Early Phase Trial Shows PB2452 Immediately Reverses Ticagrelor’s Antiplatelet Activity

The monoclonal antibody fragment PB2452 effectively and immediately reversed the antiplatelet effects of ticagrelor in healthy volunteers, according to results from a phase I trial published in the New England Journal of Medicine.

Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction, but it is associated with increased risks of spontaneous major bleeding during urgent invasive procedures, lead author Deepak L. Bhatt, MD, from the Brigham and Women’s Hospital Heart & Vascular Center in Boston, told ASH Clinical News. “[PB2452] would be extremely useful in patients [on ticagrelor] who have an intracranial hemorrhage or need emergency cardiac surgery. Right now, there is no specific antidote available in these challenging scenarios.”

In this single-center, randomized, double-blind, placebo-controlled study, researchers recruited healthy volunteers (age range = 18-50 years) who were pretreated with ticagrelor. People with a contraindication to ticagrelor, a medical history suggestive of an increased bleeding risk, or an estimated glomerular filtration rate of <60 mL/min per 1.73 m2 of body-surface area were excluded. No effort was made to balance the groups on the basis of age, race or ethnic group, or sex, the authors reported.

Sixty-four participants were randomized 3:1 to receive either PB2452 (n=48) or placebo (n=16).

A total of 10 sequential dose cohorts were included in the analysis. In cohorts 1, 2, and 3, participants received a 30-minute infusion of PB2452 0.1 g, 0.3 g, and 1.0 g, respectively, or placebo in the absence of ticagrelor pretreatment to assess the initial safety of PB2452.

“We were glad to see that the onset of reversal of ticagrelor’s effect occurred within five minutes, which makes the drug ideal in cases of life-threatening bleeding where speed of reversal may be important.”

–Deepak L. Bhatt, MD

Volunteers in cohorts 4 through 10 were pretreated with loading doses of oral ticagrelor starting 48 hours before the investigational drug. In cohorts 4, 5, and 6, people received a 30-minute infusion of PB2452 at 1 g, 3 g, and 9 g, respectively, or placebo; in cohorts 7 through 10, volunteers received a fixed dose of PB2452 18 g or placebo.

Thirty percent (n=19) of volunteers experienced an adverse event (AE): In the PB2452 group, 17 patients (35%) reported 27 AEs; in the placebo group, 2 patients (12%) reported three AEs. There were no dose-limiting toxicities or infusion-related reactions reported, and no patients died or experienced an AE that led to treatment discontinuation.

“Changes in mean clinical laboratory test results, vital signs, and electrocardiographic results were similar across cohorts among volunteers who received different doses or regimens of PB2452 and were similar among those who received PB2452 and those who received placebo,” the authors reported.

After establishing the safety of PB2452, the investigators assessed the reversal of ticagrelor’s antiplatelet effects in cohorts 4 through 10. Platelet function was evaluated using light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. Measurements were taken prior to and following the 48-hour ticagrelor pretreatment period and following the administration of either PB2452 or placebo.

Forty-eight hours after ticagrelor pretreatment, platelet aggregation was suppressed by 80% to 85% in patients who received placebo and remained suppressed for an additional 24 hours after ticagrelor was stopped.

In the PB2452 cohorts, however, volunteers experienced a greater increase in platelet aggregation than those in the placebo group. For example, in cohorts 5 and 6, people who received a 30-minute infusion of PB2452 at doses of 3 g and 9 g had platelet aggregation at approximately 80% (p<0.02). Ticagrelor reversal reached maximal levels at 30 minutes, immediately after completion of the PB2452 infusion. The duration of reversal was dose-dependent and lasted one to two hours.

To attain more rapid and sustained ticagrelor reversal in the remaining cohorts, the investigators increased the total dose of PB2452 to 18 g delivered with an initial bolus and longer infusions of 8, 12, and 16 hours. They found that when PB2452 was administered as a 6-g bolus followed by a 12- or 16-hour infusion, reversal occurred within five minutes after initiation of infusion and was sustained for 16 to 24 hours (p<0.04).

The authors also found that platelet function (measured on all three assays) was restored to baseline levels within 24 hours after PB2452 administration.

“We were glad to see that the onset of reversal of ticagrelor’s effect occurred within five minutes, which makes the drug ideal in cases of life-threatening bleeding where speed of reversal may be important,” Dr. Bhatt commented, when asked about the findings’ implications. “We hope to study PB2452 next in patients with actual bleeding complications or in need of urgent or emergent surgery, as there is no reason to think the drug would behave differently [in them] than in the healthy volunteers we have studied to date.”

The inclusion of only healthy volunteers and the lack of patients with atherosclerosis, as well as the small sample size, represent potential limitations of the study.

The U.S. Food and Drug Administration granted PB2452 breakthrough-therapy designation in April 2019. If it is approved, Dr. Bhatt believes the reversal agent could be life-saving for patients who have severe bleeding complications after receiving ticagrelor. “If PB2452 were available, it [could] accelerate adoption of ticagrelor as the preferred oral ADP receptor antagonist, as its effects could be reversed, while no specific reversal agent exists for clopidogrel, prasugrel, or even aspirin for that matter,” he added.

The authors report relationships with PhaseBio Pharmaceuticals, which supported the study.


Bhatt DL, Pollack CV, Weitz JI, et al. Antibody-based ticagrelor reversal agent in healthy volunteers. N Engl J Med. 2019 March 17. [Epub ahead of print]