treating a patient
Photo by Tom Watanabe
The US Food and Drug Administration (FDA) has granted accelerated approval for idarucizumab (Praxbind), the first reversal agent for the direct thrombin inhibitor dabigatran (Pradaxa).
Idarucizumab is now approved for use in emergency situations when there is a need to reverse the anticoagulant effect of dabigatran.
The FDA’s accelerated approval program allows the agency to approve drugs for serious conditions that fill an unmet medical need.
Accelerated approval is based on an effect on a surrogate or intermediate clinical endpoint that is reasonably likely to predict a clinical benefit to patients. So the company developing the drug is required to submit additional information after approval to confirm the drug’s clinical benefit.
About dabigatran and idarucizumab
Dabigatran is FDA-approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, as well as for the treatment and prevention of deep vein thrombosis and pulmonary embolism.
Idarucizumab is the first reversal agent approved specifically for dabigatran and works by binding to the drug compound to neutralize its effect. Idarucizumab is administered via intravenous injection.
Both idarucizumab and dabigatran are under development by Boehringer Ingelheim.
Idarucizumab has been studied in 3 randomized, double-blind, phase 1 trials of subjects who were not previously taking dabigatran and a phase 3 trial (RE-VERSE AD) of patients who were taking dabigatran and required reversal in an emergency setting.
Phase 1 trials
One phase 1 study (NCT01688830) enrolled 157 healthy male volunteers and consisted of 3 parts. Part 1 included 110 subjects who received placebo or idarucizumab at doses ranging from 20 mg to 8 g.
Idarucizumab (in the absence of dabigatran) was deemed safe and well tolerated. These results were published in Thrombosis and Haemostasis.
Parts 2 and 3 of the study included 47 subjects (part 2, n=35; part 3, n=12), and researchers investigated how well various doses of idarucizumab reversed the anticoagulant effect of dabigatran.
Results from parts 2 and 3 were published in The Lancet. The researchers said idarucizumab (given at 2 g or greater) provided immediate, complete, and sustained reversal of the anticoagulant effect of dabigatran, without producing serious adverse events.
In a second phase 1 study (NCT01955720), researchers evaluated idarucizumab in 46 subjects (males and females). This included healthy volunteers, elderly subjects, and participants with pre-existing mild or moderate kidney impairment.
Idarucizumab immediately and completely reversed dabigatran’s anticoagulant effect in these subjects, and they were able to restart dabigatran within 24 hours of receiving idarucizumab.
In addition, the researchers said there were no clinically relevant adverse events related to idarucizumab, and there were no relevant changes in any of the investigated safety parameters. These results were presented at the 2014 ASH Annual Meeting.
A third phase 1 study (NCT02028780) enrolled 80 healthy Japanese subjects. Researchers assessed the safety, tolerability, and pharmacokinetics of single, increasing doses of idarucizumab, administered both alone and after dabigatran.
Phase 3 trial
In the ongoing phase 3 trial, RE-VERSE AD, researchers are evaluating idarucizumab in emergency settings. The team reported interim results in 90 patients in NEJM and at the 2015 ISTH Congress.
Idarucizumab normalized diluted thrombin time and ecarin clotting time in a majority of patients who had uncontrolled or life-threatening bleeding complications while on dabigatran and in most patients who had to reverse dabigatran’s effects because they required emergency surgery or an invasive procedure.
The researchers said there were no safety concerns related to idarucizumab. However, 23% of patients experienced serious adverse events, 20% died, and several patients had thrombotic or bleeding events after receiving idarucizumab.
