By granting French diagnostics services provider Diaxonhit with an exclusive license to perform the multi-gene expression test AlloMap, XDx earlier this month took a major step toward growing the European market for its flagship product.
Since 2005, Brisbane, Calif.-based XDx has been marketing AlloMap in the US, where more than 25,000 patients have been tested to date. FDA-cleared AlloMap is a blood-based test that gauges the expression of 20 genes and yields a score of between zero and 40. XDx performs the test in the US through its CLIA certified lab.
Doctors can use the test scores, in addition to standard clinical measures, to determine whether heart transplant patients with stable allograft function are at low risk of rejecting their new hearts. The lower the test score, the lower the patient's risk of transplant rejection.
XDx garnered CE self-certification in the EU for AlloMap in 2011. Under the latest arrangement, Diaxonhit will market AlloMap in European countries through its subsidiary in France, InGen, which has its own sales force and access to a network of labs. Separately, CML Healthcare also holds exclusive rights to market AlloMap in Canada.
Making the test available to patients outside the US "was a major milestone and a major strategy for us," Peter Maag, CEO of XDx, told PGx Reporter. Maag joined XDx late last year from Novartis Diagnostics. "With CE marking and now with a [commercialization] partner, we believe we have all the ingredients to make [AlloMap] available to patients" in Europe, he said.
In Europe, AlloMap testing will be performed centrally by the Jean Dausset Laboratory, which is part of the Paris Hospital Group and is headed by Dominique Charron, a leading immunogeneticist and the inventor of human leukocyte antigen testing for transplantation rejection. "XDx gave a lot of thought to this, and we decided to partner with the lab in Europe because it expedites turnaround time and makes the overall process more efficient for the patients," said Matthew Meyer, XDx's chief business officer, who played a key role in inking the deal with Diaxonhit.
Maag estimated that the European market for AlloMap is equivalent to the US, where approximately 2,000 heart transplants are performed each year and approximately 20,000 patients are living with transplants. In Europe, 70 percent of heart transplants are performed in France, Germany, Italy, Spain, and the UK.
PGx Reporter has reported last year that several German hospitals were testing patients with AlloMap. According to Meyer, Diaxonhit will start to commercialize AlloMap in 2014 across Europe, focusing initially on France and Germany.
Noting that heart transplantation is a specialized market, Maag said that it is important to have "intricate knowledge of the local market realities." Diaxonhit will negotiate contracts with European payors with support from XDx, according to Maag, and the partners will tackle reimbursement for AlloMap country by country. Maag wouldn't provide any details of the reimbursement discussions that the company is currently engaged in with European government payors, but noted that the growing body of clinical utility and cost-effectiveness data on AlloMap will help make the case in favor of coverage.
Last year, XDx presented data from the Cardiac Allograft Rejection Gene Expression Observational II, or CARGO II, study, for which the company recruited patients from 13 European countries. In that trial, researchers analyzed blood samples from patients who had moderate to severe transplant rejection based on endomyocardial biopsies in order to gauge whether AlloMap could differentiate which patients were at high risk for rejection and which were at low risk (PGx Reporter 4/25/2012).
Data from CARGO II showed that AlloMap had a negative predictive value of 98.4 percent for patients between two to six months after getting a heart transplant, and a 4 percent positive predictive value. This means that a low AlloMap score indicates a patient is unlikely to experience rejection, but a high rejection score doesn't necessarily signal that a patient will experience a rejection.
In one of the first trials involving AlloMap, called IMAGE, XDx showed that AlloMap was non-inferior to endomyocardial biopsy between six months and 60 months after a heart transplant. However, most rejections occur in the first six months after transplantation.
In an effort to gauge the effectiveness of AlloMap during this risky period, researchers led by Cedars-Sinai Heart Institute's Jon Kobashigawa randomized 60 heart transplant patients two months after their surgeries to be tested for rejection either with AlloMap or by endomyocardial biopsies for a year. If patients received an AlloMap score of greater than 30 in the first six months or a score of greater than 34 in the second six months, then researchers performed a biopsy. The primary endpoint of the study was to compare the number of events between the two arms in terms of deaths or re-transplants, hemodynamic compromise with rejection, or graft dysfunction.
Full data from this study is still forthcoming. Preliminary results show there were no significant differences in the primary endpoint between those tracked by AlloMap scores and by endomyocardial biopsies. There were no deaths or re-transplants in either arm in the first year. There were four patients with graft dysfunction in the biopsy arm and one in the AlloMap arm. In the AlloMap arm two patients rejected their transplants with hemodynamic compromise and there was one such patient in the biopsy arm. Based on this data, the researchers concluded in an abstract that AlloMap was comparable to endomyocardial biopsies in detecting transplant rejection starting at two months post-transplantation and "does not compromise cardiac function in the first year."
"Within the last four months, AlloMap usage and penetration has rapidly increased based on some of the new clinical data we have introduced," Maag said of the US market, where 85 percent of all performed tests are reimbursed, according to XDx.
AlloMap is reimbursed by Medicare, and a few months ago, when California's Medicaid program Medi-Cal began reimbursing for the test, XDx highlighted that AlloMap was covered by 200 insurers in the US (PGx Reporter 3/20/2013).
In the early days of marketing AlloMap, the test was perceived by doctors as a biopsy replacement tool. This perception may have slowed adoption of the gene expression test. In the past, XDx representatives have discussed how physicians have balked at conducting AlloMap, choosing to maintain their reimbursement earnings for performing endomyocardial biopsies, which can range between $200 to $300 per procedure (PGx Reporter 4/13/2011). Doctors aren't reimbursed for sending patients' blood samples to a lab for genetic analysis.
More recently, XDx has worked to change the perception in the market that AlloMap is a replacement for endomyocardial biopsies, and has conducted studies to build the case that the test is a risk stratification tool that physicians can use to gauge which patients need more invasive follow up and interventions.
Researchers from XDx and elsewhere recently presented data from two studies in which they looked at how the stability of AlloMap scores over time correlated with patient outcomes. In one study, looking at patients enrolled in CARGO II with more than two AlloMap tests, researchers found that AlloMap scores increased and became stable in the first year after transplantation than after the first 12 months. "After 12 months, [AlloMap] score instability and [scores] greater than or equal to 34 predict future events," researchers led by Marisa Crespo-Leiro of Hospital Universitario A Coruña reported in an abstract.
In another study, researchers from XDx and multiple institutions looked at patients enrolled in the IMAGE study with at least two AlloMap test scores and found that the stability of the test scores improved the accuracy in predicting negative outcomes in transplant patients, such as death or allograft dysfunction. "In the cohort of 369 patients, race, age at transplantation, and time post-transplantation were significantly associated with future events," researchers led by Mario Deng of University of California, Los Angeles, reported in the abstract. "In the multivariate models, the [AlloMap] score stability gave a significant incremental accuracy in predicting future clinical events. [The gene expression] score alone and … scores greater than or equal to 34 did not add significant utility in predicting future events."
Based on results from this study, the researchers concluded that the stability of AlloMap scores over a period of time may predict a patient's future risk of allograft dysfunction or death, and this longitudinal data may be more prognostic than a single AlloMap score at a given point in time.
"Previously, you may have heard that AlloMap is a biopsy replacement. Now, we are a patient stratification tool," Maag said. "Subsequently, [AlloMap] makes biopsies obsolete, because for a patient who is very stable you don't need to have a very invasive procedure. … What's more important is [that AlloMap] stratifies patients" according to their risk of transplant rejection.
The data on the link between longitudinal test score stability and patient outcomes has further bolstered this strategy. "AlloMap is so much more than a singular data point," Maag noted. "In the past, we've been focusing on the single AlloMap score … but now, what these studies" by Deng et al. and by Crespo-Leiro et al. "suggest is that if you look at AlloMap scores over time, the variability actually predicts future events.
"That is huge, because … physicians now have an additional tool to stratify high-risk and low-risk patients, because if your AlloMap score is low and the variability [in subsequent scores] is low, you're really talking about a low-risk patient," Maag said.
Endomyocardial biopsies require healthcare providers to resect a small piece of the heart tissue. This procedure is extremely uncomfortable for the patient and can lead to serious complications. Some heart transplant recipients must undergo as many as 12 endomyocardial biopsies in the first year after transplantation.
XDx estimates that 80 percent of heart transplant patients are at low risk of rejection, which AlloMap can identify. If, based on AlloMap scores, a physician can avoid biopsies for some patients and reduce the level of intervention and observation, this saves healthcare dollars.
AlloMap carries a list price of more than $3,000 in the US. In comparison, cardiac biopsies can range from between $4,000 and $10,000. Based on "our communications with payors and Medicare, the value of the test is so obvious that reimbursement has recently not been an issue for us," Maag said, adding that with the move toward accountable care organizations following healthcare reform, healthcare providers are increasingly recognizing the value of AlloMap.
Protocols for how often to test patients post-transplantation on AlloMap vary across centers, Maag said. In general, however, AlloMap testing follows biopsy protocols in that physicians are testing patients six to eight times in the first year after transplantations, and then four times annually.
"Some physicians are using the term immune-privileged to describe patients that have a low [AlloMap] score and have consistently low scores," Meyer said. "AlloMap is going to be useful to identify those patients who may enjoy immune-privileged status, which can allow their physicians to be more comfortable potentially weaning [them off] immunosuppression medication more quickly. This is supporting the goal of personalized medicine in the context of the heart transplant community."