T1030-13-83 - Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ACT017, an Anti-platelet GPVI (Glycoprotein VI) Fab in Healthy Volunteers
Purpose: Platelets are central to thrombus formation, the leading cause of global mortality estimated to account for one in 4 deaths worldwide in 2010. Thrombosis is associated with cardiovascular diseases (e.g. myocardial infarction, stroke, lower limb ischemia, venous thromboembolism) and with numerous pathologies, such as cancer (Trousseau syndrome), infections or inflammatory diseases. Antiplatelet drugs, such as aspirin, P2Y12 antagonists, and GP (glycoprotein) IIb/IIIa inhibitors are of proven benefit in reducing the morbidity and mortality associated with arterial thrombosis. However, these drugs all carry an inherent risk of bleeding that restricts their use in sensitive populations e.g. elderly, and when arterial thrombosis occurs in the cerebral territory. At present, the only acute treatment option available for ischemic stroke consists of revascularization with r-tPA (recombinant tissue-type plasminogen activator) or mechanical thrombectomy.
Platelet glycoprotein VI (GPVI) is a typical example of a platelet pathway that is dispensable for physiological hemostasis but critical for thrombus formation and growth. Evidence exist that GPVI antagonists could have a specific and effective anti-thrombotic effect combined with a minimal risk of bleeding.
ACT017 is a humanized fragment of monoclonal antibody (Fab) directed against human GPVI. Pre-clinical studies with ACT017 in non-human primates have shown its ex vivo biological efficacy, its excellent tolerability, even in association with rtPA.
Here we report on the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenously administered ACT017 in this first-in-men study conducted in healthy volunteers.
Methods: This was a double blind, placebo-controlled, randomized, phase 1 study with single ascending doses of 62.5, 125, 250, 500, 1000, and 2000 mg ACT017 or matching placebo. Within each dosing cohort, 6 subjects received ACT017 and 2 subjects received placebo. Administration was as a 6-hour i.v. infusion, with ¼ of the total dose administered within 15 minutes and the rest of the dose (¾ of the total dose) administered within the next 5 hours and 45 minutes.
Safety was assessed by monitoring for local site reactions, adverse events (AEs), vital signs, ECG’s, physical examinations, and safety laboratory results, including coagulation parameters. Bleeding time was assessed frequently during and after the infusion. Serial blood samples for the pharmacokinetic and pharmacodynamic (collagen-induced platelet aggregation) analysis of ACT017 were collected over a period of 48 hours after the start of the infusion. The pharmacokinetics of ACT017 was also evaluated in urine.
In addition, the level of GPVI expression at the platelet surface as well as antidrug antibodies (ADA) were determined throughout the study.
Results: A total of 48 healthy subjects (32 males and 16 females) were enrolled in this study and all subjects completed the study as per protocol. The mean age was 51 years and the mean BMI was 24.50 kg/m2.
Overall, 17 subjects reported a total of 23 AEs. The most frequent AEs were headache (8.33%) and head discomfort (6.25%). All AEs were of mild or moderate intensity and resolved during the study. None of the AEs, considered as related to the study drug, was identified as bleeding related. Inspection of the infusion sites did not reveal any local reaction. There were no clinically significant findings or dose- and time-dependent effects on the laboratory safety values. More specifically, there were no changes in hematologic parameters, in particular red blood cells and leucocytes counts, hemoglobin levels, or any of the coagulation parameters (PT, aPTT). Furthermore, there were no clinically significant changes in vital signs, ECGs, or physical examinations.
No clinically significant changes between post-dose and pre-dose bleeding time values were noted at any of the ACT017 doses. There was no changes in the platelet count, platelet GPVI expression or plasma levels of soluble GPVI.
ACT017 inhibited collagen-induced platelet aggregation and the extent and duration of the effects were dose-dependent.
The area under the curve of the mean plasma concentration (AUC0-t) as well as the maximal plasma concentrations (Cmax) were proportional to the dose, indicating that the pharmacokinetics of ACT017 is linear across the tested dose range of 62.5 to 2000 mg.
Conclusion: Single ascending, intravenous doses of ACT017 as a 6-hour i.v. infusion in healthy subjects are considered safe, well tolerated and without clinically significant effects on bleeding time at doses between 62.5 to 2000 mg. This first in human study has also provided predictable and consistent pharmacokinetics and pharmacodynamics in healthy volunteers. Overall, these results are the basis of subsequent assessment of ACT017 in safety and efficacy studies in the target population of patients with stroke.
Peter Dogterom – Director of Clinical Pharmacology, QPS Holdings, LLC, Groningen, Groningen, Netherlands
Christine Voors-Pette – Groningen, Groningen, Netherlands
Thomas Chou – Newark, Delaware
Laurien Jullien – Paris, Ile-de-France, France
Kristell Lebozec – Paris, Ile-de-France, France
Martine Jandrot-Perrus – Paris, Ile-de-France, France
Gilles Avenard – Paris, Ile-de-France, France