By now you've noticed that we are fascinated by the potential for a pharmacogenomic marker--variability in the CYP2C19 genotype--to play a pivotal role in reshaping a blockbuster market: the antiplatelet class currently dominated by Sanofi and Bristol-Myers Squibb's Plavix, but where Lilly and Daichii Sankyo hope make an impact with the newly approved Effient.
We've written about this extensively in "The Pink Sheet" (start here) and debated it during a podcast (available here, or via iTunes).
Two new developments this week have us thinking about it some more. First is the publication of arguably the most compelling data yet about the importance of the biomarker, a study by University of Maryland researcher Alan Shuldiner and colleagues that is the lead article in the Journal of the American Medical Association this week.
To recap, it seems that people with one of the variants of the CYP2C19 polymorphism are poor metabolizers of Plavix; clopidogrel is inactive as ingested, and so poor metabolizers may in effect be taking a placebo rather than antiplatelet therapy. Prasugrel (the active ingredient in Effient) is not metabolized by that pathway, and so should be effective in all patients regardless of genotype.
Given that the faulty genotype is present in something like 30% of the population (though the percentage varies by race)--and especially given that Plavix will soon be generic, while Effient is a key product for Lilly's future--the commercial implications are huge.
Now, the study itself isn't new per se. Indeed, it was Shuldiner's presentation of the data during an Institute of Medicine workshop in March (coupled with the reaction of Food & Drug Administration officials and other IoM panelists to the study) that first convinced us this could be a milestone in the evolution of personalized medicine.
As we point out in "The Pink Sheet" DAILY, publication of the study in JAMA (which is making the full article available for free) certainly ensures greater attention from the medical community. But will it change medical practice? That is the question raised in an accompanying editorial.
Which brings us to the second new development: the public release of FDA's approval letter for a labeling change for Plavix made back in May. That label change (done with no fanfare) added information about the biomarker to labeling for Plavix first time.
Two things in the letter are news to us:
(1) The label change was initiated at the request of FDA, using its new authorities under the FDA Amendments Act.
(2) FDA's initial request included a statement that PKG screening is recommended for all Plavix patients, but that was dropped after discussions with Sanofi.
FDA declined to comment on what prompted the change of heart on an explicit recommendation for the screening--but since the new FDAAA authorities give FDA for the first time the ability to mandate exactly the labeling it wants, Sanofi must have made some strong arguments along the way.
We suspect they pointed out some of the things included in the JAMA editorial, like the perceived lack of ready access to the test and (probably more importantly) the lack of evidence to guide any specific treatment decision following screening. That is, while the hypothesis that prasugrel will work better in patients who don't metabolize clopidogrel is appealing, that hasn't been tested in prospective clinical trials.
And then there are the inevitable questions about whether FDA can or should use labeling to drive change in practice, or instead make sure labeling best supports practice as it evolves.
Use of pharmacogenomic testing in the real world, LabCorp SVP Marcia Eisenberg points out, is really about "the comfortableness of physicians using molecular testing to change the pattern of their behavior.”
So, while infectious disease specialists have made HIV viral typing a routine part of therapeutic diseases, and oncologists are increasingly comfortable with testing for markers like HER2 and now KRAS, those are still very much the outliers. LabCorp alone offers dozens of potentially useful pharmacogenomic screening tests, but--with those few exceptions--most are not routinely ordered.
LabCorp (and other diagnostic firms) have made 2C19 screening available since 2005, and (in their view at least) there is no barrier to routine use. Awareness of the test is low, Eisenberg acknowledges; indeed, Shuldiner himself said during the IoM meeting in March that the test was not readily available outside of academic centers.
FDA, in Eisenberg's view, is helping to bring the overall science of personalized medicine to the forefront, but its regulatory actions inevitably lag behind actual practice. That was certainly the case with KRAS, where oncologists embraced the utility of the biomarker well before FDA approved new labeling for Amgen's Vectibix outlining the data in support of the test.
Will cardiologists do the same with Plavix? It doesn't seem likely right now. After all, the one group with a proven track record of changing behavior in cardiology is the pharmaceutical industry and its marketing prowess. But, as far as we can tell, none of the sponsors involved will be pushing for routine testing. Bristol and Sanofi made clear that they do not want to recommend the testing (indeed, they successfully prevented FDA from directing it in labeling), while Lilly and Daichii would rather not limit prasugrel to the roughly one-third of the population who don't properly metabolize clopidogrel.
That leaves the payors--but even there, the cost-benefit calculation will be complex, since routine screening would limit the population who would be eligible for generic clopidogrel, and may not be sufficient to stop prescribing of prasugrel by physicians who view it as the superior therapy.
The one thing we do know: this won't be the end of the discussion. There is plenty more data to come on the utility of the 2C19 marker in the class, and the looming patent expiration of Plavix means there are billions of dollars at stake. Anyone interested in the future of personalized medicine and blockbuster markets will want to keep paying attention.