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Evaluation of the pharmacodynamics of a ticagrelor reversal agent PB2452

Session New developments in anti thrombotic drug therapy

Speaker Lisa Jennings

Event : ESC Congress 2019

  • Topic : cardiovascular pharmacology
  • Sub-topic : Antiplatelet Drugs
  • Session type : Advances in Science

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)

Authors:
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 ,

Topic(s):
Antiplatelet Drugs

Citation:
European Heart Journal ( 2019 ) 40 ( Supplement ), 1356

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.

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