Novel Antiplatelet Agent May Not Increase Bleeding Risk

April 18, 2019

A new approach to inhibiting platelets that may separate the antithrombotic effect from the bleeding risk has shown promising preliminary results, raising the hope of developing an agent for the treatment of acute ischemic stroke that can inhibit platelet aggregation without causing bleeding.

The approach targets the GPVI protein on platelets, a mechanism completely different from those of any currently available antiplatelet drugs.

Results of a preliminary phase 1 clinical trial of a new antibody fragment directed again the GPVI protein showed that the agent, known as ACT017 (Acticor-Biotech), inhibited collagen-induced platelet aggregation in a dose-dependent manner but without increasing bleeding events or prolonging bleeding time.

The study was published online April 18 in Arteriosclerosis, Thrombosis, and Vascular Biology.

"GPVI is important for the formation of a pathologic occluding thrombus which occurs in acute ischemic stroke, but this protein does not appear to be strictly required for physiological hemostasis. It does not have a major role in the normal formation of the hemostatic clots that occur after injury," senior author Martine Jandrot-Perrus, MD, Inserm University Paris Sorbonne Cité, France, explained to Medscape Medical News.

"The occluding thrombus in a stroke or MI [myocardial infarction] is different from the clot that occurs during normal hemostasis. The challenge has been to find a target that is more important to the pathological occluding 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 pointed out that the study was conducted in healthy volunteers. "If we can confirm that this drug indeed does not increase the bleeding risk in actual stroke patients and improves recanalization and reperfusion, then this would be the first time it has been shown possible to separate the beneficial effects of inhibiting platelets from the harmful effects," she said.

Encouragement for use of such an approach comes from the observation that individuals who have a natural deficiency of GPVI do not seem to experience an increase in major bleeding, Jandrot-Perrus noted. "They do sometimes report an increased incidence of mild bleeding, but not severe bleeding, so there is evidence in humans that GPVI deficiency is not harmful," she said.

The phase 1 study has also provided pharmacodynamic and pharmacokinetic information on optimum dosage and duration of the infusion necessary to design further trials.

The first phase 2 study, which is now starting, will investigate use of the drug in patients with acute ischemic stroke who, if eligible, are also being treated with thrombolysis and thrombectomy.

Jandrot-Perrus said the rationale is that ACT017 is expected to improve the efficacy of thrombolysis.

"An occluding clot is made up of both fibrin and platelets. Thrombolysis breaks down the fibrin in the occluding clot, but the recruitment of platelets at the site of fibrinolysis leads to the formation of a platelet thrombus. Administration of ACT017 should prevent the early formation of this secondary platelet thrombus," she said.

She noted that although antiplatelet agents such as aspirin or clopidogrel (Plavix, Sanofi-Aventis) can be used with thrombolysis for patients with MI, so far, this has not been possible for patients with acute ischemic stroke because of an increased risk for intracranial hemorrhage. There is thus a real need for safe antiplatelet agents in acute ischemic stroke, she said.

There may also be a role for such an antiplatelet agent for patients with acute stroke who arrive too late for thrombolysis, she suggested.

Another possible indication for ACT017 could be for use with thrombolysis for patients with pulmonary embolism. At present, patients with moderate to severe pulmonary embolism cannot be treated with thrombolysis because the bleeding risk outweighs the benefit, but with an antiplatelet agent such as ACT017, it might be possible to reduce the thrombolytic dose and thus reduce the bleeding risk.

In the current study, six cohorts of eight healthy male and female patients each received ascending single doses of ACT017 (n = 6) or placebo (n = 2) as a 6-hour intravenous infusion. One quarter of the total dose was administered within 15 minutes, and the rest of the dose was administered within 5 hours and 45 minutes. The six investigated doses ranged from 62.5 to 2000 mg.

The drug was well tolerated at all doses, and there were no serious side effects. Notably, the compound did not appreciably prolong bleeding time, a marker indicating increased risk for bleeding.

The study also showed that the extent and duration of the therapeutic effect was dose dependent. Maximum effectiveness and duration were achieved with a dose of 2000 mg. The most common side effects were mild to moderate headache and head discomfort, which resolved during the study.

"Our results are quite encouraging because they show the candidate compound is well tolerated at doses even twice as high as the ones targeted for a future treatment, and without any signs of bleeding," Jandrot-Perrus said. "Another encouraging finding is the fact that the drug's action on platelets is rapid, specific, and largely reversible within 24 hours," she added.

Commenting on the study for Medscape Medical News, Philip B. Gorelick, MD, Northwestern University Feinberg School of Medicine, Chicago, who was not involved in this research, said: "This was an early phase 1 study of healthy volunteers and has shown that ACT017 is a promising and novel antiplatelet agent.

"It is premature to conclude, however, that ACT017 is devoid of serious adverse events such as bleeding," he added. "Subsequent testing, especially in older patients and patients with stroke, will serve as barriers to clear on the road to future regulatory approval for this agent."

The study was funded by Acticor-Biotech. Jandrot-Perrus acts as a consultant for the company. Several coauthors are employees of Acticor-Biotech.

Arterioscler Thromb Vasc Biol. Published online April 18, 2019. Abstract

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