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New stars for stroke

There are several challengers for warfarin's crown, which may prove to be more user-friendly

Earth seen from space with the Sun rising behindWarfarin, a vitamin K antagonist, has long been the gold standard in thromboprophylaxis for the prevention of cardioembolic stroke. The drug, however, has a narrow therapeutic window and interacts with a number of common foods and medicines. As a result, patients are required to undergo routine coagulation monitoring, which is time-consuming and costly, and detrimental to their quality of life.

There are several oral anticoagulants currently in late-stage development for stroke prevention in atrial fibrillation (SPAF). They promise to be at least as effective as warfarin and friendlier to the user. So, which is going to be the first to become the new standard therapy? Hold on to your seats; the race is coming to a close, and it is going to be tight!

Boehringer Ingelheim's dabigatran etexilate (Pradax; Pradaxa; Pradaxar) began in pole position with the initiation of the multinational, phase III RE-LY trial back in November 2005. Results from the RE-LY trial were recently presented at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. They show that dabigatran etexilate, at a dosage of 220 mg/day, is as effective as warfarin and associated with a lower risk of bleeding. Dabigatran etexilate 300 mg/day is superior to warfarin, and associated with similar rates of bleeding.

Dabigatran etexilate has already been launched in the UK, Germany and several northern European countries for the prevention of venous thromboembolism in patients who have undergone total hip or knee replacement surgery. The UK National Institute for Health and Clinical Excellence (NICE) recommended dabigatran etexilate for this indication, stating that its oral administration without the need for monitoring would reduce administration costs and support patient compliance.

As a reversible thrombin inhibitor, dabigatran etexilate has the same mechanism of action as AstraZeneca's ximelagatran; which discontinued development in 2006 due to incidences of serious liver injury in the phase IIIb EXTEND trial. Results from the RE-LY trial, however, suggest no differences between dabagatran etexilate and warfarin with regard to the incidence of abnormal liver function (<0.3 per cent of recipients).

Likelihood of approval
Boehringer Ingelheim remarked in a recent press release that they "look forward to expeditiously submitting these results to regulatory authorities around the world." Research analysts inThought give dabigatran etexilate a 67 per cent probability of gaining US Food and Drug Administration (FDA) approval.

Hot on the heels of dabigatran etexilate are a couple of factor Xa inhibitors: Bristol-Myers Squibb (BMS)/Pfizer's apixaban and Bayer/Johnson & Johnson's rivaroxaban (Xarelto). Apixaban and rivaroxaban are on a par. Both are currently in multinational, phase III trials (featuring warfarin as an active comparator), which expect to be completed within the second half of 2010. According to inThought, the odds of apixaban and rivaroxaban obtaining US FDA approval for SPAF are 40 per cent and 57 per cent respectively.

Like dabigatran etexilate, rivaroxaban has been approved in a number of countries for thromboprophylaxis in hip/knee surgery patients. Rivaroxaban's multinational phase III SPAF trial, ROCKET-AF, completed enrolment in August 2009. A second phase III trial is also being conducted in Japan. Results from this trial are expected in December 2009.

Apixaban's ARISTOTLE trial is currently recruiting and aims to enrol up to 18,000 patients worldwide. BMS and Pfizer are also recruiting patients in the AVERROES trial, which will compare the efficacy of apixaban versus aspirin in patients who are unsuitable for treatment with a vitamin K antagonist. The planned completion date for AVERROES is April 2010.

Also in with a chance of a podium finish is Daiichi Sankyo's edoxaban. Like apixaban and rivaroxaban, edoxaban is a factor Xa inhibitor. Daiichi Sankyo does not expect to complete its multinational, warfarin-controlled trial (ENGAGE-AF TIMI 48) until 2012. However, it has had some positive phase II results, and inThought give them a 58 per cent chance of gaining FDA approval.

So, dabigatran etexilate is currently leading the charge; however, with only a single phase III trial in this indication, some might say that Boehringer Ingelheim has a lack of clinical data. Regulatory authorities may also question RE-LY's prospective randomised open blinded end-point (PROBE) trial design. ROCKET-AF, ARISTOTLE and ENGAGE-AF TIMI 48 have the advantage of being double-blinded and are thus less prone to performance bias.

Regardless of which drug gains approval first, after half a century of warfarin's domination, it will be great for patients and doctors to have new therapeutic options for SPAF that don't involve lifelong blood tests and dose adjustments or numerous food and drug interactions.


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The Author
Pipeline was written by Steve McMillan of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on +44 (0)20 7981 0733.

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12th January 2010


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