New Factor Xa Inhibitor Betrixaban Safe in Phase 2 AF Trial

March 15, 2010

March 15, 2010 (Atlanta, Georgia) — An investigational factor Xa inhibitor, betrixaban (Portola Pharmaceuticals/Merck), was safe and well tolerated when three doses of the drug--40 mg, 60 mg, and 80 mg--were compared with warfarin in a dose-finding phase 2 trial, EXPLORE-Xa, in patients with atrial fibrillation (AF), attendees of the American College of Cardiology (ACC) 2010 Scientific Sessions heard today.

Dr Michael D Ezekowitz

Dr Michael D Ezekowitz (Lankenau Institute for Medical Research, Wynnewood, PA) reported the results in a late-breaking trial session. He said betrixaban has "a very nice profile. It is the only [anticoagulant] that is not cleared by the kidneys, it has a rapid onset of action, permits once-daily dosing, and, unusually, has been developed with an antidote." And the study was atypical in that it enrolled a wide variety of patients with AF, regardless of renal function, age, weight, or need for other medications, he said.

Dr Lars Wallentin

But he cautioned that this was a preliminary trial, and "the next step is the more definitive evaluation of this drug in a much larger population of patients," in a multinational phase 3 trial. Discussant of the trial, Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), congratulated Ezekowitz on the study but said it must be "challenging to know how to move forward, which dose of the drug will be taken into phase 3, or whether you should go with several dosages." Ezekowitz told heartwire that the companies had not yet decided which dose to test in phase 3, but "my advice would be to go for two doses."

End of Warfarin Era, CHADS2 Scores? How Will This Field Evolve?

When asked during a press conference how this new drug could be compared with the direct thrombin inhibitor dabigatran, with the excitement that surrounded the RE-LY trial results last year, in which dabigatran showed noninferiority to warfarin with less bleeding, Ezekowitz said: "We work on evidence, not speculation. However it is clear that the RE-LY trial certainly raised the bar and was very gratifying, but it did not reach perfection." Betrixaban has some novel properties, he noted, and is dosed once daily compared with the twice-daily dosing required with dabigatran. Dr Ralph Brindis (Kaiser Permanente, San Francisco, CA), coordinator of the press conference and incoming president of the ACC, commented: "RE-LY was viewed as a game changer. However, there are some advantages with [betrixaban] that dabigatran doesn't have."

Dr Ralph Brindis

A host of other new anticoagulants are also in development for varying indications. As well as dabigatran, another investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested in a phase 3 trial in more than 16 000 patients with AF, and the ongoing ROCKET-AF and J-ROCKET-AF studies are examining yet another factor Xa inhibitor, rivaroxaban (Johnson & Johnson), for the prevention of stroke in AF. Ezekowitz said he eagerly awaits the results of the ROCKET trials, which are expected to be presented at the American Heart Association meeting in November.

"It will be very interesting to see how this field evolves, but it is very exciting, and it's rewriting the textbooks with respect to anticoagulation in stroke prevention. My view is that CHADS2 scores are going to go by the wayside--when you have a much more effective anticoagulant, then evaluating patients by CHADS2 scores is not going to be important anymore," he commented. Brindis agreed: "The excitement to me is that we are advancing from the warfarin era. That to me is the take-home message."

Recipients of 40-Mg Dose Had Less Bleeding Than Those on Warfarin

Ezekowitz explained some of the novel features of betrixaban: it has a 20-hour effective half-life, so it can be dosed once-daily; no dose adjustment is expected for renal impairment; it is not anticipated to have any major drug-drug interactions because it is not a substrate for CYP450; and it is excreted unchanged through the bile. It is also being codeveloped with an IV antidote, although he admitted that it was too early to comment on the antidote, because "there are no data in humans."

When you have a much more effective anticoagulant, then evaluating patients by CHAD 2 scores is not going to be important anymore.

The three doses of betrixaban were tested in a randomized, blinded fashion against open-label warfarin in just over 500 patients with AF and at least one additional risk factor for stroke, such as age, diabetes, or hypertension. The mean age of the study population was 74, "the oldest ever studied in an AF phase 2 trial," said Ezekowitz, and the mean CHADS2 score of the population was 2.2.

The primary end point of the study was thetime to major and clinically relevant nonmajor bleeding, and secondary end points were time to any bleeding, death, stroke, MI, or systemic embolism, after a follow-up of three to 12 months (median 147 days).

There was a dose-dependent effect of the study drug on the primary end point of major and clinically relevant nonmajor bleeding. There were fewer instances of this end point among those taking betrixaban 40 mg as compared with those taking warfarin (one vs four patients); at the 60-mg and 80-mg doses, bleeding rates with betrixaban were similar to those seen with warfarin.

40-mg Dose Is Active; 60- And 80-mg Doses Cause GI Side Effects

In terms of drug activity, the researchers measured D-dimer levels, which Ezekowitz explained are a "reflection of the activity of the coagulation system in the body." The 40-mg dose of betrixaban showed a slight increase in D-dimer, whereas the 60- and 80-mg doses showed reductions in D-dimer, but Ezekowitz said the design of the study, with a warfarin comparator, likely explained the increase seen with 40 mg, and he believes this dose "is active." This observation is also supported by data from trials with betrixaban in deep vein thrombosis (DVT) prevention, which have shown that a 30-mg dose is active, he noted.

It will be very interesting to see how this field evolves. . . . It's rewriting the textbooks with respect to anticoagulation in stroke prevention.

In terms of adverse events, there were no liver signals with any doses of the drug: no differences in alanine-aminotransferase elevations between the doses and warfarin, and no increases in bilirubin. The only adverse events that occurred more frequently in the betrixaban patients were gastrointestinal in nature--nausea, vomiting, and diarrhea--which occurred in those taking the 60-mg and 80-mg doses.

Wallentin said: "As far as I read the data, you have a low dose that definitely seems extremely safe, although it may be that the efficacy can be somewhat doubted in relation to the D-dimer data. You have higher dosages that also seem fairly safe, but they are associated with some side effects, and therefore compliance might be a problem."

Ezekowitz replied: "The questions you have asked are key. My sense of the lowest dose is that it is an active dose based on the data shown here. As far as the higher doses are concerned, there did seem to be a higher incidence of GI complaints. I need to emphasize that only one patient discontinued therapy because of this, but obviously this will be monitored very carefully in any future trials."

Is the Trial Representative of a Global Population?

Wallentin also commented on the fact that 45% of the patients in the trial weighed over 90 kg, and almost 40% of patients were on aspirin, "and this is not usual in warfarin-treated patients," so he wondered whether this trial was therefore representative of the global population.

Ezekowitz said it was surprising to him how many obese patients there were, but with regard to aspirin use, he said it "was approximately equal to what we saw in the RE-LY trial." Nevertheless, the issue of any coadministration of an anticoagulant with aspirin is "very important," he said, and issues such as this and the rate of obesity will need "serious consideration in the design of future trials, which, by their nature, would have to be multinational," he commented.

Ezekowitz has served as a consultant for Portola and Merck, has received grant support from Portola, and has a sibling employed by Merck.