When Lilly's Effient (prasugrel) finally cleared FDA July 10, the first thing everyone noticed is the "black box" warning of a potential increased risk of bleeding associated with the antithrombotic drug.

That's understandable: the whole point of a "black box" warning, after all, is that it is supposed to be the first thing physicians notice when they see the approved prescribing information for a drug.

But the long term commercial prospects of Effient may ultimately hinge on a much quieter change Bristol made two months earlier to the label of the blockbuster antithrombotic agent Plavix (clopidogrel). That change included a new precaution citing pharmacogenomic data about potential non-responders to the drug.

In contrast to a black box warning, a precaution is the least prominent warning statement in labeling, so it is tempting to view the data as less significant than the bleeding warning the Lilly drug carries.

But the change to the Plavix label dovetails with a discussion of the pharmacogenomic differences between prasugrel and clopidogrel that was included in Effient labeling upon approval ("¹ Also see "Effient Labeling Could Give Edge Against Plavix Through Pharmacogenetics" - Pink Sheet, 10 July, 2009.). And Lilly sees that discussion as a key element in the commercial positioning of Effient ² Also see "Lilly Will Play The Metabolism Card In Effient's Imminent U.S. Launch" - Pink Sheet, 22 July, 2009..

More importantly, while the marketing battle will be between Lilly/Daiichi and Bristol/Sanofi during the roll-out of Effient, in the long run the commercial prospects of Effient will depend on how the product performs against generic clopidogrel (expected to be available again in 2011).

In that climate, the precaution in Plavix labeling may be more than enough to assure that Effient retains a role, since it would make it very difficult for payors to insist on a blanket, generic-first policy in the class.

[Editor's note: To hear our editors discuss the implications of the Effient launch, visit the ³ IN VIVO Blog or download our ⁴ podcast from ⁵ iTunes .]

Label Changed in May

FDA approved a labeling supplement for Plavix on May 5 to add information about the pharmacogenomics of clopidogrel. Specifically, the new label summarizes data from the medical literature suggesting that individuals who carry a specific version of a genomic marker (CYP2C19) do not metabolize Plavix and so receive less effective therapy.

The new Plavix label includes a precaution citing the data: "Based on literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function."

About 30 percent to 40 percent of the US population carry the marker for poor response to Plavix.

That in turn raises the question of whether it would be economically justifiable for plans to run screening tests on every candidate for anti-clotting therapy, given the relatively modest cost of the drug treatment versus the potential cost of an adverse outcome like heart attack or stroke.

More Changes to Come?

It is also possible that by the time Plavix goes off patent, the labeling will be even more clear cut. The change to Plavix labeling has all the earmarks of a preliminary step, with a more definitive regulatory action still to follow.

The first indication is the decidedly understated nature of the change. Not only did FDA not announce the new label, the agency has not yet posted the new label on its website.

FDA's last formal communication on the subject of clopidogrel pharmacogenomics was a public notice in January of an emerging safety issue, noting both the non-responder data and also a likely interaction with proton pump inhibitors that also affect that metabolic pathway. The agency typically updates those notices when it considers an issue resolved.

Given the emphasis FDA has placed on prior cases of pharmacogenomic driven relabeling, the fact that it has not yet commented publicly on what is arguably the most important instance yet of the new science suggests the matter is not entirely closed.

An FDA spokesperson declined to provide any additional information beyond confirming the label change.

Bristol, Sanofi Comment

Bristol, for its part, isn't saying much about the issue either.

"Recently, published reports have highlighted the issue of pharmacogenomic factors and how they affect certain patients' response to Plavix," Bristol said.

"These factors are part of ongoing research on which Bristol-Myers Squibb and Sanofi Aventis are working closely with the FDA. The companies are engaged in a comprehensive research program in order to provide patient-specific and medication-specific guidance to health care professionals."

That is, in essence, the same comment Bristol offered when Lilly and its partner Daiichi Sankyo published an analysis of the response rate of prasugrel in the genotype associated with non-response to Plavix.

That study, ironically, was published in Circulation the day before the Plavix label was updated (⁶ Also see "Lilly, Daiichi Explore Pharmacogenomic Marker For Prasugrel" - Pink Sheet, 6 May, 2009.).

During a media call July 29, Sanofi Aventis was more definitive, declaring that no further labeling changes are expected.

Sanofi also stressed the drug interaction side of FDA's safety update - the potential for PPIs to diminish Plavix' effectiveness. The company notes that there are plenty of alternative approaches to treating ulcers or indigestion, while Plavix prevents life-threatening cardiovascular events.

Still, there is no question that there will be additional data forthcoming--especially from Lilly's ongoing post-marketing research to expand prasugrel's indications. Those trials should provide sufficient data (gathered prospectively) to resolve any uncertainty about whether the marker is in fact predictive of differential response between the two drugs.

There are also at least half-a-dozen other studies under way looking at the metabolic markers of Plavix' efficacy included in the ClinicalTrials.gov database. Most are sponsored by non-commercial entities.

Prospective studies are typically required by FDA to justify labeling changes of a more prescriptive nature for pharmacogenomics.

FDA Officials See PKG Data as Compelling

FDA officials have commented in other settings, however, on how compelling they think the data is. In addition to the discussion in Effient labeling, the subject is treated at length in review documents.

The pharmacogenomics of clopidogrel was used as an example during a March 13 Institute of Medicine Workshop, and two FDA officials participating suggested they found it persuasive.

Office of Clinical Pharmacology Associate Director for Genomics Issam Zineh noted that, while he feels strongly that randomized controlled trials may be necessary in many cases to drive pharmacogenomic labeling, in his "personal opinion... I don't need a randomized controlled trial to convince me I need a genetic screen with clopidogrel. This is consistent with everything we know about the pharmacokinetics of the drug. Its consistent with a dozen studies that have been published."

"If I were on clopidogrel, I would want to be typed," Zineh said. "I don't want to wait for a randomized controlled trial."

Center for Drug Evaluation & Research Director Janet Woodcock also offered a perspective on the medical significance of the data, suggesting that the discussion of how big an effect you need to justify routine screening may miss the point.

Thinking from the point of view of "a person with the marker" for non-response, the "difference is probably the size of the entire treatment effect" associated with Plavix therapy in the first place, she said. Given that most drugs (including Plavix) deliver "very small, incremental improvements" in outcomes, the question should not be "how big is it to justify the cost of the test," but rather "how does this [effect] size up against other incremental benefits of therapies."

- Michael McCaughan ( ⁷ m.mccaughan@elsevier.com )

Plavix Pharmacogenomic Label Update May Help Lilly With Effient Launch

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