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DewDiligence

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Re: DewDiligence post# 45768

Tuesday, 08/26/2008 6:34:53 PM

Tuesday, August 26, 2008 6:34:53 PM

Post# of 252431
Apixaban Fails to Show Non-Inferiority to Lovenox in VTE Prevention

[Apixaban is an oral FXa inhibitor being developed by BMY and PFE under a very-high-profile collaboration where PFE *received* $250M up-front and stands to make as much as $1B in total milestones: #msg-19134406. (When was the last time a Big Pharma was on the receiving end of a deal of this magnitude?)

Apixaban’s most direct competition is Xarelto (Rivaroxaban) from Bayer and JNJ, which is already approved in Europe (#msg-30972846) and is under review by the FDA (#msg-31073048).

Apixaban’s failure to achieve non-inferiority to Lovenox in the trial that is the subject of this PR is a big (but non-fatal) setback inasmuch as non-inferiority to Lovenox in orthopedic indications had been considered a given by most observers. (The “tough” trials for Apixaban and other anticoagulants are generally such indications as stroke prevention in patients with AF.) Apixaban had shown non-inferiority to warfarin in phase-2 (#msg-21044973).

Although this PR asserts that the overall Apixaban program in multiple indications will continue as planned, at the very least the NDA submission in the US will be substantially delayed relative to the prior guidance of 2H09. Thus, Xarelto will have much more time to become established without any direct competition.

The phase-3 trial that is the subject of this PR employed a rigorous NI design, which is something you don’t always see. (In many NI trials, the sponsor merely has to meet a pre-specified trial size and come within a pre-specified delta relative to the comparator drug.) Apixaban yielded an event rate of 9.0% on the primary efficacy endpoint (a composite of DVT/PE and all-cause death) vs 8.9% for Lovenox, the comparator drug.

On first glance, the nearly equal event rates would seem to assure non-inferiority; however, the (one-sided) p-value of 0.064 missed by a hair. In other words, the null hypothesis that Apixaban was inferior to Lovenox could not be rejected with 95% confidence.

Apixaban did manage to show a statsig lower rate of clinically relevant bleeding (a safety rather than efficacy endpoint) relative to Lovenox, which bodes well for other Apixaban trials in VTE prevention.]

http://biz.yahoo.com/bw/080826/20080826006372.html

›Bristol-Myers Squibb and Pfizer Provide Update on Apixaban Clinical Development Program

Tuesday August 26, 4:15 pm ET

-- Apixaban Phase II Acute Coronary Syndrome Data to be Presented at European Society of Cardiology Meeting on Sept. 2

-- U.S. Regulatory Filing for the Prevention of Venous Thromboembolism will not be submitted in 2009, as previously indicated

-- Other Clinical Programs Continue as Planned

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) and Pfizer Inc (NYSE: PFE ) provided an update on the apixaban clinical development program today. The companies announced that new Phase II data in acute coronary syndrome patients (ACS) will be presented at the upcoming meeting of the European Society of Cardiology (ESC). In addition, Bristol-Myers Squibb and Pfizer reported that an early evaluation of results from a Phase III study of apixaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement indicates that the primary endpoint of this study was not met.

The Phase III VTE prevention study known as ADVANCE-1 compared apixaban, a novel, oral Factor Xa inhibitor given at a dose of 2.5 mg, twice daily, to the FDA-approved dose of enoxaparin, 30 mg given twice daily. The primary efficacy outcome was a composite of symptomatic or asymptomatic deep vein thrombosis, pulmonary embolism, and death by any cause. The rate of the primary efficacy endpoint on apixaban was numerically similar to that observed with enoxaparin (9.0% vs. 8.9%, p=.064), but did not meet the pre-specified statistical criteria for non-inferiority compared to enoxaparin. [See the annotations in the prologue of this post.] The actual enoxaparin VTE rate of 8.9 percent was lower than the expected VTE rate of 16 percent seen in previous similar clinical trials, resulting in an inability to demonstrate non-inferiority.

In ADVANCE-1, there were no unexpected findings in adverse events for apixaban compared to enoxaparin. The major bleeding event rate for apixaban was numerically lower, but was not significantly lower, than enoxaparin (0.7% vs. 1.4%, p=.053). The composite rate of clinically relevant non-major bleeding and major bleeding was significantly less in patients who received apixaban than those who received enoxaparin (2.9% vs. 4.3%, p =.034).

Full results of the ADVANCE-1 trial have been submitted to the American Society of Hematology Meeting (ASH) for presentation in December.

ADVANCE-1 results confirm the characteristics of apixaban as reported previously in phase II studies. The companies are considering further studies with different protocols in preventing VTE in knee surgery and will not submit the U.S. filing for VTE prevention in the 2nd half of 2009, as previously communicated. The results of ADVANCE -1 do not necessitate any changes in protocols of any other ongoing apixaban studies. Programs directed towards prevention of VTE including EMEA registrational studies, treatment of VTE, and in the prevention of stroke in atrial fibrillation continue as planned.

“Bristol-Myers Squibb and Pfizer remain enthusiastic and committed to the clinical development program for apixaban,” said Jack Lawrence, vice president, Research and Development, Bristol-Myers Squibb. “Bristol-Myers Squibb and Pfizer anticipate that the results of APPRAISE-1 being presented at ESC will provide important insight into the potential use of apixaban for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, which affects an estimated 2.7 million people around the world every year.”

About the Apixaban Clinical Program

Apixaban, an oral, factor Xa inhibitor in a new class of agents that have shown therapeutic potential to prevent and treat blood clots, is currently being explored in the EXPANSE clinical trial program which includes eight Phase III clinical studies involving approximately 45,000 patients worldwide. The ADVANCE-2 and 3 trials are investigating the safety and efficacy of apixaban 2.5 mg twice daily compared to enoxaparin 40 mg once daily in patients undergoing major orthopedic surgery. The ADOPT study is investigating apixaban for one month compared to standard of care (enoxaparin 40 mg once daily for at least 6 days followed by placebo) for the prevention of VTE in hospitalized patients who are medically ill and at risk of VTE.

Apixaban is also in Phase III trials studying the prevention of stroke and other thromboembolic events in patients with atrial fibrillation (AF). The AF program consists of two trials. The ARISTOTLE trial is investigating apixaban compared to warfarin in approximately 15,000 patients with atrial fibrillation. The AVERROES trial is investigating apixaban compared to aspirin in approximately 5,600 patients with atrial fibrillation who are ineligible for vitamin K antagonists (VKA) treatment or haven’t tolerated previous VKA treatment.

The VTE treatment program consists of two trials. The AMPLIFY trial is a 6-month trial investigating apixaban compared to enoxaparin plus warfarin in approximately 4,800 patients with acute DVT or PE. The AMPLIFY-EXT trial is a 12-month trial investigating apixaban compared to placebo for extended treatment to prevent recurrent VTE in approximately 2,400 patients who have completed 6 to 12 months of treatment for DVT or PE.‹

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