1. A monoclonal antibody fragment to ticagrelor, PB2452, increased platelet function significantly in healthy patients given the oral P2Y12 inhibitor ticagrelor.
2. Adverse effects were mainly limited to the infusion site, with limited systemic events.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Antiplatelet therapy is used extensively for prevention of cardiovascular occlusive events. Many patients receive dual-antiplatelet therapy with both aspirin and a P2Y12 inhibitor. Despite stoppage of P2Y12 inhibitors, patients can be at increased bleeding risk for several days after their last dose. This puts urgent surgical or invasive procedures at increased risk for excessive bleeding or can cause delay in surgery to allow the drug effect to wear off as there is no approval or effective reversal agent. PB2452 is a monoclonal antibody fragment developed as an antiplatelet agent for ticagrelor. This phase 1 study evaluated the safety and effect of PB2452. After PB2452 infusion, volunteers treated with ticagrelor had significantly increased platelet function, with maximal effect seen at 30 minutes following infusion. Following an extended PB2452 infusion, volunteers had platelet function return for up to 20 hours. Approximately one-third of participants receiving PB2452 experienced an adverse event, with most being proximal to the infusion site.
The results of this phase 1 study suggest that PB2452 can be a clinically useful ticagrelor reversal agent. Its strengths include testing of a first-in-class drug candidate and complete evaluation of safety outcomes. Its main limitation as a phase 1 study was the limited number of participants and narrow evaluation of drug efficacy.
Click to read the study, published today in NEJM
Relevant Reading: Novel antibody-based reversal agent for ticagrelor
In-Depth [randomized controlled trial]: This phase 1, single-center, double-blind, randomized controlled trial enrolled healthy volunteers between 18 and 50 years old during 2018. Participants were pretreated with ticagrelor and then assigned in a 3:1 ratio to receive either PB2452 (n=48), with 21 volunteers receiving the highest dose (18g), or placebo (n=16). Adverse events occurred in 35% of those receiving PB2452 (17/48), with 27 adverse events being reported in the group. Of the 16 volunteers receiving placebo, 2 (12%) reported an adverse event. No adverse events necessitated drug discontinuation or hospitalization. Ticagrelor was given 48 hours before either PB2452 or placebo treatment, and at 48 hours platelet aggregation was suppressed by 80-85%. After 30 minutes of PB2452 infusion of either 3g or 9g, maximal effect was seen immediately after the infusion ended and reversal effect lasted from 1 to 2 hours. When administered a 6g PB2452 bolus, reversal effect was seen at 5 minutes. When infusions were given over 12 to 16 hours, the PB2452 reversal effect lasted up to 20 hours. Multiple laboratory measurements were used to assess platelet activity and reversal agent effect. Antibodies to PB2452 were detected in 21 of 48 participants (44%) within 28 days of drug administration.
Image: PD
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