04 Dec Monoclonal Idarucizumab Antibody May Reverse Dabigatran Anticoagulation
MedicalResearch.com Interview with:
Dr. Joanne van Ryn, PhD
Department of CardioMetabolic Disease Research
Boehringer Ingelheim GmbH & Co., Germany
MedicalResearch: What is the background for this study? What are the main findings?
Response: Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific antidote to reverse the anticoagulant effect of dabigatran. Currently, there are no specific antidotes available for any of the newer oral anticoagulants, or NOACs, to complement the existing range of bleed management options during critical care situations. Idarucizumab is being developed to provide physicians with an additional therapeutic option they could consider should a patient require emergency intervention or if a patient experiences uncontrolled bleeding.
Pre-clinical studies indicated idarucizumab binds specifically to and inhibits dabigatran. Phase I data with idarucizumab in healthy volunteers demonstrated the potential of idarucizumab to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation. In that placebo-controlled study, idarucizumab did not cause any clinically relevant side effects.
This phase I sub-study in 35 healthy volunteers showed that idarucizumab restores dabigatran-induced inhibition of fibrin formation at a small wound site. Fibrin, the main component of a blood clot, was assessed by measuring levels of fibrinopeptide A (FPA), a substance that is released when fibrin is formed. Fibrin formation was assessed after a small scratch, similar to a paper cut, was made. Measurements were conducted at baseline, after administration of dabigatran, and after subsequent administration of idarucizumab or placebo. The results showed that dabigatran almost completely inhibited the production of FPA at the wound site, and that idarucizumab restored FPA production:
- At baseline, before the volunteers took dabigatran, the average level of FPA was 3981 ng/mL.
- On day three, 2.5 hours after the volunteers took dabigatran, the average level of FPA was 208 ng/mL, an approximate 95 percent decrease compared to baseline.
- On day four, 2.5 hours after the volunteers took dabigatran and 30 minutes after they were infused with 1 g, 2 g or 4 g of idarucizumab, FPA levels were 24 percent, 45 percent and 95 percent, respectively, of the average baseline level.
The restored fibrin production at the wound site after idarucizumab dosing with 2g or 4g also correlated with reversal of the dabigatran-anticoagulation activity in circulating blood.
MedicalResearch: What should clinicians and patients take away from your report?
Response: These data are the first to show that idarucizumab restores dabigatran-induced inhibition of wound-site fibrin formation. This study was performed as a potential way to test effects of idarucizumab on bleeding. The results also complement earlier findings that showed idarucizumab provides immediate, complete and sustained reversal of the anticoagulation effects of dabigatran in human volunteers.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Response: Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD™, a phase III global case-series study investigating idarucizumab in actual clinical settings where patients taking dabigatran may require emergency intervention or experience an uncontrolled or life threatening bleeding event. This is the first trial to investigate a specific antidote in patients actively being treated with a newer oral anticoagulant.
Van Ryn J, Schmol M, Pillu H, et al. Effect of Dabigatran on the Ability to Generate Fibrin at a Wound site and its Reversal by Idarucizumab, the Antidote to Dabigatran, in Healthy Volunteers: An Exploratory Marker of Blood Loss. Abstract No. 18403. Presented at: American Heart Association Scientific Sessions 2014. November 15-19, 2014, Chicago, Illinois.