In addition to the US, the registration process for dabigatran etexilate is underway in Europe, Japan and other countries. The company expects to receive a marketing authorization for dabigatran etexilate in first countries by end of 2010 or beginning of 2011.
All applications, including the FDA New Drug Application (NDA) are based on the results of the pivotal Phase III RE-LY® study (Randomized Evaluation of Long-term anticoagulant therapY), published in the New England Journal of Medicine in August 2009, comparing the efficacy and safety of two doses of dabigatran etexilate with warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke and systemic embolism in patients with atrial fibrillation.(1)
Results from RE-LY ®, the largest AF study completed to date, showed that in patients with AF, dabigatran etexilate 150mg b.i.d. significantly reduced the risk of stroke and systemic embolism by 34% compared to warfarin, with comparable rates of major bleeding. Dabigatran etexilate 110mg b.i.d. demonstrated similar reductions in stroke and systemic embolism while delivering a reduction in major bleeding rates compared to warfarin. Additionally, both doses showed a significant reduction in haemorrhagic stroke and a significant reduction in life threatening, intracranial and total bleeding compared to warfarin.(1)
Professor Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim said, "Boehringer Ingelheim has a long term commitment to the treatment and prevention of stroke. The decision by the US FDA to grant a priority designation review is an important step in making dabigatran etexilate available for patients with atrial fibrillation to prevent them from strokes."
New practice guidelines on atrial fibrillation
Gregory Lip, Professor of cardiovascular medicine at University of Birmingham Centre for Cardiovascular Sciences, UK and a member of the Task Force writing group for the new ESC Guidelines for the management of atrial fibrillation commented, "The updated guidelines reflect the high need for novel treatments in the prevention of atrial-fibrillation related stroke. Both the personal and economic burden of AF-related stroke is high. Consideration of new prevention therapies will improve the overall standard of care."
Limitations of current therapy
Well-controlled vitamin K antagonist (VKA) therapy (warfarin), currently used for the prevention of stroke in atrial fibrillation, is highly effective in reducing the risk of stroke by approximately two-thirds(2), but is associated with an increased risk of bleeding as well as several limitations. Drug-drug and food interactions as well as the requirement for frequent monitoring result in only about 50% of eligible patients receiving VKA therapy(3) with fewer than half of these controlled within the therapeutic INR range.(4)
Stroke is more likely to be severe and fatal in patients with AF, and those who survive face persistent neurological deficits, persistent disability and poorer functional performance.(5,6)
According to Professor Jonas Oldgren, Associate Professor of Cardiology, Uppsala Clinical Research Centre (which furthermore was one of the coordinating centres in RE-LY®), "Dabigatran etexilate is the first treatment to significantly reduce stroke in patients with atrial fibrillation across all risk groups, when compared to well-controlled warfarin. This novel direct thrombin inhibitor could represent a very important advance in the prevention of stroke in patients with AF for both healthcare professionals and patients alike."
Dr. Oldgren referred to a sub-group analysis presented at this year's American College of Cardiology's annual congress in March, which assessed the rate of stroke and systemic embolism in patients defined as being at low, moderate or high risk of such events by the validated stroke risk stratification score, CHADS 2. The results of this analysis showed that dabigatran etexilate 150mg significantly reduced the number of strokes in patients with AF, irrespective of a patient’s risk profile. Dabigatran etexilate 110mg b.i.d. was associated with significantly lower major bleeding events and both dabigatran doses showed significantly lower intracranial bleeding rates when compared to well-controlled warfarin.(7)
RE-LY® is the largest AF study ever completed (18,113 patients) investigating dabigatran etexilate vs. well controlled warfarin. RE-LY® included patients with at least one risk factor of stroke, representative of a real-world setting. In addition, 50% of enrolled patients were naïve to previous oral anticoagulants, a population who may reflect a more realistic experience with anticoagulants, as they are more likely to represent the patient group with the highest percentages outside of the therapeutic INR range.(1,8)
Up to three million people worldwide suffer strokes related to AF each year,(9-11) which tend to be especially severe and disabling,(10) with half of people dying within one year.(12) Therefore, there is an clear medical need for an effective and safe anticoagulant, without the multiple limitations of VKA therapy.
RE-LY® (Randomized Evaluation of Long term anticoagulant therapy) was a global, phase III, randomized trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate (2 blinded doses) is as effective as well controlled warfarin with target INR of 2.0-3.0 for stroke prevention. Patients were followed-up in the study for a median of 2 years with a minimum of 1 year follow-up.
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 well controlled warfarin, dabigatran etexilate showed in the trial:(1)
- Significant reduction in the risk of stroke and systemic embolism – including haemorrhagic strokes with dabigatran etexilate 150 mg bid
- Significantly lower major bleeding events with dabigatran etexilate 110 mg bid
- Significantly lower life threatening and intracranial bleeding with both doses
- Significant reduction in vascular mortality with dabigatran etexilate 150 mg bid.
About AF and stroke
AF is the most common heart rhythm condition, affecting around 1% of the total population, rising to 10% in people over the age of 80.(13) A total of 6.3 million people in the US, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017 primarily due to the ageing population.(14) People with AF are at increased risk of blood clots, which raises stroke risk by five times.(15,16) Up to 3 million people worldwide suffer strokes related to AF each year. 10-12 Strokes due to AF tend to be severe, with an increased likelihood of death (20%), and disability (60%), with resultant societal costs and burden to the healthcare system.(9) AF alone is associated with a cost of up to €13.5 billion across the European Union. 15 Warfarin is the current standard of care for reducing stroke in patients with AF. It is highly effective when patients blood clotting value is maintained within the narrow therapeutic INR range of 2.0-3.0 as in a clinical trial setting. 17 However in clinical practice, due to the well-known limitations with warfarin only 51% of diagnosed patients with AF at risk of stroke receive warfarin(3) and fewer than half of these are controlled within the narrow therapeutic range.(4)
About dabigatran etexilate
Dabigatran etexilate is at the forefront of a new generation of oral anticoagulants/direct thrombin inhibitors (DTIs) (18) 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.
Dabigatran etexilate has already been approved in 75 countries under the trademark Pradaxa® for the primary prevention of venous thromboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.
About the dabigatran etexilate clinical trial programme
Boehringer Ingelheim's clinical trial program 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 surgeries
- Treatment of acute VTE
- Secondary prevention of VTE
- Secondary prevention of cardiac events in patients with acute coronary syndrome (ACS)
- Stroke prevention in atrial fibrillation (AF).
About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.
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