19 Apr Stroke: Experimental Antiplatelet Antibody Only Attacks Clots, Without Increasing Bleeding Risk
MedicalResearch.com Interview with:
Martine Jandrot-Perrus MD, PhD.
Emeritus Research Professor
Inserm University Paris Diderot
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Blood platelets are key actors in thrombosis a leading cause of global mortality estimated to account for 1 in 4 death worldwide in 2010.
Thrombosis is associated with cardiovascular diseases (myocardial infarction, stroke, lower limb ischemia, venous thromboembolism), and with numerous pathologies such as cancer, infections or inflammatory diseases. Currently available antiplatelet drugs are the cornerstone of therapy for patients with acute coronary syndromes. However, these drugs all carry an inherent risk of bleeding that restricts their use in sensitive populations and when arterial thrombosis occurs in the cerebral territory. At present the only acute treatment option available for ischemic stroke consists in revascularization by thrombolysis, and/or mechanical thrombectomy. But the number of patients eligible to these treatments is low (» 15% of all patients) and the success rate does not exceed 50%. The responsibility of platelets in the failure for thrombolysis / thrombectomy to restore vascular patency is strongly suspected.
There is thus a clear medical need for new antiplatelet drugs with an improved safety profile. We set out to develop ACT017, a novel, first in class, therapeutic antibody to platelet glycoprotein VI with potent and selective antiplatelet effects. The interest of GPVI resides in the fact that it’s a receptor involved in the development of occlusive thrombi but that it is not strictly required for physiological hemostasis.
MedicalResearch.com: What should readers take away from your report?
Response: The phase 1 clinical trial carried out in the Netherlands aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT017 in 48 healthy subjects. All doses of ACT017 (from 125 to 2000 mg) were well tolerated and no serious adverse events occurred during the study. Bleeding time was not affected by any of the ACT017 doses. There was neither modification in the platelet count nor in platelet GPVI expression. Administration of ACT017 inhibited GPVI function and the extent and duration of the effect were dose-dependent. The novel antiplatelet agent ACT017 has consistent pharmacokinetic/pharmacodynamic properties and favourable safety and tolerability profiles in healthy volunteers.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: This first-in-human study paves the way for the subsequent assessment of ACT017 safety and efficacy in patients with acute thrombosis. A phase 2a, randomized, double blind, multicentre, multinational, placebo controlled, single parallel escalating dose, safety and efficacy study of ACT017 used as an add on therapy on top of standard-of-care in the 4.5 hours post onset of acute ischemic stroke (ACTIMIS) is just starting. The primary objective is to assess the safety of the treatment with a specific focus on hemorrhagic events. Secondary outcomes will be the change from baseline of 24 hr NIHSS score (a direct measure of handicap), and from imaging, the extent of brain lesions and vessel recanalization.
Disclosures: The study was funded by Acticor-Biotech.
Christine Voors-Pette, Kristell Lebozec, Peter Dogterom, Laurie Jullien, Philippe Billiald, Pauline Ferlan, Lionel Renaud, Olivier Favre-Bulle, Gilles Avenard, Matthias Machacek, Yannick Plétan, Martine Jandrot-Perrus. Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab. Arteriosclerosis, Thrombosis, and Vascular Biology, 2019; DOI: 1161/ATVBAHA.118.312314
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