Value through Innovation25 October 2014
05 November 2012

Pradaxa® - Development of antidote may expand range of methods to reverse anticoagulant effect during emergency situations

  • New data presented at the AHA Scientific Sessions demonstrate antibody fragment antidote to be highly selective and specific for rapid reversal of the anticoagulant effect of dabigatran
  • After successful completion of the pre-clinical research phase, Boehringer Ingelheim initiated the clinical phase I trial development of a specific antidote as a potential additional option for patient management during rare critical care situations and/or emergency surgery
  • Despite the absence of a specific antidote, dabigatran proven to be highly effective for stroke prevention without increasing rate of bleeding versus warfarin

Ingelheim, Germany, 5 November 2012 – New findings presented at the 2012 American Heart Association Scientific Sessions in Los Angeles provide early indications that a highly specific and selective antidote currently in development can, when approved, deliver safe and effective rapid reversal of the anticoagulation effect of Pradaxa® (dabigatran). If needed, the potential antidote may be used during critical care situations or where existing reversal strategies may not be sufficient.1 Following the successful completion of the early research phase, the progression into phase 1 clinical trial development was initiated for the investigational antidote (a fully humanized monoclonal antibody fragment – Fab).

The investigational antidote should be regarded as an additional option for patient management in critical care situations and may support the established reversal strategies already available in emergency medicine. In research, the Fab holds promise as one of the first specific antidotes developed for any of the novel oral anticoagulants (NOACs) used for stroke prevention in atrial fibrillation (AF).1

A risk of bleeding is a known possible treatment complication of all anticoagulant therapies used for stroke prevention in AF.2 Even in the absence of a specific antidote, both doses of dabigatran etexilate demonstrated significantly lower life-threatening and intracranial bleeding than warfarin during the landmark clinical trial RE-LY® clinical trial programme . Additionally, significantly lower major and fatal bleeding events were experienced with dabigatran etexilate 110mg bid.3,4

Further to existing reversal strategies, Boehringer Ingelheim is developing a specific antidote to dabigatran. Driven by the company’s commitment to scientific innovation, the antidote is expected to provide physicians with an additional option for management of bleeding during critical care situations where rapid reversal is required.

The results from the preclinical studies show the Fab to offer:1

  • Very tight binding affinity to dabigatran molecules – high specificity with no effect on other molecules including warfarin
  • Rapid, dose-dependent decrease in experimentally-induced blood loss, sustained for up to 6 hours after intravenous injection
  • Safe reversal of the anticoagulation effect of dabigatran (demonstrated in ex vivo clotting tests)

The management of severe bleeds in clinical practice remains the same for all anticoagulant treatments,5,6 with dabigatran having the additional option of removal from the blood system via hemodialysis.7

No specific fast acting antidote is currently available to reverse the anticoagulant effect of any of the NOACs or warfarin.6 In the case of warfarin, vitamin K is frequently misunderstood as an antidote while it is actually a supplement, which simply replaces the vitamin K needed for the synthesis of the coagulation factors blocked by warfarin. Reversal of the anticoagulant effect of warfarin is a rather slow and complex procedure which may take up to 36 hours.8

Boehringer Ingelheim remains dedicated to advancing science and ensuring that physicians have all the tools they may require to effectively manage critical care situations, improving the overall benefit of treatments and optimising patient management. As such, the development of the Fab progressed to phase I clinical trials.

"These new findings are encouraging and demonstrate the potential of an antibody for rapid reversal of the anticoagulant effect of Pradaxa®, restoring a patient’s coagulation. Although emergency situations are relatively rare in clinical practice, Boehringer Ingelheim is committed to ensuring the best brain protection for people living with atrial fibrillation, which includes ensuring that physicians have every option they may require in the critical care situation", stated Dr. Joanne van Ryn, Department of CardioMetabolic Disease Research, Boehringer Ingelheim.

It is widely accepted that the benefits of anticoagulant treatment for stroke prevention in AF far outweigh the risk of bleeding.9,10 The benefits of Pradaxa® have been recognised worldwide, leading to widespread regulatory approvals and recent reconfirmation of the positive benefit/risk profile by the European Medicines Agency.11,12 Clinical trial and real-life experience of dabigatran now equates to over one million patient-years in all licensed indications and exceeds that of all other novel oral anticoagulants used for stroke prevention in AF.11,13

NOTES TO THE EDITORS

Stroke Prevention in Atrial Fibrillation
AF is the most common sustained heart rhythm condition14, with one in four adults over the age of 40 developing the condition in their lifetime15. People with AF are more likely to experience blood clots, which increases the risk of stroke by five-fold.15,16 Up to three million people worldwide suffer strokes related to AF each year.17-20 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%).21

Ischaemic strokes are the most common type of AF-related stroke, accounting for 92% of strokes experienced by AF patients and frequently leading to severe debilitation.22-26 Appropriate anticoagulation therapy can help to prevent many types of AF-related strokes and improve overall patient outcomes.27

Worldwide, AF is an extremely costly public health problem, with treatment costs equating to $6.65 billion in the US and over €6.2 billion across Europe each year.28,29 Given AF-related strokes tend to be more severe, this results in higher direct medical patient costs annually.30 The total societal burden of AF-related stroke reaches €13.5 billion per year in the European Union alone.16

About RE-LY®
RE-LY® (Randomized Evaluation of Long term anticoagulant therapY) was a global, phase III, PROBE (prospective, randomized, open-label with blinded endpoint evaluation) trial of 18,113 patients enrolled in over 900 centres in 44 countries designed to compare two fixed doses of the oral direct thrombin inhibitor dabigatran (110mg and 150mg bid) each administered in a blinded manner, with open label warfarin (INR 2.0-3.0, median TTR 67%5).3,4 Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.3

The primary endpoint of the trial was incidence of stroke (including haemorrhagic) or systemic embolism. Secondary outcome measures included all-cause death, incidence of stroke (including haemorrhagic), systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death (including death from bleeding).

Compared to warfarin, dabigatran etexilate showed in the trial: 3,4

  • Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150mg bid
  • Similar rates of stroke/systemic embolism with dabigatran etexilate 110mg bid
  • Significantly lower major bleeding events with dabigatran etexilate 110mg bid
  • Significantly lower life threatening and intracranial bleeding with both doses
  • Significant reduction in vascular mortality with dabigatran etexilate 150mg bid.

About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs)31 targeting a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.

Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation. In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran etexilate provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or dose adjustment.

About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim’s clinical trial programme to evaluate the efficacy and safety of dabigatran etexilate encompasses studies in:

  • Primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgery
  • Treatment of acute VTE
  • Secondary prevention of VTE
  • Stroke prevention in AF
  • Prevention of thromboembolism after heart valve replacement.

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 44,000 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.

As a central element of its culture, Boehringer Ingelheim pledges to act with social responsibility. 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 endeavors.

In 2011, Boehringer Ingelheim achieved net sales of about 13.2 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 23.5% 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 USA, UK or Canada.

References

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2. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1,Suppl.):108S–121S.
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11. Boehringer Ingelheim data on file
12. European Medicines Agency. Press Release, dated May 25th 2012. Available at http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/public_health_alerts/2012/05/human_pha_detail_000061.jsp&mid=WC0b01ac058001d126
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23. Petrea RE, et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-7.
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