Boehringer Ingelheim Presents New idarucizumab (Praxbind®) Analyses on Reintroduction of Antithrombotic Therapy after Reversal of Dabigatran

  • RE-VERSE AD™ interim analysis shows reintroduction of alternate antithrombotic therapy possible at any time after idarucizumab administration1
  • Findings from an in vitro study show idarucizumab does not impact the effect of other commercially available blood thinners2
  • In vitro study results also show that the reversal effect of idarucizumab on dabigatran is not affected by the presence of coagulation factor concentrates2

Ingelheim, Germany, 10 November 2015 – Boehringer Ingelheim announces results from two new analyses evaluating idarucizumab, recently approved under the Accelerated Approval pathway and marketed in the U. S. as Praxbind®, a specific reversal agent for Pradaxa® (dabigatran etexilate), that were presented at the American Heart Association (AHA) Scientific Sessions 2015 in Orlando.1,2 One analysis examined reinitiation of antithrombotic therapy after administration of idarucizumab.1 The reinitiation of antithrombotic therapy in patients with nonvalvular atrial fibrillation (AF) is important in order to address the underlying risk of stroke.

An interim analysis of data from the ongoing phase III RE-VERSE AD™ trial showed reinitiation of alternative antithrombotic therapy was possible any time after idarucizumab use. Reinitiation of alternative antithrombotic therapy (e.g. heparin) after treatment with idarucizumab ranged from 0.2 days to 77.2 days in patients who presented with uncontrolled or life-threatening bleeding and 0 days to 40.8 days in patients requiring emergency surgery or an urgent procedure. Reinitiation of dabigatran after treatment with idarucizumab ranged from 1.3 days to 90.6 days in patients with uncontrolled or life-threatening bleeding, and 1 day to 63.31 days in patients requiring emergency surgery or an urgent procedure.1

“Reinitiation of antithrombotic therapy as soon as medically appropriate should be considered to reduce the underlying stroke risk for patients with nonvalvular atrial fibrillation,” said Charles Pollack, MD, Associate Provost and Professor of Emergency Medicine, Thomas Jefferson University in Philadelphia, and lead investigator of RE-VERSE AD™. “The findings from this interim analysis from the phase III RE-VERSE AD™ study may provide physicians added insight into the reinitiation of antithrombotic therapy after dabigatran reversal in the rare emergency situations where administration of idarucizumab is deemed necessary.”

A second presentation on idarucizumab included findings from an in vitro study investigating the efficacy of idarucizumab in the presence of coagulation factor concentrates [e.g., blood-clotting proteins recombinant Factor VIIa, 3- or 4-factor prothrombin complex concentrates (PCC), and activated PCC]. Results showed that the reversal effect of idarucizumab on dabigatran was not affected by the presence of coagulation factor concentrates.2 This result is important as these agents are frequently used in the management of patients presenting with acute hemorrhages. The study also showed that the use of idarucizumab did not inhibit the anticoagulation effects of other commercially available blood thinners (direct factor Xa inhibitors, heparins, or other direct thrombin inhibitors).

“The findings from this interim analysis from the phase III RE-VERSE AD™ trial suggest that idarucizumab may give physicians flexibility in managing antithrombotic therapy and greater control in making treatment decisions for patients taking dabigatran,” said Professor Jörg Kreuzer, Vice President Medicine, Therapeutic Area Cardiovascular, Boehringer Ingelheim. “Although idarucizumab will be rarely used in clinical practice, a specific reversal agent may provide an important therapeutic option for physicians and patients.”

NOTES TO EDITORS

About the RE-VERSE AD™ study
RE-VERSE AD™ is a phase III global study that includes patients taking dabigatran who have uncontrolled bleeding or require emergency procedures.3 The interim analysis from RE-VERSE AD included data from 90 patients with either uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident (n= 51), or patients requiring emergency surgery or an urgent procedure, e.g. surgery for an open fracture after a fall (n=39). The study met its primary endpoint, achieving 100 percent maximum reversal as the median value within four hours of administration across all patients. Reversal was evident immediately after administration of the first vial of idarucizumab and was complete in all but 1 patient. In this interim analysis there were 18 deaths. Mortality could be attributed to a complication of the underlying reason for admission or associated with comorbidities. Thrombotic events occurred in five patients, none of whom was receiving antithrombotic therapy at the time of the event.4

About idarucizumab (Praxbind®)
Idarucizumab is a humanized antibody fragment, or Fab, designed as a specific reversal agent to dabigatran. Idarucizumab binds specifically to dabigatran molecules only, neutralising their anticoagulant effect without interfering with the coagulation cascade.5

In the US, idarucizumab is now indicated in patients treated with dabigatran when reversal of the anticoagulant effects of dabigatran is needed:6

  • For emergency surgery/urgent procedures
  • In life-threatening or uncontrolled bleeding

Regulatory reviews and submissions in other countries are ongoing.7 Idarucizumab is the only specific reversal agent for a NOAC currently in regulatory review.7 Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.7

About dabigatran etexilate (Pradaxa®)
Clinical experience of dabigatran equates to over 4 million patient-years in all licensed indications worldwide.7 Dabigatran has been in the market for more than 6 years and is approved in over 100 countries.7

Currently approved indications for dabigatran are:8,9

  • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and a risk factor for stroke
  • Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery or total knee replacement surgery
  • Treatment of DVT and PE and the prevention of recurrent DVT and recurrent PE in adults

Dabigatran, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.8,10 Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation.11 In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or mandatory dose adjustment.10,12

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 146 affiliates and a total of more than 47,700 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2014, Boehringer Ingelheim achieved net sales of about 13.3 billion euros. R&D expenditure corresponds to 19.9 per cent of its net sales.

For more information please visit www.boehringer-ingelheim.com

Intended audiences

This press release is issued from our Corporate Headquarters in Ingelheim, Germany and is intended to provide information about our global business. Please be aware that information relating to the approval status and labels of approved products may vary from country to country, and a country-specific press release on this topic may have been issued in the countries where we do business.

Referências

  1. Pollack C.V. et al. Reinitiation of Antithrombotic Therapy After Emergency Procedures or After an Uncontrolled or Life-Threatening Bleeding Event: Initial Experience from the RE-VERSE AD Trial. Presentation #187 on 8 November 2015 at the American Heart Association (AHA) Scientific Sessions, Orlando, USA.
  2. van Ryn J. et al. Reversal Of Dabigatran Anticoagulation By Idarucizumab In The Presence Of Coagulation Factor Concentrates And The Lack Of Potential Non-specific Effects Of Idarucizumab On Heparins, Factor Xa Inhibitors And Other Direct Thrombin Inhibitors Like Bivalirudin, Hirudin Or Argatroban. Presentation #299 on 9 November 2015 at the American Heart Association (AHA) Scientific Sessions, Orlando, USA.
  3. Pollack C. V. et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198-205.
  4. Pollack C. V. et al. Idarucizumab for dabigatran reversal. NEJM. 2015;373(6):511-20.
  5. Schiele F. et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554-62.
  6. PRAXBIND® US Prescribing Information, 2015
  7. Boehringer Ingelheim Data on File.
  8. PRADAXA® US Prescribing Information, 2015
  9. Pradaxa® European Summary of Product Characteristics, 2015.
  10. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
  11. Di Nisio M. et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40.
  12. Stangier J. et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.