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Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.

The new oral anticoagulants have many advantages over vitamin K antagonists, but they are still associated with a troublesome incidence of major bleeding. Additionally, the absence of a reversal agent for the new oral anticoagulants is a barrier to their more widespread use. Currently, there are 3 potential reversal agents in development: idarucizumab is a humanized murine monoclonal antibody fragment directed specifically at dabigatran; andexanet alfa is a recombinant modified decoy factor Xa that binds to factor Xa inhibitors; and PER977 is a small molecule that binds to factor Xa and IIa inhibitors and to heparin-based anticoagulants through charge interaction. These agents have undergone phase I clinical testing, appear to be well tolerated in healthy volunteers, and are effective in neutralizing their respective targets. All 3 are currently undergoing or entering into a phase II or III clinical study. This article reviews the available data for idarucizumab, andexanet alfa, and PER977.