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

Jack E Ansell, Sasha H Bakhru, Bryan E Laulicht, Solomon S Steiner, Michael A Grosso, Karen Brown, Victor Dishy, Hans J Lanz, Michele F Mercuri, Robert J Noveck, James C Costin, Jack E Ansell, Sasha H Bakhru, Bryan E Laulicht, Solomon S Steiner, Michael A Grosso, Karen Brown, Victor Dishy, Hans J Lanz, Michele F Mercuri, Robert J Noveck, James C Costin

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01826266.

Keywords: Ciraparantag; anticoagulant; edoxaban; reversal; whole blood clotting time.

Conflict of interest statement

Conflicts of interest Dr. Ansell is a consultant to Perosphere, Inc. Drs. Bakhru, Costin, Laulicht, and Steiner are employees of Perosphere, Inc. Drs. Lanz, Mercuri, Grosso and Dishy are employees of Daiichi-Sankyo Pharma Development, the co-sponsor of this study. Dr. Brown was an employee of Daiichi Sankyo Pharma Development at the time this work was performed. Dr. Noveck is an employee of Duke Clinical Research Unit, the clinical research organization which conducted the study.

Figures

Figure 1: Study design
Figure 1: Study design
. All cohorts: n=10 (8 active + 2 placebo); 7 days between patient dosing within a cohort and 3 days between cohorts; in Period 2, ciraparantag or placebo administered approximately 3 h post edoxaban (EDX). The 25 mg dosing cohort was repeated using the WBCT to achieve a total of eight dosing cohorts.
Figure 2: Correlation of WBCT after a…
Figure 2: Correlation of WBCT after a 60 mg dose of edoxaban (A) and lack of effect of ciraparantag administration on WBCT (B).
Figure 3: Mean WBCT following a single…
Figure 3: Mean WBCT following a single i.v. dose of 25, 100, and 300 mg ciraparantag versus pooled saline placebo
. Data in subjects administered a single oral dose of edoxaban 60 mg (see Suppl. Table 2 for statistical assessment of differences, available online at www.thrombosis-online.com ).
Figure 4: Visual examination of blood clots…
Figure 4: Visual examination of blood clots from WBCT assay pre-and post- ciraparantag versus saline
. Scale bar: 1 inch (A) and clot fibrin structure pre- and post- ciraparantag (B) (upper and lower photos represent lower and higher magnification. Computer algorithm-based quantification of clot fibrin diameter showed a significant difference between saline vs native fibrin (p

Figure 5: Ciraparantag effect on D-dimer, prothrombin…

Figure 5: Ciraparantag effect on D-dimer, prothrombin fragment F1.2 and tissue factor pathway inhibitor (TFPI)

Figure 5: Ciraparantag effect on D-dimer, prothrombin fragment F1.2 and tissue factor pathway inhibitor (TFPI)
. Lower doses of ciraparantag (PER977) are deleted from panel C to make it visually more clear.
Figure 5: Ciraparantag effect on D-dimer, prothrombin…
Figure 5: Ciraparantag effect on D-dimer, prothrombin fragment F1.2 and tissue factor pathway inhibitor (TFPI)
. Lower doses of ciraparantag (PER977) are deleted from panel C to make it visually more clear.

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Source: PubMed

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