Plavix Label Change: Good For Effient Now, Bad For Brands in the Long Run?

The Food & Drug Administration's public health alert on Plavix is, as we point out in "The Pink Sheet" DAILY, a nice boost for Eli Lilly and Daiichi Sankyo, who market the competing platelet agent Effient.

But the back story to this regulatory action merits closer attention by all pharmaceutical sponsors. This is no ordinary labeling change, and the implications of how the regulatory response came about only underscore how difficult it will be for all sponsors who hope to sustain (or revive?) the blockbuster model in the years to come.

This labeling change suggests a model for application of pharmacogenomic research that biopharma companies will find very threatening: it sure looks like sponsors hoping to build blockbuster franchises are at a huge disadvantage against payors hoping to limit those opportunities.

And that's why this labeling change may end up being bad news for all brands in the long run--very much including Effient.

First, the news: FDA has revised Plavix labeling to emphasise that the Bristol-Myers Squibb/Sanofi Aventis blockbuster doesn't work too well in patients who are poor metabolizers of the drug. In particular, FDA is concerned about impairment of the CYP2C19 metabolic pathway, whether because of genetic variations or coadministration of other drugs, including the widely used proton pump inhibitor omeprazole (Prilosec).

Okay, none of that is actually news. FDA first issued the warning in January, and quietly modified Plavix labeling in May.

What is news is that FDA has decided that information is now a formal warning, rather than a milder precaution--and, more importantly, the agency chose to amplify that warning (especially regarding PPI use) via a media conference call.

It is easy to see why Lilly and Daiichi would be pleased: anything that complicates the decision to prescribe Plavix will help them make the case that doctors should prescribe Effient (and, as we've already pointed out, they need all the help they can get).

Okay, so this sounds almost reassuringly like a classic story of head-to-head competition in a blockbuster class, and how the regulatory process can play to one side's advantage. Plavix is dinged, Effient benefits.

But this is nowhere near that simple.

Because there are third parties involved: payors and pharmacy benefit managers. The interaction between PPIs and Plavix was first publicized by Aetna and by Medco, both of whom used claims data to suggest an association between PPI use and diminished outcomes for patients treated with Plavix.

Its not just that payors capitalized on a safety issue: they really drove the regulatory response and the application of a newly discovered pharmacogenomic marker. In Medco's case at least, Chief Medical Officer Robert Epstein told us, the whole idea was to find a way to test the emerging theory that CYP2C19 genotyping may predict Plavix response. Since Medco didn't have genotyping data on patients in its database, it looked at concomitant use of omeprazole instead, since the PPI is a known inhibitor of the 2C19 pathway.

FDA's first public health alert followed the Aetna and Medco claims studies; the latest one came after Bristol and Sanofi conducted a drug interaction study confirming the observational results. That's certainly not a regulatory model sponsors are eager to consider--especially since we would be willing to bet that the observational research that triggered the warning cost Medco much less than the clinical trial the sponsors were forced to conduct to confirm it.

Medco, at least, isn't done. As we reported here, the company is now taking the next step, conducting a large scale observational study to test the hypothesis that the superior efficacy demonstrated by Lilly in its head-to-head study of Effient vs. Plavix can be explained by the inclusion of poor metabolizers of Plavix in the comparator group.

And Medco's interest most definitely is NOT in helping either brand in this class.

Medco's interests include advancing the company's positioning as a leader in therapy management, particular as it comes to applying pharmacogenetic knowledge. And Medco certainly wants to work with its payor clients to make sure insured members receive the best possible care.

But what Medco wants above all is to carve out a long term market for generic clopidogrel--and in effect limit Effient's share (as well as the share of all future brands in the class)--to whatever slice can't be held for the generic.

The study design, as Epstein explained to us, is simple: Medco will (at its own cost) run a genetic screen on patients prescribed Plavix to identify those who properly metabolize the drugs. It will then compare 14,000 of those patients to 14,000 Medco members who receive Effient, and see if there is a difference in cardiovascular outcomes.

Medco clearly expects to demonstrate that there is no meaningful difference between the two.

Now this whole thing could backfire on Medco. Its data could end up suggesting superior outcomes even when the comparison arm is enriched for Plavix response. (And Medco has registered the trial on ClinicalTrials.gov, so while we doubt they would trumpet that result, they can't just bury it either.)

And the study could by itself end up promoting the launch of Effient. Certainly, Lilly and Daiichi are only too happy to have Medco's support in spreading the message that their drug is active regardless of that specific genomic marker.

Indeed, as part of the screening effort, Medco is likely to drive some conversions from Plavix to Effient: patients who are genotyped as poor metabolizers will be informed of that status (as will their physician). Medco will not make any recommendations, but it is safe to bet that many identified as poor responders to Plavix will switch therapies. Given that 30% or so of the population has the genotype in question, Medco is likely to notify about 6,000 people that they may not be getting the full benefit of their antiplatelet therapy with Plavix.

But that only underscores the bigger point. Medco is willing to make a relatively big investment--and even to help grow a potential blockbuster franchise in the short term--in order to help limit the size of that market in the long run.

And it will cost Medco far less to do that than it costs for sponsors to bring potential blockbusters to the market in the first place.

Now, Epstein wasn't willing to disclose how much this undertaking will cost, but he did suggest it isn't terribly expensive. Medco collects the outcomes data already, so the only cost will be running the genotyping program. Medco will be doing the tests in house, via its own CLIA-certified lab test, so that expense will be kept as low as possible.

All in all, that is not a trivial expense for a pharmacy benefit management company to take on spec, but we're willing to bet it is less than 1% what it cost for Lilly to "prove" the superiority of Effient in a head to head trial.

Which is why, when it comes to trying to establish blockbusters in an era of high payor influence and ever advancing knowledge of the heterogeneity of drug response, it seems like the odds are stacked in favor of those who want to keep market sizes small.

Look for much more on this topic in an upcoming issue of The RPM Report.

image from flickr user mafleen used under creative commons.

Plavix Pharmacogenomics: To Test or Not to Test?

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.

The Effient Launch: Cracking the Door to Primary-Care Marketing

So will personalized medicine be the death of primary care? Maybe not. Maybe just the opposite.

In this edition of the IN VIVO Blog Podcast, Mike McCaughan, our editor-in-chief, gives a decidedly positive (albeit counterintuitive) spin to what some of us in the editorial group thought was a pretty obviously bad piece of news: Effient’s black-boxed approval last July 10.

Yes, Effient (prasugrel) had beaten the competitor, Sanofi/Bristol-Myers’ Plavix, in Lilly’s head-to-head pivotal trial (fewer heart attacks and strokes for Effient’s users, though more bleeding) but still, we wondered, would Lilly – which depends on Effient to get it past the Zyprexa cliff – be able to build much competitive momentum against Plavix while dragging along its black-box warning about bleeding? And even if it manages to gain that momentum, won’t it be stopped dead in its commercial tracks when Plavix goes generic in 2011?

Mike’s notion: that the black-box warning and mandated two-year REMS requirement create the basis for primary-care marketing success – thanks to pharmacogenetics. Not because the data suggests the right population to get Effient – but because it argues that a third of the population getting Plavix get no benefit from it (an argument the FDA evidently agreed with because it added it to Plavix’s label). Lilly reps thus get an FDA-mandated foot-in-the-door to talk to docs about Effient’s risks (and Plavix’s deficiencies)…and, within two years, face a generic with no marketing effort behind it that they will argue doesn’t work in a third of a very high-risk population.

So click below to hear Mike’s full explanation (or you can access the podcast via iTunes).








Image from Flickr user twenty questions and used under a Creative Commons license.