Bristol-Myers Squibb and Pfizer have suffered a major setback after the firms said they will not be seeking approval for their investigational anticoagulant apixaban in 2009, as expected, after the drug failed in a late-stage trial.

The New York-based firms said that an early evaluation of results from a Phase III study of apixaban, called Advance-1, for the prevention of venous thromboembolism in patients undergoing total knee replacement indicates that the primary endpoint was not met. The 3,195-patient study compared apixaban, a novel, oral Factor Xa inhibitor given at a dose of 2.5 mg, twice daily, to twice-daily 30mg injections of Sanofi-Aventis’ Lovenox (enoxaparin).

The data demonstrated that while the response to apixaban was numerically similar to that observed with enoxaparin (9.0% vs 8.9%), but did not meet the pre-specified statistical criteria for non-inferiority. The actual enoxaparin VTE rate of 8.9% was lower than the expected rate of 16% seen in previous similar clinical trials of Lovenox. The major bleeding event rate for apixaban was numerically lower, but not significantly so (0.7% vs 1.4%).

The result of all this is that B-MS and Pfizer are considering further studies with different protocols in preventing VTE in knee surgery and will not submit the US filing in the second half of 2009. However, the companies said that they are committed to the compound both for the prevention and treatment of VTE, and in the prevention of stroke in atrial fibrillation. They are running eight Phase III studies of the compound involving 45,000 patients.

Indeed, Jack Lawrence, vice president of R&D at B-MS, said that the results of the Appraise-1 study being presented at the European Society of Cardiology meeting in Munich next week
will provide “important insight” into the potential use of apixaban for the secondary prevention of cardiovascular events in patients with acute coronary syndrome. The latter affects 2.7 million people around the world every year.

Despite the upbeat messages, not being able to show superiority over Lovenox is a blow and for Pfizer, yet another late-stage failure is particularly irksome.