New Eliquis And Pradaxa Filings Promise To AMPLIFY Competition In VTE

Bristol reports positive data for Eliquis in the AMPLIFY study, paving the way for new VTE filings. Boehringer recently finally filed its competing Pradaxa in VTE treatment and prevention indications in Europe.

Bristol-Myers Squibb Co. and Pfizer Inc. say they are planning regulatory filings for Eliquis as a single agent for treatment and prevention of VTE after airing more positive Phase III data in this setting.

Newer oral anticoagulants are being positioned for a range of indications related to venous thromboembolism, which includes pulmonary embolism and deep vein thrombosis. About one million people in the European Union and 900,000 in the U.S. are diagnosed with VTE each year, according to the sponsors’ estimates. Currently, the standard of care in this setting for treatment and prevention of recurrent VTE consists of a short course of enoxaparin followed by warfarin, which is a cumbersome regimen that carries a risk of major bleeding.

Bristol and Pfizer announced on June 30 that Eliquis (apixaban) met the endpoints in the AMPLIFY study, demonstrating noninferiority with much less risk for major bleeding than standard of care therapy in acute treatment and prevention of recurrent VTE. Results were published in a July 1 online article in the New England Journal of Medicine and presented at the International Society on Thrombosis and Haemostasis, meeting June 29-July 4 in Amsterdam.

“After 60 years of warfarin, it is an exciting time in thrombosis care. Shifting with care to new treatments is essential to safe and effective practice,” NEJM editorial says.

This outcome complements the results from the positive AMPLIFY-EXT study of long-term treatment and prevention of recurrent VTE, which were released in late 2012 (Also see "AMPLIFY-EXT Puts Eliquis In Position For A New VTE Indication" - Pink Sheet, 8 Dec, 2012.).

With results from these two trials in hand, Bristol and Pfizer say they are going ahead with regulatory filings for initial and long-term treatment of VTE, extended prevention of recurrent VTE and extended treatment of VTE.

In the U.S., Eliquis is currently indicated for stroke prevention in atrial fibrillation. In Europe, it is cleared for stroke prevention in atrial fibrillation and prevention of VTE in patients who have undergone orthopedic surgery.

As with the publication of previous studies of novel anticoagulants in VTE treatment and prevention, comments made in an NEJM editorial accompanying the AMPLIFY results suggest clinicians are ready to embrace a change in the standard of care in this setting, though they have concerns about the transition, such as the need for reversal strategies and monitoring for bleeding complications (Also see "New NEJM Analyses Contrast Pradaxa, Eliquis and Xarelto In VTE" - Pink Sheet, 25 Feb, 2013.).

“After 60 years of warfarin, it is an exciting time in thrombosis care. Shifting with care to new treatments is essential to safe and effective practice,” the University of Vermont’s Mary Cushman wrote in the editorial.

Boehringer Also Pursuing New VTE Claims

Eliquis – a Factor Xa inhibitor – is one of three novel anticoagulants on the market, along with Johnson & Johnson/Bayer AG’s Factor Xa inhibitor Xarelto (rivaroxaban) andBoehringer Ingelheim GMBH’s direct thrombin inhibitor Pradaxa (dabigatran).

Currently, only Xarelto is approved for treatment and prevention of venous thromboembolism and J&J’s mission has been to have the broadest labeling (Also see "Xarelto Takes Lead In Exploiting VTE Market Opportunity" - Pink Sheet, 24 Dec, 2012.). The other two drugs are approved for VTE prevention in patients undergoing orthopedic surgery in Europe, but are not cleared for use after VTE.

But Xarelto’s days of having the VTE prevention and treatment market to itself appear numbered following the Eliquis announcement.

In addition to the Eliquis AMPLIFY news, privately held Boehringer announced on June 24 that it had submitted a marketing authorization for Pradaxa for the treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrent DVT and PE in Europe.

Boehringer has run four trials in this setting. The RE-COVER and RE-COVER II studies tested Pradaxa for acute treatment and prevention. And RE-MEDY and RE-SONATE evaluated Pradaxa in long-term treatment and prevention. Results from all four trials had been presented at medical meetings by the end of 2011.

Boehringer is set to present a new pooled safety analysis from RE-COVER and RE-COVER II studies at the ISTH meeting on July 3.

The company declined to comment on its plans to file in the U.S.

Safer Than Standard Of Care

The existing standard of care in VTE treatment and prevention typically consists of five to 10 days of treatment with enoxaparin, followed by warfarin for three to 12 months. The AMPLIFY study tested Eliquis as a single agent given twice daily – 10 mg for seven days, followed by 5 mg for six months – versus a short course of subcutaneous enoxaparin (at least five days) followed by six months of warfarin in 5,395 patients with acute VTE.

Eliquis proved noninferior to the current standard of care on the primary efficacy endpoint of reducing the development of recurrent VTE and VTE-related death. Potency was as good for PE as DVT, Giancarlo Agnelli, University of Perugia, et al., reported in the NEJM article detailing results.

Importantly, Eliquis also significantly reduced the risk for major bleeding – the primary safety endpoint. The rate of major bleeding was 0.6% for patients on Eliquis versus 1.8% for the standard of care arm. The test drug also demonstrated a significant reduction on a secondary safety endpoint, a composite of major and clinically relevant bleeding rates (4.3% for Eliquis vs. 9.7% for conventional therapy). Rates of other adverse events were similar, the investigators reported.

Efficacy and safety results in study centers where warfarin management was particularly good were consistent with the overall findings.

“The efficacy and safety of apixaban were consistent across a broad range of subgroups, including those based on clinically important features such as an age of more than 75 years, a body weight of more than 100 kg, use of parenteral anticoagulant treatment before randomization, and the duration of such treatment. The reduction in major bleeding was paralleled by a decrease in clinically relevant nonmajor bleeding, which provides further evidence for the safety of this apixaban regimen,” the NEJM article states.

The authors acknowledged that more information is needed about safety and efficacy in patients with cancer, low body weight and kidney impairment.

But they concluded overall that the AMPLIFY findings “add to the evidence that the new oral anticoagulants are simple alternatives to conventional therapy for patients with acute venous thromboembolism.”

Minding The Gaps In Trial Data

While reflecting excitement about a change from a long-time mainstay of treatment, Cushman’s editorial about AMPLIFY also had cautionary notes.

“Notably, the current trial had many exclusion criteria and the study was completed in 28 countries, with no results provided according to geographic region. For these and other reasons, much additional information is needed,” she said.

And the novel anticoagulants have short half lives. If patients miss doses, anticoagulation can be rapidly reversed, exposing patients to risk for VTE.

On the other hand, while the half life is shorter, the lack of approved antidotes for novel anticoagulants for emergency use has proven problematic in practice. Cushman called for more information about reversal strategies.

Furthermore, she said, comparative effectiveness studies and post-marketing surveillance are needed.