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Editorials
was discontinued in favor of TTP. After proof-of-concept in a pre-clinical baboon model of acquired TTP7 in 2012, capla- cizumab rapidly emerged as a new strategy of first-line treatment of acute TTP in association with TPE and immunomodulating agents.26,27 Caplacizumab was evaluat- ed in two major multicenter, randomized, double-blind, placebo-controlled phase II8 and phase III9 trials involving 36 and 72 TTP patients and published in 2016 and 2019, respectively: intravenous and subcutaneous caplacizumab showed superiority to placebo in terms of reduction of mor- tality, reduction of time to platelet recovery allowing an ear- lier stop of TPE, prevention of formation of further microthrombi and protection of organs from ischemia.8,9 Bleeding adverse event were common, affecting roughly half of the patients, but mostly mild or moderate and thus self-limited or resolved.8,9 Caplacizumab approval for acute TTP was obtained in 2018 in the EU and in 2019 in the US.
Here, the authors open the door to the new anti-VWF- A1 aptamer as a promising molecule for future preclinical and clinical trials devoted to VWF-mediated thrombotic disorders, either the frequent ACD or the rare TTP.22 They emphasize that TAGX-0004 may get an antidote as already developed for other aptamers11,28 which may be a great advantage to control adverse bleeding events and thus to improve its main safety concern. In ischemic stroke and myocardial infarction, TAGX-0004 may be a rival of current antithrombotic and thrombolytic agents which are irreversible and associated with a significant risk of haemorrhage.5 In addition, in contrast to antiplatelet drugs which bypass platelet adhesion and inhibit only platelet aggregation, TAGX-0004 is able to prevent the initial step of thrombus formation by inhibit- ing platelet adhesion and, as a consequence, also platelet aggregation. In acute TTP, TAGX-0004 may appear as a rival of caplacizumab. However, considering the complex- ity of TTP as a rare and life-threatening disease, several questions require specific attention during preclinical and clinical studies. First, acute TTP management relies on a mandatory concomitant use of first-line multiple targeted therapies26,27 i.e., TPE and future recombinant ADAMTS13 as the replacement therapy for severely deficient ADAMTS13, steroids and rituximab as immunomodula- tors against anti-ADAMTS13 autoantibodies and now caplacizumab as an inhibitor of VWF-A1 preventing the adhesion of UL VWF to platelets. Thus, potential interac- tions of aptamers with ADAMTS13-replacing products and immunomodulators are unknown so far. Second, whether TAGX-0004 is able, like caplacizumab, to form a complex with VWF which clearance leads to a partial decrease of VWF antigen and coagulation factor VIII ben- eficial for the thrombotic atmosphere of TTP, is also unknown. Third, the superiority of TAGX-0004 to capla- cizumab in terms of the bleeding risk remains to be fur- ther investigated as i) caplacizumab-associated bleeding events are mostly moderate and easily resolved,8,9 and ii) the potential TAGX-0004 antidote constitutes an extra drug that may exhibit specific adverse events. Fourth, even if the in vivo half-life of TAGX-0004 is upgraded by a mini-hairpin DNA structure conferring resistance to degradation by nucleases,22 it has to be compatible with a daily regimen adjusted to TPE. Fifth, as aptamers also have the capacity to be used as diagnostic reagents (their com-
bined therapeutics and diagnostics potential being sum- marized as “theranostic”),28 the potential interference of TAGX-0004 with ADAMTS13 biologic assays crucial for therapy-driven monitoring in acute TTP28, should also be a point of attention.
Today, aptamer technology remains one step behind the humanized monoclonal antibody research and devel- opment, mostly because antibodies biotech industry’s financial investment has been highly prioritized for the last three decades. In 2020, only one aptamer targeted to vascular endothelial growth factor (Macugen/Pegaptanib sodium) has gained approval by the US Food and Drug Aminsitration for patients with age-related macular degeneration and few aptamers have successfully entered clinical trials for different therapeutic indications.28 However, considering their advantages over antibodies (low price, small size, easy production) together with the efforts made to overcome their limitations (improvement of stability, target affinity, in vivo retention and corrective approaches to potential unmethylated 2’-deoxycytidine- phosphate-2’-guanine toxicity),28 aptamers begin to slow- ly penetrate niche markets and bring promising therapeu- tic perspectives.
References
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