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Get on your hip-boots, campers: The Plavix-CYP2C19 quagmire has just become thicker.

As I wrote last week, a new, widely reported study claims that reports of adverse events tied to CYP2C19's effect on Plavix metabolism are virtually non-existent — despite the gobs of data supporting the link between the gene and the anticoagulant's efficacy, and the FDA's recent Black Box warning urging cardiologists to perform the test before prescribing the drug.

But now comes news that could cause cardiologists to shelve Plavix altogether — and with it any CYP2C19 testing that might have tagged along.

A pair of studies that followed a combined 28,624 patients found that two next-generation anticoagulants (one on the market and the other soon to be) do not need genetic testing to determine dosing; that a pair of CYP2C19 alleles, *2 and *3, do not affect their efficacy in the way that affects Plavix patients; and that the drugs may even be superior to Plavix.

Brilliant Efficiency?

In one study, of AstraZeneca's new anticoagulant Brilinta, researchers found that the two 2C19 alleles that help determine how patients metabolize Plavix didn’t hurt Brilinta's efficacy.

In a second trial, this one studying the clot buster Effient, which is being co-developed by Eli Lilly & Co. and Daiichi Sankyo, one of the two alleles did not reduce the drug's effectiveness

Both studies were published in the last issue of The Lancet; the Brilinta research was funded by AstraZeneca and the Effient trial was paid for by Lilly and Daiichi Sankyo.

Brilinta has not been approved for sale in the US but won the backing of an FDA advisory panel in July. The agency is expected to issue a decision later this month.

Effient was approved by the FDA last summer.

But there could be one bright spot on the horizon for clinical labs banking on revenue from CYP2C19 testing: If cardiologists accustomed to Plavix — it's the second-most prescribed drug in the world — fail to become convinced that Brilinta or Effient are better, then the fact that Plavix will lose its patent protection in two years would make it much more affordable, and could therefore embolden payors to reimburse for the test.

In fact, pharmacy-benefit management companies have been banking on this outcome, and Medco, the biggest in the country, has been studying since at least last year ways in which such pharmacogenetic + pharmacoeconomic testing can help improve drug efficacy, patient outcomes, and, of course, lower reimbursement costs.

However, the finding that the newer anticoags won't threaten cardiologists with the genetic-testing Sword of Damocles — most aren't even sure what to make of the Black Box warning — may add another complication because, as Bloomberg recently quoted one cardiologist, "physicians don’t like complications."

“If I told you there was an alternative to [Plavix] that worked the same way without the [gene] variations, they would jump on it," said the physician, Alfred Bove, immediate past president of the American College of Cardiology.

Conflicting, Confounding, Confusing, Confirming

These cluster bombs of data — call them conflicting, confounding, confusing, or confirming — made me want to plunge my head in a bucket of ice water. I doubt most clinical lab managers will find the results any less frustrating.

Still, some physicians aren't entirely assured that Plavix, and 2C19 testing for it, is doomed. Last week, a cardiologist at the Cleveland Clinic told me that "Plavix PGx will become standard of care despite these recent publications and reports."

He gave a couple of compelling reasons: First, Brilinta "will not succeed on [its] own … because [it] is reversible and needs to be taken twice a day, meaning that noncompliance is quite likely, which can lead to serious adverse events," said the cardiologist, who asked to remain anonymous because he is involved in launching a new company that is in stealth mode.

In addition, the drug "causes breathlessness in 20 percent of patients," which he said "applies to all next-generation antiplatelets."

Plus, he said, unlike the impending generic Plavix onslaught, "the new agents will be expensive." For instance, he said, Effient costs around 18 percent more than Plavix in the US.

Indeed, he said, when generic versions of Plavix start flooding the market the issue will morph into "a cost-saving argument." He backed up this claim by mentioning a pharmacoeconomic study in New Zealand, where Plavix is already sold as a generic, which showed that 2C19 "testing saves money and improves outcomes." He predicted that "this will also apply in the US." The paper has been submitted for publication
http://www.genomeweb.com/blog/get-your-hip-boots-plavix-cyp2c19-quagmire-has-just-gotten-thicker