Boston, MA - An investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested as a once-daily drug in a phase 3 trial in over 16 000 patients with atrial fibrillation, following unexpected results from a pharmacokinetic analysis of the agent in a phase 2 study. The latter was presented at the International Society of Thrombosis and Haemostasis (ISTH) 2009 Congress this week [1].
The phase 2 pharmacokinetics data, which was a subanalysis of an international phase 2 study presented at the American Society of Hematology 2008 Annual Meeting, were reported at ISTH by Dr Robert P Giugliano (Brigham and Women's Hospital, Boston, MA). The findings were "a little surprising," Giugliano told heartwire, because "what we learned was that once-daily dosing caused less bleeding than twice-daily dosing, even when you used the same total dose."
Delivering a compound twice a day generally allows for more consistent drug levels in the blood, he explains, because the Cmin (trough) levels of the agent do not dip as low and the Cmax (peaks) do not go as high as when the drug is given once daily. But "we found the most important parameter that predicted bleeding was the Cmin, the trough level," he noted.
Consequently, in the multinational phase 3 study, known as ENGAGE-AF TIMI 48, patients will be randomized either to 30 mg or 60 mg of edoxaban once daily or to warfarin, dosed once daily with adjustments to maintain an internalized normalized ratio (INR) between 2.0 and 3.0. Giugliano said that the 30-mg once-daily dose of edoxaban "looks to have less bleeding than warfarin and the 60-mg dose looks to have bleeding similar to warfarin."
The primary end point of ENGAGE-AF will be the prevention of stroke and systemic embolic events (SEE), and the primary safety assessment will be the incidence of bleeding. The trial is expected to conclude in the first half of 2012.
Learning from the mistakes of others
Giugliano says he feels "pretty confident" about this drug. "Because it's not the first one out, we've been able to learn from other people's mistakes, and right from the get-go we wanted to pick two doses. We realized it would be difficult to beat warfarin, so we're happy to be just as good as warfarin but to have equal or less bleeding. Even if we have equal bleeding to warfarin and are as good as it on the efficacy side, you don't have to monitor [edoxaban], it doesn't have a lot of drug-drug interactions, and it doesn't matter what you eat, so it's easier to use."
Another investigational, once-daily factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is currently in limbo in the US after the FDA declined to approve it for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- or knee-replacement surgery, despite a recommendation for approval from its Cardiovascular and Renal Drugs Advisory Committee earlier this year, as reported by heartwire. Bristol-Myers Squibb also has a factor Xa inhibitor in development, apixaban.
Warfarin analog disappoints in phase 2
Meanwhile, tecarfarin (Aryx Therapeutics), another new potential competitor to warfarin, has disappointed in a recent phase 2/3 trial [3]. Tecarfarin, like warfarin, is a selective inhibitor of vitamin-K epoxide reductase (VKOR), but unlike warfarin, it is not dependent upon cytochrome P450 enzymes for metabolism.
In the study, EmbraceAC, in 600 patients with a variety of underlying conditions—such as AF, implanted prosthetic heart valves, and a history of venous thromboembolic disease—tecarfarin failed to show superiority (as measured by time in the therapeutic INR range) over warfarin. The company says this is because the warfarin patients did much better than expected in the trial, due to the centralized dosing control center employed. It is still analyzing the data to determine a future strategy for tecarfarin.
Sources
- Giugliano R, Rohatagi S, Kastrissios H, et al. The relationship between oral factor Xa inhibitor DU-176B pharmacokinetics and the probability of bleeding events (BE) in patients with atrial fibrillation (AF). International Society of Thrombosis and Haemostasis 2009 Congress; July 11-16, 2009; Boston, MA. Abstract OC-WE-003.
- Daiichi Sankyo. Analysis of edoxaban phase II data provides insight into reduced bleeding events seen in once-daily dosing [press release]. July 15, 2009.
- Aryx Therapeutics. Efficacy of tecarfarin mirrors earlier studies while primary end point missed [press release]. July 8, 2009.
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