The Phase III APPRAISE-2 trial of Bristol-Myers Squibb/Pfizer's apixaban in acute coronary syndrome has been terminated due to increased bleeding, on the recommendation of a data safety monitoring committee.

While bleeding excessive enough to stop a clinical trial is a significant setback for any developmental anticlotting agent, increased bleeding is an expected side effect that can be deemed manageable for such products. And in terms of the apixaban development program, ACS was not the most important indication for the drug.

The APPRAISE-2 study, one of nine Phase III programs for apixaban, tested the agent as an add-on therapy to treatment with antiplatelet drugs in 10,800 patients with recent ACS at risk of ischemic events. All patients were already taking antiplatelet therapy. The aim was to prevent ischemic events, but Bristol reported that the increased bleeding was not offset by clinically meaningful gains in efficacy from the dual therapy (reduction in ischemic events).

In a press statement announcing the termination late Nov. 18, Bristol maintained that the results only applied to the high-risk patient population in APPRAISE-2.

The company also asserted that it remains "committed to the development of apixaban in other patient populations."

Apixaban is one of several novel oral anticoagulants seeking to replace warfarin. Boehringer Ingelheim's Pradaxa (dabigatran) was cleared by FDA in October, and Bayer/Johnson & Johnson's Xarelto (rivaroxaban) is next in line. Apixaban is further behind in development and it was thought that it might be able to differentiate based on better safety.

The acute coronary syndrome segment represents a smaller piece of a big pie for novel anticoagulants - it's an indication where antiplatelet therapies are the preferred antithrombotic modality. For the anticoagulant class, the major market is stroke prevention for patients with atrial fibrillation, followed by indications related to venous thromboembolism (Also see "Oral Anticoagulants Market Snapshot: Big Bucks, But Payers Are On Guard" - Pink Sheet, 25 October, 2010.).

For apixaban, the vital study is ARISTOTLE, which tests the drug against warfarin for stroke prevention in patients with atrial fibrillation. Results are not due until next year.

Analysts Not Fazed By APPRAISE-2 Failure

Increased bleeding for a novel anticoagulant on top of antiplatelets is not a surprise, Barclays analyst Tony Butler commented in a Nov. 18 note on the trial termination of APPRAISE-2. Butler concluded that the APPRAISE-2 trial results have limited implications for ARISTOTLE.

Similarly, Bernstein analyst Timothy Anderson observed that its sales forecast of $1.7 billion for apixaban in 2015 remains unchanged: "In this particular indication, we did not have high hopes, and we built nothing into our sales forecasts for this."

The value of novel anticoagulants in ACS has been questionable because ACS is an arterial clotting problem, usually treated with antiplatelet therapies. In contrast, stroke prevention for artrial fibrillation is a venous clotting problem, typically treated with warfarin, Anderson explained. The novel anticoagulants have already proven effective in a range of indications related to venous clotting disorders, he noted.

"While a setback to some degree, failing in ACS is of little real consequence in our view," Anderson wrote. "However, some investors may begin to fear that this new news reveals some sort of weakness in apixaban's overall profile. We do not share this view."

Some expert clinicians also had not been counting on the novel anticoagulants to play a big role in ACS; based on unmet need, stroke prevention in atrial fibrillation is seen as the most important indication (Also see "Amid Torrent Of Next-Gen Anticoagulant Data, Trial Design Differences Complicate Comparisons Between Potential Competitors" - Pink Sheet, 8 November, 2010.).

In an interview after the European Society of Cardiology meeting in August/September 2010, McMaster University's Jeffrey Weitz had highlighted stroke prevention in afib as by far the most important indication, followed by treatment of VTE and any other indication where warfarin is extensively used already and a simpler anticoagulant is needed.

At the time, Weitz highlighted venous thromboembolism prophylaxis treatment in medically ill patients and ACS as among the less likely indications for novel anticoagulants, in terms of meeting the balance of benefits versus risks. Speaking about ACS for secondary prevention in particular, Weitz commented: "I think it's going to be challenging to find the right dose - the dose with efficacy without causing bleeding, particularly given the developments in new antiplatelet agents. The background therapy is changing all the time. So it's going to be very challenging there."

- Emily Hayes (e.hayes@elsevier.com)

Apixaban Study Halted - But It May Not Cause Much Damage To The Program

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