SAN FRANCISCO—An investigational, humanized antibody fragment known as idarucizumab can reverse the anticoagulation effects of dabigatran, new research suggests.
In a small study, idarucizumab led to sustained reversal of dabigatran’s effects in healthy subjects, elderly volunteers, and participants with mild to moderate renal impairment.
Furthermore, dabigatran anticoagulation could be re-established 24 hours after the subjects had received idarucizumab.
Joachim Stangier, PhD, of Boehringer Ingelheim Pharma GmbH & Co KG in Biberach, Germany, presented these results at the 2014 ASH Annual Meeting as abstract 344*. Boehringer Ingelheim is the company developing idarucizumab.
Dr Stangier said idarucizumab binds dabigatran with high affinity, off-target binding is not expected, and no procoagulant effects have been observed with the drug.
In a previous study of healthy volunteers, idarucizumab provided immediate, complete, and sustained reversal of dabigatran’s anticoagulant effect. The effect was sustained when idarucizumab was given at 2 g and 4 g doses.
For the current study, Dr Stangier and his colleagues wanted to evaluate whether and to what extent doses of up to 5 g of idarucizumab would reverse the anticoagulant effects of dabigatran in healthy subjects, elderly participants, and renally impaired volunteers. The team also wanted to determine the effects of dabigatran given after subjects had received idarucizumab.
The study included 46 male and female subjects who were 45 to 80 years of age. Healthy subjects received dabigatran etexilate at 220 mg twice daily, and subjects with mild to moderate renal impairment received 150 mg twice daily, both over 4 days.
Subjects then received idarucizumab at 1 g, 2.5 g, 5 g, or 5 g given as 2 x 2.5 g 1 hour apart. They received these doses as 5-minute intravenous infusions 2 hours after their last dose of dabigatran.
The researchers found that dabigatran-prolonged clotting times—thrombin time, diluted thrombin time, ecarin clotting time, and activated partial thromboplastin time—were reversed to baseline immediately after the end of idarucizumab infusion.
And the team observed sustained reversal of dabigatran’s anticoagulant effects in all subjects.
The researchers then readministered dabigatran to healthy subjects 24 hours after idarucizumab treatment and to subjects who received placebo instead of idarucizumab.
Dabigatran-mediated anticoagulation was similar in subjects who received idarucizumab and those who received placebo. And anticoagulation was restored to levels comparable to initial levels.
Dr Stangier said there were no clinically relevant adverse events (AEs) related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. There were no AEs indicative of immunogenic reactions.
AEs and local tolerability reactions were similar for placebo and idarucizumab. And there was no relationship between the frequency of AEs and drug dose, gender, or renal function.
The researchers did observe a dose-dependent, transient increase in urine protein and low-weight proteins, but values returned to the normal range within 4 hours to 24 hours.
Based on these results, Dr Stangier said idarucizumab fulfills the requirements for a fast-acting and specific antidote to dabigatran with a favorable safety profile. Additional clinical testing of the antidote is ongoing.
*Information in the abstract differs from that presented.