Canadian molecular diagnostics developer Spartan Bioscience said this week that the US Food and Drug Administration has granted 510(k) clearance to the Spartan RX CYP2C19 assay.
The PCR-based test screens for mutations in the CYP2C19 gene that affect the metabolism of common drugs, and provides genetic results from raw sample in about one hour — faster than any other commercial assay. According to at least one clinical expert, the approval marks an "important step forward" in terms of enabling physicians to conduct rapid genotyping to help guide treatment in cardiac stent patients.
Even though the approval is just a few days old and does not cover point-of-care use, Ottawa-based Spartan is already working to reduce the size of its testing system and make the assay easier to use in a bid to make it truly conducive to the point of care, a company official said.
According to the FDA's approval letter, issued earlier this month, Spartan RX CYP2C19 is indicated for use as an aid to clinicians in determining strategies for therapeutics that are metabolized by the cytochrome P450 2C19 gene product, and that are specifically affected by the *2, *3, and *17 alleles.
The CYP2C19 enzyme metabolizes approximately 15 percent of all prescribed drugs, including drug classes such as anti-platelet therapies, beta blockers, anti-depressants, proton pump inhibitors, and anti-epileptics. Specific examples of commonly prescribed drugs in these categories include clopidogrel, marketed as Plavix by Bristol-Myers Squibb/Sanofi; propranolol, marketed as Inderal by AstraZeneca; and citalopram, marketed as Celexa by Forest Pharmaceuticals.
About 30 percent of Caucasians, 40 percent of Africans, and more than 50 percent of Asians and Indians carry CYP2C19 gene variants that reduce response to drugs metabolized by the gene product. The CYP2C19 *2 and *3 variants account for the majority of reduced drug metabolism, while the *17 variant is associated with increased drug metabolism.
The availability of the test may change the way physicians choose and administer some of the aforementioned therapies, in particular clopidogrel.
"I think this represents an important step forward for use of clopidogrel in patients undergoing stenting," Eric Topol, director of the Scripps Translational Science Institute and chief academic officer of Scripps Health, told PCR Insider in an email.
Topol, who in the past has worked with Quest Diagnostics subsidiary Focus Diagnostics (PCR Insider, 3/17/2011) and DNA Electronics (PCR Insider, 3/22/2012) to develop and test rapid CYP2C19 genotyping platforms, added that "most centers do not do genotyping because there is a long time delay of multiple days and this rapid, point-of-care CYP2C19 genotyping approval — with both loss- and gain-of-function variants — should help override a key logistic obstacle."
Even though Topol referred to the Spartan RX CYP2C19 assay as a "point-of-care" test, it is not technically indicated for point-of-care use, according to the FDA. Instead, the assay must be used in a clinical lab by a trained technician. The assay is also not indicated to be used to predict drug response or non-response, FDA said.
"Companies seeking point-of-care claims perform studies to demonstrate that the typical users in point-of-care settings — [for example] nurses, et cetera — can perform the test and get reliable and accurate results," an FDA spokesperson wrote in an email to PCR Insider. "In this case, Spartan did not choose to seek a point-of-care claim."
The assay currently runs on the Spartan RX, a fully automated, endpoint PCR system that can identify the CYP2C19 variations from a patient's cheek swab in less than an hour with minimal intervention by the technician.
The workflow comprises swabbing the inside of a patient's cheek, placing the swab in a sample tube, scanning the test's barcode, placing the tube into the Spartan RX system, and pressing a start button on a linked laptop or netbook.
According to the company, the entire workflow takes less than an hour, which is faster than any other FDA-approved CYP2C19 genotyping test on the market. For instance, Nanosphere's Verigene CYP2C19 test identifies the CYP2C19 *2, *3, and *17 variations directly from a patient's whole blood sample in less than 2.5 hours, according to the company. Meantime, Autogenomics' Infiniti CYP2C19 assay contains a thermal cycling step of just under two hours, which is just one component of the overall workflow, according to the assay's package insert.
Still, it remains to be seen whether obtaining clinically actionable information in less than an hour will spur physician usage. Further, Spartan's test will still need to be performed in a hospital laboratory. That may change with future iterations of the platform, however. Lem told PCR Insider that "moving forward, we're working towards something the size of a coffee cup that we can connect to either a tablet or a smartphone." The current platform is about the size of a desktop printer, but a platform like the one Lem described would be more conducive to true point-of-care use.
Lem also said that Spartan is aiming to obtain a CLIA waiver for both the current and future versions of the platform, which would enable operation by relatively unskilled workers.
The current version of Spartan RX CYP2C19 received CE marking for in vitro diagnostic use in December 2010. Since that time, Spartan has signed on several distributors for the test in Europe, including the Germany subsidiary of Alere.
Lem declined to comment on the uptake of the platform thus far, noting that as a private company, Spartan does not generally disclose such sales figures.
However, he said that the company has been "really happy that key opinion leaders have really embraced CYP2C19 testing … [and] the evidence base is really building up now."
In December, Spartan announced the commencement of a 5,945-patient trial to study the use of Spartan RX CYP2C19 for personalized therapy in cardiac stent patients (PCR Insider, 12/20/2012).
The study, sponsored by the Center for Individualized Medicine at the Mayo Clinic, is "Tailored Antiplatelet Initiation to Lessen Outcomes due to Clopidogrel Resistance after Percutaneous Coronary Intervention," or TAILOR-PCI. The trial will evaluate whether genotyping cardiac stent patients at the time of angioplasty can help improve patient outcomes by informing providers about drug selection of either Plavix or ticagrelor, marketed by AstraZeneca as Brilinta.
Lem noted that this trial, which is slated to wrap up in June 2016, may serve as the ultimate tipping point for the use of rapid CYP2C19 genotyping as a common tool for guiding treatment with certain drugs metabolized by the gene product.
"When [an organization] like Mayo takes a look at the evidence base and say[s] this is really important, we're going to do a 6,000 patient trial with Spartan, that's really great momentum," Lem said. "We are hearing people say, 'Let things like the Mayo Clinic trial finish, and that will be the evidence that will be required to convince everyone to do this.' The medical profession is conservative by nature, and it makes sense. With the evidence base so far, it's enough for early adoption. But to really get widespread adoption, the Mayo Clinic trial is going to have to finish."
The FDA clearance may also open up other markets overseas, such as Korea and the Middle East, for Spartan, since FDA approval is a prerequisite for allowing marketing in those territories.
"One of the really big advantages of FDA clearance is, of course, it opens up the US, which is the most lucrative market. But it also opens up those other markets, and we have a waiting list of people who were ready to go as soon as we got FDA [clearance]," Lem said.
Of course, in order to fulfill these potential orders, Spartan may need to beef up its sales and marketing force, or strike a deal with additional distributors.
"We're definitely looking to expand," Lem said. "Now that we have FDA [clearance] we can go in, and there is reimbursement. We think there is a very exciting market in the US. In the early days we will use a mix of direct [sales] and distributors, and see which works best, then ramp it up from there."
Lem said that Spartan already has deals in place with additional distributors, but hasn't yet made those relationships public.