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FDA Clears Nanosphere's CYP2C19 Test to Guide Therapeutic Strategy, Not Predict Response

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The US Food and Drug Administration has granted 510(k) marketing clearance for Nanosphere's CYP2C19 mutation test for use in guiding treatment with drugs metabolized by the CYP450 2C19 genetic pathway, including the antiplatelet agent clopidogrel.

The test, which will run on the company's Verigene System, detects whether patients have CYP2C19 *2 and *3 variants, which make them more likely to respond poorly to drugs metabolized by the CYP450 2C19 genetic pathway. The test also gauges the CYP2C19 *17 variant, which studies have shown to enhance patients' response to such drugs compared to those who don't have this marker.

In a statement, Nanosphere noted that the CYP2C19 enzyme metabolizes around 15 percent of prescribed drugs, such as the antidepressant amitriptyline, the anti-epileptic phenytoin, proton pump inhibitors such as lansoprazole, and clopidogrel. The price of the test is $75, the company said.

The FDA indicated that the test, marketed as the Verigene CYP2C19 Nucleic Acid Test, be used "in clinical laboratories upon prescription by the attending physician as an aid to clinicians in determining therapeutic strategy for therapeutics that are metabolized by the CYP450 2C19 gene product, specifically *2, *3, and *17."

The agency states, however, that "the Verigene CYP2C19 Nucleic Acid Test is not indicated to be used to predict drug response or non-response." The test results are meant to "supplement" doctors' decision making, the agency adds, advising physicians to routinely monitor patients for whom they have used CYP2C19 test results to inform treatment strategies.

The FDA does not specify any drugs metabolized by the CYP450 2C19 pathway for which the test should be used. "Because of the variability in the knowledge of clinical utility with specific drugs that are metabolized by CYP2C19, clinicians should use professional judgment in the interpretation of results from this test," it states in its clearance determination.

In order to gain clearance for the CYP2C19 test, Nanosphere submitted data analyzing 670 whole blood samples by the Verigene platform and compared the results to bi-directional sequencing. In this study, the "samples were deidentified and the individuals' therapeutic drug history and status was not collected or reported," a Nanosphere spokesperson said. The concordance between the two platforms was 99.6 percent.

Not Just Plavix

Nanosphere previously sought FDA approval for a molecular diagnostic to specifically gauge best responders to clopidogrel, known by the brand name Plavix. Last year, Nanosphere received a negative decision from the FDA on its marketing application for the so-called Verigene CYP2C19 Plavix Metabolism Test. Following the "not approvable" letter from the FDA, Nanosphere said it would delay development of the test (PGx Reporter 6/22/2011).

William Moffitt, president and CEO of Nanosphere, told PGx Reporter this week that the CYP2C19 test and the original Plavix test are "analytically the exact same test," though they measure different alleles. While the CYP2C19 test measures the *2, *3, and *17 variants, the clinical version of the Plavix assay measured *1A wild-type, *2A, and *3, while an investigational-use version of the Plavix test measured *1A wild-type, *2A, *3, *4, *5A, *6, *7, *8, *9, *10, and *17.

Moffitt said that the FDA considered the Plavix-branded test a companion diagnostic for clopidogrel and therefore would have required premarket approval for it. Instead, Nanosphere elected to "go back through the 510(k) route" with an assay to detect CYP2C19 mutations associated with metabolism of a broader spectrum of drugs.

While the FDA's label for the test stops short of saying that it can be used to guide treatment with Plavix, Moffitt noted that this "doesn't matter very much," since most customers already "understand what the assay does and how to use it."

Similarly, the FDA two years ago granted 510(k) clearance to AutoGenomics' Infinity CYP2C19 Assay, but the test's label did not specifically mention that it could be used as a pharmacogenetic test to predict which patients would likely respond to Plavix. An FDA spokesperson told PGx Reporter at the time that AutoGenomics submitted data to demonstrate the analytical validity of the test, and that more evidence on the safety and efficacy of the test would have been required in order for it to receive approval as a Plavix PGx test (PGx Reporter 10/27/2010).

Although the FDA has included a "black box" warning on clopidogrel's label informing doctors and patients that those harboring certain loss-of-function CYP2C19 variants are likely to be poor metabolizers, the agency has so far not approved any test that physicians can specifically use to make go/no-go decisions for treatment with the drug. The label only states that "tests are available to determine patients' CYP2C19 status."

Clopidogrel, which recently became a generic, is facing competition from several branded agents, such as Eli Lilly's Effient, which aren't affected by CYP2C19 genotypes. Some healthcare providers view CYP2C19 testing as a way to save money since they can provide the cheaper generic clopidogrel for best responders and the pricier branded agents for poor CYP2C19 metabolizers.

Although the majority of the available clinical data on CYP2C19 testing suggests that it is useful particularly in patients who have undergone a stent procedure, there has been conflicting data from meta-analysis studies that challenge the notion that CYP2C19 poor metabolizers have a worse outcome compared to normal metabolizers of the drug (PGx Reporter 3/28/2012). As a result, some healthcare providers have resisted adopting genetic testing in this setting, arguing that the clinical utility of CYP2C19 genotyping for clopidogrel hasn't yet been proven.

While the clinical evidence for CYP2C19 genotyping is still evolving, the FDA is likely being cautious in green-lighting a test that would be used as the sole determinant of whether to administer clopidogrel. "Results from this type of assay should not be used in predicting a patient's response to drugs for which the drug metabolizing enzyme activity of the allele, or the drug metabolic pathway, has not been clearly established," the FDA notes in its review of Nanosphere's test.

Speedy Results

Additionally, broad adoption of CYP2C19 testing has been slowed by lengthy turnaround times for getting test results back to physicians. Nanosphere highlighted that its test can analyze patients' blood samples in two and a half hours, a feature that may make the test useful in treatment planning for patients with acute conditions.

A potential competitor to Nanosphere in this space may be Spartan Bioscience, which has garnered CE IVD self certification in the EU for its Spartan RX CYP2C19 point-of-care test. That test boasts a turnaround time of around one hour. The company is in the process of conducting the necessary trials to validate the test, and previously said it is shooting to garner FDA's okay this year (PGx Reporter 11/30/2011).

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