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BMY, PFE Begin Phase-3 Trials of Apixaban to Treat VTE

[Apixaban is one of a select group of drug candidates vying to replace the much-maligned warfarin as the standard anticoagulant in a wide range of indications (#msg-18759853). Its main competitors are rivaroxaban from Bayer/JNJ and LY517717 from LLY. All three drugs are FXa inhibitors and thus have a fundamentally different MoA from heparin (and MNTA’s M118), which inhibits both FXa and FIIa (see diagrams in #msg-26897966 and #msg-26898084).

The phase-3 program for Apixaban is one of the largest ever conducted for any drug in any class. (That’s why even a company as big as BMY could not afford to run the program on its own and enlisted PFE to share the burden.) All told, the phase-3 Apixaban program includes eight trials and 45,000 (!) patients: four trials in VTE prevention for patients who are either undergoing orthopedic surgery or hospitalized with limited movement; two trials in VTE prevention for patients with atrial fib; and the two trials described below for the treatment of patients with VTE. Control arms in the various trials consist of warfarin, aspirin, Lovenox, or placebo.

As a FXa inhibitor with no activity against FIIa, Apixaban is well-suited to indications pertaining to venous thromboembolism (such as the ones described above) and is less suited to indications pertaining to arterial thromboembolism such as ACS. Nonetheless, BMY/PFE have run a phase-2 trial in ACS for which data will be reported at a medical conference in September. (Please see #msg-29698599 for a discussion of how MNTA’s proprietary anticoagulant, M118, fits into this competitive landscape.)]

http://biz.yahoo.com/bw/080610/20080610006500.html

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First patient dosed in 12-month study examining the effects of the investigational drug apixaban in patients with blood clots in the leg veins or lungs

Tuesday June 10, 4:00 pm ET

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) and Pfizer (NYSE: PFE ) announced today the start of a new Phase 3 clinical trial to assess the effect of apixaban in patients with venous thromboembolism (VTE), a potentially fatal disease process that begins with blood clots in the leg veins or lungs. Apixaban, which is currently being developed by the two companies, is an investigational oral, highly selective factor Xa inhibitor, a new class of agents with therapeutic potential to prevent and treat blood clots.

The AMPLIFY (Apixaban after the initial Management of Pulmonary embolism and deep vein thrombosis with First-line therapy) trials are part of the EXPANSE program - the global Phase 3 clinical development trial program for apixaban. AMPLIFY and AMPLIFY-EXT are two major clinical trials involving approximately 7,300 patients with deep vein thrombosis (DVT), a blood clot in the vein, or pulmonary embolism (PE), a potentially fatal condition caused by a blood clot blocking a vessel in the lung.

“The initiation of this apixaban Phase 3 trial represents Bristol-Myers Squibb’s and Pfizer’s commitment to furthering research in the treatment of VTE, a serious disease that affects 1.3 million people annually in the US and Europe,” said Jack Lawrence, Vice President, Research and Development, Bristol-Myers Squibb. “Current oral drug treatment options for the treatment of patients with VTE are primarily vitamin K antagonists (VKA), such as warfarin. Limitations of VKAs include a slow onset of action, a narrow therapeutic window necessitating regular coagulation monitoring and dose adjustment, and multiple food and drug interactions.”

New Apixaban Phase 3 Clinical Trials

The AMPLIFY-EXT (Apixaban after the initial Management of PuLmonary embolism and deep vein thrombosis with First-line therapY- EXTended treatment) trial has initiated enrollment and will include approximately 2,430 patients who will receive, for an extended 12-month period, apixaban 2.5 mg dose or 5 mg twice daily compared to patients taking placebo to determine the effects of apixaban on recurrent VTE. Prior to entering the trial, patients will have completed 6 to 12 months of treatment for DVT or PE.

The AMPLIFY trial is expected to begin in the next few months, and will enroll approximately 4,800 patients with acute DVT or PE and will investigate the safety and efficacy of apixaban 10 mg twice daily for 1 week followed by 5 mg twice daily for 6 months compared to enoxaparin plus warfarin, the two drugs used as the current standard of care.

About Venous Thromboembolism (VTE)

Venous thromboembolism can take two forms: either as a deep vein thrombosis (DVT), a blood clot in a vein, usually in the leg that partially or totally blocks the flow of blood, or as a pulmonary embolism (PE), a blood clot blocking a vessel in the lungs. PE can be associated with significant hemodynamic deterioration or death.

VTE continues to be a major cause of morbidity and mortality in the western world, with an incidence of one to two per 1000 people, and represents one in 10 hospital deaths. In addition, post-thrombotic syndrome and pulmonary hypertension occur in 10 percent of DVT and five percent of PE patients, respectively.

The first year incidence of recurrent VTE is approximately 7.7 percent, and the risk of recurrence continues after anticoagulant treatment ends at an average of 3% per year over the next ten years.

About the Apixaban Phase 3 Program: EXPANSE

The EXPANSE apixaban clinical trial program has seven [eight if one counts AMPLIFY-EXT as a separate trial] ongoing Phase 3 clinical studies involving approximately 45,000 patients worldwide. In addition to the recently initiated VTE treatment program, the EXPANSE program also includes trials studying potential use for prevention of venous thromboembolism in patients undergoing orthopedic surgery and in hospitalized medically ill patients at high risk of VTE, and trials studying prevention of stroke and other thromboembolic events in patients with atrial fibrillation (AF). The VTE prevention program consists of:

• ADVANCE-1, 2, and 3 trials are investigating the safety and efficacy of apixaban 2.5 mg twice daily compared to enoxaparin in patients undergoing major orthopedic surgery. Results from the first trial are targeted for presentation at the American Society of Hematology in December 2008.

• The ADOPT study is investigating apixaban 2.5 mg twice daily for one month compared to standard of care (enoxaparin 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 3 trials studying the prevention of thrombotic events, such as stroke in patients with atrial fibrillation (AF). The AF program consists of:

• The ARISTOTLE trial, which is investigating apixaban 5 mg twice daily compared to warfarin in approximately 15,000 patients with atrial fibrillation.

• The AVERROES trial, which is investigating apixaban 5 mg twice daily compared to aspirin in approximately 5,600 patients with atrial fibrillation who are ineligible for VKA treatment or haven’t tolerated previous VKA treatment.

Apixaban has also recently completed enrollment in a Phase 2 trial in patients with acute coronary syndrome (the APPRAISE trial). The results of this trial will be presented at the European Society of Cardiology meeting in September 2008.
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