Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab

Abstract

Objective— ACT017 is a novel, first in class, therapeutic antibody to platelet GPVI (glycoprotein VI) with potent and selective antiplatelet effects. This first-in-human, randomized, placebo-controlled phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT017 in healthy subjects. Approach and Results— Six cohorts of 8 healthy male and female subjects each received ascending single doses of ACT017 (n=6) or placebo (n=2) as a 6-hour intravenous infusion, with ¼ of the total dose administered within 15 minutes and the rest of the dose (¾ of the total dose) administered within 5 hours and 45 minutes. The 6 investigated doses ranged from 62.5 to 2000 mg. 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. Template bleeding time was not affected in a clinically significant manner by any of the ACT017 doses. Plasma concentrations, determined by liquid chromatography-tandem mass spectrometry, increased linearly with the dose received as were the established pharmacokinetics values. There was no change in the platelet count, platelet GPVI expression assessed by flow cytometry, or plasma levels of soluble GPVI assessed by ELISA. In contrast, administration of ACT017 inhibited collagen-induced platelet aggregation measured by light transmission aggregometry on platelet-rich plasma, and the extent and duration of the effect were dose-dependent. Conclusions— The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favorable safety and tolerability profiles warranting further clinical development.

NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects

“…10,13,14 Pharmacological inhibition of GPVI has been shown to reduce thrombotic responses without affecting hemostasis in a manner similar to what we observed for NOX1 −/− and GPVI targeting has previously been proposed as a potential strategy for the prevention of atherothrombosis. 42 Because only peptides or antibodies with notable limitations about pharmacokinetics and deliverability have so far been successfully utilized as GPVI inhibitors, [43][44][45] this receptor remains an interesting drug discovery target. In this study, we investigated the possibility of targeting NOX1 and indirectly dampening GPVI signaling with small molecule inhibitors.…”

Loxoscelism: Advances and Challenges in the Design of Antibody Fragments with Therapeutic Potential

“…Of course, diabodies may not be appropriate for human injection due to short half-life and potentially low thermal stability [64]. However, these molecules can be re-designed into Fab fragments which format has yet been proven to be more stable, suitable for human infusion and efficient for the treatment of several diseases [65]. In a Fab, both VH/VL and CH/CL interactions contribute to the functional stability of the antibody fragment and potentially to the in vivo toxin neutralization capacity as suggested previously [66].…”

Platelet-Reactive Antibodies in Patients after Ischaemic Stroke—An Epiphenomenon or a Natural Protective Mechanism

“…However, further assessment of bleeding risk while on anti-platelet drugs outside of this time period would be an important outcome for future studies in this area. Recently, a novel monoclonal antibody fragment targeting platelet glycoprotein VI (GPVI) caused an inhibition of platelet aggregation in healthy human subjects with no change in the platelet count [38]. A similar approach offers neuroprotection in a mouse model of stroke with no increase in bleeding complications [39].…”