Bristol-Myers Squibb and Pfizer end study on anti-clotting drug due to bleeding

The discontinuation of this apixaban study is yet another pipeline setback for Pfizer -- following stumbles with the development of candidates like tanezumab, Sutent and Dimebon -- but with some high expectations for efficacy in stroke patients, some analysts are saying the drug still has plenty of market potential

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PRINCETON, N.J. & NEW YORK—Bristol-Myers Squibb Co. and Pfizer Inc. recently discontinued the Phase III APPRAISE-2 clinical trial in patients with recent acute coronary syndrome (ACS) treated with apixaban or placebo in addition to mono or dual antiplatelet therapy—but in the end, apixaban looks promising despite this setback.

The decision to end the study early came after an independent data monitoring committee noted clear evidence of a clinically important increase in bleeding among patients randomized to apixaban, and that this increase in bleeding was not offset by clinically meaningful reductions in ischemic events.

The APPRAISE-2 Trial (Apixaban for Prevention of Acute Ischemic Events - 2) was one of nine clinical trials evaluating apixaban in patients at risk of various ischemic events, but its cessation has not brought the other trials to a halt.

"We remain committed to the development of apixaban in other patient populations," asserts Dr. Brian Daniels, senior vice president of global development and medical affairs for Bristol-Myers Squibb. "We are focused on the rolling submission of data for the prevention of stroke in patients with atrial fibrillation who are expected or demonstrated to be unsuitable for treatment with warfarin to the Food and Drug Administration and the application to the European Medicines Agency for venous thromboembolism (VTE) prevention. Other ongoing studies investigating apixaban in different patient populations are being monitored by independent data monitoring committees and are continuing."

"Our recommendation to discontinue APPRAISE-2 concerns only the population of high-risk ACS patients receiving anti-platelet therapy enrolled in APPRAISE-2," notes Dr. Robert Harrington, co-chair of the APPRAISE-2 Steering Committee. "Recent Phase III clinical trials of apixaban have demonstrated promising results in patients with VTE and atrial fibrillation. We look forward to reviewing the complete APPRAISE-2 data, when it is available, to better understand this apparently different risk profile in patients with ACS."

Jack Lawrence, who is in charge of apixaban development at Bristol-Myers Squibb, admitted that the company knew there would be an increase in bleeding in the study, but added that "The question was whether we could achieve enough incremental efficacy to offset the incremental bleeding."

Analysts aren't exactly calling for investors to jump ship at the news of the clinical trial's discontinuation, in part because, as Leerink Swann estimates, apixaban has potential for $1.3 billion in annual sales, and only some $200 million of that was expected come from the ACS indication.

Although Sanford C. Bernstein & Co. analyst Tim Anderson acknowledges that "some investors may begin to fear that this new news reveals some sort of weakness in apixaban's overall profile," he says that his firm doesn't share that view. He and other analysts have noted that the majority of patients that suffered hemorrhages in the trial were also receiving sanofi-aventis' Plavix (clopidogrel), which may mean it is a drug combination causing the problem, and not simply apixaban. In stroke prevention, Bristol-Myers Squibb and Pfizer's drug would be used as a single therapy, Anderson points out, adding that because ACS is linked to the clotting of arteries, and atrial fibrillation causes venous clogging, it is also difficult to draw conclusions about the risk of bleeding in the larger indication.

Looking at the good results for apixaban in a Phase II study for stroke prevention, Bankhaus Metzler analyst Sebastian Frericks reminded investors that while "the bleeding concerns that have now emerged have increased the project's overall risks" it has always been stroke prevention, not ACS, that has been the focus of this drug. He adds that from the point of view of Bayer, which is developing the anticoagulant Xarelto (rivaroxaban) in partnership with Johnson & Johnson, "I would not write apixaban off as a competitor."

On the other hand, Zacks Investment Research sees the discontinuation of the apixaban study as "the latest pipeline setback for Pfizer" following announced setbacks over the past year with the development of candidates like tanezumab, Sutent and Dimebon.

"In October 2010, Boehringer Ingelheim's Pradaxa was the first new oral anticoagulant to gain FDA approval in more than 50 years. Currently, Pfizer/Bristol-Myers and Johnson and Johnson/Bayer are jostling for second position in the U.S. anticoagulant market," Zacks notes. "Johnson and Johnson/Bayer recently reported positive results on their blood thinner, Xarelto (rivaroxaban), which is currently available in Europe."

As such, Zacks currently offers a Neutral recommendation on Pfizer because of the mounting pressures on the company, of which this setback is just the latest example. As Zacks notes, looking to other events recently with Pfizer, "While Wyeth brings with it an attractive biologics platform and some complementary products and businesses, we do not believe they are enough to sustain long-term top-line growth. We see the merger as mostly an opportunity for Pfizer to cut additional costs. Longer-term growth at Pfizer will be dependent on the success of drug development. The Lipitor patent expiration in 2011 remains a big concern."

Apixaban is an investigational oral factor Xa inhibitor, a new class of agents being studied for the prevention and treatment of blood clots. Apixaban is being investigated within the EXPANSE Clinical Trials Program, which is projected to include nearly 60,000 patients worldwide across multiple indications and patient populations and includes a total of eight completed or ongoing, randomized, double-blind Phase III trials. The apixaban Phase III trial program is evaluating the prevention of venous thromboembolism, prevention of stroke and other thromboembolic events in patients with atrial fibrillation and the treatment of venous thromboembolism. In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an investigational oral anticoagulant discovered by Bristol-Myers Squibb, with an eye toward combining Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field.

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