Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban

Ansell, Jack; Bakhru, Sasha; Laulicht, Bryan; Steiner, Solomon S.; Grosso, Michael; Brown, Karen; Dishy, Victor; Noveck, Robert J.; Costin, James

doi:10.1056/nejmc1411800

Cited by 395 publications

(226 citation statements)

References 2 publications

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“…Despite the overall positive benefit–risk profile of dabigatran, life‐threatening bleeding in patients being treated with anticoagulant therapies remains an infrequent but real risk 9. Hence, reversal agents for dabigatran and the other non‐vitamin K oral anticoagulants are in development 10, 11, 12, 13, 14.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Norris

Ramael

Ikushima

et al. 2017

Brit J Clinical Pharma

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AimsIdarucizumab, a humanized monoclonal anti‐dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre‐existing and treatment‐emergent anti‐idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre‐existing and treatment‐emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab.MethodsData were pooled from three Phase I, randomized, double‐blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre‐existing ADA.ResultsPre‐existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre‐existing and treatment‐emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre‐existing ADA had no impact on dose‐normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran‐induced anticoagulation by idarucizumab. Treatment‐emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C‐terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions.ConclusionPre‐existing and treatment‐emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre‐existing ADA.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Norris

Ramael

Ikushima

et al. 2017

Brit J Clinical Pharma

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“…Aripazine (PER977; Perosphere, Bedford, New York, USA) is a small synthetic molecule that binds to TSOACs via non-covalent bonding and charge-charge interactions and is currently undergoing clinical development as a nonspecific TSOAC reversal agent [26]. Although it has not been shown to reverse TSOAC-related coagulation test abnormalities in vitro, it reduced bleeding in a rivaroxabantreated rabbit liver laceration model [27,28].…”

Section: Aripazinementioning

confidence: 99%

“…Although it has not been shown to reverse TSOAC-related coagulation test abnormalities in vitro, it reduced bleeding in a rivaroxabantreated rabbit liver laceration model [27,28]. In a doubleblind, placebo controlled study aripazine decreased wholeblood clotting times in edoxaban-treated healthy volunteers (60 mg single dose) [26]. A phase II study of aripazine in volunteers receiving edoxaban is currently underway (clinicaltrials.gov identifier NCT02207257).…”

Section: Aripazinementioning

confidence: 99%

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

Siegal

2015

J Thromb Thrombolysis

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Target-specific oral anticoagulants (TSOACs) dabigatran, rivaroxaban and apixaban are approved for the prevention and treatment of thromboembolism in several clinical settings. Bleeding is the major complication of anticoagulant therapy, including TSOACs, and anticoagulant reversal strategies are highly desired for the management of anticoagulant-associated major bleeding in addition to maximum supportive care and procedural/surgical intervention. Unlike VKAs for which vitamin K and coagulation factor replacement with prothrombin complex concentrate (PCC) can restore hemostasis, there are no clinically available agents proven to reverse TSOAC anticoagulant effect and ameliorate TSOAC-related major bleeding. This narrative review critically evaluates the evidence for TSOAC reversal using non-specific reversal agents PCC, activated PCC (APCC) and recombinant activated factor VII (rVIIa) which have been assessed primarily using in vitro experiments, animal models and healthy human volunteers. Aripazine is a novel agent undergoing clinical development for non-specific anticoagulant reversal, including TSOACs. Data are presented regarding specific reversal agents idarucizumab (dabigatran) and andexanet alfa (oral factor Xa inhibitors) currently being evaluated in clinical trials. A practical approach to management of patients with TSOAC-associated bleeding is also provided. There is an urgent need for clinical studies that evaluate the efficacy and safety of reversal strategies for TSOAC-related major bleeding with assessment of clinical outcomes such as bleeding and mortality.

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“…The preferred method for monitoring NOAC according to latest British guidelines 4 include the ecarin clotting time and the dilute thrombin time for monitoring dabigatran, and the anti-factor Xa assays for monitoring the direct factor X inhibitors. Now a recent phase I clinical trial has appeared 5 …”

Section: Newer Oral Anticoagulantsmentioning

confidence: 99%

Oral surgery: Checklists and double checks

2015

Br Dent J

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Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban

Cited by 395 publications

References 2 publications

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents

Oral surgery: Checklists and double checks

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