Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen‐Induced Platelet Aggregation

Renaud, Lionel; Lebozec, Kristell; Voors-Pette, Christine; Dogterom, Peter; Billiald, Philippe; Jandrot‐Perrus, Martine; Pletan, Yannick; Macháček, Matthias

doi:10.1002/jcph.1616

Cited by 24 publications

(13 citation statements)

References 18 publications

(16 reference statements)

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“…In the antithrombotic field, current strategies aim at optimizing cerebral reperfusion pharmacologically as an adjunct to current recommended therapies with IVT and EVT. In this context, ACT017, an antibody fragment targeting platelet GPVI receptor, seems to be a new antiplatelet agent that safely improves reperfusion (103). After showing its safety profile in preclinical and phase I studies, the ACTIMIS trial (NCT03803007) is currently evaluating this first-in-class antiplatelet agent following tPA within 4.5 h from stroke onset.…”

Section: Future Directions: How To Decrease Hemorrhagic Complicationsmentioning

confidence: 99%

Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients

2020

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Reperfusion therapies are the mainstay of acute ischemic stroke (AIS) treatments and overall improve functional outcome. Among the established complications of intravenous (IV) tissue-type plasminogen activator (tPA), intracranial hemorrhage (ICH) is by far the most feared and has been extensively described by seminal works over the last two decades. Indeed, IV tPA is associated with increased odds of any ICH and symptomatic ICH responsible for increased mortality rate during the first week after an AIS. Despite these results, IV tPA has been found beneficial in several pioneering randomized trials and improves functional outcome at 3 months. Endovascular therapy (EVT) combined with IV tPA for AIS patients consecutive to an anterior circulation large-vessel occlusion does not increase ICH occurrence. Of note, EVT following IV tPA leads to significantly higher rates of early reperfusion than with IV tPA alone, with no difference in ICH, which challenges the paradigm of reperfusion as a major prognostic factor for ICH complications. However, several blood biomarkers (glycemia, platelet and neutrophil count), clinical factors (age, AIS severity, blood pressure management, diabetes mellitus), and neuroradiological factors (cerebral microbleeds, infarct size) have been identified as risk factors for ICH after reperfusion therapy. In the years to come, the ultimate goal will be to further improve either reperfusion rates and functional outcome, while reducing hemorrhagic complications. To this end, various approaches being investigated are discussed in this review, such as blood-pressure control after reperfusion or the use of new antiplatelet agents as an adjunct to IV tPA and exhibit reduced hemorrhagic potential during the early phase of AIS.

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Section: Future Directions: How To Decrease Hemorrhagic Complicationsmentioning

confidence: 99%

Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients

2020

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“…A direct antiplatelet effect was shown for ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase that affects the platelet glycoprotein VI signaling and may reduce collagen-mediated platelet aggregation [ 55 ]. Glenzocimab, an inhibitor of the platelet glycoprotein VI, involving collagen-induced platelet aggregation, is another option to consider as an antiplatelet agent in the acute phase of ischemic stroke [ 56 ]. Studies on the possible usefulness of these drugs in medical practice should be continued, whereas they were not still approved for clinical application.…”

Section: Discussionmentioning

confidence: 99%

Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention

Wiśniewski

2021

Medicina

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Effective platelet inhibition is the main goal of the antiplatelet therapy recommended as a standard treatment in the secondary prevention of non-embolic ischemic stroke. Acetylsalicylic acid (aspirin) and clopidogrel are commonly used for this purpose worldwide. A low biological response to antiplatelet agents is a phenomenon that significantly reduces the therapeutic and protective properties of the therapy. The mechanisms leading to high on-treatment platelet reactivity are still unclear and remain multifactorial. The aim of the current review is to establish the background of resistance to antiplatelet agents commonly used in the secondary prevention of ischemic stroke and to explain the possible mechanisms. The most important factors influencing the incidence of a low biological response were demonstrated. The similarities and the differences in resistance to both drugs are emphasized, which may facilitate the selection of the appropriate antiplatelet agent in relation to specific clinical conditions and comorbidities. Despite the lack of indications for the routine assessment of platelet reactivity in stroke subjects, this should be performed in selected patients from the high-risk group. Increasing the detectability of low antiaggregant responders, in light of its negative impact on the prognosis and clinical outcomes, can contribute to a more individualized approach and modification of the antiplatelet therapy to maximize the therapeutic effect in the secondary prevention of stroke.

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“… 32 Safety of glenzocimab, in addition to alteplase at the acute phase of cerebral infarction, is currently assessed. 33 …”

Section: Discussionmentioning

confidence: 99%

Clinical imaging factors of excellent outcome after thrombolysis in large-vessel stroke: a THRACE subgroup analysis

et al. 2021

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BackgroundFor patients with stroke with large-vessel occlusion (LVO), study of factors predicting response to intravenous thrombolysis (IVT) would allow identifying subgroups with high expected gain, and those for whom it could be considered as futile, and even detrimental. From patients included in the Mechanical Thrombectomy After Intravenous Alteplase vs Alteplase Alone After Stroke trial, we investigated clinical-imaging factors associated with optimal response to IVT.MethodsWe included patients receiving IVT alone. Excellent outcome was defined by a 3-month modified Rankin Scale (mRS) score ≤1. Clinical-imaging predictors were assessed on multivariate analysis after multiple imputations. The predictive performance of the model was assessed with the C-statistic.ResultsAmong 247 patients with LVO treated with IVT alone, 77 (31%) showed 3-month mRS ≤1. Predictors of 3-month mRS ≤1 were no medical history of hypertension (OR 2.43; 95% CI 1.74 to 3.38; p=0.007); no current smoking (OR 2.76; 95% CI 1.79 to 4.26; p=0.02); onset-to-IVT time (OR 0.47 per hour increase; 95% CI 0.23 to 0.78; p=0.003); diffusion-weighted imaging (DWI) volume (OR 0.78 per 10 mL increase; 95% CI 0.68 to 0.89; p=0.0004); presence of susceptibility vessel sign (SVS) (OR 7.89; 95% CI 1.65 to 37.78; p=0.01) and SVS length (OR 0.87 per mm increase; 95% CI 0.80 to 0.94; p=0.001). The prediction models showed a C-statistic=0.79 (95% CI 0.79 to 0.80).ConclusionsIn patients with stroke with anterior-circulation LVO treated with IVT alone, predictors of excellent outcome at 3 months were no medical history of hypertension or current smoking, reduced onset-to-IVT time, small DWI volume, presence of SVS and short SVS length. These predictive factors could help practitioners in decision-making for IVT implementation in reperfusion strategies, all the more for the drip and ship paradigm.Trial registration numberNCT01062698.

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Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen‐Induced Platelet Aggregation

Cited by 24 publications

References 18 publications

Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients

Intracranial Hemorrhage After Reperfusion Therapies in Acute Ischemic Stroke Patients

Multifactorial Background for a Low Biological Response to Antiplatelet Agents Used in Stroke Prevention

Clinical imaging factors of excellent outcome after thrombolysis in large-vessel stroke: a THRACE subgroup analysis

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