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Editorials
an avidity of bivalent entity is not straightforward, imply- ing that this result should be considered with caution. Also, this study identified only a partial overlap of VWF-A1 bind- ing sites for TAGX-0004 and caplacizumab, including how- ever crucial amino acid residues (i.e., R1395 and R1399) found to be in common to all three: TAGX-0004, ARC1779 and caplacizumab.
To better consider preclinical and clinical trials’ perspec- tives of this new anti-VWF-A1 aptamer, the historical back- ground of both ARC1779 and caplacizumab is certainly important to recall. Since 2007, ARC1779 has been demon- strated to be efficient in vivo in a primate model14 and to pro- duce dose- and concentration-dependent inhibition of VWF activity and platelet function in a first-in-human evaluation led in healthy volunteers.10 In addition, proof-of-concept of ARC1779 was provided in patients with VWD type 2B,25 a genetic model of hyperadhesive VWF in which the mutated VWF-A1 exhibits a hyper-affinity for platelet GPIb leading to spontaneous binding to platelets and sometimes to thrombocytopenia. In ex vivo studies, ARC1779 effectively inhibited VWF activity in plasma samples of both TTP patients18 and ACS patients.13,15 Some clinical experiences
Figure 1. Von Willebrand factor–related pathophysiology for arterial and microvas- cular thrombosis in acute thrombotic thrombocytopenic purpura and atheroscle- rotic cardiovascular disease, and mecha- nisms for thrombus prevention by aptamers and antibodies to VWF A1 domain. VWF: von Willebrand factor; UL: ultralarge; ADAMTS13: a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13; GPIb: glycopro- tein Ib.
were first reported in three studies involving a total of 11 TTP patients.17,19,20 Then, two randomized, double-blind, placebo-controlled phase II studies were initiated in carotid endarterectomy16 and in acute TTP21 but both of them underwent premature closure due to cessation of funding. The first study16 was led in 36 patients and reported that intravenous ARC1779 reduced cerebral embolization post- carotid endarterectomy with however, a higher rate of per- operative bleeding complications in patients requiring sur- gery. The second study21 led in only seven TTP patients, showed that intravenous ARC1779 (loading dose followed by daily infusion performed after each therapeutic plasma exchange [TPE]) induced a suppression of VWF activity cor- related to the plasma concentration of ARC1779, apparent- ly decreased the number of TPE to achieve a normal platelet count and was well tolerated with no bleeding complica- tions. Despite of the latter promising results in TTP, no ARC1779 trial has been published since 2012. The capla- cizumab story is significantly different. However, originally, caplacizumab was under development for the prevention of thrombosis in ACS patients undergoing percutaneous coro- nary intervention6 but the development for this indication
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