NEW ORLEANS — An antidote to ticagrelor (Brilinta) provided quick and sustained reversal of the antiplatelet’s effects in a small phase I trial, according to researchers here.
Experiments showed healthy volunteers recovering more platelet function after 48-hour ticagrelor pretreatment if they then took PB2452 instead of placebo, reported Deepak Bhatt, MD, of Brigham and Women’s Hospital in Boston, and colleagues at the American College of Cardiology (ACC) annual meeting, and simultaneously in the New England Journal of Medicine.
Based on the results of multiple assays, “Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours,” they stated.
PB2452 is a monoclonal antibody fragment that binds to ticagrelor “with high affinity and specificity,” the authors noted. “The mechanism of action is expected to be specific to ticagrelor and not work with clopidogrel [Plavix] or prasugrel [Effient], which are irreversible P2Y12 receptor antagonists.”
As for safety, those who received the ticagrelor antidote exhibited some “low-grade toxic effects,” most commonly infusion site bruising and other reactions, the researchers said.
For the trial, Bhatt and colleagues randomized healthy volunteers (ages 18-50; BMI 18-35) to intravenous PB2452 (n=48) or placebo (n=16). They tested the reversal agent group with different initial doses and prolonged infusions of 8, 12, or 16 hours.
The duration of reversal depended on dose and infusion time, which led ACC session panelist Barbara Wiggins, PharmD, of the Medical University of South Carolina in Charleston, to comment that there is the possibility that clinicians can “tailor” their use of PB2452 depending on the situation.
Aside from immediate ticagrelor reversal in intracranial hemorrhage, sustained reversal may be helpful for those undergoing emergency heart surgery and heart transplantation, she suggested.
Ticagrelor pretreatment resulted in an approximately 80% reduction in platelet aggregation for both placebo and experimental groups. The assays used to assess platelet function were the VerifyNow P2Y12 assay and a modified CY-QUANT VASP P2Y12 assay.
It cannot be said that the results will be replicated in patients with atherosclerosis, or whether reversing the antiplatelet effects of ticagrelor by PB2452 would lead to more rapid hemostasis in bleeding patients, or prevent bleeding during urgent invasive procedures, Bhatt’s group cautioned.
But without an antidote for oral P2Y12 antagonists, the only choice now is to wait out their effects over 3-5 days, “a method that is problematic in patients who have life-threatening bleeding or a high risk of thrombosis,” they said.
It’s important to have a “safety net” for patients in the case of a major bleeding episode, commented Robert Rosenson, MD, of The Mount Sinai Hospital in New York City, who was not involved in the trial.
Yet the rarity of such catastrophic bleeds will make it difficult to evaluate PB2452’s efficacy in a randomized trial, so this is a therapy that will need to be tested in the real world, Rosenson told MedPage Today.
The trial was funded by PhaseBio Pharmaceuticals. Some co-authors are company employees.
Bhatt disclosed multiple relevant relationships with industry including PhaseBio.
Rosenson disclosed institutional funding from AstraZeneca.