Value through InnovationSeptember 18 2014
August 26, 2011

Boehringer Ingelheim to Launch RE-ALIGN™ Trial to Evaluate Dabigatran Etexilate in Patients with Mechanical Heart Valves

Multi-National Prospective Study Will Assess Dosing of Dabigatran Etexilate in New Patient Population

Ridgefield, CT, August 26, 2011 – Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) today announced plans to launch RE-ALIGN™, a global, Phase II trial evaluating the safety and pharmacokinetics of dabigatran etexilate in 400 patients who have mechanical heart valves.1 The 12-week study will compare three doses of dabigatran etexilate (150mg bid, 220mg bid and 300mg bid) to warfarin in patients with both aortic valve replacements and mitral valve replacements.1 A RE-ALIGN extension study will evaluate the ongoing safety of dabigatran etexilate in this patient population for up to 84 months.1

Mechanical heart valves are used to treat heart valve disease, which occurs when one or more valves in the heart does not function properly.2 An estimated 2.5 percent of the American population has heart valve disease.3 Approximately 100,000 patients undergo heart valve replacement in the U.S. each year,4 55 percent of which are mechanical heart valves.5 Patients with mechanical heart valves require lifelong anticoagulation to help prevent blood clots from forming on or around the valve.6 A meta-analysis of 46 studies involving patients with mechanical heart valves found the annual incidence of thromboembolism for those who are untreated to be 8.6 percent.7

"Boehringer Ingelheim is committed to ongoing research that will expand our understanding of dabigatran etexilate as a treatment option for patients with a variety of cardiovascular and thromboembolic conditions," said John Smith, MD, PhD, senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We are proud to announce the launch of RE-ALIGN and plans for a RE-ALIGN extension study, to assess dabigatran etexilate as a potential treatment option to reduce stroke risk in patients with mechanical heart valves."

Dabigatran etexilate was approved by the FDA in October 2010 as the first oral anticoagulant in more than 50 years to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and is sold under the brand name Pradaxa®.8 In the first eight months after approval, nearly 300,000 patients in the U.S. were prescribed PRADAXA.9
 
"PRADAXA has almost a full year of clinical use for the reduction of stroke risk in patients with non-valvular atrial fibrillation," said Chris Barrett, senior vice president, marketing, Boehringer Ingelheim Pharmaceuticals, Inc. "We continue to see a steady growth in the number of patients treated with PRADAXA and are proud of the widespread formulary coverage that has been achieved, providing access to 90 percent of covered lives in the U.S."

Findings from the Phase III RE-LY® trial showed that PRADAXA 150mg taken twice daily significantly reduced stroke and systemic embolism by 35 percent beyond the reduction achieved with warfarin (dosed to international normalized ratio (INR) 2.0 to 3.0, mean time in therapeutic range = 64.4 percent)8 in patients with NVAF.8 Effects of PRADAXA were more apparent in patients with lower levels of INR control.8 Dabigatran is recommended in an update to atrial fibrillation treatment guidelines.

About RE-LY®
RE-LY® was a global, Phase III, randomized trial of 18,113 patients8 enrolled in 951 centers in 44 countries,10 investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0 - 3.0 – (open label) for stroke prevention.8 Patients with non-valvular AFib and at least one other risk factor for stroke (i.e., previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age > 75 years, age > 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension) were enrolled in the study for two years8 with a minimum follow-up period of one year.11

The RE-LY® trial utilized the established PROBE (prospective, randomized, open-label, blinded endpoint evaluation) clinical trial protocol,11 which has been used in the previous trials of anticoagulation for stroke prevention in patients with AFib.11 A PROBE design may reflect the differences in the management of warfarin and dabigatran in clinical practice.11

The primary endpoint of the trial was incidence of stroke (including hemorrhagic) and systemic embolism.11 Safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction and other adverse events.11

In the RE-LY® trial, all clinical outcomes were adjudicated in a blinded manner to minimize bias in assessment of outcomes for each treatment.11

About Pradaxa® (dabigatran etexilate) Capsules

Indications and Usage
PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.

WARNINGS AND PRECAUTIONS
Risk of Bleeding
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding.

Risk factors for bleeding include:
- Medications that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs).
- Labor and delivery

Promptly evaluate any signs or symptoms of blood loss, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding.

Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke.  Lapses in therapy should be avoided, and if PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

Effect of P-gp Inducers and Inhibitors on PRADAXA Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces dabigatran exposure and should generally be avoided. P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin, do not require dose adjustments. These results should not be extrapolated to other 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 a higher rate 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

The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.

For full PRADAXA prescribing information and medication guide, please visit www.pradaxa.com or contact Boehringer Ingelheim's Drug Information Unit at 1-800-542-6257.

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 145 affiliates and more than 42,000 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.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. 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 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24% of net sales in its largest business segment Prescription Medicines on research and development.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

1. RE-ALIGN Presentation. ESC 2011.

2. NHLBI website. "What is Heart Valve Disease?" Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/hvd/hvd_whatis.html. Accessed on August 18, 2011.

3. Roger, L.V., et al. "Heart Disease and Stroke Statistics – 2011 Update: A Report From the American Heart Association." Circulation. 2011; 123:e18-e209.

4. American Heart Association. "Heart Disease and Stroke Statistics – 2008 Update". Dallas, Texas: American Heart Association; 2008.

5. Butany, J., et al. "Mechanical Heart Valve Prostheses: Identification and Evaluation (erratum)." Cardiovascular Pathology. 2003; 12:322-344.

6. Bonow, R.O., et al. "ACC/AHA 2006 Practice Guidelines for the Management of Patients With Valvular Heart Disease: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease)." Journal of the American College of Cardiology. 2006; 48:598-675.

7. Cannegieter, S.C., et al. "Thromboembolic and Bleeding Complications in Patients with Mechanical Heart Valve Prostheses." Circulation. 1994; 89:635-641.

8. Pradaxa Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; March 2011.

9. IMS Health, Custom LRx Study for the period Oct-10 to June-11, excludes Long-Term Care Channel.

10. Connolly, S.J., et al. "Dabigatran versus Warfarin in Patients with Atrial Fibrillation." New England Journal of Medicine. 2009; 361:1139-1151.

11. Ezekowitz, M.D., et al. "Rationale and design of RE-LY: Randomized evaluation of long-term anticoagulation therapy, warfarin, compared with dabigatran." American Heart Journal. 2009; 157:805-810.