Originally approved under the accelerated approval pathway, the promising efficacy observed in the study will prompt a future regulatory submission for traditional.
In line with recommendations from an Independent Data and Safety Monitoring Board review, AstraZeneca has stopped its phase 4 post-marketing study (NCT02329327) of andexanet alfa (Andexxa) in patients on oral inhibitors of activated coagulation factor Xa (FXa). The decision was based on the achievement of prespecified criteria of superior hemostatic efficacy.
Andexanet alfa was FDA-approved under the accelerated approval pathway as a therapy designed to reverse the anticoagulation effects of direct oral FXa inhibitors such as rivaroxaban or apixaban, when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding. Following a planned interim assessment of efficacy in 450 enrolled individuals followed for 1 month, treatment with andexanet alfa showed reversal benefits earlier than originally anticipated, prompting the company to stop the trial early. AstraZeneca will proceed with regulatory filings in the US and EU to convert the therapy to full traditional label approval.
"We are pleased that the study has met its efficacy endpoint at the planned interim analysis, showing improved control of bleeding with targeted anticoagulation reversal, compared to usual care," Stuart J. Connolly, MD, FRCPC, a senior scientist at the Population Health Research Institute and professor emeritus at McMaster University, said in a statement.1 "We look forward to sharing the full efficacy and safety results after further analysis, with the hope that the data will pave the way for further guidance on the treatment of potentially life-threatening bleeds."
The phase 4 post-marketing trial, dubbed ANNEXA-1, was a randomized, multicenter trial that featured adult patients aged at least 18 years old with intracranial hemorrhage who’ve received oral FXa inhibitors, including apixaban and rivaroxaban. Intended to confirm the efficacy and safety of andexanet alfa, the primary end point of the study was the rate of effective hemostasis, or stopping the flow of blood, compared with usual care, including 4-factor prothrombin complex concentration.
"Millions of people worldwide depend on FXa inhibitors to prevent harmful blood clots from forming, but these agents also carry a small but significant risk of increasing the likelihood that an acute major bleed could occur,” Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca, said in a statement.1 "We are proud to offer the first and only approved treatment to specifically reverse FXa inhibitor activity and help achieve hemostasis, providing an effective and reliable treatment when immediate care is required."
Previous research has shown that direct or indirect factor Xa inhibitors are effective anticoagulants for the treatment and prevention of thromboembolism, and stroke prevention in atrial fibrillation. Despite showing a better bleeding risk profile compared with vitamin K antagonists, the risk of bleeding complications still exists. Andexanet alfa acts as a decoy and binds to factor Xa inhibitors, neutralizing the anticoagulant effects of factor Xa inhibitors by preventing the inhibitors from binding to endogenous factor Xa.
Andexanet alfa received FDA approval under the accelerated approval pathway in May 2018 based on 2, randomized, placebo-controlled phase 3 trials—ANNEXA-A (NCT02207725) and ANNEXA-R (NCT02220725). In the studies, among the apixaban-treated participants, anti-factor Xa activity, a measure of factor Xa inhibition, was reduced by 94% among those who received an andexant bolus (n = 24) compared with those on placebo (P <.001. In addition, rivaroxaban-treated individuals saw a 92% reduction in anti-factor Xa activity relative to placebo (P <.001). In a subgroup of participants, investigators observed transient increases in levels of D-dimer and prothrombin fragments 1 and 2, which were resolved within 24 to 72 hours.2