Value through Innovation30 October 2014
30 June 2014

U.S. FDA grants Breakthrough Therapy Designation to Pradaxa® (dabigatran etexilate) specific investigational antidote

• Idarucizumab rapidly reverses anticoagulation induced with Pradaxa® and may broaden existing range of reversal options available to physicians in emergency situations 1,2
• Previous results from study in healthy volunteers show antidote to be well-tolerated with immediate, complete and sustained effect 1

Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim

Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim

Ingelheim, Germany, 30 June, 2014 – The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to the investigational antidote idarucizumab* (a humanized antibody fragment), currently being studied as a specific antidote for the oral anticoagulant Pradaxa® (dabigatran etexilate).3

“In light of Boehringer Ingelheim’s core mission to provide value through innovation, we are pleased that the FDA has granted Breakthrough Therapy Designation to idarucizumab to help expedite its development,” said Professor Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim. “It’s important to note that the positive efficacy and safety profile for Pradaxa® is well-documented in both clinical trials and real-world evaluations, which were all conducted in the absence of an antidote. The specific investigational antidote for Pradaxa®, which our scientists at Boehringer Ingelheim are developing, would give physicians an additional and highly targeted option beyond the already existing measures for treatment in case of certain emergency situations.”

The FDA established the Breakthrough Therapy Designation as a means to accelerate the development and review of drugs for serious or life-threatening conditions if preliminary clinical evidence indicates the therapy may demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints.4

Prior clinical research of the antidote in a healthy volunteer study with 145 participants has already demonstrated the potential of the antidote for immediate, complete and sustained reversal of the anticoagulant effect of dabigatran.1 In the placebo-controlled study, the antidote was well tolerated and did not cause any clinically relevant side effects.1 These aspects are especially valuable in clinical situations where rapid reversal of dabigatran-induced anticoagulation may be beneficial for patients taking Pradaxa®.

REVERSE-AD, a global patient study, is now underway to investigate the potential antidote in the clinical setting in patients taking Pradaxa® who have uncontrolled bleeding or require emergency procedures.3 The study will be open to eligible patients in more than 35 countries and at over 500 sites.3 This is the first time that an antidote under development for a novel oral anticoagulant is investigated in a study in patients.3

The antidote is still under investigation and has not yet been approved for clinical use.

NOTES TO THE EDITORS

About Pradaxa® (dabigatran etexilate)
All studies in the RE-VOLUTION® clinical trial programme, which demonstrated the positive benefit-risk-profile of Pradaxa® and resulted in worldwide regulatory approvals, were conducted in the absence of an antidote.5-16 Pradaxa® is now benefiting patients in over 100 countries worldwide with clinical experience equating to over 3 million patient-years in all licensed indications.3

Currently approved indications for Pradaxa® are:17

  • 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 or total knee replacement surgery
  • Treatment of DVT and PE and the prevention of recurrent DVT and PE in adults

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.17,18 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.19 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 mandatory dose adjustment.18,20

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 142 affiliates and a total of more than 47,400 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.

Taking 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 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.

* Idarucizumab is the recommended International Nonproprietary Name (INN).

References

1.Glund S, et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. American Heart Association Scientific Sessions, Dallas, TX, USA, 16-20 November 2013, abstract 17765.
2.Schiele F, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-62.
3.Boehringer Ingelheim Data on File.
4.U.S. Food and Drug Administration. Fact Sheet: Breakthrough Therapies. Available at: http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm.  Last Accessed: June 2014.
5.Ezekowitz MD, 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 Scientific Sessions, Dallas, Texas, USA.
6.Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.
7.Connolly SJ, et al. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.
8.Connolly SJ, et al. The Long Term Multi-Center Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) study. Circulation. 2013;128:237-43.
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;105:721-9.
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. 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;24:1–9.
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, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-772.
15.Schulman S, et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med. 2013;368:709–18.
16.Oldgren 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.
17.Pradaxa® European Summary of Product Characteristics 2014.
18.Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
19.Di Nisio M, et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028–40.
20.Stangier 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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