FDA's approval of Boehringer Ingelheim GmbH's oral direct thrombin inhibitor Pradaxa seems to be the result of a compromise over the issues raised at the recent advisory committee review of dabigatran - but one that works out well for the company. Labeling includes a back-door superiority claim over warfarin, but the approval is limited to the 150 mg strength that won the claim, with a 75 mg dose available for patients with kidney problems.

Left behind in the apparent compromise is the 110 mg dabigatran dose that was just non-inferior to warfarin, which the company had proposed as an alternative for some patients at high risk of bleeding and for the elderly. At the Sept. 20 review, members of FDA's Cardiovascular and Renal Drugs Advisory Committee had mixed feelings about whether both doses should be cleared, but FDA reviewers were clear in their briefing materials that they favored the 150 mg option.

At issue is the tradeoff between increased risk for bleeding events and better prevention of strokes. The 110 mg dose performed comparably to warfarin in the pivotal RE-LY trial, which compared both doses to the vitamin K antagonist, but it had a better safety profile (Also see "Pradaxa Shines On Strength Of Results, But Panelists Wary Of Future Trials With Similar Design" - Pink Sheet, 20 September, 2010.).

The advisory committee decided that if both strengths were approved, physicians might gravitate toward the lower one for safety's sake and not take advantage of the higher dose's increased efficacy (Also see "FDA's Pradaxa Quandary: Clearing Both Doses Could Mask Dabigatran's Superiority" - Pink Sheet, 27 September, 2010.). In the end, the panel voted 6-4, unofficially, to clear both doses and left it to the agency to find a way to guide physicians toward the most efficacious use of the drug.

The first anticoagulant to enter the market since warfarin was approved in the 1950s, Pradaxa is indicated for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, or abnormal heart rhythm. The Clinical Studies portion of labeling notes, alongside the actual study findings, that "relative to warfarin and to Pradaxa 110 mg twice daily, Pradaxa 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism."

The inclusion of that language, acknowledging the significantly better result, can be turned into a more overt superiority claim in promotions for the drug.

Approval Comes With A REMS

The Pradaxa approval, which came during the evening of the drug's Oct. 19 user fee action date, carries with it a Medication Guide, which under FDA's current policy constitutes a Risk Evaluation and Mitigation Strategy.

The MedGuide emphasizes the bleeding risk with the drug, starting out with the statement "Pradaxa can cause bleeding which can be serious, and sometimes lead to death." It also takes the unusual step of emphasizing the importance of compliance. A bolded message warns patients to "take Pradaxa exactly as prescribed" and not to stop taking the drug without consulting a physician because of the increased risk for stroke. Office of Drug Evaluation I Director Bob Temple had tipped to that possibility at the advisory committee meeting.

The REMS does not address the increased rate of myocardial infarctions with Pradaxa compared to warfarin in the RE-LY study, which was brought up during the advisory panel's discussions and in FDA briefing papers (Also see "FDA Supports Pradaxa Approval, But Without Superiority Claim" - Pink Sheet, 16 September, 2010.). A sentence in the Clinical Studies section of labeling notes that "the risk of myocardial infarction was numerically greater in patients who received Pradaxa (15% for 150 mg dose) than in those who received warfarin (1.1%)."

BI Has First Shot At Sizeable Market

According to Boehringer Ingelheim, an estimated 2.3 million Americans live with atrial fibrillation, a number that is expected to increase with the aging population to 5.6 million by 2050. The condition is associated with up to 15% of all strokes in the U.S., and those strokes are about twice as likely to be fatal or severely disabling than strokes from other causes. The company has been conducting a disease awareness campaign that highlights that information through a website and television ads in anticipation of the approval.

For venerable family-owned Boehringer Ingelheim, the approval means the firm can continue its pattern of steady growth despite loss of income due to its top-selling dopamine agonist pramipexole (Mirapex/Sifrol) and its prostatic hyperplasia drug tamsulosin (Flomax) going off patent. Pradaxa has the potential to generate between $2 billion and $6 billion in sales, according to analyst predictions (Also see "Boehringer Ingelheim: Privacy Has its Virtues" - In Vivo, 1 October, 2009.).

In an Oct. 20 note on the Pradaxa approval, Barclays Capital analysts peg the anticoagulant market at as much as $12 billion to $15 billion in 2021.

The approval is also a dose of good news after the failure of the "little pink pill" flibanserin. Boehringer Ingelheim announced it was dropping development of the investigational female sexual desire drug earlier in October, after an FDA advisory committee voted against approval and an FDA "complete response" letter laid out extensive requirements (Also see "BI Drops Flibanserin; BioSante Gets Excited" - Pink Sheet, 8 October, 2010.). That too could have been a sizeable market.

Although the Boehringer Ingelheim drug won the first-to-market advantage, as many as eight other anticoagulants are in the industry pipeline. Key among them are Bayer Healthcare/Johnson & Johnson's Xarelto and Bristol-Myers Squibb/Pfizer's apixaban.

An apixaban filing is expected by the end of this year. After halting the Phase III AVERROES study in June to report their factor Xa inhibitor had bested aspirin at preventing strokes in atrial fibrillation patients who can't take warfarin, Bristol/Pfizer said they were considering an initial filing in that indication (Also see "Apixaban Impresses At ESC, Leading To Speculation About An Early Filing" - Pink Sheet, 31 August, 2010.).

However, FDA may require data due in mid-2011 from the ARISTOTLE trial comparing apixaban with warfarin in atrial fibrillation patients before it will grant approval, the Barclays analysts acknowledge. Still, they assert that although it will be as much as a year behind Pradaxa, apixaban could be a competitive threat because of its potentially superior safety/bleeding profile.

Bayer and J&J have been waiting for data from the ROCKET-AF study, which compares their oral factor Xa inhibitor, Xarelto (rivaroxaban), to warfarin in atrial fibrillation patients, before resubmitting their application, which was met with a "complete response" in May 2009. Those data are slated to become public at the American Heart Association scientific sessions in Chicago Nov. 13-17.

-Shirley Haley (s.haley@elsevier.com)

FDA Plays It Safe With Boehringer Ingelheim's Pradaxa By Approving A Single Dosing Option

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