This article has been updated to clarify the information Spartan Bioscience plans to announce on upcoming studies.
A recent blinded trial by University of Ottawa researchers showed that Spartan Bioscience's point-of-care CYP2C19 test successfully identified patients carrying the CYP2C19 *2 allele associated with poor response to the anti-platelet therapy Plavix following a cardiac stent insertion.
The results of the study also indicated that the test could guide treatment with anti-platelet therapy in order to reduce levels of on-treatment platelet reactivity in patients.
The Ottawa group, which has worked with Spartan through the development of its CYP2C19 test, presented the data from the "Reassessment of Anti-platelet Therapy Using an Individualized Strategy Based on Genetic Evaluation," or Rapid Gene, study at the Transcatheter Cardiovascular Therapeutics conference in San Francisco earlier this month.
The study included 200 patients. It evaluated standard treatment with Sanofi-Aventis/Bristol Myers Squibb's Plavix (clopidogrel) with no genetic testing against immediate testing with Spartan's assay and a switch to Eli Lilly's Effient (prasugrel) for all patients testing positive for the CYP2C19 *2 allele. Over 30 percent of patients in the standard treatment group experienced poor response to Plavix, while none of those in the personalized arm had high platelet reactivity.
Because the study did not evaluate actual outcomes, the results only suggest, rather than demonstrate, that the Spartan test could lead to more effective, safer treatment, Derek So, the study's leader and an interventional cardiologist at Ottawa's Heart Institute, told PGx Reporter.
However, he said, the trial lays an important foundation for future outcome studies "in terms of showing that the test is possible and can be done without lab expertise."
"Is it enough at this point to alter clinical care? No, but I think it’s a first step," he said.
"An outcome study is absolutely the gold standard," Paul Lem, Spartan's founder, told PGx Reporter. "But that takes at least a year of follow up, and in order to have enough statistical power and a meaningful result you probably have to enroll 1,000 patients."
"So this is a first step with a proxy endpoint in preparation to do the big study," he said.
The US Food and Drug Administration in 2010 added a black box warning to Plavix highlighting mutations that affect the drug's metabolism, potential genetic tests by which these variants could be identified, and potential alternative dosing strategies or new medications for such patients.
At the time, most available tests had a turnaround time of up to a week. Acknowledging that doctors can't always wait for genetic test results, the agency noted in the warning that 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 (PGx Reporter 10/27/2010).
Since that time, a number of companies have begun developing rapid tests for Plavix response in an effort to speed the turnaround time. One factor fueling that development has been the emergence of Effient, Plavix's major competitor in the anti-platelet therapy market. Plavix is slated to lose patent protection in 2012, opening up a market for tests that can determine whether doctors can prescribe the lower-cost generic version of Plavix, reserving the more expensive Effient for those patients with CYP2C19 variants.
In addition to Spartan, Nanosphere has also been pursuing a point-of-care test called the Verigene CYP2C19 Plavix Metabolism Test. Earlier this year, however, following a negative decision from the FDA on a premarket approval application for the test, Nanosphere said it would delay its commercialization in the US (PGx Reporter 6/22/2011).
Lem said Spartan entered this race after being approached by So, who argued that a rapid test that could be run by untrained nurses was necessary to genomically guide anti-platelet therapy within the window of greatest risk for patients undergoing cardiac stenting — about 24 to 48 hours.
"If we can't have our answer within the first couple of hours, we can't change therapy when patients are at the higher risk of events, which is within the first couple of days," So said.
"Based on [national] guidelines," he said, "right now there is no endorsement of either using platelet function or genetic testing to alter [anti-platelet] therapy because there hasn't been a big clinical trial to prove the efficacy of this approach."
So said one of the main impediments to such a trial has been the lack of an appropriate point-of-care test. "So this could really be a first step," he said.
So's team at the University of Ottawa participated in the development of the Spartan test and then embarked with the company on the Rapid Gene study, which enrolled 200 patients that were undergoing stenting either for acute coronary syndrome or stable coronary disease.
The researchers assigned patients at the time of their stenting or immediately afterwards to one of two study arms in a one-to-one ratio. One group received standard therapy — a continuation of the standard-of-care 75 mg Plavix dose. The other group received rapid genotyping with the Spartan device. Those who were positive for the CYP2C19 *2 allele were switched to 10 mg of Effient while those who were negative continued their Plavix treatment.
In the study, the Spartan RX-CYP2C19 assay proved its rapidity, So said. Testing — performed by nurses who received a 30-minute training session but had no prior laboratory training — took an average of one hour from taking a buccal swab sample to getting a reading on the patient's CYP2C19 *2 carrier status.
The test had a sensitivity of 100 percent and a specificity of 99.4 percent compared with DNA sequencing, Spartan reported.
The team measured platelet function using the VerifyNow P2Y12 Assay at baseline, and then after seven days, for all patients, comparing the P2Y12 reactivity units value at both time points for both arms of the study.
At the one-week mark, more than 30 percent of patients in the unguided arm had "high" on-treatment platelet reactivity, measured as a PRU greater than 234, while none of those in the tested arm had PRU over this cutoff point.
"What we were able to show is that at day seven with the personalized therapy, there were no patients in the rapid genetic group who continued to have impaired response to the anti-platelet regimen," said So, suggesting a beneficial effect of switching to Effient for those carrying problematic mutations. "Whereas in the standard therapy group over 30 percent of the patients still had ongoing impairment of their response to anti-platelet drugs," he said.
Medco is currently conducting a head-to-head study of Plavix and Effient called the Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcome Study, or GeCCO, which is measuring how genetics impacts patients' response to these drugs. In GeCCO, Medco researchers will compare outcomes of “extensive metabolizers” of Plavix with patients taking Effient (PGx Reporter 10/21/2009).
Newer Isn't Always Better
While patient outcome wasn't an endpoint of the Rapid Gene study, the researchers did note that there was some difference in outcome between the two arms: a numerical, though not statistically significant, increase in bleeding for the rapid genotyping group, mostly in patients taking Effient, but also in at least one patient on Plavix, according to the group's presentation.
This is important, So said, because "there are lots of people out there, especially drug companies, that would like to advocate that doctors forget Plavix, forget the whole drug, and use the newer generation, such as Effient."
However, for drugs like Effient that have been linked to increased bleeding risk, a study like Rapid Gene "highlights the whole concept of personalized therapy, meaning, we try to identify the people that respond to the less potent drug and spare them the possible bleeding risk, and at the same time, for people who are non-responders, give the more potent medicine so they are protected."
Spartan is now in the process of seeking FDA approval for its test, which received a CE IVD Mark in the European Union in late 2010.
Lem said that Spartan had a "pre-IVD meeting" with FDA in August. "We thought it went quite well, and now we're working as hard [and] fast as we can to get 510(k) clearance," he said.
He also said the company plans to compare its test to Autogenomics' FDA-cleared non-point-of-care Infinity system, which gauges the *2, *3, and *17 SNPs in the CYP2C19 gene, as a predicate for 510(k) approval.
The company's goal, "if everything works out OK," is to receive approval by the agency next year, he said.
According to Lem, the FDA wants Spartan to conduct a separate evaluation of the test's accuracy in detecting the CYP2C19 mutations it claims to measure, and the company is making plans for this now.
So's team also has plans for additional validation of the test. In the Rapid Gene study, the Ottawa researchers tested only for the *2 risk allele, but according to So, the researchers now plan to evaluate a more recent version of the assay that interrogates three variants: CYP2C19 *2, ABCB1 3435 TT, and the CYP2C19 *17 gain-of-function allele.
"It's essentially moving from a pharmacogenetics to a pharmacogenomics approach," So said.
In this next study, the group will also be working with higher risk patients immediately after they have suffered an infarction, he said. "From a cardiology perspective, this will demonstrate we can [successfully tailor treatment] in the sickest of the sick patients, while making decisions based on multiple SNPs rather than just one."
Additionally, Lem said, Spartan plans in the next few months to announce several larger studies using the company's test that will have more direct outcome information.
"We are working with various [investigators] on big studies with thousands of patients, and that will start coming out from us in the next few months," he said. He did not detail when this additional data would be presented, or which research groups will participate.
Lem also said the test's speedy performance in the Ottawa study should help distinguish it from competing assays as the company works toward regulatory approval in the US.
"You look at all the competitors out there, Nanosphere for example," he said. "Their [assay] takes three hours to run and needs a trained technician. And at the end of a three-hour run, they have a ten minute window to read the results. If you're not right there after three hours, you have to repeat the test."
"We think the most important thing for this [study] was that it was nurses running this at the point of care," he said.
According to Lem, when the Ottawa researchers presented their results at the conference, the response was enthusiastic. "Several investigators came up and said this is a big advance," he said.
In a recent European multi-center study published in the Journal of the American Medical Association, researchers reported that a combination of clinical features and genetic testing results was better than genetic or clinical factors alone at gauging which patients treated with the Plavix after a coronary stent procedure were at higher risk of dangerous side effects (PGx 11/2/2011).
So agreed that a combined approach makes sense. "I think the future of this field will be essentially doing a quick test that gives a panel of potential risk variants and making decisions based on the whole panel … and I think for sure combining with clinical [factors] has to be the future," he said.
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