Value through Innovation23 October 2014
18 November 2013

First human data show promise of Boehringer Ingelheim's specific antidote for immediate, complete and sustained reversal of Pradaxa®-induced anticoagulation

• AHA Congress 2013 - Positive results from first investigation in 145 healthy volunteers showed antidote to be well tolerated, producing immediate, complete and sustained reversal of dabigatran-induced anticoagulation1
• Investigational antidote intended to further broaden the existing range of reversal options available to physicians during critical care situations
• Pradaxa® (dabigatran etexilate) offers a favourable safety and efficacy profile as was shown during clinical trials and confirmed in real-world observations2-14

Ingelheim, Germany, November 18, 2013 – 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 (Fab) as a specific antidote for immediate, complete and sustained reversal of dabigatran-induced anticoagulation.1 The development of the antidote is part of Boehringer Ingelheim’s commitment to further broadening the range of reversal options available to physicians in rare critical care situations. The antibody fragment has not yet been approved for clinical use and is still undergoing investigation to further establish its efficacy and safety profile.

The clinical study examined the safety, tolerability, pharmacokinetics and pharmacodynamics of the antibody fragment antidote in a randomised, double-blind, placebo controlled study involving 145 healthy male volunteers. In a first step, the tolerability of the antibody fragment was tested as an intravenous infusion of rising doses (up to 8 g). In a second step, the potential for reversal of dabigatran-induced anticoagulation was evaluated, with 5-minute infusions using three different doses (1 g, 2 g and 4 g) administered following Pradaxa® pre-treatment (220 mg twice daily for 3 days).1

The results demonstrated: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 achieve immediate, complete and sustained reversal of the anticoagulant effect of dabigatran
  • For the 2 g and the 4 g doses, the reversal effect was maintained for more than 12 hours after the end of infusion
Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim

Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim

"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 antibody fragment is ongoing. Boehringer Ingelheim is planning to initiate the next phase of investigation including studies in patients in 2014.

Preventing stroke is the primary goal of treatment in patients with atrial fibrillation for which anticoagulation therapy is essential.15,16 An increased risk of bleeding is a known possible treatment complication of all anticoagulant therapies.17 While no specific antidote is approved or available in clinical practice to counteract the anticoagulant effect of any novel oral anticoagulant therapy,18 well established measures are currently available for patients treated with Pradaxa® to reverse the anticoagulant effect or to manage bleeding during an emergency situation.19,20 A dedicated sub-analysis from the landmark RE-LY® trial showed that in RE-LY®, patients had better survival prognosis and spent less time in intensive care following a major bleed with Pradaxa® than with warfarin.21 It is expected that the development of a specific antidote to Pradaxa® will further broaden the range of reversal options available to physicians in clinical practice.

The efficacy and safety profile of Pradaxa® in its licensed indications is well documented in an extensive clinical trial programme,2-12 which has led to worldwide regulatory approvals in over 100 countries to date.22 This favourable efficacy-safety profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency and the U.S. Food and Drug Administration (FDA).13,14 Clinical experience with Pradaxa® continues to grow and equates to over 2 million patient-years in all licensed indications to date supporting Pradaxa® as the leading novel oral anticoagulant.23

NOTES TO THE EDITORS

About Pradaxa® (dabigatran etexilate)
Clinical experience of Pradaxa® (dabigatran etexilate) exceeds that of all other novel oral anticoagulants, equating to over 2 million patient-years in all licensed indications worldwide.22 Pradaxa® has already been in the market for more than 5 years and is approved in over 100 countries.21 Currently approved indications for Pradaxa® are:20

  • Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) and a risk factor for stroke
  • Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery
  • Primary prevention of venous thromboembolic events in patients undergoing elective total knee replacement surgery

In June 2013 Boehringer Ingelheim started submitting new applications to regulatory authorities for Pradaxa® for the following indications:22

  • Treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and prevention of related death
  • Prevention of recurrent deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and related death

Important Notice: Pradaxa® is currently not approved for the acute treatment or prevention of recurrent DVT and/or PE20

Pradaxa®, 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.20,23 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.24 In contrast to vitamin-K antagonists, which variably act via different coagulation factors, Pradaxa® 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 dose adjustment.22,25

About Boehringer Ingelheim
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. 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 endeavours.

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

Please be advised
This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the U.S., the UK or Canada.

References
1Glund 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.
2Eriksson 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.
3Eriksson 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.
4Eriksson 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.
5Ginsberg 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.
6Schulman S. et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.
7Schulman 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.
8Schulman S. et al. Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. N Engl J Med. 2013;368:709–18.
9Connolly SJ. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
10Connolly SJ. et al. Newly identified events in the RE-LY® trial. N Engl J Med. 2010;363:1875-6.
11Ezekowitz M, et al. RE-LY and RELY-ABLE: Long-term Follow-up of Patients With Non-valvular Atrial Fibrillation Receiving Dabigatran Etexilate for Up to 6.7 Years. Oral presentation #10684 on Monday 18 November 2013 at the American Heart Association’s Scientific Sessions, Dallas, Texas, USA.
12Oldgren J. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32:2781-9.
13European Medicines Agency Press release - 25 May 2012: EMA/337406/2012. European Medicines Agency updates patient and prescriber information for Pradaxa. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2012/05/news_detail_001518.jsp&mid=WC0b01ac058004d5c1 Last accessed 13 November 2013.
14FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran) – 2 November 2012 http://www.fda.gov/Drugs/drugsafety/ucm326580.htm  Last accessed 13 November 2013.
15Marini C, et al. From a Population-Based Study Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke: Results From a Population-Based Study. Stroke. 2005;36:1115-9.
16Aguilar 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.
17Levine MN, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S–21S.
18Siegal DM, Cuker A, et al. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013;35:391–8.
19Kaatz S, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl.1):S141–5.
20Pradaxa® European Summary of Product Characteristics 2013.
21Majeed 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
22Boehringer Ingelheim data on file
23Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
24Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40.
25Stangier J, et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabagitran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.

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