Update on Antidotes for New Oral Anticoagulants

CardioBuzz: Update on Antidotes for New Oral Anticoagulants

Published: Nov 10, 2014

By Stephan Moll, MD

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In this guest blog, Stephan Moll, MD, lays out how antidotes are shaping up for the new oral anticoagulants (NOACs).

The New England Journal of Medicine reported last week a phase I study of a new drug (PER977, Aripazine) that may be effective as an antidote for several of the new oral anticoagulants, as well as some of the established anticoagulants. But it's not the only one in the works. Here is an update on the pipeline.

Aripazine (PER977, ciraparantag)

• What is the drug? Aripazine is a synthetic small molecule (D-arginine compound) that has broad activity against various old (heparin, low-molecular-weight heparin) and new oral anticoagulants (dabigatran [Pradaxa], rivaroxaban [Xarelto], apixaban [Eliquis], and edoxaban [Savaysa; not yet FDA approved for any indication]). It binds to the anticoagulants through noncovalent hydrogen bonding and charge-charge interactions. It is being developed by Perosphere.
• What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban, dabigatran, heparin, low-molecular-weight heparin (LMWH).
• Clinical trial status: This week's NEJM reports -- as a letter-to-the editor -- a study in which 80 healthy volunteers received one dose of the new oral anticoagulant edoxaban, followed by intravenous PER977 at various doses. Whole-blood clotting times that were prolonged as expected with edoxaban markedly shortened (to within 10% above the pre-edoxaban baseline value) within 10 minutes after dosing with PER977. Another healthy volunteer study is presently ongoing.

Andexanet (PRT064445)

• What is it? Recombinant, modified factor Xa molecule that is being developed as a direct reversal agent for patients receiving a factor-Xa inhibitor who suffer a major bleeding episode or who require emergency surgery. It sort of sops up the anti-Xa anticoagulant, making a patient's own factor Xa again available to participate in the coagulation process. The drug is being developed by Portola.
• What anticoagulant drugs might it reverse? Apixaban, edoxaban, rivaroxaban.
• Clinical trial status: Healthy volunteer studies to evaluate the ability of andexanet to reverse the effects of several anticoagulant drugs on laboratory tests are presently ongoing.

Idarucizumab (BI 655075)

• What is it? It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment. It is being developed by Boehringer-Ingelheim.
• What anticoagulant drugs might it reverse? Dabigatran.
• Clinical trial status: A phase III study of patients on dabigatran with major bleeding or needing emergency surgery is ongoing. Three phase I studies to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers have been completed.