Efficacy and safety of open‐label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study

Knoebl, Paul; Cataland, Spero R.; Peyvandi, Flora; Coppo, Paul; Scully, Marie; Hovinga, Johanna A. Kremer; Metjian, Ara; Rubia, Javier de la; Pavenski, Katerina; Edou, Jessica Minkue Mi; Winter, Hilde De; Callewaert, Filip

doi:10.1111/jth.14679

Cited by 46 publications

(50 citation statements)

References 24 publications

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“…BT200 is a pegylated synthetic RNA oligonucleotide drug candidate belonging to the medicinal chemical family known as aptamers, which offers the opportunity to rapidly develop a reversal agent. Based on the mechanism of action of BT200, mucosal bleeding will likely be the predominating type of bleeding, such as epistaxis observed under caplacizumab . Consistent with the effect of caplacizumab in baboons, BT200 also prolonged the bleeding time in cynomolgus monkeys.…”

Section: Discussionmentioning

confidence: 64%

The development and characterization of a long acting anti‐thrombotic von Willebrand factor (VWF) aptamer

Zhu

Gilbert

Hatala³

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Thrombus formation involves coagulation proteins and platelets. The latter, referred to as platelet-mediated thrombogenesis, is predominant in arterial circulation. Platelet thrombogenesis follows vascular injury when extracellular von Willebrand factor (VWF) binds via its A3 domain to exposed collagen, and the free VWF A1 domain binds to platelet glycoprotein Ib (GPIb). Objectives:To characterize the antiplatelet/antithrombotic activity of the pegylated VWF antagonist aptamer BT200 and identify the aptamer VWF binding site.Methods: BT100 is an optimized aptamer synthesized by solid-phase chemistry and pegylated (BT200) by standard conjugation chemistry. The affinity of BT200 for purified human VWF was evaluated as was VWF inhibition in monkey and human plasma.Efficacy of BT200 was assessed in the monkey FeCl 3 femoral artery thrombosis model. Results: BT200 bound human VWF at an EC 50 of 5.0 nmol/L and inhibited VWF A1 domain activity in monkey and human plasma with mean IC 50 values of 183 and 70 nmol/L. BT200 administration to cynomolgus monkeys caused a time-dependent and dose-dependent effect on VWF A1 domain activity and inhibited platelet function as measured by collagen adenosine diphosphate closure time in the platelet function analyzer. BT200 demonstrated a bioavailability of ≥77% and exhibited a half-life of >100 hours after subcutaneous injection. The treatment effectively prevented arterial occlusion in an FeCl 3 -induced thrombosis model in monkeys. Conclusions: BT200 has shown promising inhibition of human VWF in vitro and prevented arterial occlusion in non-human primates. These data including a long half-life after subcutaneous injections provide a strong rationale for ongoing clinical development of BT200.

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Section: Discussionmentioning

confidence: 64%

The development and characterization of a long acting anti‐thrombotic von Willebrand factor (VWF) aptamer

Zhu

Gilbert

Hatala³

et al. 2020

Journal of Thrombosis and Haemostasis

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“…While VWF presents an obvious and attractive target to prevent or treat arterial thrombosis, VWF inhibitors have only relatively recently reached the stage of clinical development, and then only in the form of macromolecules such as the monoclonal antibody AJW-200 30 , the nanobody caplacizumab used in thrombotic thrombocytopenic purpura [31][32][33] and the aptamer ARC1779 used in various indications [34][35][36][37][38] . Proof of concept for VWF inhibition in patients was first established with an anti-VWF aptamer conjugated to a 20 kDa polyethylene glycol molecule (ARC1779).…”

Section: Discussionmentioning

confidence: 99%

“…This is likely due to the fact that VWF requires calcium to facilitate platelet adhesion 53 and hirudin, unlike citrate, does not complex calcium ions 45 . When comparing BT200 with the anti-VWF nanobody caplacizumab, which has already been authorized for acquired thrombotic thrombocytopenic purpura 32,33,54 , a potential benefit of BT200 would be a longer half-life, which was > 100 h in non-human primates 12 vs. 5-36 h for caplacizumab 55 . This means that BT200 is likely suited to being administered once a week as a subcutaneous injection, instead of the daily injections required with caplacizumab.…”

Section: Discussionmentioning

confidence: 99%

The aptamer BT200 effectively inhibits von Willebrand factor (VWF) dependent platelet function after stimulated VWF release by desmopressin or endotoxin

Kovačević

Buchtele

Schoergenhofer

et al. 2020

Sci Rep

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Von Willebrand factor (VWF) plays a major role in arterial thrombosis. Antiplatelet drugs induce only a moderate relative risk reduction after atherothrombosis, and their inhibitory effects are compromised under high shear rates when VWF levels are increased. Therefore, we investigated the ex vivo effects of a third-generation anti-VWF aptamer (BT200) before/after stimulated VWF release. We studied the concentration-effect curves BT200 had on VWF activity, platelet plug formation under high shear rates (PFA), and ristocetin-induced platelet aggregation (Multiplate) before and after desmopressin or endotoxin infusions in healthy volunteers. VWF levels increased > 2.5-fold after desmopressin or endotoxin infusion (p < 0.001) and both agents elevated circulating VWF activity. At baseline, 0.51 µg/ ml BT200 reduced VWF activity to 20% of normal, but 2.5-fold higher BT200 levels were required after desmopressin administration (p < 0.001). Similarly, twofold higher BT200 concentrations were needed after endotoxin infusion compared to baseline (p < 0.011). BT200 levels of 0.49 µg/ml prolonged collagen-ADP closure times to > 300 s at baseline, whereas 1.35 µg/ml BT200 were needed 2 h after desmopressin infusion. Similarly, twofold higher BT200 concentrations were necessary to inhibit ristocetin induced aggregation after desmopressin infusion compared to baseline (p < 0.001). Both stimuli elevated plasma VWF levels in a manner representative of thrombotic or pro-inflammatory conditions such as arterial thrombosis. Even under these conditions, BT200 potently inhibited VWF activity and VWF-dependent platelet function, but higher BT200 concentrations were required for comparable effects relative to the unstimulated state. Von Willebrand factor (VWF) is driving the first step and is a key component in platelet thrombus formation when vascular injury occurs under conditions of moderate to high shear force 1,2. High shear force is commonly found in stenotic arteries and it is known to cause myocardial infarction 3 or stroke 4,5. It has been shown previously that plasma levels of VWF are predicting major adverse cardiovascular events in patients with asymptomatic carotid stenosis 6 , as well as in those with acute coronary syndrome 7. At high shear rates, the main mediator of platelet plug formation is VWF, which is why inhibitors of GPIIb/IIIa, P2Y12 receptor or cyclooxygenase-1 are less potent in conditions where VWF levels are increased 8-10. Moreover, those antiplatelet drugs typically only produce a limited relative risk reduction in some patients groups such as those with acute coronary syndrome or patients undergoing percutaneous coronary intervention (PCI) 11. On one end VWF binds to platelets via GpIb, and on the other end it binds to collagen and forms a bridge between platelets and collagen. BT200 is a third-generation aptamer inhibitor of the A1 domain of VWF and prevents VWF from binding to platelet GPIb 12. BT200 has low nanomolar K d for VWF 12 and has previously been proven to be effective in human

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“…VWF has recently become an interesting therapeutic target, since it has been shown that VWF inhibition is beneficial in treating thrombotic thrombocytopenic purpura, which can cause myocardial damage 41,42 or stroke. 43 The role of VWF as a mediator of the first step in platelet thrombus formation under high shear forces is well known. 2,4-7, 44,45 This is the first study to demonstrate that VWF is an independent predictor of mortality in ACS patients even under contemporary DAPT, in particular with prasugrel or ticagrelor.…”

Section: Discussionmentioning

confidence: 99%

von Willebrand Factor Predicts Mortality in ACS Patients Treated with Potent P2Y12 Antagonists and is Inhibited by Aptamer BT200 Ex Vivo

et al. 2020

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Background von Willebrand factor (VWF) is crucial for arterial thrombosis and its plasma levels are increased in acute coronary syndromes (ACSs). The effects of conventional platelet inhibitors are compromised by elevated VWF under high shear rates. BT200 is a third-generation aptamer that binds and inhibits the A1 domain of human VWF. This article aims to study whether VWF is a predictor of mortality in ACS patients under potent P2Y12 blocker therapy and to examine the effects of a VWF inhibiting aptamer BT200 and its concentrations required to inhibit VWF in plasma samples of patients with ACS. Methods VWF activity was measured in 320 patients with ACS, and concentration effect curves of BT200 were established in plasma pools containing different VWF concentrations. Results Median VWF activity in patients was 170% (interquartile range % confidence interval [CI]: 85–255) and 44% of patients had elevated (> 180%) VWF activity. Plasma levels of VWF activity predicted 1-year (hazard ratio [HR]: 2.68; 95% CI: 1.14–6.31; p < 0.024) and long-term (HR: 2.59; 95% CI: 1.10–6.09) mortality despite treatment with potent platelet inhibitors (dual-antiplatelet therapy with aspirin and prasugrel or ticagrelor). Although half-maximal concentrations were 0.1 to 0.2 µg/mL irrespective of baseline VWF levels, increasing concentrations (0.42–2.13 µg/mL) of BT200 were needed to lower VWF activity to < 20% of normal in plasma pools containing increasing VWF activity (p < 0.001). Conclusion VWF is a predictor of all-cause mortality in ACS patients under contemporary potent P2Y12 inhibitor therapy. BT200 effectively inhibited VWF activity in a target concentration-dependent manner.

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Efficacy and safety of open‐label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study

Cited by 46 publications

References 24 publications

The development and characterization of a long acting anti‐thrombotic von Willebrand factor (VWF) aptamer

The development and characterization of a long acting anti‐thrombotic von Willebrand factor (VWF) aptamer

The aptamer BT200 effectively inhibits von Willebrand factor (VWF) dependent platelet function after stimulated VWF release by desmopressin or endotoxin

von Willebrand Factor Predicts Mortality in ACS Patients Treated with Potent P2Y12 Antagonists and is Inhibited by Aptamer BT200 Ex Vivo

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