Antidote for Rapid Reversal of Pradaxa® (dabigatran etexilate) Progresses Into Next Stage of Clinical Investigation with Study in Canadian Patients

Antidote (idarucizumab)* already shown to provide immediate, complete and sustained reversal of anticoagulant effects of dabigatran in healthy adults1

BURLINGTON, ON – September 22, 2014 – Today Boehringer Ingelheim announces the next phase in the clinical development program of the investigational antidote idarucizumab* for rapid reversal of Pradaxa® - induced anticoagulation. The specific antidote has already demonstrated immediate, complete and sustained reversal of the anticoagulant effect of dabigatran in healthy volunteers.1 Now the antidote will be investigated in the clinical setting in patients taking Pradaxa®. This is the first antidote to be used to reverse the effects of a new anticoagulant for patients in an emergency situation due to bleeding.

“For patients who require rapid reversal of Pradaxa’s anticoagulant effect, the antidote would provide physicians an additional option beyond their current management strategies,” says Dr. John Eikelboom, Associate Professor, Department of Medicine, McMaster University. “By removing the blood thinning effect of dabigatran in patients, physicians can focus on the other aspects of patient management and treatment.”

All blood thinning medications carry an increased risk of bleeding.2 Boehringer Ingelheim is committed to the development of a Pradaxa®-specific antidote and to improving the standard of care by broadening the range of reversal options available to physicians.1,3 The pivotal study will provide knowledge on the potential of the specific antidote to support the treatment of patients taking Pradaxa®. A pivotal trial is traditionally the last stage of clinical development before market authorization of a medication.

A global phase III study, RE-VERSE AD™, is underway in patients taking Pradaxa® who have uncontrolled bleeding or require emergency surgery or procedures (NCT02104947).4 Emergency rooms in more than 35 countries worldwide (including Canada) will participate in this study.4 Sites in Canada have now  been initiated. Physicians will be provided with the investigational antidote idarucizumab* as a ‘ready to use’ solution for infusion.

The following Canadian hospital emergency rooms are participating in this study:
•Hôpital Maisonneuve-Rosemont (Montreal, QC)
•Jewish General Hospital (Montreal, QC)
•Hamilton General Hospital (Hamilton, ON)
•Foothills Medical Centre  (Calgary, AB)
•St. Paul’s Hospital (Vancouver, BC)

“Commencing trials of idarucizumab* with patients taking Pradaxa® is the next step in providing physicians with a product of the highest possible standard to ensure patient safety,” said Dr. Martina Flammer, Vice President, Medical and Drug Regulatory Affairs, Boehringer Ingelheim (Canada) Ltd. “By supplying physicians more options to safely treat their patients, they are better equipped to confidently manage them knowing they are helping prevent debilitating strokes.”

In the previous placebo-controlled healthy-volunteer study, the antidote was well tolerated and did not cause any clinically relevant side effects.1 The antidote was able to produce immediate, complete and sustained reversal of dabigatran induced anticoagulation.1 These three aspects are especially valuable in clinical situations where rapid reversal of dabigatran-induced anticoagulation may be required for patients taking Pradaxa®.

The U.S. Food and Drug Administration (FDA) has granted “Breakthrough Therapy Designation” to idarucizumab*. A "breakthrough drug" is intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening condition.5

About Pradaxa® (dabigatran etexilate)

Pradaxa® is a novel, reversible oral direct thrombin inhibitor.2 It provides its anticoagulant effect by selectively blocking the activity of thrombin, the central enzyme in clot formation.2

Pradaxa® was first approved for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.2 It was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate.2 Pradaxa® was recently approved for the treatment of venous thromboembolism events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE.2

Pradaxa® has been in the market for more than five years and is approved in over 100 countries.6 The efficacy and safety profile of Pradaxa® in its licensed indications is well documented in an extensive clinical trial programme.7-14 The favourable benefit-risk profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency and the Food and Drug Administration (FDA).15-17

Most recently in May 2014, in one of the largest real-world analyses of its kind, the FDA once again re-affirmed the favourable benefit/risk profile of Pradaxa® when it issued results from this study in clinical practice.18 This latest FDA study included more than 134,000 patients with atrial fibrillation.

As the first novel oral anticoagulant to market, clinical experience with Pradaxa® continues to grow and equates to over three million patient-years in all licensed indications to date.6 To date, over 130,000 Canadians with atrial fibrillation have received Pradaxa® for stroke prevention.6

For dosing, side effects, warnings and precautions, please refer to the Pradaxa® Product Monograph: http://www.boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product-monograph/PradaxaPMEN.pdf

About Boehringer Ingelheim (Canada) Ltd.
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.

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.

For more information, please visit www.boehringer-ingelheim.ca.

* Idarucizumab is an investigational compound. Its safety and efficacy has not yet been fully established and it is currently not authorized for sale in Canada.

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.PRADAXA Product Monograph. June 24, 2014.

3.Schiele F, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554-62.

4.Reversal of Dabigatran Anticoagulant Effect with Idarucizumab https://clinicaltrials.gov/ct2/show/NCT02104947?term=idarucizumab&rank=1 (Accessed June 25, 2014)

5.FDA Fact Sheet:  Breakthrough Therapies. http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm (Accessed June 27, 2014)

6.Boehringer Ingelheim Data on File.

7.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.

8.Connolly SJ. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-51.

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.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.

12. Schulman S. et al. Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism. N Engl J Med. 2009;361:2342–52.

13.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.

14. Schulman S. et al. Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism. N Engl J Med. 2013;368:709–18.

15. FDA 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 July 22, 2014..

16. European 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. Last accessed 22 July 2014

17.FDA Safety Announcement. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm (Accessed June 25, 2014)

18. FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin – 13 May 2014. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm  Last accessed May 2014.