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Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of ACT017, an Anti-platelet Glycoprotein VI Fab: First in Human Healthy Volunteer Trial
ISTH Academy. Jandrot-Perrus M. Jul 10, 2019; 273796; OC 78.2
Martine Jandrot-Perrus
Martine Jandrot-Perrus
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OC 78.2

Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of ACT017, an Anti-platelet Glycoprotein VI Fab: First in Human Healthy Volunteer Trial

C. Voors-Pette1, L. Kristell2, P. Dogterom1, L. Jullien2, P. Billiald3, P. Ferland2, L. Renaud4, O. Favre-Bulle2, G. Avenard2, M. Machacek4, Y. Pletan2, M. Jandrot-Perrus5
1QPS Holdings LLC, Groningen, the Netherlands, 2Acticor-Biotech, Paris Cedex, France, 3University Paris Sud, Châtenay Malabry, France, 4LYO-X GmbH, Allschwil, Switzerland, 5INSERM / University Paris Diderot, UMR_S 1148, Paris Cedex, France

Main Topic: Platelets and Megakaryocytes
Category: Platelet Antagonists & Novel Therapeutics

Background: Glycoprotein VI (GPVI) is accepted as being a target to develop effective antiplatelet agents without bleeding risk. ACT017 is an anti-GPVI clinical-grade fragment of monoclonal antibody. Preclinical studies of ACT017 in non-human primates have shown its ex vivo biological efficacy, excellent tolerability and established a protocol of administration.
Aims: This first-in-human study aimed to evaluate the safety and tolerability, PK and PD of single ascending intravenous doses of ACT017.
Methods: Protocol, subject information and informed consent form, were approved by the Independent Ethics Committee (IEC) of QPS the competent authority of the Netherlands (CCMO). Six cohorts of eight healthy male and female subjects each, received ascending single doses (62.5 to 2000 mg) of ACT017 as a 6-hour i.v. infusion, with ¼ of the total dose administered within 15 minutes and the rest of the dose within the next 5 hours and 45 minutes. Safety and tolerability parameters, including bleeding time platelet counts and platelet GPVI expression, biological efficacy on collagen-induced platelet aggregation, and plasma concentrations of ACT017 were evaluated up to 48 hours post dose.
Results: All doses of ACT017 were well tolerated and no serious adverse events occurred during the study. None of the subjects reported an infusion site reaction. Bleeding time was not affected in a clinically significant manner by any of the ACT017 doses. Plasma concentrations increased linearly with the dose received and PK values were established. There was no modification in the platelet count and platelet GPVI expression. Administration of ACT017 inhibited collagen-induced platelet aggregation and the extent and duration of the effect were dose-dependent.
Conclusions: The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favourable safety and tolerability profiles in healthy volunteers. This first in human study paves the way for the subsequent assessment of ACT017 safety and efficacy in patients with thrombosis.

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