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AutoGenomics Gets FDA Clearance for CYP2C19 Test, But Cannot Mention Plavix PGx

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By Turna Ray

Although AutoGenomics has garnered clearance from the US Food and Drug Administration for its Infinity CYP2C19 Assay — which gauges the *2, *3, and *17 SNPs in the gene — the test's label makes no mention of its use as a pharmacogenetic test to administer Plavix.

AutoGenomics announced this week that it received 510(k) clearance from the US Food and Drug Administration to market its Infiniti CYP2C19 Assay.

According to the FDA-cleared labeling for the assay, which will run on AutoGenomics' multiplex, random-access microarray platform, called the Infiniti Analyzer, the test is "indicated for use as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP450 2C19 gene product, specifically *2, *3, *17."

Although several studies have shown that carriers of these alleles do not respond to Plavix as well as non-carriers, and the FDA has updated the drug's label to notify physicians of the role of these alleles in Plavix metabolism, the label for AutoGenomics' CYP2C19 assay specifically notes that it "is not intended to be used to predict drug response or non-response."

Similarly, Roche's FDA-cleared AmpliChip can also gauge alleles in CYP450, but it is not indicated for making go/no-go decision on specific drugs. The agency has recently indicated that for a diagnostic to garner a labeling claim indicating it can predict which patients will respond to a specific drug, the manufacturer will have to submit data analyzing samples from patients treated with that particular drug.

"AutoGenomics provided sufficient data to demonstrate analytical validity of the test and provided literature data to demonstrate that there are links between the SNP detected and level of enzyme activity in metabolizing drugs through the CYP450 2C19 pathway," FDA spokesperson Erica Jefferson told PGx Reporter this week. "The FDA has not cleared or approved any Plavix PGx [test], including this one.

"The data provided supported the intended use cleared," Jefferson added. "If the sponsor wants to claim this test as a Plavix PGx [assay] the sponsor will need to submit that claim for review with sufficient data for the agency to determine its safety and efficacy."

FDA's clearance of AutoGenomics' test follows the agency's addition of a boxed warning to the anti-platelet drug's label alerting physicians that patients with diminished CYP2C19 function, or poor metabolizers of the drug, are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention than normal metabolizers of Plavix. The labeling, updated in March, also informs doctors that there are tests on the market that identify patients' CYP2C19 genotype, which "can be used as an aid in determining a therapeutic strategy" (PGx Reporter 03/17/10).

When FDA issued the black box warning for Plavix, agency officials acknowledged that depending on the urgency of their patients' medical condition, doctors can't always wait for genetic test results. According to labeling language, it is up to doctors to determine when they should genetically test patients before Plavix administration, or if they should see how patients react to a particular dose of Plavix and then decide whether to switch to another drug depending on the outcome.

In the press release announcing the clearance of the Infiniti CYP2C19 assay, AutoGenomics makes no mention of the test's use to guide Plavix therapy. Still, in clinical practice, it is likely that cardiologists will use the test to help determine treatment strategies for cardiac patients receiving the antiplatelet drug.

Recently published studies on the CYP2C19*17 SNP suggest that patients with this gain-of-function allele derives greater benefit from Plavix. Meanwhile, CYP2C19* 2,*3,*4,*5,*6,*7 and *8 loss-of-function alleles have shown in clinical studies to be linked to a greater risk of ischemic events and stent thrombosis.

Elusive Advantages

"The necessity of this genetic test has been implicated in literature now for several years," AutoGenomics CEO Fareed Kureshy said in a statement announcing the assay's clearance. However, the company did not specify in which disease settings or for which therapeutics the CYP2C19 *2, *3, and *17 SNPs are implicated in published data.

AutoGenomics is entering a market crowded with laboratory test providers that perform CYP2C19 testing, which doctors are using to make therapeutic decisions involving Plavix. As such, the fact that AutoGenomics cannot outright market its assay as a PGx test for Plavix administration means that the FDA approval is unlikely to provide a competitive advantage for the company.

According to cardiologist and geneticist Eric Topol, "The FDA approval doesn’t make a difference at this point." He told PGx Reporter this week that there are as many as 20 laboratories offering CYP2C19 genotyping services.

Other non-FDA-cleared, laboratory-developed CYP2C19 assays currently being marketed as pharmacogenetic tests to guide Plavix therapy include Quest's AccuType CP, which gauges the *2,*3,*4, and *5 alleles. Roche also markets the PCR-based LightTyper Genotyping System, which can test for alleles in various CYP450 genes.

In a statement announcing the FDA clearance of its assay, AutoGenomics highlighted that the Infinity CYP 2C19 test is "unique in evaluating *17, which can help clinicians identify ultra metabolizers."

Lab-developed CYP2C19 tests for Plavix administration are estimated to cost around $500. AutoGenomics did not respond to questions for this article.

Point-of-Care Competition

As the chief academic officer at Scripps Health, Topol has been a strong proponent of PGx testing for Plavix in cardiac patients who have undergone stent procedures. Plavix is given to patients after a coronary artery stent procedure to reduce the risk of sudden death from blockages in the artery. As such, gauging CYP2C19 loss-of-function alleles can help cardiologists predict which patients will not respond to Plavix after stent procedures.

Cardiologists at the Scripps Green Hospital have adopted genetic testing to guide treatment with the anti-platelet drug and conduct CYP2C19 genotyping through a number of labs, including Quest. In addition, Scripps has started "a point-of-care 20-minute genotyping project," Topol said.

"We are using [the point-of-care] test for the patients who are going to have a stent procedure to determine the loading dose of Plavix," he added. "For this purpose it appears to be very helpful." Scripps plans to report more information from this project as the data mature.

There are several companies developing point-of-care PGx tests for Plavix. When these tests come on the market, they will likely pose stiff competition for laboratories and diagnostic developers providing standard CYP2C19 genotyping services with turnaround times of up to a week.

For example, Spartan Bioscience announced in August that researchers at the University of Ottawa Heart Institute are using its Spartan RX point-of-care testing system to gauge CYP2C19 mutations that may impair cardiac patients' response to Plavix (PGx Reporter 08/11/10).

Similarly, Nanosphere's investigational Verigene point-of-care CYP219 test is being used by the Center for Thrombosis Research at Sinai Hospital of Baltimore in a study to identify which patients are at risk for a cardiac event after coronary stenting.

At this point, Spartan's platform, which boasts a one-hour turnaround time, is available for research use only. Nanosphere's investigational-use-only point-of-care test gauges a large number of CYP2C19 SNPs and can return results in "a matter of hours."

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