differently. The XDx model relieves the burden of coverage or reimbursement for the patient and the medical center. XDx can and does bill all insurers directly in most cases, which preempts the concern of coverage or reimbursement. They also manage the appeals process for any denied claims and work with the insurer to help them understand the AlloMap test and its value, with the goal of obtaining coverage for the claim. AlloMap testing is reimbursed by Medicare and many insurers.
The Future is Now
Today, technology is harnessing the human genome and unlocking the secrets of genes and gene expression. Out of approximately 30,000 genes found in nearly every human cell, XDx has identified 20 genes critical to assessing the risk of rejecting a transplanted heart. Their scientists and research collaborators are now working on discovering the genes that will identify rejection of transplanted lungs. XDx has also begun to work on identifying the genes that come into play when a lupus patient experiences flare – an exacerbation of their autoimmune disease that can cause permanent damage. The common thread in the work ongoing at XDx is the identification of immune and inflammatory processes from blood samples before end organ damage occurs. The specific quantitative performance and reproducibility of the AlloMap test enable the physician to monitor patients longitudinally by comparing changes from one test result to another. This approach allows for truly individualized patient management based on the patient’s immune response. This test and others that may follow from the work at XDx are providing a basis for personalized medicine.
The continuation of the work started by XDx will lead to a better understanding of diseases and disorders of the immune system. Further, as this understanding of diseases at the molecular level increases, it may provide pharmaceutical companies the basis to develop newer targeted therapies for these critical disease mechanisms. In combination, new biomarker tests that assess these mechanisms may enable physicians to identify the specific therapies for which individual patients will best respond. Other possible outcomes of this development work are tests that correlate with drug efficacy, enabling clinicians to optimize the therapeutic regimen for each patient by maximizing therapeutic efficacy while minimizing undesirable side effects. Patients will reap the benefits as gene expression technology is widely adopted.
The early detection of immune mediated disorders through molecular diagnostics will allow clinicians to intervene before the patient becomes very sick. The early detection of disease could be expected to have several benefits such as lower treatment costs and enhanced quality of life for the patient owing to the fact that the patient will not reach the late stages of disease at which they are currently being treated. As this happens our healthcare system would finally earn its name ¬– as opposed to today’s system which would be more aptly named a sickcare system.