Data from First Phase I Study of Antidote for Pradaxa® (dabigatran etexilate) Presented at American Heart Association Scientific Sessions

Study shows antidote can lead to immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy humans

BURLINGTON, ON, Nov. 20, 2013 /CNW/ - Presented for the first time at the American Heart Association's (AHA) Scientific Sessions, results from the first clinical study in healthy volunteers demonstrate the potential of an antibody fragment as a specific antidote for immediate, complete and sustained reversal of dabigatran-induced anticoagulation.1 The antidote has not yet been approved for clinical use and is still undergoing investigation to establish its efficacy and safety profile.

In this randomized, double-blind, placebo-controlled study of 145 healthy male volunteers, investigators evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of the antidote. In part one of the study, subjects received single, progressively increasing intravenous doses of up to 8 g of the antidote. In part two, doses of 1 g, 2 g and 4 g were administered as 5-minute intravenous infusions in the presence of dabigatran 220 mg twice-daily for 4 days.1

The results of the study showed:1

  • All administered doses of the antibody fragment antidote were well tolerated
  • A 5-minute infusion of the antidote following Pradaxa® pre-treatment was able to revert prolonged clotting times induced by dabigatran to baseline. There was a dose-dependent reversal with increasing doses of the antidote
  • For the 2 g and the 4 g doses, the reversal effect was maintained for more than 12 hours after the end of infusion

"These first results from the clinical study investigating the antibody fragment as a specific antidote to dabigatran are very encouraging," commented Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "Boehringer Ingelheim led the field by bringing the first novel oral anticoagulant treatment to patients with atrial fibrillation. As part of our commitment to scientific innovation, our scientists continue to conduct research to further improve the care of patients treated with Pradaxa® by broadening the range of reversal options that are available to them in clinical practice."

The clinical development of the antidote is ongoing. Boehringer Ingelheim is planning to initiate the next phase of investigation including studies in patients in 2014, which will likely include several sites in Canada.

Preventing stroke is the primary goal of treatment in patients with atrial fibrillation, making anticoagulation therapy essential.2,3 As a result, an increased risk of bleeding is a known possible treatment complication of all anticoagulant therapies.4 While no specific antidote is approved or available in clinical practice to counteract the anticoagulant effect of any novel oral anticoagulant therapy5, well established measures are currently available for patients treated with Pradaxa® to reverse the anticoagulant effect or to manage bleeding during an emergency situation.6,7 A sub-analysis from the landmark RE-LY® trial showed that patients had better survival prognosis and spent less time in intensive care following a major bleed with Pradaxa® than with warfarin.8

About Pradaxa® (dabigatran etexilate)
The efficacy and safety profile of Pradaxa® in its licensed indications is well documented in an extensive clinical trial programme,9-19 which has led to worldwide regulatory approvals in over 100 countries to date.20 The favourable efficacy-safety profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency, the U.S. and the Food and Drug Administration (FDA).17,18 Clinical experience with Pradaxa® continues to grow and equates to over two million patient-years in all licensed indications to date supporting Pradaxa® as the leading novel oral anticoagulant.20

Pradaxa® is a novel, reversible oral direct thrombin inhibitor. It provides its anticoagulant effect by selectively blocking the activity of thrombin, the central enzyme in clot formation.21

The Canadian approval of Pradaxa® for stroke prevention in atrial fibrillation is based on data from the landmark  RE-LY® Trial (Randomized Evaluation of Long term anticoagulant therapY) published in 2009 the New England Journal of Medicine.16 The study population included patients with high, moderate, and low risk of stroke. Pradaxa® 150 mg twice-daily was proven to be more effective than warfarin at preventing strokes in AF patients, with comparable safety.16 To date, over 130,000 Canadians with atrial fibrillation have received Pradaxa® for stroke prevention.20

Specifically, Pradaxa® 150 mg twice-daily significantly reduced the risk of stroke and systemic embolism by 35 per cent versus warfarin, (p=0.0001) without increasing the risk of major bleeding, and reducing the risk of intracranial bleeding by 59 per cent (p0.0001).22  In addition, Pradaxa® 150 mg twice-daily statistically significantly reduces ischemic and hemorrhagic stroke better than well-controlled warfarin.22

The adverse events reported in the RE-LY® trial that were  more common with dabigatran etexilate than with warfarin were gastrointestinal (GI) disorders, such as abdominal pain, diarrhea, dyspepsia and nausea22. In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including aspirin and clopidogrel) and NSAID therapies increases the risk of bleeding, by about two-fold.22 This higher rate of bleeding events by ASA or clopidogrel co-medication was, however, also observed for warfarin. Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment.22

Health Canada has approved the 150mg dose of Pradaxa® to be taken twice-daily for prevention of stroke and systemic embolism in patients with atrial fibrillation in whom anti-coagulation is appropriate.22 The 110mg dose has been recommended for use in patients 80 years of age or older and may be considered for patients at higher risk of bleeding.22

Pradaxa® was first approved in 2008 for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.  In 2010, it was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate. In the RE-LY® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.

About Boehringer Ingelheim (Canada) Ltd.
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in its Prescription Medicines business corresponds to 22.5% of its net sales.

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Montreal, Quebec and is now located in Burlington, Ontario.  Boehringer Ingelheim employs more than 550 people across Canada.

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  1. Glund S, et al. A Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Healthy Male Volunteers. Oral presentation #17765 on Monday 18 November 2013 at the American Heart Association's Scientific Sessions, Dallas, Texas, USA.
  2. Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Syst Rev. 2005;(3):CD001927.
  3. Marini C, et al. Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Based Study. Stroke. 2005;36:1115-9.
  4. Levine MN, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S-21S.
  5. Siegal DM and Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013;35:391-8.
  6. Kaatz S, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl.1):S141-5.
  7. Pradaxa® European Summary of Product Characteristics 2013.
  8. Majeed A, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013; published online before print September 30 2013, doi:10.1161/CIRCULATIONAHA.113.00233
  9. Eriksson BI. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-56.
  10. Eriksson BI. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, doubleblind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-9.
  11. Eriksson BI. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-85.
  12. Ginsberg JS. et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthoplasty. 2009;24(1)1-9.
  13. Schulman S. et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342-52.
  14. Schulman S. et al. A Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism  (RE-COVER II). Oral presentation from Session 332: Antithrombotic Therapy 1. Presented on 12 December at the American Society of Hematology (ASH) Annual Meeting 2011.
  15. Schulman S. et al. Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. N Engl J Med. 2013;368:709-18.
  16. Connolly SJ. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
  17. FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) - 2 November 2012  Last accessed 13 November 2013.
  18. European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa.
  19. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285-95.
  20. Boehringer Ingelheim. Data on file.
  21. Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-40.
  22. PRADAXA® Product Monograph. May 14, 2013.

SOURCE: Boehringer Ingelheim

For further information:

Jeanelle Awa 
Environics Communications
(416) 969-2670 

Jennifer Mota 
Boehringer Ingelheim (Canada) Ltd.
(905) 631-4739 

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