Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban

Abstract

SummaryOf 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.Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA

Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy

“…164 In healthy volunteers, it was found to completely reverse the anticoagulant effects of both enoxaparin and edoxaban. 165,166 However, further clinical studies are needed before both of these compounds will become available.…”

Pharmacological reversal of the direct oral anticoagulants—A comprehensive review of the literature

“…Scanning electron micrographs also demonstrated a dose‐dependent increase in fibrin structure formation following ciraparantag administration. There was no evidence of procoagulant effects following administration of ciraparantag as assessed by D‐dimer, prothrombin fragment 1 + 2 and tissue factor pathway inhibitor (TFPI) levels . Ciraparantag is currently under further investigation in phase 2 clinical trials (NCT03288454, NCT03172910).…”

“…102 Ciraparantag has been assessed in healthy volunteers following administration of a single 60-mg dose of edoxaban. 103,104 In a placebo-controlled, double blind, escalating dose study involving 80 healthy subjects, whole-blood clotting time (WBCT) was used to assess the effects of edoxaban on coagulation and reversal with ciraparantag which reduced the WBCT to within 10% of baseline at 10 minutes post-administration and persisted for 24 hours. Clot structure (as assessed by scanning electron microscopy) was restored to baseline following a single 100 mg IV dose of ciraparantag.…”

“…There was no evidence of procoagulant effects following administration of ciraparantag as assessed by D-dimer, prothrombin fragment 1 + 2 and tissue factor pathway inhibitor (TFPI) levels. [103][104][105] Ciraparantag is currently under further investigation in phase 2 clinical trials (NCT03288454, NCT03172910).…”

Recent advances in the understanding and management of atrial fibrillation: a focus on stroke prevention

“…In addition, andexanet alfa (a truncated form of enzymatically inactive factor Xa which binds factor Xa inhibitors and reverses their anticoagulant effects) was investigated for the reversal of oral factor Xa inhibitors 65 . Also under development is ciraparantag 66 , which is at an earlier stage of development as a universal reversal agent for all NOACs.…”