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Ahead of Pending Studies on PGx-Based Plavix Administration, Is Quest/Scripps CYP2C19 Testing Alliance Premature?

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By Turna Ray

WASHINGTON, DC — Quest Diagnostics' partnership with Scripps Health to offer CYP2C19 testing to stent procedure patients prior to treatment with the anti-platelet agent Plavix may be premature pending randomized controlled trials investigating the patient outcomes associated with testing, genomically guided Plavix dosing, and alternative treatments for CYP2C19 poor metabolizers, presenters at a conference on personalized medicine suggested this week.

Earlier this month, Quest announced the launch of a CYP2C19 testing service for stent procedure patients before receiving Plavix (clopidogrel) at Scripps Green Hospital in San Diego. According to Quest, Scripps Health is "the first health system in the US to deploy this genetic testing service for coronary stent patients" receiving Plavix.

According to Alan Shuldiner, a professor at the University of Maryland Medical Center who has conducted pharmacogenomics studies on Plavix, Quest’s decision to commercially introduce the test "falls a little short" since it was not done in the context of a clinical trial and the benefit of alternative medical strategies for CYP2C19 poor metabolizers have not been confirmed in randomized controlled trials.

Once patients are tested, "it is up to the doctors to determine what to do," Shuldiner said at a personalized medicine meeting this week hosted by the American Association for the Advancement of Science. "They can do nothing at all or prescribe other treatments."

In a statement, Quest noted that patients who test positive for the mutated alleles "may receive alternative treatments based on a variety of factors," including increased monitoring, an increased dosage of clopidogrel, or the use of alternative therapies, including treatment with Effient."

However, the validity of these other treatment options, particularly the suggestion to increase Plavix dosing, has not been studied in clinical trials, Steven Averbuch, head of pharmacodiagnostics at Bristol-Myers Squibb, pointed out during the AAAS meeting

The labeling for Bristol-Myers Squibb/Sanofi-Aventis' Plavix was recently updated by the US Food and Drug Administration to inform doctors and patients that poor CYP2C19 metabolizers have diminished response to the drug and increased risk of heart attack [see PGx Reporter 06-17-2009].

However, the FDA has held off on PGx-guided dosing recommendations until the completion of relevant studies, the agency has said.

Effient, a competitor to Plavix, was approved by the FDA in 2009 and is marketed by Eli Lilly. Effient carries a boxed warning on its label warning doctors and patients of fatal bleeding events associated with the drug.

Reimbursement Questions

For Quest, patients receiving stent procedures represent a sizeable market in which to introduce its test. The company estimates that the majority of the one million patients who undergo stent procedures in the US annually receive Plavix to help prevent blood clots.

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However, according to Shuldiner the test is not widely reimbursed by insurance companies. "Data from randomized-controlled trials will be required before payors begin reimbursing for the test," he said at the AAAS meeting.

According to a Quest spokesperson, the maximum amount that Medicare would reimburse Quest for performing the test for a Medicare beneficiary is around $200.

"Coverage for any test depends on many factors, including the health plan and the nature of a patient's coverage," the spokesperson added.

CYP2C19 testing ranges from between $200 to $400. The Quest spokesperson did not provide the price of its CYP2C19 test.

Quest’s saliva-based CYP2C19 gene test detects mutations through amplification of selected exons of the CYP2C19 gene by multiplex PCR, then by single nucleotide primer extension, and finally by detection of fluorescent extension products on an automated DNA sequencer. The test is able to gauge whether a stent procedure patient has the wild-type or CYP2C19*1 allele and will metabolize Plavix normally, or is at increased risk of cardiac events due to the presence of the CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5 alleles.

Quest claims it is the first national laboratory to combine testing for the normal version of the CYP2C19 gene and four mutations that appear in the genetics of 90 percent of Caucasians and 99 percent of Asians who are poor metabolizers of clopidogrel.

According to the studies, between 20 percent and 25 percent of patients receiving Plavix are resistant to the drug due to polymorphisms in CYP2C19.

"Our collaboration with Quest Diagnostics represents a landmark program in individualized medicine, based on considerable new data and new choices for one of the most commonly prescribed medications and medical procedures in the world," Eric Topol, chief academic officer of Scripps Health, said in a statement.

This isn’t the first time Scripps has invested in genomics-guided personalized medicine efforts. Scripps Translational Science Institute last year launched a long-term study with Navigenics, Affymetrix, and Microsoft investigating the behavioral effects of personal genetic testing. Collaborators plan to offer genetic scans to up to 10,000 Scripps Health system employees, family members, and friends to determine whether participating in personal genomic testing spurs individuals to make beneficial lifestyle changes such as improving their diet and exercise regimes [see PGx Reporter 10-09-2009].

Additional Studies

Shuldiner earlier this year published in the Journal of the American Medical Association a genome-wide association study confirming the CYP2C19*2 allele’s association with Plavix response [see PGx Reporter 08-26-2009]. At the time the study was published, Shuldiner told Pharmacogenomics Reporter that his team is planning a prospective RCT comparing genotype-directed anti-platelet therapy to standard-of-care anti-platelet therapy.

Shuldiner’s group is also working with other groups to discover new variants linked to Plavix response, in the Clopidogrel Pharmacogenomics Consortium. The consortium is open to all investigators and clopidogrel research groups who wish to participate.

One study that might further drive adoption of PGx-guided Plavix administration is a study currently being conducted by the pharmacy benefit manager Medco.

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As part of its Genetics for Generics program, Medco is planning a comparative effectiveness study of Plavix and the more expensive Effient to assess whether it will be clinically useful and cost-effective to genetically test Plavix patients to establish their CYP2C19 status [see PGx Reporter 10-21-2009].

The Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study will enroll more than 14,000 acute coronary syndrome patients who have been newly prescribed either Effient or Plavix, and compare the efficacy of these drugs by measuring the rate of cardiovascular deaths, nonfatal heart attacks, and nonfatal strokes. Patients will be followed for six months.

The Quest spokesperson would not say whether the company would collect data or conduct studies within the Scripps system that would further inform the genomic underpinning of Plavix metabolism.

"We are working with Scripps Health on a number of R&D collaborative projects in the area of genomic testing and cardiovascular disease," the Quest spokesperson told Pharmacogenomics Reporter. "However, we are not providing details on these specific projects at this time."

Driving Physician Adoption

When discussing barriers to personalized medicine, a difficult reimbursement environment, a dearth of prospective, randomized controlled trials on the clinical utility of PGx tests, and the lack of physician education are always at the top of the list.

Many argue that one way to educate physicians and get them comfortable with genetic tests is through programs such as the one for CYP2C19 testing service promoted by Quest and Scripps.

At the AAAS meeting, in response to a question about the best way to educate physicians about personalized medicine, Mark Ratain of the University of Chicago responded that adoption and education should begin with "a subset of physicians" who are interested in genomic medicine and are willing to be early adopters.

Earlier this year, El Camino Hospital partnered with DNA Direct to offer genetic testing and consulting services through its Genomic Medicine Institute. The partners noted that the affluence and technological savvy of the Silicon Valley community the hospital serves was a major factor in the decision to begin offering genomic services [see PGx Reporter 04-01-2009].

Green Hospital serves residents of La Jolla and adjacent communities. La Jolla residents are highly educated and rank among the top 1 percent of the US population economically.

Being one of the first US hospitals to offer CYP2C19 testing for stent procedure patients isn’t necessarily out of the ordinary for Green Hospital, as it prides itself on being the "first" to introduce new technologies to its communities. According to Scripps, the hospital has "offered a variety of medical ‘firsts’ — including San Diego’s first liver transplant program and one of the nation’s first hospitals to provide stem cell transplants."

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