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Celera IDs Gene Variant for Coronary Heart Disease; Launching Dx In Coming Months

Celera in the coming months plans to launch a genetic test designed to identify individuals with an increased risk of developing coronary heart disease, and who can benefit from statin therapy. 
The company has published three studies in the Journal of the American College of Cardiology showing that a variant of the KIF6 gene confers a 55-percent increased risk of developing CHD. in the showing that a variant of the KIF6 gene confers a 55-percent increased risk of developing CHD.
However, this heightened risk was “virtually eliminated” when individuals with the mutation were treated with pravastatin, marketed by Bristol-Myers Squibb as Pravachol.
Also, in these studies of acute coronary syndrome patients, high doses of Pfizer’s Lipitor, also known as atorvastatin, reduced the risk of developing CHD among carriers of the KIF6 variant more effectively than moderate-dose therapy with Pravachol.
“The increased risk of clinical events observed in KIF6 carriers and its reduction by statin therapy was independent of other well-known CHD risk factors, including smoking, hypertension, cholesterol level, age, and sex [and] further [supports] the conclusion that a KIF6 gene variant is a new, independent predictor of risk for CHD and clinical benefit from statin therapy,” Celera said in a statement this week.
According to the study researchers, patients with the KIF6 gene variation treated with a statin are on average less than 30 percent less likely than noncarriers to develop CHD. Celera’s three studies followed more than 30,000 people, and together, represent one of the largest pharmacogenetic investigations to date linking KIF6 to statin response.
However, in an editorial accompanying the three published studies, Ali Marian of the Texas Heart Institutes’ Center for Cardiovascular Genetics writes that "these studies collectively raise interest in KIF6 as a possible candidate gene in susceptibility to myocardial infarction, coronary atherosclerosis, and response to statins. They have considerable strengths, including the relatively large sample size of the study populations, carefully phenotyped participants, and concordant findings in separate databases. Nonetheless, the results at best should be considered provisional, pending validation through experimentation."
Other researchers have acknowledged the potential in Celera’s studies, but have noted the need for independent validation of the company’s findings before the KIF6 SNP is utilized commercially to predict CHD risk or assess statin benefit. 
Regardless of the study’s detractors, Celera is moving ahead with developing a KIF6 in vitro diagnostic kit that it plans to take through the US Food and Drug Administration. In the meantime, Berkeley Heartlab, a CLIA-certified laboratory that Celera acquired in October, will develop a homebrew test for the KIF6 variant. The company expects to launch that assay in the coming months.
“Part of the rationale for acquiring Berkeley Heartlab was that they have a sales force focused on the cardiovascular space, and we have a series of new genetic findings that could be the basis for new diagnostic tests,” Celera President Kathy Ordoñez told Pharmacogenomics Reporter this week. “We have licensed our findings in the cardiovascular space, specifically the KIF6 finding, to Berkeley Heartlab and they have been working on a laboratory developed test for the KIF6.”
The Tests
The platforms for the first- and second-generation tests will “slightly differ,” according to Ordoñez. The homebrew assay being developed by Berkeley Heartlab runs on a real-time PCR platform with a custom extraction procedure developed at the lab. The IVD test Celera is developing, meantime, would “be packaged in a way that virtually any laboratory can use it.”
“The important thing is that carriers are not only at greater risk but that statins lower the risk, especially well compared to noncarriers,” Frank Sacks, professor of cardiovascular disease prevention at Harvard School of Public Health, and the senior author of one of the papers, said in a statement.
“Since reduction in LDL does not explain the KIF6 effect on cardiovascular disease, a KIF6 test could give physicians new information to identify patients in whom statins work particularly well,” Sacks added. “This is really personalized medicine based on genetics for a common condition.”
Moreover, since the KIF6 variant can identify CHD risk independent of other risk factors, a genetic test could potentially improve compliance for statin therapies, which has been traditionally low.
“We believe that knowing your KIF6 status could become a routine risk factor, like today when your physician monitors your blood pressure or looks at your LDL cholesterol level, or considers your age or gender and other risk factors in determining whether you should be on a statin,” Ordoñez said. “So this may identify people whose cholesterol level may be normal but have one or two of the other risk factors and push them over the edge so that their doctor may consider the prescription of a statin.”

“The important thing is that carriers are not only at greater risk but that statins lower the risk especially well compared to noncarriers.”

Additionally, since in clinical trials approximately 60 percent of participants were carriers of the KIF6 risk variant, a genetic test that identifies best responders can potentially be a financial boon for Bristol-Myers Squibb and Pfizer, the makers of the two blockbuster statins studied by Celera.
According to Celera, KIF6 testing would probably cost patients around $200. For high-dose 80 mg Lipitor, as used in one of the published studies, the yearly cost for the drug can be as high as $1,400.
“Knowledge that the elevation in heart disease risk conveyed by the KIF6 gene variant can be virtually eliminated by statin therapy provides physicians with new genetic information in considering treatment options for their patients and also supports long-term therapy compliance among patients carrying the risk variant,” Ordoñez said. 
Although Ordoñez would not discuss whether Celera was shopping for pharmaceutical partners, she noted that Bristol-Myers Squibb has “followed this work from its inception.” 
Celera discovered the KIF6 variant in collaboration with Bristol-Myers Squibb, and the pharma company provided Celera clinical samples from the Cholesterol and Recurring Events (CARE) study and the West of Scotland Coronary Prevention Study (WOSCOPS). Bristol-Myers Squibb, however, does not own any of these finding in the diagnostics space, Ordoñez noted. 
Bristol-Myers Squibb has previously told Pharmacogenomics Reporter that it intends to apply pharmacogenomic strategies to enhance the blockbuster drugs in its pipeline [see PGx Reporter 01-10-2007].
The Studies
According to Ordoñez, the study findings “make a compelling case for testing for KIF6 status in the substantial number of Americans considered to be at moderate risk of developing heart disease based on traditional risk factors such as cholesterol levels and blood pressure.”
The first paper, which analyzed samples from the CARE and the WOSCOPS studies, showed that carriers of the KIF6 Trp719Arg polymorphism had a 50 percent higher incidence of myocardial infarction and a 55 percent greater risk of CHD. However, therapy with Pravachol “virtually eliminated” this risk in those carrying the gene variant.
The second paper, based on a genetic sub-study of the Pravastatin and Atorvastatin Evaluation and Infection Therapy – Thrombosis in Myocardial Infarction 22 (PROVE IT-TIMI 22), showed that high-dose atorvastatin was more effective at reducing CHD risk in KIF6 carriers than in noncarriers.
“These results show that the clinical benefit has a statin-class effect rather than a specific-drug effect since the two different statins tested had different characteristics: one hydrophilic and the other lipophilic,” Celera said in a statement.
The third paper demonstrates the KIF6 gene variants’ association with CHD events in 25,283 initially healthy Caucasian women aged 45 and over. As part of the Women’s Health Study, the women were followed for 12 years for a cardiovascular event. Study results showed that carriers of the 719Arg variant had a 34 percent higher risk of experiencing an MI and a 24 percent higher risk of developing CHD compared to noncarriers.
The KIF6 gene variant also predicted CHD in two other prospective studies conducted by Celera and its collaborators. In the 13,907-patient Atherosclerosis Risk in Communities study, KIF6 was associated with increased risk for CHD in Caucasians and African Americans. In the almost 4,000-patient Cardiovascular Health Study, KIF6 was associated with increased risk for MI.
Combining the three recently published studies and the ARC and CHS, the KIF6gene variant has been linked with CHD events in clinical trials involving more than 49,000 people, Celera said.
“These findings provide us with a better understanding of genetic predisposition to coronary heart disease and should motivate further studies that explore the biological role of the kinesin motor encoded by KIF6 in the development of coronary heart disease,” James Shepherd, University of Glasgow’s department chair for biochemistry and a co-author of one of the papers, said in a statement.

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