In June 2010, Bristol Myers Squibb and Pfizer announced that they are halting the Phase III AVERROES trial of apixaban for stroke prevention in atrial fibrillation (SPAF) due to the drug's greater efficacy over aspirin. Results from this trial, which have not yet been disclosed, could trigger an earlier than expected filing for an AF indication in the United States and Europe, and alter the competitive landscape of the SPAF market.
Apixaban is one of a handful of agents in late stage development vying to fill the large unmet need of a safe and effective novel oral anticoagulant with significant benefits over warfarin. Warfarin's effectiveness is offset by its drawbacks, which include a risk of bleeding, regular dose adjustment and patient monitoring. With its risk/benefit profile proven in the setting of VTE prevention, and its low renal clearance, apixaban has the potential to herald a new era in stroke prevention.
The aim of the AVERROES study was to assess the effectiveness of apixaban in AF patients who have failed or are unsuitable for warfarin treatment; these patients are typically assigned either aspirin alone or in combination with clopidogrel to reduce their stroke risk. The primary efficacy endpoint in AVERROES was stroke or systemic embolism, whereas the primary safety outcome was major bleeding.
BMS/Pfizer very recently announced that they would be halting the AVERROES study because an interim analysis of the study revealed clear evidence of a clinically important reduction in stroke and systemic embolism in patients with atrial fibrillation considered intolerant of or unsuitable for vitamin K antagonist therapy. As a result of this development the companies could seek approval for an AF indication earlier than expected, and BMS CEO is reportedly considering whether these data will be adequate for U.S. regulatory approval.
We do not consider approval of apixaban for an AF indication at this stage to be a likely scenario for a number of reasons. Firstly, from a regulatory standpoint, we do not expect that positive data from AVERROES alone will be sufficient for approval in an AF indication. AVERROES was a relatively small trial with only 5,600 patients enrolled; Pradaxa's RELY trial studied over 18,000 patients. Additionally, given regulator's experience with AstraZeneca's Exanta, whose development was discontinued after liver safety signals were detected, we expect the FDA and European Medicines Agency to demand a considerable body of long term safety data from a much larger sample of patients.
Finally, an earlier approval could result in the drug competing with Pradaxa, and at this stage in apixaban's development this will be difficult; Pradaxa's strong results from the RELY trial, which studied the drug at low and high doses to yield superior safety and efficacy effects over warfarin, have fuelled physician enthusiasm for the drug. We also expect that BMS/Pfizer will face an uphill struggle in driving sales of the drug without any head-to-head warfarin comparator data (apixaban's ARISTOTLE trial, which is a noninferiority trial against warfarin, is due to finish in April 2011), even in the warfarin intolerant sector of the SPAF market.
We expect BMS/Pfizer to seek approval of apixaban for SPAF upon completion of the large ARISTOTLE trial (this has enrolled 18,183 patients), and we anticipate a first launch of the drug in 2012. Combining data from AVERROES and ARISTOTLE will create a powerful value proposition for the drug by demonstrating its efficacy and safety across a broad spectrum of patients. In a market facing the entry of at least 8 novel oral anticoagulants for SPAF, product differentiation strategies will play an increasingly important role for the novel oral anticoagulants.