ORLANDO, FL — The novel agent andexanet alfa (PRT064445, Portola Pharmaceuticals) can immediately reverse the anticoagulant effect of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Janssen) in older patients and continue the reversal through use of both a bolus and continuous infusion, according to newly released results from the phase 3 ANNEXA series of studies.
As previously reported by heartwire from Medscape, part one of the ANNEXA-A trial evaluated reversal of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), whereas the ANNEXA-R trial evaluated reversal of rivaroxaban. In both, all primary and secondary efficacy end points were met, including significantly reversing anti-Xa activity, in healthy volunteers who received a bolus only of the study drug vs placebo. In part two of the evaluations, the active-drug groups also received continuous infusion; ANNEXA-A part 2 results were released earlier this year.
Findings from ANNEXA-R part 2 were presented last week at the American Heart Association (AHA) 2015 Scientific Sessions, with a summary of all phase 3 results simultaneously published in the New England Journal of Medicine.
In his presentation at the AHA meeting, principal investigator Dr Mark Crowther (McMaster University, Hamilton, ON) reported that in 39 healthy volunteers who received rivaroxaban for 4 days, those randomized to an initial 800-mg IV bolus followed by a 2-hour 8-mg/min infusion of andexanet alfa had a significantly greater change in anti-factor Xa compared with those who received matching placebo (P<0.0001).
And, "as in all of our previous work presented at other meetings, we did not see any toxic effects," said Crowther. He added to heartwire that "when we get [FDA] approval for this agent, we'll finally have a reversal agent that will change our approach to bleeding in these patients. Because right now, we don't have that."
Official discussant Dr Jerrold Levy (Duke University School of Medicine, Durham, NC) agreed, noting that despite the impressive safety of novel oral anticoagulants (NOACs), reversal strategies are critical for emergencies.
"For the patient who comes in bleeding, we can take the anticoagulant out of the picture with this specific reversal. But clinicians have to be clinicians and treat the patients and treat the underlying issues," added Levy.
All Prespecified End Points Met
"Andexanet is a recombinant-engineered derivative of factor Xa and was designed to counter the bleeding effects" seen with NOACs, said Crowther.
In ANNEXA-R part 2, 39 participants (56% women) between the ages of 50 and 75 were randomized 2:1 to receive either the andexanet alfa bolus-plus-infusion regimen (n=26) or placebo (n=13) 4 hours after their last treatment with rivaroxaban.
By the end of infusion, none of the participants dropped out or experienced any infusion-related reactions. In addition, there were no reports of any serious or severe treatment-related adverse events, including any thrombotic events.
The primary end point of percent change in anti-Xa activity at the end of infusion was met in the andexanet group (97%). In addition, there was a significant mean 95% change postbolus vs placebo (P<0.0001).
In other secondary end points, postinfusion occurrence of >80% reduction in anti-Xa activity was greater in the andexanet vs placebo groups (26 vs 13, respectively), as was the mean change in free rivaroxaban concentration (nadir 1.9 ng/mL) and change in thrombin generation (all comparisons P<0.0001).
In addition, thrombin generation was restored to above a mean 1-standard deviation in all 26 of the andexanet participants vs none of the placebo subjects (P<0.0001) "and it was restored to prerivaroxaban levels," said Crowther.
Overall, "andexanet alfa administration was well tolerated, met the prespecified primary efficacy end point, and met all of the prespecified secondary efficacy end points with high statistical significance," he said. It also produced "near-complete normalization of coagulation parameters immediately postbolus, which was sustained during the 120-minute infusion."
He reported that the investigators plan to have an FDA Biologics Licensing Application (BLA) completed by the end of this year and are planning an open-label phase 4 outcomes study (ANNEXA-4) in bleeding patients. ANNEXA-4 is currently enrolling patients from 35 sites in the US, and researchers hope to increase that number to more than 60 sites in North America and Europe.
"Impressive" but Questions Remain
"This study supports the importance of andexanet as a specific reversal agent for all anti-Xa agents," said Levy after the presentation.
He added that he was impressed that the investigators looked at a subset of older patients, who are more likely to get the reversal strategy. "This adds further understanding and an important perspective." He also noted that the infusion increased the time duration for which the reversal occurred, shining light on "some of the pharmacokinetics."
Levy said that the study's most important question was whether a 2-hour reversal "is sufficient for a facilitation of clot formation" in an emergent reversal.
"I think it is, because it allows for thrombin generation to occur and to seal off those particular wounds as part of a global strategy of treating. But, if you have a longer procedural intervention surgery, do you need a longer infusion? And what other adjuncts may be needed?" he asked.
"Hopefully, their current study in bleeding patients will further define the role of the agent and of Xa reversal."
ANNEXA is funded by Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer. Crowther reported receiving research grants from the Heart and Stroke Foundation of Ontario and from Leo Pharmaceuticals; being on the speaker's bureau for Leo, Bayer, Celgene, Shire, and CSL Behring; and being a consultant and/or on the advisory board for Leo, Janssen, Portola, and AKP America. Disclosures for the coauthors are listed in the abstract. Disclosures for authors of the summary article are listed on the journal website. Levy reported being on the scientific advisory board for Boehringer-Ingelheim, CSL Behring, Grifols, Instrumentation Labs, Janssen, and Medco.
Heartwire from Medscape © 2015
Cite this: ANNEXA-R: Novel Agent Sustains Anticoagulant Reversal From Rivaroxaban - Medscape - Nov 20, 2015.