乌鸦传媒

ROME — A novel compound designed to reverse any of the newer oral anticoagulants targeting Factor Xa appears to do just that, a finding that may be cold comfort a week after the FDA said it wants more evidence before it can approve the drug.

Upon administration of a bolus of andexanet alfa, a recombinant modified human Factor Xa decoy protein, anti-Factor Xa activity decreased by 89% in patients taking rivaroxaban (Xarelto) and 93% in patients using apixaban (Eliquis).

from McMaster University in Hamilton, Ontario reported the results of the ANNEXA-4 study in a . The paper was also simultaneously published online in the New England Journal of Medicine.

Connolly noted that the trial is ongoing, but he and the other investigators decided to publish these initial data at this time because they anticipated that the drug would be approved in August.

He said that among the reasons for the FDA’s decision to delay approval were questions about the study design, but he declined to describe any methodological concerns.

The trial was designed to enroll 250 patients for safety criteria and 180 patients to meet efficacy criteria, with 180 patients needed to meet efficacy criteria. The data reported here included 67 patients in the safety population and 47 in the efficacy population. He added that the trialists plan to file an amendment to the design in order to expand enrollment.

ESC spokesperson Kurt Huber, MD, of the Wilhelminenhospital in Vienna, told 乌鸦传媒 that he believed the need for a reversal agent is greatest in the surgical setting, rather than in treating patients who have bleeding events.

He noted that 12 of the patients in ANNEXA-4 had thrombotic events occuring within 30 days of treatment, which raised a concern that the drug may be prothrombotic.

Since the arrival of the novel oral anticoagulants or NOACs, which are heavily marketed as patient-friendly substitutes for warfarin, a barrier to their acceptance has been the lack of a reversal agent.

Dabigatran (Pradaxa) was the first NOAC approved by the FDA and it is the only one that is a direct thrombin inhibitor. A reversal agent for it, idarucizumab (Praxbind), received U.S. marketing approval in October 2015.

That approval added to a sense of urgency about the need for an agent to reverse the anticoagulant effect of the Factor Xa inhibitors including rivaroxaban, apixaban, and the newest NOAC, edoxaban (Savaysa), as well as the IV anticoagulant enoxaparin (Lovenox).

In mid-August the FDA withheld approval for the agent and instead sent Portola Pharmaceuticals a “complete response letter” citing manufacturing concerns and directing the company to provide additional information in order to include indications for both edoxaban and enoxaparin on its label. The FDA also said the company’s postmarketing proposals required additional review.

The ANNEXA-4 study included data from 67 evaluable patients, but none of them were receiving edoxaban.

The mean age of the patients was 77 years and most of them had “advanced cardiovascular disease” and most bleeding events were gastrointestinal or intracranial. On average, the andexanet bolus was administered less than 5 hours after NOAC dosing. The bolus was followed by a 2-hour infusion.

“Four hours after the end of the andexanet infusion, there was a relative decrease from baseline of 39% in the measure of anti–factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban,” the NEJM authors wrote. “Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI 64%-89%). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.”

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