A sugammadex-analogue, per-6-O-carboxyhexyl-thio-gamma-CD (OKL-1111) is a highly potent and universal reversal agent for anticoagulants

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Antithrombotic therapy is undoubtedly associated with a risk for bleeding and these bleeding complications sometimes can be life-threatening. Recently, specific reversal agents were developed for the direct factor Xa and thrombin inhibitors (direct oral anticoagulants). However, besides the fact that these agents are relatively expensive, the use of selective reversal agents complicates treatment of bleeding patients in clinical practice.
In a recently published work, Joost C.M. Meijers and co-workers reported on the discovery of a universal reversal agent derived from gamma-cyclodextrin against anticoagulants [1].
In a series of screening experiments, delineated in the above paper, scientists discovered a class of cyclodextrins with procoagulant properties. The selected lead compound, a per-O-6 substituted gamma-cyclodextrin derivative (Octakis-((carboxyhexyl)thio)-6-deoxy-gamma-cyclodextrin), (See Figure) developed under the name of OKL-1111, was found to demonstrate high potency as a universal reversal agent. The discovery of OKL-1111 by the Dutch Alveron Pharma offers a promising new therapeutic method to reverse the effects of all the major anticoagulants including all direct oral anticoagulants and vitamin K antagonists, such as warfarin and platelet aggregation inhibitors, such as clopidogrel.
This cyclodextrin-based API enables clinicians to intervene immediately in emergencies without knowing exactly which type of anticoagulant to target and reverse, so it potentially accelerates and simplifies treatment protocols in the emergency units.
OKL-1111 in a concentration-dependent manner, reversed the in vitro anticoagulant effects of dabigatran, rivaroxaban, apixaban and edoxaban in the thrombin generation assay.
The reversal effect was also seen for all oral anticoagulants in the rat tail cut bleeding model. In addition, when tested with other anticoagulants, OKL-1111 also reversed the anticoagulant effect of the vitamin K antagonists, the low molecular weight heparinoids, enoxaparin, the pentasaccharide fondaparinux and the platelet inhibitor clopidogrel, in vivo.
OKL-1111 is positioned as a rapid, first line therapy as it has a truly universal mode of action, not requiring anticoagulant identification. OKL-1111 is being developed as a ready-to-use solution for injection so eliminating a time-consuming preparation step. OKL-1111 has therefore the potential for rapid administration with greatly improved outcomes. The gamma-CD derivative drug – in contrast to leading marketed competitors – is not a biologic nor is a blood-derived material, thus providing both cost and safety advantages.
Despite the fact, the OKL-1111 procoagulant cyclodextrin acts with a currently unknown working mechanism, it seems to have a great potential to become a universal reversal agent for anticoagulants and platelet inhibitors meeting an unmet medical need.
Latest news: in Pharmaceutical Technology GlobalData, it was reported on June 10 that OKL-1111 is under clinical development by Alveron Pharma and currently is in Phase I for Blood Coagulation.

OKL-1111                                                                 sugammadex                                          the two gamma-cyclodextrin brothers

[1] Joost C.M. Meijers, Kamran Bakhtiari, Alex Zwiers, Stephan L.M. Peter: OKL-1111, A modified cyclodextrin as a potential universal reversal agent for anticoagulants. Thrombosis Research 227. 2023, 17-24. https://doi.org/10.1016/j.thromres.2023.05.003

See also: https://cyclodextrinnews.com/2023/05/19/a-new-cyclodextrin-based-antidote/

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