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Celera Finds Genetic Basis for CV Risk, Statin Benefit; Dx Under Development

Celera is hoping to further expand the already booming statin market through genetic research.
In the December 2006 edition of Arteriosclerosis, Thrombosis and Vascular Biology, Celera and a team of collaborators published a study linking a polymorphism in the gene encoding the myeloid IgA Fc receptor, the FCAR Asp92Asn polymorphism, with increased risk for myocardial infarction and coronary heart disease.
Frank Sacks, Harvard Medical School professor and the leader of a cholesterol clinical trial from which Celera gleaned genetic samples, characterized the research as “among the first to describe genetic polymorphisms that could identify individuals who are not only at greater risk for coronary heart disease and heart attacks, but who also derive significant benefit from preventative statin treatment,” including Bristol-Myers Squibb’s Pravachol and others.  
“This genetic information increases the accuracy of identifying people who are at high risk of heart attacks, and whose risk can be lowered by statin therapy,” Sacks added.
In an interview with Pharmacogenomics Reporter this week, David Speechly, Celera’s senior director of investor relations, noted that identifying the genetic basis for cardiovascular risk has market-wide implications and could ultimately broaden the patient population for statins.
“Individuals carrying these [FCAR Asp92Asn] polymorphisms have an elevated risk of CHD and MI, and when they take a statin that risk is virtually ameliorated, which makes them better than average responders to statins, and that makes for a compelling argument in terms of increasing market,” Speechly said.
John Sninsky, Celera’s vice president of discovery research, told Pharmacogenomics Reporter that the research opens up opportunities for Celera to develop diagnostics to gauge patients’ predisposition for disease risk and their response to drugs.
Celera’s Expansionist PGx View
Results from this study are “not going to be used to say, ‘You know what, you don’t carry this polymorphism, so you don’t need the statin.’ That’s not it at all,” Speechly said. “What this is going to do is, if you are carrying this gene, then you need to take the statin, and that’s the opportunity.”
Speechly’s emphasis on the fact that the study is “not about market segmentation” but about “market expansion” appears to reflect the sentiment of Bristol-Myers Squibb, a collaborator on the study.
Bristol officials recently told Pharmacogenomics Reporter that the company uses PGx studies to expand the indications of its oncologics. Celera and Bristol’s expansionist view of PGx is a departure from the perspective held by some industry observers who say the discipline forebodes the end of the blockbuster model [see PGx Reporter 01-10-07].  
If, with this study, Celera and BMS are teaming up to dispel that bit of conventional wisdom regarding PGx’s deleterious impact on the blockbuster, then the statin market provides a fertile testing ground. Pfizer’s Lipitor, also called atorvastatin, topped the list of blockbuster drugs in 2006, with $7.8 billion in US sales.
“Right now there is this opportunity to identify carriers of these genetic polymorphisms that are not on statins. We think that this may well present a market expansion opportunity for pharmaceutical companies,” Speechly said.
In contrast to this view, Eric Topol, provost of the Cleveland Clinic, has noted that Celera’s heart attack risk markers could actually have the opposite effect and shrink the statin market since physicians would no longer rely on LDL cholesterol level as a marker to broadly prescribe statins. Instead, genetic markers would allow doctors to prescribe statins to only those patients who would derive the most benefit [see PGx Reporter 02-17-05]. 
“I think that whole blockbuster concept is questionable,” Topol said, noting that statins, at $100 per month, amount to a hefty sum for patients using them for life.
Study Details
Celera conducted the study in partnership with the Harvard Medical School, the Harvard School of Public Health, the University of Glasgow and Royal Infirmary, and Bristol-Myers Squibb Pharmaceutical Research Institute. Using samples from two large prospective randomized clinical trials – the Cholesterol and Recurrent Events study and the West of Scotland Coronary Prevention Study – researchers investigated the efficacy of pravastatin on the prevention of MI and CHD.
Analysis of the genetic samples from the CARE trial involving 2,523 men and the WOSCOPS study with 1,562 participants revealed that those carrying the FCAR Asp92Asn mutation had 68 percent higher incidence of MI in CARE and 49 percent higher risk of CHD in WOSCOPS compared to non-carriers of the allele.
Additionally, researchers found that the 14 percent of patients in the study with the FCAR Asp92Asn polymorphism could significantly reduce their associated risk of MI and CHD with pravastatin treatment.

Celera has completed additional studies that indicate that the FCAR allele is not restricted to Pravachol, but may be applied to other statins as well.

Furthermore, in both CARE and WOSCOP, the risk of coronary events associated with the FCAR risk allele was independent of other known risk factors. “The risk estimates for the FCAR polymorphism were similar in magnitude to risk estimates for smoking,” Celera reported.
However, pravastatin treatment for those study participants stratified by genotype achieved greater risk reduction than for those not stratified by genotype. “Pravastatin treatment reduced the absolute risk in carriers of the FCAR risk allele by 10 percent and 4 percent in CARE and WOSCOPS, respectively,” Celera said in a statement announcing the publication of the study results in September. “To put these numbers in perspective, when male patients were not stratified by genotype, absolute risk reduction was 2.8 percent in CARE and 2.5 percent in WOSCOPS.”  
During its second-quarter earnings call last week, Celera President Kathy Ordoñez noted that the company has completed additional studies that indicate that the FCAR allele is not restricted to Pravachol, but may be applied to other statins as well. Celera has not published these findings, yet. “We are now working on the most effective means of commercializing these findings,” Ordoñez said. (See article, this issue, for further details on Celera’s second quarter earnings.)
Celera’s Diagnostic Development Plans
Although the company hasn’t announced any collaborations with statin developers, “it makes real sense” for Celera to forge such alliances with pharma companies “and it is something we’re doing,” Speechly said.
Last year, Celera had announced its plans to collaborate with undisclosed partners for two diagnostics in 2008: a test for predicting patient benefit from statin drugs and a genetic risk-scoring test for thrombosis [see PGx Reporter 06-28-06].
Celera did say that it is developing a diagnostic test to gauge a person’s genetic risk for developing a heart attack or coronary heart disease. Additionally, the diagnostic test would also give a statin benefit score “that would complement that particular risk score,” Speechly said.
Celera’s Sninsky noted that the findings from the study open up opportunities to develop diagnostics and pharmacogenomic tests.
“I think people make the distinction that if you’re developing a test that identifies differential risk, then it is a diagnostic test or a prognostic test,” Sninsky explained. “When you develop a test for identifying or targeting a drug, people sometimes refer to that as a diagnostic test, but more frequently they refer to it as a pharmacogenomic test. So, I think the take-home message here is that there are opportunities for both diagnostic, as well as pharmacogenomic tests.”
According to Sninsky, “it is too early to say” if this research has meaning for statin/CETP-inhibitor combination therapies.
In December, Pfizer notified FDA that it will suspend a highly anticipated Phase III trial for the investigational torceptrapib/atorvastatin (T/A) combination therapy due to an increased rate of mortality in patients receiving the treatment compared to those receiving atorvastatin alone. An independent Data Safety Monitoring Board discovered the increased mortality risk during its monthly analysis of the data and its quarterly analysis of a number of outcomes including stroke, heart attack, and revascularizations.
For the time being, Celera appears to be reveling in the opportunity to enter into the profitable and growing statin market. “The point is that although we have speculated that this polymorphism was likely to be pravastatin-specific, we expected it to address multiple statins,” Sninsky said.  

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