FDA Grants Priority Review to BI’s Idarucizumab®

First and only investigational, specifically targeted reversal agent for a novel oral anticoagulant under BLA review

Ridgefield, CT, April 23, 2015 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted Priority Review to the Biologics License Application (BLA) for idarucizumab, which is being investigated to specifically reverse the anticoagulant effect of dabigatran, the active ingredient in Pradaxa® (dabigatran etexilate mesylate) in patients needing emergency intervention or experiencing an uncontrolled or life-threatening bleeding event. The idarucizumab BLA will be reviewed under Accelerated Approval and is the first review for a reversal agent in the novel oral anticoagulant (NOAC) class. Currently, no NOACs have an approved reversal agent.

“The FDA’s decision to grant Priority Review to the idarucizumab application is an important milestone and a step toward bringing a new innovative option in anticoagulation care to physicians and patients,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “If approved, idarucizumab has the potential to be a significant evolution in care by providing physicians with an option for PRADAXA patients in rare emergency situations that may require rapid reversal of the anticoagulation effect of dabigatran.”

A Priority Review designation is granted when a drug, if approved, exhibits the potential to offer a significant improvement in the safety or effectiveness of the treatment of serious conditions when compared to standard applications. The FDA instituted its Accelerated Approval program to allow for earlier approval of drugs that both treat a serious condition and fill an unmet medical need based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Additionally, the FDA granted Breakthrough Therapy Designation for idarucizumab in June 2014.

The application includes phase I data showing the potential for idarucizumab to provide immediate reversal of the anticoagulant effect of dabigatran, the active ingredient in PRADAXA. In these studies, no clinically relevant adverse reactions to idarucizumab were observed. Additionally, no procoagulant effect was observed after the administration of idarucizumab when measured by coagulation assay. Interim data from the ongoing RE-VERSE AD™ trial, a phase III global study investigating idarucizumab in actual clinical settings, was also included in the application.

Boehringer Ingelheim has a rich history in contract manufacturing and supporting the development of biopharmaceutical products. The discovery and continued development of idarucizumab by Boehringer Ingelheim scientists is an example of this dedication and experience. Over the past 35 years, Boehringer Ingelheim has brought more than 20 biopharmaceutical products to market for pharmaceutical customers through the company’s world-leading contract development and manufacturing services operation, Boehringer Ingelheim BioXcellence.

About Idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific reversal agent for the anticoagulant effect of dabigatran in patients needing emergency surgery or urgent procedures or for life-threatening or uncontrolled bleeding events. The safety and efficacy of idarucizumab has not been established.

Boehringer Ingelheim scientists discovered and are developing idarucizumab. The research program was initiated in 2009, before PRADAXA was launched in the U.S. in 2010. The company has a rich history in supporting the development and manufacturing of biopharmaceutical products, and idarucizumab is an example of this dedication and experience.

The company completed three phase I trials of idarucizumab in human volunteers, and included these data in the idarucizumab Biologics License Application (BLA) submitted to the FDA. Interim data from RE-VERSE AD™ was also included in the idarucizumab BLA.

Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD, a phase III global study that includes patients taking PRADAXA who have uncontrolled or life-threatening bleeding or require emergency procedures. The study is the first of its kind in patients, and has been underway since May 2014 enrolling patients in more than 35 countries.

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;
for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
a history of traumatic or repeated epidural or spinal punctures
a history of spinal deformity or spinal surgery
optimal timing between the administration of PRADAXA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.

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 Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, 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.
Reversal of Anticoagulant Effect: 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 use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. 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
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.
Reduction of Risk of Stroke/Systemic Embolism in NVAF

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.

Treatment and Reduction in the Risk of Recurrence of DVT/PE

For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P-gp inhibitors

ADVERSE REACTIONS
The most serious adverse reactions reported with PRADAXA were related to bleeding.

NVAF

Most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding & gastrointestinal (GI) events
PRADAXA 150 mg resulted in higher rates of major and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA vs 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).

DVT/PE

Rates of any GI bleeds were higher in patients receiving PRADAXA 150 mg vs warfarin and placebo
In the active-controlled studies, there was a higher rate of clinical myocardial infarction (MI) in PRADAXA patients [20 (0.66/100) patient-years)] vs warfarin [5 (0.17/100 patient-years)]. In the placebo-controlled study, there was similar rate of non-fatal and fatal clinical MI in PRADAXA patients [1 (0.32/100 patient-years)] vs placebo [1 (0.34/100 patient-years)].
GI adverse reactions were similar in patients receiving PRADAXA 150 mg vs warfarin. They were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage).

Drug hypersensitivity reactions were reported in ≤ 0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 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 142 affiliates and more than 47,400 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.

Social responsibility is a central element of Boehringer Ingelheim's culture. 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 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% of its net sales.

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

Pradaxa® and PRADAXA with associated design® are registered trademarks of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.

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