New data presented at American Society of Hematology (ASH) shows specific antidote idarucizumab* reverses dabigatran-induced anticoagulation independent of age, and kidney function

• ASH 2014: Administration of investigational idarucizumab* resulted in immediate, complete and sustained reversal of dabigatran-induced anticoagulation in middle aged, elderly and renally-impaired volunteers¹
• Treatment with dabigatran could successfully be restarted 24 hours after idarucizumab* administration¹
•  Idarucizumab* was well tolerated following a second administration two months later¹

BURLINGTON, ON, Dec. 18, 2014 /CNW/ - New Phase I data demonstrated that a five-minute intravenous infusion of 2.5 g, 5 g and two doses of 2.5 g of the investigational specific antidote idarucizumab* in healthy male and female volunteers between 45 - 80 years of age and volunteers with mild or moderate kidney impairment, resulted in immediate, complete and sustained reversal of the anticoagulant effect of Pradaxa® (dabigatran etexilate).¹ In elderly individuals and those with mild or moderate kidney impairment, all doses of idarucizumab* tested were found to be safe and well tolerated. Dabigatran treatment could successfully be restarted 24 hours after the antidote had been administered, resulting in full re-anticoagulation.¹ The new data were presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition, San Francisco, USA. The dabigatran-specific antidote is still under investigation and has not yet been approved for clinical use.

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* 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.

"These latest data are important because the study also included elderly patients and those who had impaired kidney function – characteristics that are common among patients who require anticoagulation," said Dr. Martina Flammer, Vice President, Medical and Drug Regulatory Affairs, Boehringer Ingelheim (Canada) Ltd. "The growing evidence supports idarucizumab* as a specific antidote for dabigatran which can provide immediate, complete and sustained reversal. It would be an option for use in clinical situations where patients might benefit from a fast reversal of the anticoagulant effect of Pradaxa®."

The randomized, double-blind, placebo-controlled cross-over study included 46 male and female volunteers ranging from 45 to 80 years of age. For three days, investigators gave a high dose of dabigatran (220 mg twice daily^†) to healthy mid-aged adults (aged 45-64 years), and elderly individuals (aged 65-80 years) and 150 mg twice daily to those with mild or moderate renal impairment with one final dose on the fourth day.² On the fourth day, two hours after taking dabigatran, volunteers received a five-minute intravenous infusion of 5 g of idarucizumab* or, for volunteers with moderate renal impairment, two doses of 2.5 g idarucizumab* given one hour apart. In some subjects, treatment with dabigatran was restarted 24 hours later. Measurements of the anticoagulant effect of dabigatran as well as its reversal by idarucizumab* were taken at baseline, after administration of dabigatran, and after subsequent infusion of idarucizumab* or placebo. After two months, the test was repeated in a subset of healthy subjects.¹

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†} Please refer to approved Canadian Product Monograph for dosing information.
* 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.

The findings from the new Phase I study showed:¹

• Administration of 5 g of idarucizumab* resulted in immediate, complete and sustained reversal of dabigatran-induced anticoagulation in both age groups tested and also in subjects with reduced renal function.
• Complete reversal was shown right at the end of the five minute infusion of idarucizumab*.
• Treatment with dabigatran could successfully be restarted 24 hours after idarucizumab* administration.
• A second administration of idarucizumab*, two months after the first one, achieved the same degree of reversal of dabigatran anticoagulation as the first administration.
• Idarucizumab* was well tolerated– no clinically relevant adverse events were reported although idarucizumab* was associated with a dose-related, transient increase in urine protein and low-weight protein levels which returned to normal within 4-24 hours.
• Adverse events and tolerability reactions were similar with idarucizumab* and placebo. No adverse events were indicative of immunogenic reactions.
• For the 5g dose of idarucizumab*, the reversal effect was consistent, independent of age and kidney function. This dose is currently being investigated in the clinical setting.

Boehringer Ingelheim is developing idarucizumab* as a highly specific and selective antidote to Pradaxa®.  RE-VERSE AD™, a global patient study, is investigating the reversal of anticoagulation in clinical situations where fast reversal is required. This is the first time that an antidote under development for a novel oral anticoagulant is being investigated in a study in patients, instead of volunteers.³

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* 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.

NOTES TO THE EDITORS

About Pradaxa® (dabigatran etexilate)
Pradaxa® is a novel, reversible oral direct thrombin inhibitor.⁴ It provides its anticoagulant effect by selectively blocking the activity of thrombin, the central enzyme in clot formation.⁴

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.⁴ It was then approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), in whom anticoagulation is appropriate.⁴ Pradaxa®  was most recently approved for the treatment of venous thromboembolism events (deep vein thrombosis [DVT], pulmonary embolism [PE]) and prevention of recurrent DVT and PE.⁴ To date, over 130,000 Canadians with AF have received Pradaxa® for stroke prevention.³

Pradaxa® has been in the market for more than five years and is approved in over 100 countries.³

The efficacy and safety profile of Pradaxa® in its licensed indications is well documented in an extensive clinical trial programme.^5-12 In addition, the favourable benefit-risk 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).^13-15 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, including more than 134,000 patients.¹⁵

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. Pradaxa® has the longest clinical trial experience in DVT and PE patients of any novel oral anticoagulant (NOAC).^{5, 16-21} DVT and PE patients can start taking Pradaxa® in a simple fixed dose regimen after initial treatment with an injectable anticoagulant such as low-molecular-weight heparin (LMWH).⁴

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.

References:

1. Glund S. et al. Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects [Abstract]. Presented on 8th December at the 56^th American Society of Hematology Annual Meeting & Exposition, San Francisco, USA. Available at: https://ash.confex.com/ash/2014/webprogram/Paper74960.html  Last accessed December 2014.
2. Glund S. et al. Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects. Presented on 8th December at the 56^th American Society of Hematology Annual Meeting & Exposition, San Francisco, USA.
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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. 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.
13. 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.
14. 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.
15. 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 (Accessed June 25, 2014).
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17. The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010;363:2499–2510.
18.  The EINSTEIN–PE Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:1287-97.
19. Prins MH. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thrombosis Journal 2013, 11:21.
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21. The Hokusai-VTE Investigators. Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism. N Engl J Med 2013;369: 1406-15.

SOURCE Boehringer Ingelheim (Canada) Ltd.