Idarucizumab Overview

Introduction of Idarucizumab

Direct oral anticoagulants (DOACs), such as the direct factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban, and the direct thrombin inhibitor dabigatran etexilate (Pradax, Pradax, and Prazaxa). However, as with all anticoagulants, bleeding complications are still a concern, and there is a need for anticoagulant reversal in specific clinical situations, such as in patients experiencing spontaneous or traumatic bleeds or in those requiring emergency surgery or other invasive procedures. As a result, DOAC-specific reversal agents have been developed for clinical situations, in which, urgent anticoagulation reversal is required. Idarucizumab (BI 655075) is a murine-derived, humanized, IgG1κ monoclonal antigen-binding fragment (Fab) developed by Boehringer Ingelheim Pharmaceuticals for the reversal of anticoagulant effects of dabigatran. It binds to and inactivates dabigatran and its active acylglucoronide metabolites. This drug effectively reversed anticoagulation by dabigatran within minutes, and with the trade name Praxbind, it has gained the approval for marketing in USA, Europe Union, Canada, Australia, and Japan.

Mechanism of Action of Idarucizumab

Idarucizumab was identified by screening dabigatran-specific monoclonal antibodies (mAbs) generated by immunizing mice with dabigatran-derived haptens coupled to carrier proteins. Mab fragments that were produced in Chinese hamster ovary (CHO) cells were selected according to potency of dabigatran-binding affinity. These were then humanized to minimize immunogenicity. With respect to the molecular recognition and binding of dabigatran, idarucizumab has structural similarities to thrombin, but idarucizumab lacks enzymatic activity. Idarucizumab’s binding to dabigatran is mediated by hydrophobic interactions, Hbonds, and a salt bridge, which result in a high affinity for dabigatran. This high affinity corresponds with a rapid on rate and very slow off rate, resulting in an almost irreversible binding of idarucizumab to dabigatran. Despite the structural similarities with thrombin, idarucizumab does not bind to thrombin substrates, including FV, FVIII, FXIII, or fibrinogen. Furthermore, idarucizumab does not exhibit thrombin-like activity, as demonstrated by a lack of activity in coagulation or platelet aggregation tests. Idarucizumab added to plasma in vitro did not alter clotting in the diluted thrombin time (dTT) assay, nor shorten the clotting time of prothrombin-depleted plasma. Idarucizumab did not convert the main substrate of thrombin, fibrinogen, into fibrin, as measured by fibrinopeptide A (FPA), nor increase thrombin generation when added to plasma, as demonstrated by thrombin generation assays. In in vitro platelet aggregation studies, idarucizumab did not induce platelet aggregation alone or affect protease-activated receptor 1 (PAR1)-induced platelet aggregation by the thrombin receptor-activating peptide SFLLRN.

Fig.1 Mechanism of action of idarucizumab

Clinical Projects of Idarucizumab*

Approved Drugs of Idarucizumab**

INN (trade name)	Therapeutic area	Dose	Strength	Route	Company	Marketing start	Market
Praxbind	Treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed	Concentrate for solution	50 mg/mL	Intravenous infusion	Boehringer Ingelheim	October 16, 2015
Praxbind	Hemorrhage	Concentrate for solution	50 mg/mL	Intravenous infusion	Boehringer Ingelheim International GmbH	November 20, 2015
Praxbind	Treated with Pradaxa® when rapid specific reversal of the anticoagulant effects of dabigatran is required	Concentrate for solution	50 mg/mL	Intravenous infusion	Boehringer Ingelheim (Canada) Ltd.	April 29, 2016
Praxbind	Treated with dabigatran etexilate when rapid reversal of the anticoagulant effects of dabigatran is required	Concentrate for solution	50 mg/mL	Intravenous infusion	Boehringer Ingelheim Pty Ltd	May 11, 2016
Praxbind	Neutralization of anticoagulant action of dabigatran	Concentrate for solution	50 mg/mL	Intravenous infusion	Boehringer Ingelheim Japan K.K.	September 28, 2016

What We Provide

Therapeutic Antibody

Idarucizumab

We provide high-quality Idarucizumab for use in WB, FC, IP, ELISA, Neut, FuncS, IF and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

Resources
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Idarucizumab

** Information presented in the table were collected from the following websites:
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/3399412A1
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=94091
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo= 761025
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003986/human_med_001938.jsp
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=237761

For research use only. Not intended for any clinical use.