Ticagrelor Reversal Agent on the Horizon

March 25, 2019

NEW ORLEANS — A reversal agent for the P2Y12 inhibitor antiplatelet drug ticagrelor (Brilinta/Brilique, AstraZeneca) may soon be available after results of a new study showed immediate and sustained reversal of the antiplatelet effects of the drug.

The reversal agent, an antibody known as PB2452 (PhaseBio Pharmaceuticals), is specific for ticagrelor and is not thought to work for clopidogrel (Plavix, Sanofi) or prasugrel (Effient, Eli Lilly).

The new study, which was conducted in healthy volunteers, was presented at the American College of Cardiology 68th Annual Scientific Session (ACC) 2019 on March 17 and was published simultaneously in the New England Journal of Medicine.

"We found the antibody reverses the effects of ticagrelor within 5 minutes of administration, and the effect is sustained for as long as the infusion is given," lead author Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, Massachusetts, commented to Medscape Medical News.

"The reason this is so exciting is that, if this drug is approved, then we will have something for patients on ticagrelor who are having a catastrophic bleed, such as a brain hemorrhage. Right now, there's not much we can do in that situation, as platelet transfusions do not work well for reversing the effects of P2Y12 inhibitors," Bhatt explained.

"It will also be very useful for patients on ticagrelor who need emergency surgery," he added.

Bhatt noted that beyond these emergency situations, the reversal agent will also be useful for patients who need urgent but not necessarily emergency surgery. "At present, patients on ticagrelor or similar drugs have to wait 5 days for surgery, but in future, this agent could be given and the patient could have surgery straight away," he said.

Bhatt hopes that on the basis of this study, the reversal agent will be approved by the US Food and Drug Administration (FDA). "My hope is that the US FDA might consider approval for emergency use on the basis of these data in heathy volunteers," he said. "This is what happened for the reversal agents for the novel oral anticoagulant drugs that have now become available."

In the NEJM article, the authors explain that ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk for ischemic events for patients with acute coronary syndrome or who have previously experienced myocardial infarction (MI).

They point out that a limitation of all three oral P2Y12 receptor antagonists is the increased bleeding risk, 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," Bhatt said.

If an emergency procedure is indicated, the surgeon or proceduralist must proceed while accepting the increased bleeding risk, he noted. "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."

The authors note that no reversal agents for P2Y12 receptor antagonists are currently available. Unlike the other P2Y12 receptor antagonists, ticagrelor is a reversible inhibitor, which makes the development of a specific reversal agent for ticagrelor feasible.

PB2452 is a neutralizing monoclonal antibody fragment that binds ticagrelor and its major active circulating metabolite with high affinity.

The current double-blind, placebo-controlled, phase 1 trial included 64 healthy volunteers. Platelet function was assessed before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay.

Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%.

PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours.

There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to problems involving the infusion site.

The researchers note that PB2452 is a recombinant human IgG1 monoclonal antibody antigen–binding fragment that binds with high affinity and specificity to rapidly neutralize ticagrelor and its active metabolite.

"The high affinity and specificity of PB2452 enables it to neutralize free ticagrelor and prevent binding to the P2Y12 receptor. These properties explain the immediate reversal that was observed with PB2452, and such reversal is a key feature for patients with hemorrhage," they write. The mechanism of action is expected to be specific to ticagrelor and not to work with clopidogrel or prasugrel, which are irreversible P2Y12 receptor antagonists, they note.

The authors caution that the trial involved healthy volunteers, so the results may not be predictive of the reversal or safety profile of PB2452 in a patient population or the effect of PB2452 on the establishment of hemostasis or the prevention of bleeding.

The study was supported by PhaseBio Pharmaceuticals, Inc. Bhatt reports having received grants from PhaseBio Pharmaceuticals, Inc, during the conduct of the study. Other disclosures for Bhatt and other coauthors are available at www.nejm.org.

N Engl J Med. Published online March 17, 2019. Abstract

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