Phase III Study of Dabigatran Etexilate Mesylate Met Primary Endpoint for Six-Month Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

Ridgefield, CT, December 17, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from the RE-COVER^™ II study evaluating dabigatran compared to warfarin in patients diagnosed with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE). In this Phase III study, published online in the American Heart Association’s journal Circulation, dabigatran met the primary endpoint of non-inferiority to warfarin for recurrent, symptomatic, objectively-confirmed DVT and/or PE and related deaths during six months of treatment.

DVT and PE are collectively referred to as venous thromboembolism (VTE), which is the third most common cardiovascular disorder after coronary artery disease and stroke. A DVT occurs when a blood clot develops in a deep vein, usually in the leg or pelvis, and either partially or totally blocks the flow of blood through the vein. A PE occurs when a DVT, or part of it, breaks off and travels through the bloodstream to the lungs, blocking a vessel. This is considered a life-threatening condition.

RE-COVER II also showed that dabigatran was associated with a 31 percent reduction in the risk of major bleeding (15 dabigatran patients vs. 22 warfarin patients), which did not reach statistical significance. Additionally, the study demonstrated significantly less overall bleeding (33 percent reduced risk; 200 dabigatran vs. 285 warfarin patients) and major or clinically relevant non-major bleeding (38 percent reduced risk; 64 dabigatran vs. 102 warfarin patients).

A pooled analysis of data from both RE-COVER II and a similar trial, RE-COVER, showed comparable results.

“RE-COVER II was initiated to confirm findings from a similar trial, RE-COVER. Both trials showed an overall low rate of recurrent DVT and/or PE in both the dabigatran and warfarin treatment arms,” said Sam Schulman, MD, PhD, FRCP(C), lead study author and professor, Department of Medicine, McMaster University, Ontario, Canada. “RE-COVER II will allow for more thorough subgroup analyses as a result of a patient population with a wider spectrum of ethnicities.”

RE-COVER II was a randomized, double-blind, double-dummy study in 2,589 patients with acute symptomatic DVT and/or PE recruited at 208 study sites in 31 countries. The trial was designed to determine if dabigatran 150 mg twice daily is non-inferior to warfarin for the primary endpoint of preventing a recurrence of DVT and/or PE and related deaths, and to compare the safety of the two drug regimens during six months of treatment. In the trial, patients were treated with either dabigatran or warfarin after initial parenteral anticoagulation therapy (approximately 9 to 10 days). Patients in the warfarin group had their doses adjusted to maintain an International Normalized Ratio (INR) of 2.0-3.0.

The efficacy analysis included 2568 patients analyzed randomly assigned to the treatment groups. All patients received at least one dose of the study drug (1279 in the dabigatran group and 1289 in the warfarin group).* The analysis showed that dabigatran was non-inferior to warfarin for the prevention of recurrent or fatal DVT and/or PE (P<0.001 for both hazard ratios and difference in absolute risk criteria). Specifically, recurrent nonfatal or fatal DVT and/or PE was confirmed after central adjudication in 30 patients in the dabigatran group (2.3 percent) and in 28 patients (2.2 percent) in the warfarin group (hazard ratio, 1.08; 95 percent CI, 0.64 to 1.80).

The safety analysis included 2568 patients and was performed according to the treatment received (1280 in the dabigatran group and 1288 in the warfarin group).* The safety findings were:

• Major bleeding occurred in 1.2 percent (15) of dabigatran patients and 1.7 percent (22) of warfarin patients (HR 0.69, 95 percent CI 0.36 to 1.32).
• Overall (any) bleeding occurred in significantly fewer patients in the dabigatran group compared to the warfarin group: 15.6 percent (200) vs. 22.1 percent (285), respectively (HR 0.67, 95 percent CI, 0.56 to 0.81).
• Major or clinically relevant non-major bleeding also occurred in significantly fewer dabigatran than warfarin patients: 5.0 percent (64) vs.7.9 percent (102), respectively (HR 0.62, 95 percent CI, 0.45 to 0.84).
• The overall rate of deaths and adverse events were similar in both groups, with the exception of dyspepsia, which was more common in the dabigatran group (1.0 percent) than in the warfarin group (0.2 percent).
• The incidence of acute coronary syndrome (ACS) was numerically higher with dabigatran than with warfarin (absolute risk increase of 0.1 percent).

“Boehringer Ingelheim is pleased with the results from RE-COVER II and is committed to addressing the complex medical need of patients with deep vein thrombosis and/or pulmonary embolism,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. “Based on these studies and other dabigatran research conducted in DVT/PE, the U.S. Food and Drug Administration accepted for review a supplemental New Drug Application (sNDA) for PRADAXA for its use in patients with DVT or PE.”

A pooled analysis of RE-COVER II and RE-COVER demonstrated similar results to RE-COVER II. The combined studies randomized 5,107 patients who were all initially treated with parenteral anticoagulation therapy followed by warfarin or dabigatran. The hazard ratio for recurrent DVT and/or PE or related death for dabigatran compared to warfarin was 1.09 (95 percent CI, 0.76 to 1.57). The pooled analysis also showed lower rates of bleeding with dabigatran. The hazard ratio for major bleeding, with dabigatran compared to warfarin, was 0.73 (95 percent CI, 0.48 to 1.11); for any bleeding, 0.70 (95 percent CI, 0.61 to 0.79); and for major or clinically relevant non-major bleeding, 0.62 (95 percent CI, 0.50 to 0.76). Although RE-COVER and RE-COVER II individually showed a non-significant reduction in major bleeding with dabigatran, the reduction was statistically significant in the pooled analysis during the period following discontinuation of parenteral anticoagulation  (i.e., during the double-dummy period): HR 0.60, 95 percent CI, 0.36 to 0.99. ACS occurred more with dabigatran (9 patients, 0.4%) than with warfarin (5 patients, 0.2%).

Dabigatran is currently marketed as Pradaxa^® (dabigatran etexilate mesylate) in the United States to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation; dabigatran is currently not approved by the FDA to treat DVT and/or PE.

*One patient who was assigned to receive dabigatran mistakenly received warfarin during the entire study and one per group received the opposite treatment the first month.

Deep Vein Thrombosis and Pulmonary Embolism: Statistics and Standard of Care
There are an estimated 900,000 DVT and PE events per year in the U.S., approximately one-third of which result in death from PE. Roughly one-third of people with DVT and/or PE will have a recurrence within 10 years. The standard of care for patients with acute DVT and/or PE is anticoagulation. Specifically, vitamin K antagonists such as warfarin are often used to treat DVT or PE after an initial course of parenteral anticoagulation. However, warfarin requires regular INR monitoring and dietary restrictions.

About RE-COVER and RE-COVER II
RE-COVER and RE-COVER II are global, phase III, randomized, double-blind, double-dummy, parallel-group studies comparing the efficacy and safety of oral dabigatran etexilate (150 mg BID) to warfarin (target INR 2.0-3.0) for six months of treatment of acute symptomatic DVT and/or PE, following initial treatment with a parenteral anticoagulant approved for this indication. RE-COVER randomized 2,564 patients, and RE-COVER II randomized 2,589 patients to either treatment group. The primary efficacy endpoint for both trials was a composite of recurrent symptomatic VTE (DVT and/or PE) and related deaths. Safety endpoints included bleeding events, adverse events and acute coronary syndromes. RE-COVER II and RE-COVER differed in the ethnic composition of the study populations, with more Asians in RE-COVER II than in RE-COVER (20 percent vs. 3 percent). There were also fewer patients with previous DVT and/or PE in RE-COVER II compared to RE-COVER (18 percent vs. 26 percent).

About Pradaxa^® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

WARNING: DISCONTINUING PRADAXA IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE.  Discontinuing PRADAXA places patients at an increased risk of thrombotic events.   If anticoagulation with PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant. 

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
-     active pathological bleeding;
-     known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to
       PRADAXA;
-     mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS
Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

Risk of Bleeding

• PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
• Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
• A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited.  Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated.  Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity.  Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial.  RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin.  Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided.  P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran.  Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

• For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
• For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events.

• PRADAXA 150 mg resulted in higher rates of major GI bleeds and any GI bleeds compared to warfarin.
• In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
• Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions.
• These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer).  Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Please see full Prescribing Information including Boxed WARNING, and Medication Guide. 

About the Boehringer Ingelheim Cares Foundation Patient Assistance Programs
For more than 125 years, Boehringer Ingelheim has been focused on improving the lives of patients. In keeping with the company commitment to do the most good for the most people, Boehringer Ingelheim works hard to ensure its medicines are accessible to everyone who needs them, including senior citizens and families on limited incomes. The Boehringer Ingelheim Cares Foundation Patient Assistance Programs (BI-PAP) make Boehringer Ingelheim medicines available free of charge to patients who are without pharmaceutical insurance coverage, and who meet certain household income levels.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 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 has a demonstrated commitment to corporate 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 2012, Boehringer Ingelheim achieved net sales of about $19.1 billion (14.7 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

For more information please visit www.us.boehringer-ingelheim.com

PRADAXA^® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

RE-COVER^® and RE-COVER II^® are registered service marks of Boehringer Ingelheim International GmBH and used under license.

PX592501PR