December 10, 2010 ( Updated December 21, 2010) (Munich, Germany) — The investigational factor Xa inhibitor edoxaban (Daiichi-Sankyo) will not be developed for the prevention of venous thromboembolism (VTE) in major markets such as the US and EU, heartwire has learned. Instead, the company is concentrating its efforts on completing phase 3 trials with the compound in the treatment of VTE and in atrial fibrillation (AF), a company spokesperson has confirmed.
Edoxaban is nearest to the market for AF and "may very well be the next kid on the block; that's where Daiichi-Sankyo has put their money," Dr Harry R Büller (Academic Medical Center, Amsterdam, the Netherlands) told heartwire . That phase 3 trial, ENGAGE AF-TIMI 48, is comparing edoxaban 30 mg or 60 mg once daily with warfarin for the prevention of stroke and systemic embolism in around 20 000 patients with AF and has completed recruitment.
The findings from this study will undoubtedly be compared with those of the RE-LY trial with the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer-Ingelheim)--which was the basis for the recent US and Canadian approvals of that drug for the prevention of stroke in patients with AF--and also with the ROCKET AF study with another factor Xa inhibitor, rivaroxaban (Xarelto, Bayer/Johnson & Johnson), for the same indication, reported last month at the AHA meeting.
Assuming that rivaroxaban gains approval for AF, edoxaban will be racing with another factor Xa inhibitor, apixaban (Bristol-Myers Squibb/Pfizer), to be the third new anticoagulant for this indication. The Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation(ARISTOTLE) trial, a comparison of apixaban 5.0 mg twice daily vs warfarin in AF, is also currently under way, and results are expected in April 2011.
Edoxaban and Apixaban in Treatment of VTE
Meanwhile, the study of edoxaban in the treatment of VTE, Hokusai, is "the biggest program ever" for a new anticoagulant in this indication, Dr Ander Cohen (Kings College Hospital, London), who is on the steering committee of the trial, told heartwire . It is being conducted worldwide and has so far enrolled about 1000 out of a planned 7500 patients, around 70% of whom will have suffered deep vein thrombosis and 30% pulmonary embolism.
This study is similar to the RECOVER trial with dabigatran in the treatment of VTE in that patients in Hokusai will first receive the low-molecular-weight heparin enoxaparin for several days and then switch to either edoxaban 60 mg once a day or warfarin. In the EINSTEIN study, by contrast, rivaroxaban was given from the beginning, replacing both enoxaparin and warfarin, the so-called "single-drug approach." Büller, who is chair of the steering committee for Hokusai, said an arm where edoxaban is given right from the start of the trial is currently being considered as an addition to the protocol.
The treatment duration in Hokusai will be flexible, with all patients treated for at least three months, but some receiving treatment for six months and others a year. There is currently much uncertainty and debate with regard to how long anticoagulant therapy should continue in patients who have had a thrombotic event, as debated last week at the American Society of Hematology (ASH) meeting when the EINSTEIN data with rivaroxaban were discussed.
Although they say the first is the best-dressed, I can't see any reason why they won't all have a place.
Apixaban is also being developed for the treatment of VTE in the AMPLIFY and AMPLIFY-Extension studies, and Cohen, who is also on the steering committee for these trials, says he thinks apixaban might just beat edoxaban to the finish line for this indication, because "although AMPLIFY was slow to start, it's now ahead of target." In these trials, apixaban 10 mg twice daily is being compared with the standard regimen of enoxaparin followed by warfarin.
All in all, this is an exciting time for doctors treating VTE, with lots of new drugs due to come onto the market in the next few years, says Cohen. "Although they say the first is the best-dressed, I can't see any reason why they won't all have a place," he told heartwire , adding, "I wouldn't want to predict which one will fare best."
Of interest, he also says that Portola Pharmaceuticals, which has another factor Xa inhibitor, betrixaban, in earlier trials, "is working on a factor Xa inhibitor antidote."
Edoxaban Filed for Prevention of VTE in Japan Only
Although edoxaban has been studied in prevention of VTE, this has mainly been in Japan. In a trial presented at the ASH meeting earlier this week , STARS J-V, "edoxaban appeared more effective than the Japanese regimen of enoxaparin" for prevention of VTE in hip replacement, Cohen said. But he explained that "this doesn’t really give us a proper assessment of what happens in the rest of the world, since the Japanese start enoxaparin late and at a low dose."
There is a feeling among some of the experts who spoke with heartwire that edoxaban may have missed the boat with respect to prevention of VTE for orthopedic-surgery indications, with dabigatran and rivaroxaban having been on the market in the EU for this purpose for some time now.
Dr Michaela Paudler-Debus (Daiichi-Sankyo Europe) confirmed to heartwire that while edoxaban has been filed for approval in Japan for the VTE-prevention indication, the company would not be seeking this indication in either the EU or US markets.
An earlier version of this story erroneously stated that dabigatran was given at the start of the RECOVER trial, replacing both low-molecular-weight heparin and warfarin and that the ENGAGE AF-TIMI 48 trial would be completed in six to eight months.
Cohen is a member of the steering committee for the Hokusai and Amplify trials; Büller is chair of the steering committee for Hokusai and is also on the steering committee for Amplify.
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: Edoxaban Gunning for AF, Treatment of VTE - Medscape - Dec 12, 2010.