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'Not Approvable' Letter Thwarts Nanosphere's Hopes to Launch FDA-Approved Plavix PGx Test


Originally published June 21.

This article has been updated on June 22 with comments from a Nanosphere official and analyst quotes.

By Turna Ray

Following a negative decision from the US Food and Drug Administration on a premarket approval application for its Verigene CYP2C19 Plavix Metabolism Test, Nanosphere said it will delay the commercialization of the test in the US.

"The issuance of the [FDA 'not approvable'] letter means that the company will encounter a delay in its plans to commercialize this product in the US," Nanosphere said in a statement. "The initial US revenue ramp from this product will likely not commence until 2012."

Nanosphere filed its PMA application in August 2010, which received expedited review status from the FDA. According to Nanosphere, the deficiencies noted in the agency's letter "are resolvable" and it plans to provide additional data to the agency regarding its application. Although the company is hoping that its PMA will eventually be approved by the FDA, "there can be no assurance of such approval," Nanosphere said in a statement.

According to Nanosphere CFO Roger Moody, FDA's letter listed additional data and studies that are required "before [the agency] can continue the process of reviewing the PMA submission."

Meanwhile, Nanosphere is already selling a version of the Plavix Metabolism Test in various European regions with a CE marking, and is planning to expand the test's market in new European and Asian markets before year end.

Nearly four years ago, Nanosphere held the distinction of being the first company to receive FDA approval for a warfarin sensitivity test. The company's Warfarin Metabolism Nucleic Acid Test also runs on its Verigene platform and detects variants in the CYP2C9 and VKORC1 genes (PGx Reporter 09/26/2007).

Since 2007, however, FDA's requirements for phamacogenomic tests ─ both diagnostics that are developed simultaneously with a new drug and those tests that are developed after a drug comes on the market ─ have evolved.

AutoGenomics' experience seeking clearance for its own CYP2C19 test suggests that the agency has likely raised the bar for the evidence needed to establish the clinical validity of a PGx test. Last year, the FDA 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 will 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 be required in order for it to receive approval as a Plavix PGx test (PGx Reporter 10/27/2010).

According to Moody, Nanosphere followed FDA's guidance documents, and submitted data that "was commensurate with the requirements for a PMA, including analytical studies, method comparison data, reproducibility data, and other studies."

Nanosphere's website notes that it is developing two versions of the Verigene CYP2C19 Test: one that is available for investigational use, and provides "broad coverage of potentially clinically relevant CYP2C19 alleles: *1A wild-type, *2A, *3, *4, *5A, *6, *7, *8, *9, *10, and *17." A second version of the test is in late-stage development for clinical use and gauges three CYP2C19 alleles: *1A wild-type, *2A, and *3.

The Verigene system is a benchtop molecular diagnostics workstation that utilizes a patented gold nanoparticle technology to gauge nucleic acids and proteins in a patient's sample. "Our test currently on the market in Europe does include an additional allele that the FDA will not currently consider for inclusion in the US," Moody said in an e-mail. "The originally developed assay contains all of the relevant alleles listed in the Plavix label warning, but our PMA submission is currently only for those the FDA deems to have sufficient clinical evidence to support. As additional clinical evidence is developed (broadly in the market) for inclusion of other alleles, we believe our multiplexing capability will enable us to offer a more comprehensive assay."

Although the FDA has included a "black box" warning on Plavix's label informing doctors and patients of the availability of genetic tests that assess a patient's CYP2C19 genotype to identify poor metabolizers, the agency has so far not approved any test specifically indicated to gauge best responders to the drug. The genetic testing recommendation in the drug's label leaves it up to the doctor to decide when to use a genetic test to guide decision making.

Similarly, the FDA-cleared indication for AutoGenomics' Infiniti CYP2C19 Assay is broad enough that doctor could certainly use it, alongside other tools and clinical data, to gauge best responders to Plavix and other drugs. 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."

Nanosphere has chosen not to follow Autogenomics' path. Moody confirmed that Nanosphere is seeking an FDA-approved indication for its test where the test's label will specifically note that it can be used to guide therapeutic decisions with Plavix.

Unfortunately, the "not approvable" letter may have taken Nanosphere by surprise.

Earlier this month, at the 2011 Jefferies Global Healthcare Conference, Moody appeared optimistic that Nanosphere would be able to launch the first FDA-approved Plavix PGx test. As reported by PGx Reporter sister publication GenomeWeb Daily News, Moody didn't give a timeline on when Nanosphere anticipated an FDA approval for the test, but said that he expected the company to have the first test approved in the US for evaluating whether a patient is successfully metabolizing the anti-platelet drug.

Other non-FDA-cleared, laboratory-developed CYP2C19 assays currently being marketed as 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, and Spartan Bioscience markets the Spartan RX CYP2C19 test for research use only.

Eric Topol, a geneticist, cardiologist, and the chief academic officer at Scripps Health, previously speculated that physician adoption of genetic testing to guide Plavix therapy is outpacing regulation. "The FDA approval doesn’t make a difference at this point," Topol told PGx Reporter after AutoGenomics received 510(k) clearance for its CYP2C19 test.

Cardiologists at the Scripps Green Hospital, with guidance from Topol, 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 project to develop a point-of-care 20-minute genotyping test, according to Topol.

Nanosphere believes, however, that there is a market advantage to launching the first FDA-approved Plavix PGx Test. One way to differentiate Nanosphere's test from other marketed tests is "by seeking approval for the PMA, which will carry an intended use to guide decision making regarding the dosing of Plavix," Moody said.

Upon news that Nanosphere had received the "not approvable" letter for the Plavix PGx test, analyst Jon Wood of investment bank Jefferies lowered 2011 and 2012 revenue forecasts for the company, from $4.5 million to $3.3 million, and $17 million to $9 million, respectively.

"While the near-term financial impact appears manageable, the event may spark concerns over the value of Nanosphere's sizable (though distant) pipeline, where the bolus of its enterprise value seems concentrated," Wood wrote. "Further, the setback could inhibit its ability to place new instruments with customers and impair its installed base growth trajectory, given what we perceive as few significant pipeline milestones until 2012."

Even though the FDA has apparently set a high regulatory hurdle for the company, Wood characterized Nanosphere's PMA as "salvageable" if it successfully fulfills the agency's study requirements.

On June 21, the day Nanosphere announced the negative regulatory decision, the company's stock fell nearly 24 percent to close at $1.64.

Nanosphere shares were trading at $1.56 in mid-morning trading on June 22 as PGx Reporter went to press.

Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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