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Plavix, one of the few anti-clotting drugs on the market today, could take a big hit to its $8.5 billion sales rate (2007) as the result of two recent revelations which are resulting in the FDA reviewing the drug’s labeling. We believe it is inevitable that the FDA will impose a more restrictive label which will substantially reduce the use of Plavix by as much as 30%.

The Losers: Plavix is prescribed to prevent blood clots. As the second most prescribed drug in the world (25 million prescriptions in 2007), Plavix is widely prescribed for patients that have experienced heart attack, stroke, or other vascular events and who are believed to be at high risk for a recurrent event caused by a blood clot. However, approximately 30% of patients taking Plavix do not metabolize the drug because of genetic variation thus receiving little or no benefit. Bristol-Myers Squibb (BMY) co-markets Plavix with Sanofi-Aventis SA (SNY) of France.

The Winners: The winners are those companies that will benefit from providing millions of PCR (polymerase chain reaction) based tests mandated by the FDA to detect the genetic variations that renders Plavix ineffective. We believe Roche Molecular Diagnostics and indirectly, Affymetirix (AFFX) which supplies the test to Roche, will be the major beneficiary of the label change but other PCR companies will also benefit.

In the December 22, 2008 issue of the New England Journal of Medicine, there are two studies that strongly suggest that data from patients taking Plavix over a number of years found that individuals with a particular gene variation had higher rates of heart attack, death and other cardiac-related events. The gene variant appears to reduce the function of an enzyme needed to activate the medicine. A third study in the British journal Lancet found that in patients under the age of 40 who had previously had a heart attack, the risk of having a new heart attack or death was three times greater for those with the gene variation. Two of the studies suggested the drug was less effective in about 30% of the population that has the mutated gene from one parent, while one study indicated the drug is less effective in the 5% of the population that has the gene from both parents.

In a study done in France, 2208 patients with myocardial infarction and taking Plavix were enrolled in a nationwide registry. The study assed the relation of allelic variants (alteration in the normal sequence of a gene) of genes modulating Plavix absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19) and biological activity (P2RY12 and ITGB3) to the risk of death from any cause, non-fatal stoke or myocardial infarction during one year of follow-up. PLAVIX is a prodrug that must be metabolized in the liver by several CYP proteins, including CYP3A and CYP2C19, to become active.

Death occurred in 225 patients and non-fatal myocardial infarction in 94 patients. Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51).

The authors of the study further conclude that since Plavix with aspirin is widely prescribed for patients that have experienced a myocardial infarction or a stent placement for which it has become mandatory, genotyping, rather than repeated platelet monitoring could be an affordable strategy to identify patients at high risk for atherothrombotic events.

The second NEJM study was performed at the Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston and compared the metabolic response to Plavix of 162 health subjects to 1477 subjects with acute coronary syndromes. The study concluded that in healthy subjects who were treated with Plavix, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of Plavix, as compared with non-carriers. It was further concluded that carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of Plavix, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did non-carriers.

Genotyping is possible at a reasonable cost using PCR based diagnostic tests. Roche Molecular Diagnostics Products offers the first pharmacogenetic microarray-based test approved for clinical use. The AmpliChip CYP450 Test identifies a patient's genotype by analyzing CYP2D6 and CYP2C19, two genes in the cytochrome P450 system that can greatly influence drug metabolism. These two genes code for enzymes that metabolize many antidepressants, antipsychotics, and ADHD drugs, as well as other medications. The AmpliChip CYP450 Test can help physicians adjust dosing and select drugs by predicting a phenotype based on a genotype so that patient treatment can be individualized to get the best therapeutic results possible. The test is based on technology provided in partnership with Affymatrix (AFFY). PCR technology is widely available from other companies such as Applied Biosystems, a division of Life Technologies (LIFE), GE Healthcare (GE), Agilent Technologies (A) and BD Biosciences a division of Becton-Dickinson (BDX).

The other bump in the road occurred following a report released in November by pharmacy benefits manager Medco Health Solutions Inc., showing that a class of commonly used heartburn medicines, such as Prilosec, frequently taken to reduce risk of internal bleeding and ulcers linked to Plavix, seem to interfere with the anticlotting drug. The 16,690-person suggests that people who combine a heartburn pill like Nexium or Prilosec with Plavix at their doctors' direction have a 50% higher risk of a heart attack or other cardiac event compared with those taking Plavix by itself.

At the time the study was released, Dr. Paul Gurbel a cardiologist at Sinai Hospital in Baltimore and one of the first researcher to identify in 2003 that 30% of patients taking Plavix do not metabolize the drug properly, said if it comes to a choice between Plavix and a proton-pump inhibitor (PPIs), doctors should generally keep the patient on Plavix and drop the other drug, because Plavix can prevent fatal heart attacks. "We rely on this drug to keep patients from having the most dreaded event," he said. "Any potential interaction ... is serious, and doctors need to look at whether they are directing patients to also take PPIs too much."

Conclusion:

Larry Lesko, Ph.D., director of the FDA's office of clinical pharmacology, said the agency is in discussions with Plavix's maker, Bristol-Myers Squibb Co., about updating the label. Dr. Lesko said the agency is considering adding a recommendation to Plavix's label that patients get a genetic test to screen them for the gene mutation. We believe a change in the label will occur requiring genetic testing and that will lead to better individualized medicine and a reduction in the use of Plavix.

Disclosure: None

Source: Plavix: Winners and Losers