By Turna Ray
Clinical Data is working toward developing a new companion diagnostic test for the anti-platelet agent Plavix that will incorporate new gene markers and have an improved predictive value for drug response compared to existing tests on the market.
In the latter part of December, Clinical Data’s PGxHealth division inked a research collaboration with the German Heart Institute, Deutsches Herzzentrum, or DHZ, to “conduct one of the largest retrospective case/control studies to date to validate genetic variants associated with response” to Plavix, also known as clopidogrel. Sanofi-Aventis’ partner Bristol-Myers Squibb markets Plavix in the US.
“Our goal is to identify new genes that are predictive of clopidogrel response that will significantly improve the predictive value of the test,” Theresa McNeely, Clinical Data’s VP of corporate communications, told Pharmacogenomics Reporter via e-mail.
Last year, the US Food and Drug Administration updated the labeling for Plavix twice. The first labeling change informed healthcare providers that poor CYP2C19 metabolizers have limited response to Plavix [see PGx Reporter 06-17-2009]. The second update warned doctors and patients against the concomitant use of the anti-platelet agent and CYP2C19-inhibiting agents [see PGx Reporter 11-18-2009]. Both updates came with the caveat that additional study is necessary to further hone in on the link between CYP2C19 and clopidogrel metabolism.
Meanwhile, Quest Diagnostics last year began offering genetic testing for Plavix response in a Scripps Health hospital in California [see PGx Reporter 10-28-2009]. The move raised questions from researchers as to whether CYP2C19 testing should be broadly marketed without results from randomized controlled trials providing additional information on patient outcomes associated with testing, genomically guided Plavix dosing, and alternative treatments for CYP2C19-poor metabolizers.
Clinical Data is working with DHZ — a cardiovascular research center that has collected “a large cohort” of clopidogrel-treated patients who have undergone percutaneous coronary interventions — in hopes of gathering the clinical data that will heighten doctors’ confidence about the clinical utility of using pharmacogenomics to administer Plavix. Currently, DHZ has collected follow-up and platelet function data for a subset of patients who have experienced a “very low” cardiovascular event rate.
Patients who have undergone PCI and have a poor ability to metabolize Plavix may be at increased risk for cardiovascular events. Researchers from Clinical Data and DHZ will seek new gene markers and evaluate several known genetic variants, as well as Clinical Data’s proprietary markers, for their ability to determine which patients are at higher risk for cardiovascular events while treated with Plavix. As a second direct measure of Plavix response, researchers will also monitor platelet function of patients.
Preliminary data from the studies is anticipated later this year.
“By doing a retrospective analysis, we have the opportunity to include enough cases — such as patients that have suffered a cardiovascular event — to design a very highly powered study,” McNeely said. “Assuming that [researchers identify] new variants that are predictive clopidogrel response ... a prospective validation study is also planned.” McNeely added that although the exact size of the DHZ cohort is confidential, Clinical Data will select more than 600 cases and matched controls for the Plavix studies.
Currently, the CYP2C19*2 allele is the most well-established gene variant linked to clopidogrel response. Patients who have the wild-type allele or the CYP2C19*1 variant respond normally to the treatment.
Quest’s PCR-based companion diagnostic for Plavix response detects CYP2C19*2, *3, *4, and *5 variants. The test, which became available to customers in the Scripps Health system and to other Quest customers late last year, has saliva and blood-based versions.
Ultimately, the goal of Clinical Data’s research with DHZ is to develop a companion test under its PGxPredict brand. According to McNeely, Clinical Data’s test will be “differentiated from Quest’s and potentially others because it will incorporate other, new markers [that] have been demonstrated to be predictive of clopidogrel response.
“As we validate markers and potentially discover new markers, the predictive value of a potential test increases ... incrementally,” McNeely said. “Addition of new markers should more accurately predict response and therefore enable better treatment decisions/patient management.”
Those with mutated alleles in CYP2C19 that are linked to reduced Plavix response may require an increased Plavix dose or alternative treatments, such as the recently FDA-approved blood thinner Effient (Eli Lilly's prasugrel). However, the FDA has not issued PGx-guided dosing recommendations, awaiting data from ongoing studies.
Under its Genetics for Generics program, the pharmacy benefit manager Medco is offering genetic testing to its customers to encourage more efficient administration of Plavix [see PGx Reporter 10-7-2009]. Plavix will go off patent in November 2011.
Clinical Data did not estimate when it could potentially launch a PGxPredict:Clopidogrel. The company already markets PGxPredict:Clozapine, which gauges patients at risk of clozapine-induced agranulocytosis, and PGxPredict:Rituximab, which determines which patients are likely to respond to the follicular non-Hodgkin’s lymphoma treatment.
McNeely noted that Clinical Data is planning to launch a potential companion test for Plavix as a home-brew assay first, and possibly pursue FDA clearance for a test kit later on.