In line with the ESC mission, newly presented content is made available to all for a limited time (4 months for ESC Congress, 3 months for other events). ESC Professional Members, Association Members (Ivory & above) benefit from year-round access to all the resources from their respective Association, and to all content from previous years. Fellows of the ESC (FESC), and Professionals in training or under 40 years old, who subscribed to a Young Combined Membership package benefit from access to all ESC 365 content from all events, all editions, all year long. Find out more about ESC Memberships here.
Evaluation of the pharmacodynamics of a ticagrelor reversal agent PB2452
Authors : L Jennings (Memphis,US), BJ Curry (Memphis,US), DL Bhatt (Boston,US), CV Pollack Jr (Philadelphia,US), JI Weitz (Hamilton,CA), S Xu (Malvern,US), JS Lee (Malvern,US)
L. Jennings1
,
B.J. Curry1
,
D.L. Bhatt2
,
C.V. Pollack Jr3
,
J.I. Weitz4
,
S. Xu5
,
J.S. Lee5
,
1CirQuest Labs - Memphis - United States of America
,
2Harvard Medical School - Boston - United States of America
,
3Thomas Jefferson University - Philadelphia - United States of America
,
4McMaster University - Hamilton - Canada
,
5PhaseBio Pharmaceuticals, Inc - Malvern - United States of America
,
Background: Ticagrelor is a P2Y12 antagonist used in combination with aspirin to reduce the risk of recurrent thrombotic cardiovascular events in patients with acute coronary syndrome. Ticagrelor is associated with a risk for spontaneous major bleeding or bleeding associated with invasive procedures, particularly cardiac surgery. A rapid-acting reversal agent for ticagrelor would be advantageous. The pharmacodynamic effects of ticagrelor and a ticagrelor reversal agent are best evaluated using a panel of platelet function tests that have different sensitivities and methodologies and using a variety of agonists at different concentrations.
Purpose: In a first-in-human randomized, double-blind, placebo-controlled, healthy volunteer Phase 1 study, intravenous (IV) PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, was evaluated as a ticagrelor reversal agent.
Methods: Platelet function was assessed using light transmission aggregometry (LTA) and 5 and 20 μM adenosine diphosphate (ADP), 1.6 mM arachidonic acid (AA), and 15 μM thrombin receptor agonist peptide (TRAP-6) as agonists. The VerifyNow P2Y12 cartridges, which assess whole blood platelet function, were evaluated as a point-of-care test. A modified vasodilator-stimulated phosphoprotein (VASP) ELISA was used to assess the extent of P2Y12 signaling. These assessments were performed 48 h prior to ticagrelor administration and at multiple time points up to 48 h after administration of PB2452 or placebo.
Results: 64 subjects were randomized; 48 received PB2452 and 16 received placebo. After ticagrelor administration, LTA response to 20 μM ADP was inhibited by 87% compared to the pre-ticagrelor values. Platelet function as measured by the VerifyNow P2Y12 cartridge was completely inhibited (<10 platelet reactivity units [PRU]). The VASP platelet reactivity index (PRI) was inhibited by 82%. Ticagrelor reduced TRAP-6 induced LTA by 30% reflecting the effect of ADP on platelet aggregate stability. PB2452 administered as a 10 min IV bolus followed by 16 h infusion, significantly restored platelet function to >80% and >90% of baseline as measured by LTA using ADP and TRAP-6, respectively, to >180 PRU using VerifyNow, and to >90% PRI as measured by VASP. The VASP assay enabled batch analyses in a central laboratory, eliminating the need for special equipment on-site and reducing operator variability. When platelet function was assessed by VASP, PB2452 administration produced rapid ticagrelor reversal within 5 min consistent with restoration of P2Y12 signaling. Onset of reversal by all measurements occurred within 15 min of PB2452 administration and was sustained for 20–24 h.
Conclusions: PB2452 is a specific reversal agent for ticagrelor and produces a rapid and sustained reversal of ticagrelor inhibition of platelets. Utilizing multiple platelet function assays provided a broader understanding of the PB2452 pharmacodynamics in this first-in-human Phase 1 study.
In line with the ESC mission, newly presented content is made available to all for a limited time (4 months for ESC Congress, 3 months for other events). ESC Professional Members, Association Members (Ivory & above) benefit from year-round access to all the resources from their respective Association, and to all content from previous years. Fellows of the ESC (FESC), and Professionals in training or under 40 years old, who subscribed to a Young Combined Membership package benefit from access to all ESC 365 content from all events, all editions, all year long. Find out more about ESC Memberships here.