Rapid and sustained reversal of P2Y12 inhibitor-induced platelet inhibition with reversal agent

Introduction and methods

The oral P2Y12 receptor antagonist ticagrelor is associated with increased bleeding risk, that persists for several days after drug cessation [1]. Guidelines recommend drug cessation at least 3-7 days before surgery {2,3]. Establishing hemostasis can be a challenge in patients who take P2Y12 inhibitors and have spontaneous major bleeding (intracranial or gastrointestinal) or in those who require urgent invasive procedures [4,5]. Platelet transfusions have shown to be ineffective in reversing the antiplatelet effects of ticagrelor.

Currently, there are no reversal agents for P2Y12 receptor antagonists. Ticagrelor is a reversible antagonist, which makes it feasible to develop a specific reversal agent. PB2452 has been developed as a neutralizing monoclonal antibody that binds ticagrelor and its active metabolite with high affinity [6].

This single-center, randomized, double-blind, placebo-controlled, single-ascending-dose, phase 1 trial examined the safety, efficacy and pharmacokinetic profiles of intravenous PB2452 in healthy volunteers (n=64) who were pretreated with ticagrelor 48 hours before. Ten sequential dose cohorts were done and volunteers in all cohorts were randomized in a 3:1 ratio to receive PB2452 (n=48) or placebo (n=16). Primary efficacy outcome was reversal of antiplatelet effects of ticagrelor assessed by platelet aggregation using light transmission aggregometry. Primary safety outcome was frequency and severity of adverse events.

Main results

• Of the volunteers that took PB2452, 17 (35%) reported 27 adverse events, mainly issues involving the infusion site, and of the volunteers that took placebo, 2 (12%) reported 3 adverse events. There were no toxic effects, or infusion-related reactions. Also, there were no deaths, hospitalizations or discontinuation of the trial drug due to adverse events.
• Of those who received PB2452, 21 (44%) individuals had detectable antidrug antibodies after exposure, with 15 (31%) already positive before exposure. In those who received placebo, 3 (19%) individuals had antidrug antibodies, with 2 (12%) having preexisting antibodies.
• 30-minute infusion of 3.0 and 9.0 g PB2452 resulted in a significantly greater increase in platelet aggregation compared to placebo. Maximal reversal occurred at 30 minutes and lasted 1-2 hours.
• Initial 3.0 g bolus and 8.0 hours infusion of 18.0 g PB2452 resulted in extended reversal of ~12 hours, but onset of reversal was delayed by ~2 hours.
• Bolus of 6.0 g PB2452 followed by 12 or 16 hours infusion of 18.0 g PB2452 resulted in rapid reversal (within 5 min after bolus) and was sustained for 16-24 hours.
• In cohorts 7-10 (with initial bolus and prolonged infusion of PB2452), volunteers who received PB2452 had a significantly greater increase in platelet aggregation compared to those who received placebo across all time points (5 min-20 hours, P<0.001). Data was confirmed with point-of-care P2Y12 platelet-reactivity test and vasodilator-stimulated phosphoprotein (VASP) assay (significant correlation for all comparisons).
• In cohort 9 and 10, mean platelet aggregation was restored after initiation with PB2452 (≥80% of baseline) at all time points up to 20 hours. Similar data were found with point-of-care P2Y12 platelet-reactivity test and VASP assay.
• No prothrombotic rebound effect in platelet reactivity after acute ticagrelor reversal was detected.

Conclusion

References

Find this article online at N Eng J Med