In vitro assessment and phase I randomized clinical trial of anfibatide a snake venom derived anti-thrombotic agent targeting human platelet GPIbα

Abstract

The interaction of platelet GPIbα with von Willebrand factor (VWF) is essential to initiate platelet adhesion and thrombosis, particularly under high shear stress conditions. However, no drug targeting GPIbα has been developed for clinical practice. Here we characterized anfibatide, a GPIbα antagonist purified from snake (Deinagkistrodon acutus) venom, and evaluated its interaction with GPIbα by surface plasmon resonance and in silico modeling. We demonstrated that anfibatide interferds with both VWF and thrombin binding, inhibited ristocetin/botrocetin- and low-dose thrombin-induced human platelet aggregation, and decreased thrombus volume and stability in blood flowing over collagen. In a single-center, randomized, and open-label phase I clinical trial, anfibatide was administered intravenously to 94 healthy volunteers either as a single dose bolus, or a bolus followed by a constant rate infusion of anfibatide for 24 h. Anfibatide inhibited VWF-mediated platelet aggregation without significantly altering bleeding time or coagulation. The inhibitory effects disappeared within 8 h after drug withdrawal. No thrombocytopenia or anti-anfibatide antibodies were detected, and no serious adverse events or allergic reactions were observed during the studies. Therefore, anfibatide was well-tolerated among healthy subjects. Interestingly, anfibatide exhibited pharmacologic effects in vivo at concentrations thousand-fold lower than in vitro, a phenomenon which deserves further investigation.Trial registration: Clinicaltrials.gov NCT01588132.

The GPIb-IX complex on platelets: insight into its novel physiological functions affecting immune surveillance, hepatic thrombopoietin generation, platelet clearance and its relevance for cancer development and metastasis

“…Owing to GPIb-IX´s role in the first interaction between platelets and damaged vessels at sites of arterial stenosis where blood flows with high shear rates, GPIb-IX is an attractive target in attenuating thrombosis. Several inhibitors are currently tested as novel anti-platelet approaches with the assumption that they will have a favorable profile compared to state-of-the-art drugs like aspirin, clopidogrel, and tirofiban [ 241 – 243 ].…”

Platelets, Thromboinflammation and Neurovascular Disease

“…A novel snake venom-derived GPIb antagonist, Anfibatide, showed dramatically improved ischemic lesions by way of dose modulation. Compared to untreated MCAO mice, these mice had smaller infarct volumes and reduced the amount of GPIba, vWF, and fibrin(pro) accumulation in the ischemic hemispheric vascular system (110,111). Unfortunately, neither immunoreactive cytostatic agents nor inflammatory mediator reduction have yielded good results in the immune response after ischemic stroke.…”

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

“…The effect of this agent may be based on the preservation of the blood-brain-barrier integrity driven by the upregulation of Epac1 [ 197 ]. Concerning clinical trials, anfibatide inhibited VWF-induced platelet aggregation in healthy volunteers, an effect that lasted for 8 h, without alteration of coagulation parameters or serious adverse events [ 198 ]. In the subsequent phase IIa study of 90 patients with non-ST segment elevation myocardial infarction, anfibatide dose-dependently inhibited ex-vivo platelet aggregation, significantly higher compared to placebo [ 199 ].…”