The stroke prevention for atrial fibrillation (SPAF) drug market is witnessing a sea change. Following the much welcomed launch of Pradaxa (Boehringer Ingelheim's dabigatran etexilate) in the U.S. in October 2010, and the presentation of data from Xarelto's (Bayer/J&J's rivaroxaban) ROCKET-AF study, in November 2010, physicians are eagerly awaiting the results from Eliquis's (BMS/Pfizer's apixaban) Phase III ARISTOTLE trial. Although Eliquis is expected to be the third of the new oral anticoagulants to launch for this increasingly lucrative indication, will its profile and clinical performance enable it to gain a foothold in this market?

Eliquis has undergone a unique clinical development program for SPAF. Its first Phase III study, the AVERROES trial, compared the drug to aspirin for stroke prevention in patients who were unable or unwilling to take warfarin. Based on Eliquis's clearly superior efficacy over aspirin, seen in an interim analysis, AVERROES was prematurely terminated and its positive results were presented in August 2010 at the European Society of Cardiology (ESC) conference. While experts interviewed by Decision Resources welcomed new Phase III data for another replacement to warfarin, Eliquis's superiority over aspirin was seen as no great surprise (in the ACTIVE-W SPAF trial, for example, warfarin clearly out performed a combination of aspirin and Plavix).

Eliquis's bleeding profile in AVERROES garnered a great deal of attention from experts that we interviewed the rates of major bleeding were not significantly different between Eliquis and aspirin and we believe that this is one area where it has the greatest potential to differentiate itself from rival drugs (Pradaxa and Xarelto were both shown to have comparable rates of bleeding to warfarin in their Phase III trials). Indeed new results from Eliquis's Phase II SPAF trial in Japanese patients (the ARISTOTLE-J Study), published last week, revealed that the drug was associated with a reduced rate of major or clinically-relevant non-major bleeding compared to warfarin (1.4% vs. 5.3%). Although these data are encouraging, the overall rates of bleeding with both drugs were vey low in this small 222 patient study. A true measure of Eliquis's safety and efficacy, relative to warfarin, will be provided from the pivotal Phase III ARISTOTLE trial, results from which are expected later this year. Based on currently available data, and thought leader insight, what are some likely outcomes from ARISTOTLE.

We expect Eliquis to have similar efficacy to warfarin in ARISTOTLE alongside a stronger safety profile. At the very least, we expect the drug to have a significantly reduced risk of intracranial haemorrhage, relative to warfarin, as has already been seen with Pradaxa and Xarelto. We also expect that Eliquis has the potential to show a trend towards lower rates of major bleeding in ARISTOTLE; a statistically significantly reduction in this endpoint, however, will be much tougher to achieve.

We predict a first launch for Eliquis in 2012 for SPAF. Eliquis is therefore likely to enter the market behind Pradaxa and Xarelto and, although these prior launches may further prime physicians to the concept of new oral agents to replace warfarin, overcoming these more established brands will be no simple feat. Alongside its first-to-market advantage, for example, Pradaxa was shown to have superior efficacy over warfarin in its Phase III trial (Xarelto, on the other hand, had a similar level of efficacy to warfarin in its study). Finally, as with Pradaxa, Eliquis is dosed twice daily and any advantages that it could offer in terms of lower rates of bleeding could be offset by this dosing requirement. Given the expected long treatment durations with the new anticoagulants for SPAF, a once daily drug, such as Xarelto, may well emerge as the preferred choice.

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