Bentracimab for Ticagrelor Reversal in Patients

BACKGROUND Ticagrelor is a reversible oral P2Y12 platelet inhibitor used to treat patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack, or ischemic stroke. A healthy volunteer study showed that the intravenous monoclonal antibody bentracimab rapidly reverses ticagrelor, but the effect in patients was unknown. METHODS In a prespecified interim analysis of a single-arm, prospective study, bentracimab was evaluated in ticagrelor-treated patients who required urgent surgery or had major hemorrhage. The extent of reversal was determined using the VerifyNow P2Y12 assay. Clinical hemostasis was assessed by central adjudication using validated criteria. Treatment-emergent safety events were evaluated. The trial is ongoing and will enroll approximately 200 patients with evaluable data. RESULTS Of 150 enrolled patients, 142 required urgent surgery and 8 had major hemorrhage. For the end-point analysis, 129 patients had analyzable platelet data; 122 had data on adjudicated hemostasis. Bentracimab provided a rapid reversal of ticagrelor’s antiplatelet effects within 5 to 10 minutes. The reversal was sustained for more than 24 hours, as measured with the VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays (P,0.001, with both assays and in all subgroups). Adjudicated hemostasis was achieved for more than 90% of patients (P,0.001); approximately 5% of patients had thrombotic events. No allergic or infusion-related reactions were reported. CONCLUSIONS Bentracimab provided immediate and sustained reversal of the antiplatelet effects of ticagrelor in patients undergoing surgical procedures. (Funded by PhaseBio Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT04286438.) The author affiliations are listed at the end of the article. Dr. Bhatt can be contacted at dlbhattmd@post.harvard.edu or at Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. *The REVERSE-IT investigators are listed in Supplementary Appendix S1. For personal use only. No other uses without permission. Copyright © 2021 Massachusetts Medical Society. Published December 1, 2021 DOI: 10.1056/EVIDoa2100047 Introduction T icagrelor is a potent oral antiplatelet medication that is a P2Y12 receptor antagonist. Randomized clinical trials have demonstrated its efficacy in reducing ischemic events in patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack, and stroke, based on multiple randomized clinical trials. Several regulatory agencies worldwide, including the Food and Drug Administration (FDA), have approved ticagrelor for use in such patients. A major limitation of antithrombotic therapy is the risk for bleeding during urgent surgical or invasive procedures and the risk of spontaneous hemorrhage. Unlike irreversible antiplatelet agents such as aspirin, clopidogrel, and prasugrel whose effects persist for the lifetime of the platelet, ticagrelor and its major metabolite bind reversibly to the P2Y12 receptor. 10 Consequently, ticagrelor and its metabolite can bind to P2Y12 receptors on transfused platelets, rendering platelet transfusion of limited value in ticagrelor-treated patients requiring urgent surgery or with serious bleeding. Bentracimab (also known as PB2452) is a neutralizing recombinant human immunoglobulin G1 monoclonal antibody antigen-binding fragment that binds ticagrelor and its major active circulating metabolite with high affinity and specificity. In healthy volunteers, bentracimab appeared to be safe and effective for the reversal of ticagrelor’s antiplatelet effects and was granted a Breakthrough Therapy designation by the FDA in 2019. We aimed to study bentracimab in patients in need of ticagrelor reversal to determine its effects on platelet inhibition and hemostasis.