PB2452: A ticagrelor reversal agent

PB2452 is a novel recombinant human monoclonal antibody antigen-binding fragment, designed to reverse the antiplatelet activity of ticagrelor. Ticagrelor is an antiplatelet therapy widely prescribed to reduce the rates of death, heart attack and stroke in patients with acute coronary syndrome (ACS), or who have previously experienced a heart attack. The American College of Cardiology, American Heart Association and European Society of Cardiology guidelines recognize ticagrelor as the preferred antiplatelet therapy for ACS.

Ticagrelor binds to platelets to prevent them from forming blood clots, which could restrict blood flow. Due to ticagrelor’s antiplatelet activity, patients on ticagrelor have an elevated risk of spontaneous bleeding. In addition, patients on ticagrelor who need urgent surgery cannot wait the recommended five days for ticagrelor’s effect to dissipate and are at increased risk of major bleeding during and after surgery. There are currently no known reversal agents approved or in clinical development for ticagrelor or any of the other antiplatelet drugs.

PB2452 binds to ticagrelor with high affinity and specificity to reverse ticagrelor’s antiplatelet activity, as illustrated below:

We conducted a Phase 1 dose escalation clinical trial of PB2452 in healthy subjects who had been pre-dosed with ticagrelor. In this trial, we observed rapid and complete reversal of ticagrelor’s antiplatelet activity within five minutes following initiation of infusion, and sustained reversal for over 20 hours in later dosing cohorts in which we administered PB2452 over an extended infusion period. There were no PB2452-related adverse events or serious adverse events in any of the dose cohorts. The results of the Phase 1 study were published in the New England Journal of Medicine in a paper entitled, “An Antibody-Based Ticagrelor Reversal Agent in Normal Volunteers”. We recently completed a Phase 2a trial in which PB2452 achieved immediate and sustained reversal of the antiplatelet effects of ticagrelor in older (ages 50-64) and elderly subjects (ages 65-80) on dual antiplatelet therapy of ticagrelor and low-dose aspirin. Additionally, the Phase 2a trial investigated a PB2452 regimen for the reversal of supratherapeutic doses of ticagrelor in healthy younger subjects, which demonstrated immediate and sustained reversal of the antiplatelet effects of ticagrelor and was well tolerated, consistent with the earlier cohorts in the Phase 2a trial and the Phase 1 trial. We are currently conducting a Phase 2b trial to evaluate the safety and efficacy of PB2452 in approximately 200 older and elderly subjects (aged 50-80).

PhaseBio plans to initiate a single pivotal Phase 3 clinical trial of PB2452 in the first quarter of 2020 to support a Biologics License Application for PB2452 in both major bleeding and urgent surgery indications.

We believe that the availability of a reversal agent could expand ticagrelor’s use by mitigating concerns regarding bleeding risk and uniquely position ticagrelor as the only oral antiplatelet drug with a reversal agent.

We exclusively licensed PB2452 from MedImmune Limited, a wholly owned subsidiary of AstraZeneca.