ARTICLE IN BRIEF
Vascular neurologists said they welcome the approval of andexanet for reversing Factor Xa inhibitor activity, but cautioned that certain risks may be a concern, and they welcomed more data from a phase 4 study.
The US Food and Drug Administration (FDA) has approved the first antidote to reverse the effects of coagulation Factor Xa inhibitors, a promising new class of blood thinners that includes rivaroxaban and apixaban.
Stroke experts interviewed by Neurology Today said they welcomed the approval as it met a critical need as 1 to 4 percent of patients treated with Factor Xa inhibitors every year experience major bleeding, and 1 percent may require emergency surgery. But they also said the FDA decision to require a post-marketing phase 4 trial was important as some of the pivotal studies that led to the approval left important clinical questions unanswered.
The agency's May 3 announcement marks an end, at least for now, to an uncertain approval road for andexanet alfa (Andexxa, Portola Pharmaceuticals, Inc.), which was granted orphan drug and accelerated approval status but failed to gain approval in August 2016, the first time the company filed a Biologics License Application,
At that time, the FDA asked Portola to provide additional efficacy data to support including edoxaban and enoxaparin, an indirect Factor Xa agent, in its labeling. The proper name of andexanet alfa is coagulation Factor Xa (recombinant), inactivated-zhzo.
In its letter, the FDA explained that its approval is conditional, requiring the company to further verify clinical benefits in a post-marketing, randomized, phase 4 clinical trial testing rivaroxaban, apixaban, and the Japanese product edoxaban.
Factor Xa inhibitors are increasingly used as alternatives to older blood thinners like warfarin for preventing stroke during atrial fibrillation as well as treating and preventing deep vein thrombosis (DVT) and pulmonary embolism. Andexanet alfa is a modified human Factor Xa molecule that prevents Factor Xa inhibitors from binding to, native Factor Xa. In clinical trials, this process allowed for the restoration of normal hemostasis in patients within 12 hours; however the agent has been associated with serious and life-threatening events.
A May 2 memorandum from Wilson W. Bryan, MD, director of the Office of Tissues and Advanced Therapies at FDA's Center for Biologics and Evaluation and Research summarized the need for a phase 4 trial. He expressed his concerns about the drug, including evidence of serious and life-threatening events, including arterial and venous thromboembolic events, ischemic events including myocardial infarction and ischemic stroke, cardiac arrest, and sudden death.
“Andexanet has a documented procoagulant effect that provides biological plausibility that andexanet caused these adverse events. However, these adverse events occurred in patients who were receiving anticoagulation and had an underlying disorder with increased risk for such events.”
Dr. Bryan said that the andexanet “study population may have important but unidentifiable differences compared to the historical control population. Thus, the comparison to the historical control is problematic.”
He said that in the absence of a reliable control, it is difficult to discern the actual proportion of these serious and life-threatening events and the proportion of these that would have occurred even in the absence of andexanet.
“A randomized clinical trial would provide a much better estimate of the true rate at which andexanet causes these serious adverse events. Pending such a randomized trial, the presumption is that andexanet may have caused these serious and life-threatening events.”
THE CLINICAL TRIALS
The company's application was based on the results a two parallel randomized, double-blind, placebo-controlled studies, which evaluated the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers ages 50-75 years. Published in the New England Journal of Medicine in December 2015, the primary endpoint of the two-part studies was anticoagulation reversal, with secondary endpoints including plasma levels of free unbound apixaban and endogenous thrombin potential, a measure of thrombin generation.
The study was conducted at two clinical sites, and each was done in two-parts: In the ANNEXA-A study, 33 subjects were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio of andexanet alfa as a 400 mg IV bolus (n=24) or placebo.
In the second part of the study, 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa as a 400 mg IV bolus, followed by a continuous infusion of 4 mg per minute for 120 minutes or placebo.
In the ANNEX-R study, 41 participants were randomized to receive 20 mg of rivaroxaban orally once daily for four days or placebo. On day four, at four hours after the last dose, andexanet was administered as an 800 mg IV bolus or as an 800 mg IV bolus followed by continuous infusion of 8 mg per minute for two hours.
The primary endpoint for both studies was the percent change in anti-factor Xa activity from baseline to after administration of andexanet or placebo. The results showed that following administration of a bolus of andexanet alfa, anticoagulant activity was reversed by 94 percent in the apixaban-treated participants compared with 21 percent in the placebo group (p<0.001). Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92 percent for those who received an andexanet bolus compared with 18 percent who received placebo (p<0.001). The results were sustained for both apixaban and rivaroxaban when andexanet was administered as a bolus plus an infusion.
Interim results from the company's ongoing phase 3b/4 trial were announced in March at the American College of Cardiology's 67th Annual Scientific Session.
Data showed treatment rapidly and significantly reversed anti-Factor Xa activity, with 83 percent of the patients achieving excellent or good hemostasis over a 12-hour period following treatment. During the 30-day follow-up, thrombotic events occurred in 11 percent of the subjects and the death rate was 12 percent, consistent with previous trial results.
“We will definitely use andexa for reversing both rivaroxaban and apixaban in patients who present with ICH while on those meds,” said Scott E. Kasner, MD MSCE, distinguished professor and vice chair for clinical affairs in the department of neurology at the Perelman School of Medicine of the University of Pennsylvania.
Dr. Kasner, who also serves as director of the university's Comprehensive Stroke Center, told Neurology Today that the requirement to further test the drug in the phase 4 trial is not uncommon.
“The FDA often requires post marketing studies, so I don't think that tempers my enthusiasm for using andexanet in this situation. The only real concern from my perspective is the need to repeat dosing until the drug effect is gone. The phase 4 study will help provide more data about how to optimize its use.”
Steven R. Levine, MD, professor of neurology and emergency medicine at State University of New York Downstate Medical Center, and vice chair of neurology at University Hospital of Brooklyn, said emergency departments need to be better prepared to administer treatment in a timely manner.
“We need rapid, effective antidotes when anticoagulants need reversing, but often in the ER, by the time a reversal order is given, it is already too late,” he told Neurology Today. “It is important to have Xa inhibitor reversal agents more readily available as soon as possible. Another potential issue that can cause a delay will be whether or not a hematologist is required to order the drug per hospital policy.”
It may be some time before answers to some of the questions surrounding use of the drug are answered, he acknowledged.
“Clinical trials do not always mirror real life, and there may still be more problems with andexanet,” Dr. Levine said. “We've had some experience with idarucizumab to reverse dabigatran, but it always takes real-life experience with something new like this. We also do not know how useful it will be for brain bleeds as there is typically a delay in reversing brain bleeds due to anticoagulation. There are no data on that — it's a big unknown at this point.”
Larry B. Goldstein, MD, FAAN, FANA, professor and chairman of the department of neurology at the University of Kentucky in Lexington, told Neurology Today that while clinical trial data indicate that andexanet alfa can rapidly reverse the anticoagulant effect of Factor Xa, there remain some issues that need to be addressed.
“This was an open-label study with no controls, and with clotting events occurring in 18 percent of patients within 30-days, including stroke, deep vein thrombosis, and myocardial infarction, all of which are potentially consistent with a procoagulant effect that was suggested in some healthy volunteers.
“The availability of rapid, effective reversal agents for patients having major bleeding while receiving one of the Factor Xa inhibitors is an important unmet need, and having these agents available is a significant advance,” he said.
However, the lack of control data, which he said will now be impossible to obtain, together with the potential for thromboembolic complications are a concern and prompted the FDA requirement for phase 4 data.
“Patients need to be informed of this uncertain risk, but faced with uncontrolled bleeding, the use of this or a similar agent is quite justified.”
Dr. Levine disclosed that he receives an honorarium from Medlink for review and editing of chapters on cerebrovascular disease topics.