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The Clinical Need
The Clinical Need

Antiplatelet therapy is an essential part of secondary prevention of cardiovascular events.  In particular, dual antiplatelet therapy (DAPT) — the combination of aspirin with an oral P2Y12 receptor antagonist — is the predominant approach in patients with acute coronary syndromes (ACS), coronary-artery stenting, or previous myocardial infarction (MI). The three oral P2Y12 receptor antagonists that are in use are clopidogrel, prasugrel, and ticagrelor.

An unavoidable limitation of all three oral P2Y12 receptor antagonists is increased bleeding risk from platelet inhibition, which persists for several days after drug cessation. Establishment of hemostasis can be challenging in patients with major bleeding, such as intracranial or gastrointestinal hemorrhage. In addition, urgent invasive procedures, especially emergency procedures, are associated with an increased risk of periprocedural bleeding. If an emergency procedure is indicated, the surgeon or proceduralist must proceed while accepting the increased bleeding risk, often after empirically providing platelet transfusions, despite the ineffectiveness of such transfusions in reversing the antiplatelet effects of P2Y12 inhibitors. If an urgent procedure is indicated, the proceduralist must either proceed while anticipating the increased bleeding risk or postpone the procedure for several days while accepting the risks associated with delaying a clinically indicated procedure. American College of Cardiology Foundation–American Heart Association, European Society of Cardiology, and other society guidelines recommend cessation of oral P2Y12 receptor antagonists at least 3 to 7 days before surgery.  Currently, no reversal agents for P2Y12 receptor antagonists are known. Unlike the other P2Y12 receptor antagonists, ticagrelor is a reversible inhibitor, which makes the development of a specific reversal agent for ticagrelor feasible.

Acknowledgement of this important gap in clinical care is evidenced by regulatory action in both the US and Europe.  In April 2019, PB2452 received Breakthrough Therapy designation from the FDA. Breakthrough Therapy designation may be granted by FDA when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapy. There currently is no alternative reversal therapy for the antiplatelet effects of ticagrelor or any other antiplatelet drugs.  Similarly, in February 2020, the European Medicines Agency granted bentracimab PRIME Designation.  PRIME designation is granted by the EMA to enhance support for the development of medicines that demonstrate the potential to address substantial unmet medical need based on early clinical data. The EMA prioritizes PRIME designated drugs for special support, including enhanced interactions and dialogue with EMA during development, as well as a pathway for accelerated evaluation and review for marketing authorization. The program is intended to optimize development plans and potentially expedite the review and approval process so that these medicines may reach patients as early as possible.  In its review comments for PRIME designation, EMA recognized the unmet need for an effective reversal agent for ticagrelor-induced platelet inhibition. EMA acknowledged that, while infrequent, ticagrelor-related major bleeding events are associated with relevant morbidity and mortality. Urgent surgical interventions (such as coronary artery bypass grafting) that cannot be delayed to allow full washout of ticagrelor are associated with an increased risk for intra- and post-procedural bleeding events. EMA also acknowledged that there are no established effective treatment options to reverse ticagrelor-induced platelet inhibition.