Bristol/Pfizer's Apixaban Bests Lovenox At Preventing VTE In Knee Surgery In Second Attempt

After failing to show non-inferiority in ADVANCE I, the Bristol/Pfizer anticoagulant was soundly superior to enoxaparin in ADVANCE II.

With the positive results of the ADVANCE II study of Bristol-Myers Squibb/Pfizer's apixaban now offsetting the failed non-inferiority of the earlier ADVANCE I study, the ADVANCE III study is shaping up to the tie-breaker for how the investigational anticoagulant stacks up against Sanofi-Aventis' low molecular weight heparin Lovenox (enoxaparin) in patients undergoing orthopedic surgery.

Data from the 5,400 patient ADVANCE III study, testing apixaban against enoxaparin in hip replacement patients, has been submitted for presentation at the International Congress on Thrombosis in July, Brian Daniels, Bristol's senior VP for global development and medical affairs, said during the firm's March 4 R&D day.

The EU submission for VTE prevention in orthopedic surgery will be completed "very shortly," and "there is potential" for a U.S. submission, Daniels said. According to Bernstein Research Senior Analyst Tim Anderson, the company plans a U.S. filing decision in the fourth quarter.

At issue is the failure of apixaban to prove non-inferior to enoxaparin in ADVANCE I, which examined its safety and efficacy in venous thromboembolism against enoxaparin in knee replacement surgery using North American enoxaparin dosing versus its superiority over the heparin product in ADVANCE II, which employed the European dosing for enoxaparin.

The ADVANCE II results were published in the March 6 issue of The Lancet.

In ADVANCE II, apixaban, an oral direct Factor Xa inhibitor, was found statistically superior on the composite endpoint of all venous thromboembolism and all-cause death. In the apixaban group 15 percent of patients experienced a primary endpoint event, compared to 24 percent taking enoxaparin. Apixaban was also superior on the secondary endpoint tracking venous thromboembolism: 1.1 percent of patients in the apixaban group had VTE versus 2.2 percent receiving enoxaparin.

The absolute risk reduction was 9.3 percent for patients receiving apixaban; the risk was reduced 38 percent for the primary endpoint and 50 percent for VTE.

On the safety measure of bleeding, a critical factor for anticoagulants: major bleeding or clinically relevant minor bleeding occurred in 3.5 percent of the apixaban group and 4.8 percent of the enoxaparin group, though the difference was not statistically significant.

ADVANCE II, with 3,100 patients, followed the European labeling for enoxaparin therapy, which calls for dosing at 40 mg daily starting about 12 hours before surgery, while the failed 3,200-patient ADVANCE I study followed the so-called North American labeling, which starts heparin 30 mg twice daily after surgery. In both trials apixaban was started 12 to 24 hours after surgery at 2.5 mg twice daily.

In ADVANCE I, reported in August 2008, apixaban missed the primary endpoint of non-inferiority using the same composite primary endpoint, which foiled Bristol's plan for simultaneous European and U.S. regulatory submissions in 2009 (Also see "Apixaban Fails Phase III Knee Surgery Trial" - Pink Sheet, 27 Aug, 2008.). In the 3,200 patient trial, the VTE rates of 9.0 percent with apixaban and 8.8 percent with enoxaparin were clinically similar and did not meet statistical criteria for non-inferiority. (The trials were designed to analyze findings first for non-inferiority then for superiority.)

Differentiating Apixaban Among New Product Contenders

Bristol, of course, is using the orthopedic indication to prime the pump for more lucrative chronic uses. The medical community is eager for safer, more convenient anticoagulants - particularly with oral dosing - and with no risk of thrombocytopenia, which requires close monitoring.

A medical indication (for chronic use instead of just with surgery) is next in line for apixaban, which is being compared with warfarin for prevention of stroke in patients with atrial fibrillation in the 18,000-patient ARISTOTLE trial and with aspirin in 5,600 patients who can't take warfarin in the AVERROES trial. Studies also are ongoing in treatment of VTE, with 4,800 patients in the six-month AMPLIFY study (a head-to-head against warfarin) and 2,400 in AMPLIFY-EXT, which compares apixaban with placebo for extended prophylaxis in treated VTE patients.

APPRAISE II, a Phase III study to test apixaban in combination with platelet inhibitors to prevent major coronary events after acute coronary syndrome stabilization, is currently enrolling with a target of 10,800.

Data from the event-driven stroke prevention and atrial fibrillation studies are expected by mid-2011, with worldwide regulatory submissions to follow in the second half of the year. Bristol hopes to have ACS data from APPRAISE II by 2012.

The other potential new anticoagulant in the Factor Xa class is Bayer\Johnson & Johnson's Xarelto (rivaroxaban). Bayer recently announced that J&J would be refiling the U.S. Xarelto application for prevention of VTE in orthopedic surgery in the second half of this year, following a "complete response" letter from FDA in May 2009. The company also intends to file an application for prevention of stroke in patients with atrial fibrillation (Also see "Bayer/J&J Will Resubmit Xarelto For Acute Indication In Second Half Along With New Application For Chronic Use" - Pink Sheet, 26 Feb, 2010.).

Also a potential contender for market share is Boehringer Ingelheim's oral direct thrombin inhibitor candidate dabigatran, for which a near-term U.S. submission is also anticipated.

Apixaban's twice daily dosing offers the advantage of consistent anti-coagulation with a low peak to trough ratio - which allows a wider dosing window - according to Daniels. Comparing plasma concentration curves for apixaban with published data for once-daily rivaroxaban 10 mg, Daniels estimated the peak to trough ratio over a 24 hour dosing period to be around 30 compared to 4.1 for apixaban. Apixaban has a nominally longer half life, Daniels added.

Apixaban also has multiple routes to elimination, and therefore can be used in patients with renal insufficiencies, and it has shown no evidence of food effect, he said.

-Shirley Haley ([email protected])