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A new approach to platelet inhibition that can separate the antithrombotic effect of hemorrhagic risk has yielded promising preliminary results, hinting at the hope of developing an agent for the treatment of acute ischemic stroke. able to inhibit platelet aggregation without causing hemorrhage.
The approach targets GPVI protein on platelets, a mechanism completely different from any currently available antiplatelet drug.
The results of a preliminary phase 1 clinical trial of a new antibody fragment directed again against the GPVI protein showed that the agent, known as ACT017 (Acticor) Biotech), inhibited collagen-induced platelet aggregation in a dose-dependent manner but without increased hemorrhagic events prolong bleeding time.
The study was published online on April 18 in Arteriosclerosis, thrombosis and vascular biology.
"GPVI is important for the formation of a pathological occlusive thrombus that occurs during acute ischemic stroke, but this protein does not appear to be strictly required for physiological haemostasis. has no major role in the normal formation of hemostatic clots Martine Jandrot-Perrus, lead author, University Inserm Paris Sorbonne City, France, explained following his injury Medscape Medical News.
"The occlusive thrombus in a stroke or MI [myocardial infarction] is different from the clot that occurs during normal hemostasis. The challenge was to find a larger target for the pathological occlusal thrombus than the natural hemostatic clot, and we think we have found such a target in GPVI, "she added.
Jandrot-Perrus described the current results as "encouraging" but said that the study was conducted in healthy volunteers. "If we can confirm that this drug does not actually increase the risk of bleeding in patients with stroke and improves recbadization and reperfusion, then this would be the first time that it has been shown it is possible to separate the beneficial effects of platelet inhibition from adverse effects, "she said.
The incentive to use such an approach stems from the observation that people with a natural deficiency of GPVI do not seem to experience an increase in the number of major bleeds, noted Jandrot-Perrus. "They sometimes report an increased incidence of mild bleeding, but no serious bleeding, so that there is evidence in humans that the GPVI deficiency is not harmful," he said. she said.
The Phase 1 study also provided pharmacodynamic and pharmacokinetic information on the optimal dosage and duration of infusion needed to design further trials.
The first phase 2 study, now underway, will study the use of this drug in patients with acute ischemic stroke who, if eligible, are also treated with thrombolysis and thrombectomy.
Jandrot-Perrus explained that ACT017 should improve the effectiveness of thrombolysis.
An occlusive clot consists of both fibrin and platelets.Thrombolysis breaks down fibrin in the occlusive clot, but platelet recruitment at the site of fibrinolysis results in the formation of a platelet thrombus. ACT017 administration should prevent the early formation of this secondary platelet thrombus, "she said.
She noted that although antiplatelet agents such as aspirin or clopidogrel (PlavixSanofi-Aventis) can be used for thrombolysis in patients with IDM; so far, this has not been possible for patients with acute ischemic stroke because of an increased risk of intracranial hemorrhage. There is therefore a real need for safe antiplatelet agents in acute ischemic strokes, she said.
Such an antiplatelet agent might also play a role in patients with acute stroke who arrive too late for thrombolysis, she suggested.
Another possible indication of ACT017 could be the use with thrombolysis in patients with pulmonary embolism. Currently, patients with moderate to severe pulmonary embolism can not be treated with thrombolysis because the risk of bleeding outweighs the benefit, but with an antiplatelet agent such as ACT017, it may be possible to reduce the thrombolytic dose and therefore the risk of bleeding.
In the present study, six cohorts of eight healthy men and women received single ascending doses of ACT017 (n = 6) or placebo (n = 2) as a 6-hour intravenous infusion. One-quarter of the total dose was given within 15 minutes, and the rest of the dose within 5 hours and 45 minutes. The six doses studied ranged from 62.5 to 2000 mg.
The drug was well tolerated at all doses and did not result in any serious side effects. In particular, the compound did not appreciably prolong the bleeding time, a marker indicating an increased risk of bleeding.
The study also showed that the magnitude and duration of the therapeutic effect depended on the dose. The maximum effectiveness and duration were achieved with a dose of 2000 mg. The most common adverse events were mild to moderate headache and head discomfort, which resolved during the study.
"Our results are rather encouraging because they show that the candidate compound is well tolerated at doses twice as high as those targeted for future treatment, and without any sign of bleeding," said Jandrot-Perrus. "Another encouraging finding is the fact that the drug's action on platelets is fast, specific and largely reversible within 24 hours," she added.
The study was funded by Acticor-Biotech. Jandrot-Perrus acts as a consultant for the company. Several co-authors are employees of Acticor-Biotech.
Arterioscler Thromb Vasc Biol. Posted online 18 April 2019. Summary
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