Praxbind™ (idarucizumab), A Specific Antidote for Immediate Reversal of Pradaxa® (dabigatran etexilate)1 Now Approved in Canada With Conditions

Praxbind™ provides immediate, complete and sustained reversal of the anticoagulant effects of Pradaxa® within minutes1,2

Burlington, ON –May 16, 2016 – Boehringer Ingelheim (Canada) Ltd. today announced that Health Canada has approved Praxbind™ (idarucizumab) with conditions. Praxbind™ is a specific antidote for the immediate reversal of dabigatran, and is indicated for adult patients treated with Pradaxa® (dabigatran etexilate) when rapid specific reversal of the anticoagulant effects of Pradaxa® is required for emergency surgery/urgent procedure or life-threatening or uncontrolled bleeding.1 The approval with conditions is based on promising evidence from clinical trials. Pradaxa® is approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF), in whom anticoagulation is appropriate.  The conditional approval of Praxbind™ makes Pradaxa® the first and only novel oral anticoagulant (NOAC) in Canada with a specific antidote.1

“Patient safety is of utmost importance to Boehringer Ingelheim, and with the addition of Praxbind™ - we are providing greater peace of mind to thousands of AFib patients in Canada,” says Richard Mole, President and CEO, Boehringer Ingelheim (Canada) Ltd. “Life is unpredictable – making it difficult to know when an emergency might occur that requires urgent medical care and reversal of the blood-thinning effects of their anticoagulant. The approval of Praxbind™ provides healthcare professionals and patients with more confidence that the anticoagulant effects of Pradaxa® can be immediately reversed, if needed.As we did with the introduction of Pradaxa® back in 2010, the first NOAC to be approved in Canada, we are again leading the evolution of anticoagulant care.”

Novel oral anticoagulants have dramatically changed the way AFib is treated and managed.3 While it is evident that anticoagulant treatment reduces the risk of stroke, the fear of a potential bleed, or the need to rapidly reverse the effects of anticoagulant therapy, is the leading concern for under prescribing of OACs, as well as the lack of treatment adherence amongst patients taking OAC therapy to prevent a potentially devastating stroke.4-7

“The availability of Praxbind for immediate reversal of Pradaxa is a major advancement in anticoagulation care,” says Dr. John Eikelboom, Associate Professor, Department of Medicine, McMaster University in Hamilton. “It gives the peace of mind some patients and physicians are looking for when using anticoagulation that there is an antidote for immediate reversal, if the need arises. In my experience, I can tell you that I’ve seen complete reversal of the anticoagulation effects of Pradaxa within minutes of administering Praxbind.”

Praxbind™ has been issued a conditional marketing authorization, pending the final clinical trial results to confirm its reversal effects in patients and promising evidence of clinical benefit. Under this policy, Boehringer Ingelheim will provide Health Canada with the final clinical trial results of the case series study in patients when they are available.

To date, patient case series study results have demonstrated that 5 g of Praxbind™ provides immediate, complete and sustained reversal of the anticoagulant effects of Pradaxa® in most patients requiring urgent intervention.1,2

About AFib
Affecting 350,000 Canadians, AFib is the most common type of irregular heartbeat8 and can lead to severe and debilitating strokes,9 placing people at a three to five times greater risk of stroke.10 While all oral anticoagulants are associated with an increased risk of bleeding, treatment with oral anticoagulants has been shown to reduce the risk of stroke.11

About Praxbind™ (idarucizumab)
Praxbind™ is a humanized monoclonal antibody fragment that specifically binds to dabigatran to reverse the anticoagulant effects of Pradaxa®.1 Praxbind™ does not reverse the effects of other anticoagulants.1

Boehringer Ingelheim began research on Praxbind™ before the approval of Pradaxa® for the prevention of stroke and systemic embolism in adults with AFib, in whom anticoagulation is appropriate, in 2010.3

Praxbind™ continues to be evaluated in REVERSE-AD™, a case series study initiated by Boehringer Ingelheim in 2014 to investigate Praxbind™ in the emergency setting.1 Up to 500 patients taking Pradaxa® aged 18 years or over are expected to be enrolled from more than 400 centres in 38 countries worldwide.12-15

The safety and efficacy of Praxbind™ has been evaluated in 224 healthy subjects as part of placebo-controlled trials. In addition, 123 patients were included in an ongoing case series study who had life-threatening or uncontrolled bleeding or required emergency surgery or procedures and were on treatment with Pradaxa®.1 Mild symptoms of hypersensitivity (fever, difficulty in breathing or wheezing increased frequency of rapid breathing, rash or itching) were also reported in these patients. These were reported in a clinical trial, but may not be directly related to Praxbind™.1

In February and March 2015, Praxbind™ was submitted under an accelerated approval pathway to the U.S. Food and Drug Administration (FDA), European Medicines Agency and Health Canada for use in patients who require urgent reversal of Pradaxa®. Praxbind™ was approved by the US FDA in October, 2015, the European Medicines Agency in November, 2015, and Health Canada with conditions in April, 2016.1,16,17

About Pradaxa® (dabigatran etexilate)
Pradaxa® (dabigatran etexilate) 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.18 It was then approved for the prevention of stroke and systemic embolism in patients with AFib, in whom anticoagulation is appropriate.18 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.18 To date, over 130,000 Canadians with AFib have received Pradaxa® for stroke prevention.3

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

The efficacy and safety profiles of Pradaxa® in its licensed indications are well documented in an extensive clinical trial program.19-26 In addition, the favourable benefit-risk profile of Pradaxa® is supported by safety assessments from regulatory authorities including the European Medicines Agency, the U.S. Food and Drug Administration (FDA), and INESSS in Canada.27-30 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.29 The safety and efficacy profile of Pradaxa® has been supported by nearly 250,000 patients in the real world.30-41

As the first direct oral anticoagulant to market, clinical experience with Pradaxa® continues to grow and equates to over five million patient-years in all licensed indications to date.3

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

About 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 145 affiliates and a total of more than 47,500 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.

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 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 2015, Boehringer Ingelheim achieved net sales of about 14.8 billion euros. R&D expenditure corresponds to 20.3 per cent 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 approximately 600 people across Canada.

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

For more information, please contact:
Robbyn Walsh
Environics Communications
416-969-2759 / rwalsh@environicspr.com

Jennifer Mota
Boehringer Ingelheim (Canada) Ltd
905-631-4739 / Jennifer.mota@boehringer-ingelheim.com

References

1.Praxbind™ Product Monograph. Boehringer Ingelheim (Canada) Ltd. April 29, 2016.
2.Pollack C. V. et al. ”Idarucizumab for dabigatran reversal.“ NEJM. 2015 Aug 6; 373(6):511-20.
3.Data on File. Boehringer Ingelheim (Canada) Ltd., 2015.
4.Gumbinger C. et al. “Reasons Underlying Non-Adherence to and Discontinuation of Anticoagulation in Secondary Stroke Prevention among Patients with Atrial Fibrillation.” Eur Neurol. 2015;73(3-4):184-91.
5.Man-Son-Hing M, Laupacis A. “Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians' fears often unfounded.” Arch Intern Med. 2003 Jul 14;163(13):1580-6.
6.Sen S, Willett Dahlberg K. “Physician's Fear of Anticoagulant Therapy in Nonvalvular Atrial Fibrillation.” Am J Med Sci. 2014 Dec; 348(6):513-521.
7.Kagansky N. et al. “Safety of Anticoagulation Therapy in Well-informed Older Patients.” Arch Intern Med. 2004;164(18):2044-2050.
8.Heart and Stroke Foundation. “Atrial Fibrillation – Be pulse aware.” Retrieved from http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.5052135/k.2C86/Heart_disease__Atrial_fibrillation (Accessed Jun 24, 2015).
9.Lin HJ et al. “Stroke Severity in Atrial Fibrillation:The Framingham Study.” Stroke. 1996 Oct;27(10):1760-4.
10.Heart and Stroke Foundation. “Statistics.” Retrieved from http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/Statistics.htm (Accessed Jun 24, 2015).
11.Verma, Atul et al. “2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation.” Canadian Journal of Cardiology. 2014;30(10):1114-1130.
12.Pollack C. et al. “A Phase III Clinical Trial to Evaluate the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD™).” Poster presentation at the International Stroke Conference, Nashville, USA, 11-13 Feb 2015.
13.ClinicalTrials.gov. “Reversal of Dabigatran Anticoagulant Effect With Idarucizumab.” U.S. National Institutes of Health. Last updated: Nov 30, 2015. Retrieved from https://clinicaltrials.gov/ct2/show/study/NCT02104947?term=re-verse&rank=1&show_locs=Y (Accessed Dec 7, 2015).
14.Pollack C.V. et al. ”Reinitiation of Antithrombotic Therapy After Emergency Procedures or After an Uncontrolled or Life-Threatening Bleeding Event: Initial Experience from the RE-VERSE AD Trial.” Presentation #187 on 8 Nov 2015 at the American Heart Association (AHA) Scientific Sessions, Orlando, USA.
15.Van Ryn J. et al. ”Reversal Of Dabigatran Anticoagulation By Idarucizumab In The Presence Of Coagulation Factor Concentrates And The Lack Of Potential Non-specific Effects Of Idarucizumab On Heparins, Factor Xa Inhibitors And Other Direct Thrombin Inhibitors Like Bivalirudin, Hirudin Or Argatroban.” Presentation #299 on 9 Nov 2015 at the American Heart Association (AHA) Scientific Sessions, Orlando, USA.
16.U.S. Food and Drug Administration. “FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa.” Oct 16, 2015. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm467300.htm Last accessed Dec 3, 2015.
17.European Medicines Agency. “Praxbind: idarucizumab.” http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/human/medicines/003986/human_med_001938.jsp Last accessed Dec 3, 2015
18.Pradaxa® Product Monograph. Boehringer Ingelheim (Canada) Ltd., Nov 16, 2015.
19.Schulman S, et al. “Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism.” N Engl J Med. 2013;368:709–18.
20.Schulman S, et al. “Dabigatran versus warfarin in the Treatment of Acute Venous Thromboembolism.” N Engl J Med. 2009;361:2342–52.
21.Connolly SJ, et al. “Dabigatran versus warfarin in patients with atrial fibrillation.” N Engl J Med. 2009;361:1139–51.
22.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.
23.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.
24.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.
25.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.
26.Schulman S. et al. “Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis.” Circulation. 2014;129:764-772.
27.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.
28.FDA Drug Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa® (dabigatran) – 2 Nov 2012 http://www.fda.gov/Drugs/drugsafety/ucm326580.htm Last accessed July 22, 2014.
29.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)
30.Tremblay E. “Portrait de l’usage du dabigatran chez les personnes assurées par le régime public d’assurance medicaments INESS.” Gouvernement du Québec, 2013.
31.Graham DJ et al. “Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation.” Circulation. 2015 Jan 13;131(2):157-64.
32.Villines TC et al. “A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system.” Thromb Haemost. 2015 Nov 25;114(6):1290-8.
33.Seeger JD et al. “Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation.” Poster presentation at the American Heart Association Scientific Sessions 2015 conference, Orlando, USA, 7-11 Nov 2015.
34.Larsen TB et al. “Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation.” Am J Med. 2014 Jul;127(7):650-656.e5.
35.Larsen TB et al. “Myocardial ischemic events in ‘real world’ patients with atrial fibrillation treated with dabigatran or warfarin.” Am J Med. 2014 Apr;127(4):329-336.
36.Lauffenburger JC et al. “Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study.” J Am Heart Assoc. 2015 Apr 10;4(4). pii: e001798.
37.Avgil-Tsadok M et al. “Dabigatran Use In Elderly Patients With Atrial Fibrillation.” Thromb Haemost. 2015 Sep 10;115(1). [Epub ahead of print]
38.Sørensen, R. et al. “Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study.” BMJ Open 2013;3:3(5).
39.Tepper P, et al. “Real-world Comparison of Bleeding Risks among Non-Valvular Atrial Fibrillation Patients on Apixaban, Dabigatran, Rivaroxaban: Cohorts Comprising New Initiators and/or Switchers from Warfarin.” Presentation at the ESC Congress 365, London, UK, 29 Aug - 2 Sep 2015.
40.Lin I, et al. “Real-world Bleeding Risk among Non-valvular Atrial Fibrillation Patients Prescribed Apixaban, Dabigatran, Rivaroxaban, and Warfarin: Analysis of Electronic Health Records.” Presentation at the ESC Congress 365, London, UK, 29 Aug - 2 Sep 2015.
41.Abraham NS, et al. “Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study.” BMJ 2015;350:h1857.