NEW YORK(GenomeWeb) – A decade after launching its first and only product, CareDx is looking to expand its footprint in the organ transplant testing space with tools based on cell-free DNA technology.
The Brisbane, California-based company, which went public in July 2014, currently has two studies under way directed at cfDNA to monitor heart and kidney transplant patients, and expects that the assay for cfDNA in heart transplants could be available for clinical use by the end of the year, CareDx CEO Peter Maag told GenomeWeb. Meanwhile, the cfDNA assay for kidney transplants could be available to clinicians sometime in 2017.
If CareDx is successful, the tests would be the firm's first products to make it to market since its AlloMap test was launched in 2005.
Generally, CareDx's cfDNA technology measures donor-derived cell-free DNA as a percentage of total DNA. For its targeted sequencing approach, CareDx uses a 266-SNP panel with an Illumina MiSeq instrument, Maag said, adding that the process "is based on [a] standard sample extraction kit combined with various amplification steps."
While cfDNA has not yet been definitively proven to be predictive of transplant rejection, several studies have made it "exceptionally clear" that the technology has potential, Piper Jaffray analyst William Quirk told GenomeWeb.
In a 2011 study, Stephen Quake and colleagues at Stanford University found that levels of cell-free donor DNA rose sharply in blood samples from transplant recipients who experienced rejection, compared to those who didn't.
CareDx's technology would be used not to predict transplant rejection, but to monitor transplant patients and their response to immunosuppressive therapy. The main issue with organ transplants is no longer organ rejection, Maag said, but issues associated with the over-immunosuppression of transplant patients. "Ideally, you would like to have a titration tool to optimize immune suppression therapy," he said.
In its ongoing studies, CareDx is interested in healthy transplant patients — rather than patients who are rejecting their transplants — who may be receiving too much immunosuppressive therapy in order to assess its technology in monitoring patients and helping clinicians determine the right dosage.
The company has a study dubbed D-OAR to assess cfDNA technology for heart transplants, and another study called DART to evaluate the technology for kidney transplants. The D-OAR test builds on CareDx's registry study called OAR, which uses the gene expression-based AlloMap to follow patients longitudinally over their lifetime.
OAR comprises more than 400 patients currently, while D-OAR comprises about 100 patients. Maag pointed out that with only about 2,500 heart transplants in the US each year, studies with 500 patients in this space "are very substantial."
In April, CareDx reported preliminary results from its cfDNA work at the International Society for Heart & Lung Transplantation conference, including a finding that elevated levels of cfDNA could be detected up to 25 days before a transplant was rejected, suggesting that cell-free DNA can provide earlier detection of heart transplant rejection than biopsy histopathology grading.
The data also indicated that cfDNA combined with AlloMap provides a more accurate prediction of heart transplant rejection than either method alone, the company said.
The cfDNA heart tool is currently available for research use only, but Maag said that CareDx anticipates the test could become available as a laboratory-developed test by the end of this year.
The company will commercialize the test by piggybacking it with AlloMap: a patient and clinician wanting the cfDNA test can use the same blood draw for both assays.
Meanwhile, CareDx recently announced that the Cleveland Clinic has signed up the first patients for DART, which will be conducted in two phases. In the first phase, the firm plans to enroll 200 patients in at least six centers and to collect patient samples for 18 months. Interim results from the study are expected in the first half of 2016.
CareDx has not disclosed what other centers, if any, have signed on for DART. Maag said, however, that the company has a presence in 115 out of the approximately 130 heart transplant centers in the US and that many of those centers also perform kidney transplants, suggesting they may participate in the DART study.
The second phase of DART will be to demonstrate the clinical utility of CareDx's cfDNA kidney test to help physicians determine the right dosage of immunosuppressive therapy for a patient. Maag added that the company should be able to get results from this phase more quickly than the 18 months anticipated for the first phase, and as a result, the cfDNA kidney test could be launched commercially in 2017.
The biggest issue will be getting the study centers up and running, but once that is done, "kidney is a very high-volume transplant in comparison to the heart, so once these centers are up and running," the patients will be "very quickly" recruited, he said.
In the meantime, the cfDNA kidney test could be released as an RUO test later this year or in early 2016.
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If CareDx is successful in commercializing its cfDNA tests, they would transform the company from being a one-product business.
Maag told GenomeWeb that by launching AlloMap, obtaining US Food and Drug Administration clearance in 2008, and gaining traction in the heart transplant space, CareDx now has a "tremendous platform to apply clinical sequencing technology to the field of transplantation." Since its launch, CareDx has performed more than 67,000 commercial AlloMap tests, the company said in its Form 10-Q for the first quarter of 2015.
Maag added that the company's IPO has provided it the financial resources to bring such new solutions to the market.
According to Piper Jaffray's Quirk, CareDx's cfDNA program "is most certainly a critical pipeline initiative," for the firm moving forward. "If you think about their potential to expand into other solid organs [aside from heart] … cell-free DNA is going to play a pretty critical role in that push," he told GenomeWeb.
CareDx would have the cfDNA organ transplant space virtually to itself. While a handful of academic researchers — including Kiran Khush at Stanford and Iwijn De Vlaminck of Cornell University— are exploring the clinical use of cfDNA for organ transplants, few industry players have publicly disclosed any programs in the space, though some, such as Oxford Immunotech, have indicated interest in doing so.
Maag said that even before he joined CareDx as president and CEO in 2012, the firm was eyeing the cfDNA space, and upon joining the company he made cfDNA technology a top priority in building out CareDx's pipeline.
Last year CareDx took a major step in its cfDNA plans by acquiring ImmuMetrix, a Palo Alto, California-based transplant diagnostic firm co-founded by Quake and Dan Seligson with R&D programs and intellectual property in cfDNA.
"ImmuMetrix was perfect because we now have a targeted and a shotgun sequencing approach," Maag said. "Targeted sequencing is very useful for having a rapid turnaround option available … while I think over time this segment will probably see an increase in the utility of shotgun sequencing, especially in the context of discovery."
CareDx has applied ImmuMetrix's technology on an existing sample set for an observational trial to qualify cfDNA in heart transplants and to validate the performance characteristics for AlloMap.
Shortly after the ImmuMetrix acquisition, CareDx inked a supply agreement with Illumina for its next-generation sequencing technologies. At the time, Maag said that as his firm looked to develop cfDNA-based diagnostics, "we believe the technology solutions from Illumina will effectively support our development and commercialization efforts." Illumina also made a $5 million investment in CareDx in April 2014.
CareDx is going after the heart transplant space first with cfDNA because as a result of its AlloMap business, "We have established the infrastructure, we have capacity, we have used our existing sample sets to demonstrate that it works," Maag said. "It's very cumbersome to collect 10 samples per patient longitudinally over a long period of time, so since we have the samples, we did the analysis and demonstrated that it works."
However, the richer market opportunity longer term is in the cfDNA kidney space. According to Maag, the cfDNA heart market is worth about $100 million in the US and about $150 million worldwide. By comparison, the cfDNA kidney space is about a $1 billion opportunity in the US and $1.5 billion market globally with China poised to become a major market for kidney transplants alongside the US.
Measuring serum creatinine levels is currently the standard of care for detecting potential kidney failure but issues surrounding the specificity of the method, as well as the inability to use it for the early detection of renal failure, limits its utility.
CareDx's cfDNA approach would measure the cell death of the allograft and the organ. "The whole idea is that we monitor cell injury a lot earlier than you would be able to do with serum creatinine," Maag said.
While the transplant clinical space tends to be slow in adopting new technologies, Quirk noted that CareDx's experience launching AlloMap would be an important advantage when and if the company brings its cfDNA tests to market.
Along with assays to help clinicians personalize immunosuppressive drugs for transplant patients, Maag said that CareDx's cfDNA technology could have use in detecting infections, in particular anelloviruses, which cause chronic human viral infections.
Additionally, the technology could have applications in cancer. "One of the big issues in cancer care is that a lot of these patients — because of the immunosuppressive therapy — are developing melanomas and rare cancers," he said. "Once we detect these cancers, there might be a whole different application going forward for other companies branching into chronically ill patients moving beyond transplantation."
CareDx's strategy is to concentrate on the "highest cost patient in the healthcare system," he said, referring to heart transplant patients. "Once you have developed solutions for the highest cost patients, you can actually offer other solutions to less-complex or less-costly patients," he added.
"Once you have that solution [to] monitor the immune system, once you have the solution [to monitor] infections, once you have the solution [to] monitor cancers, you can make that available to other patient populations," Maag said.