Bristol-Myers Squibb/Pfizer released the interim data that led them to stop the Phase III AVERROES study in June and report that their anticoagulant apixaban had bested aspirin at preventing strokes in atrial fibrillation patients who can't take warfarin, during the European Society of Cardiology meeting in Stockholm Aug. 31.

The question now is whether the companies will go ahead and file for permission to market their oral anticoagulant without waiting for results due in the first half of 2011 from another study, ARISTOTLE, that pits the anticoagulant head to head with standard-of-care warfarin in atrial fibrillation patients who are eligible to take the notoriously hard to manage therapy.

The companies plan to discuss "the appropriate regulatory strategy" with authorities once they have evaluated the full AVERROES dataset, a Bristol spokesman said.

AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes) was stopped after an interim analysis by the study's data monitoring committee showed "clear evidence" of a reduction in stroke and systemic embolism in patients with atrial fibrillation who are not candidates for warfarin therapy Also see "Bristol/Pfizer Offer Some Good Apixaban Results, With Key Study Against Warfarin On Track To Report 2H 2011" - Pink Sheet, 11 June, 2010.). Currently, for those patients the only treatment option is aspirin.

One of several novel Factor Xa inhibitors moving through development, apixaban has already completed studies for prevention of deep vein thrombosis following orthopedic surgery and after acute coronary syndrome. The AVERROES data are the first in a chronic indication, which is considered key to gaining regulatory approval, but are still limited to warfarin-ineligible patients.

Bernstein Research analyst Tim Anderson was guarded about the possibility of an apixaban approval based on a niche patient population, even with a chronic indication. In an Aug. 31 note to investors, Anderson speculates that regulators would be wary of off-label use for patients who are otherwise eligible for warfarin.

Despite the fact that apixaban would be filling an unmet medical need, said Anderson, "FDA might balk at having prescribers deviate from the well-established standard of care" in the absence of comparative data.

With the medical community eagerly awaiting a safe and effective replacement for warfarin, chances are a new anticoagulant approved for one use would be used off-label to treat other conditions, something FDA has not been willing to chance with data from trials in acute settings.

Bayer Healthcare/Johnson & Johnson's U.S. filing of their competing oral factor Xa inhibitor, Xarelto (rivaroxaban), for acute use in knee and hip replacement surgery was met with a "complete response" from FDA in May 2009, and the companies decided to wait for data from the ROCKET-AF study, which compares Xarelto to warfarin in atrial fibrillation patients, before resubmitting the application. The refiling will thus have acute and chronic data. The AF study likely will be released at the American Heart Association meeting in November.

Significant Stroke Reduction, Same Bleeding Risk As Aspirin

AVERROES enrolled 5,600 patients at 520 sites worldwide. The primary efficacy endpoint was a composite of stroke or systemic embolism, while the primary safety endpoint was major hemorrhage. Other endpoints included a composite of stroke, systemic embolism, myocardial infarction or vascular death, and total death.

The interim analysis showed the annual rate of stroke or embolism for patients in the apixaban arm to be 1.7 percent compared to 3.9 percent, a statistically significant 45 percent reduction in relative risk for stroke or systemic embolism favoring apixaban.

Major hemorrhage occurred at the rate of 1.6 percent per year with apixaban and at the rate of 1.4 percent a year with aspirin. But, while major bleeding occurred at a higher rate in the apixaban group, the difference is not statistically significant (p=0.33).

The groups were essentially identical for hemorrhagic stroke, 0.2 percent in both treatment groups, with no evidence of hepatic toxicity or other major adverse events.

Apixaban's major bleeding rate in AVERROES is roughly half of historical ranges for warfarin in similar populations, analysts for Barclays Capital remarked in an Aug. 31 note in which they called AVERROES "a landmark study that will lead to change in clinical practice."

The results bode well for the outcome of ARISTOTLE, which has a non-inferiority endpoint, the Barclays team asserts. Apixaban likely will come in at the specified non-inferiority boundary of 1.38, but it remains to be seen whether the newer anticoagulant will prove superior in terms of bleeding and by what magnitude, they conclude.

While the ARISTOTLE results and the fate of contending drug candidates must be weighed, Bernstein analyst Anderson forecasts 2015 sales of $1.7 billion for apixaban.

Even if the apixaban indication is limited to the AVERROES population, there's still a sizeable market opportunity.

According to Bristol/Pfizer, atrial fibrillation is the most common serious chronic arrhythmia, affecting about 4.5 million people in Europe and another 2.2 million in the U.S. Patients with atrial fibrillation are at five times grater risk for stroke than the general population, with 15 percent of all strokes attributable to atrial fibrillation. Nonetheless, surveys of practice patterns reveal that 40 percent to 50 percent of patients who are at moderate or high risk for stroke do not receive vitamin K antagonist (warfarin) therapy for various reasons.

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

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