Boehringer Ingelheim's Investigational Antidote for Pradaxa® (dabigatran etexilate mesylate) Receives FDA Breakthrough Therapy Designation

RIDGEFIELD, Conn., June 26, 2014 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to idarucizumab*, an investigational fully humanized antibody fragment, or Fab, being studied as a specific antidote for Pradaxa (dabigatran etexilate mesylate).

"Boehringer Ingelheim is pleased that the FDA has granted Breakthrough Therapy Designation for idarucizumab to help expedite its development," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "We are committed to innovative research and to advancing care in patients taking PRADAXA. We continue to investigate the potential of idarucizumab as a therapeutic option should a patient experience uncontrolled bleeding or need to undergo emergency surgery or another invasive procedure."

The FDA established the Breakthrough Therapy Designation as a means to help accelerate the development and review of drugs for serious or life-threatening conditions if preliminary clinical evidence indicates the therapy may demonstrate a substantial improvement over existing therapies on one or more clinically significant endpoints.

Boehringer Ingelheim is planning to pursue an Accelerated Approval pathway for idarucizumab.

Data from a phase I study presented at the American Heart Association Scientific Sessions in 2013 showed that idarucizumab was able to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy humans.

A global phase III study, RE-VERSE AD™, is underway in patients taking PRADAXA who have uncontrolled bleeding or require emergency surgery or procedures (NCT02104947). Currently, no U.S. sites have been initiated; however, European sites are actively enrolling.

"We are confident in PRADAXA's benefits and safety profile, which were established in five pivotal trials that collectively include more than 27,000 patients and were conducted without the use of an antidote," said Luik. "As a company whose core mission is always to improve patient care, we are evaluating whether idarucizumab could be an additional therapeutic option in certain emergency situations."

Currently, no specific antidotes for newer oral anticoagulants (NOACs) are available. Idarucizumab is still under investigation and has not been approved for clinical use.

About Idarucizumab

Idarucizumab is a fully humanized antibody fragment, or Fab, being investigated as a specific antidote for PRADAXA. Pre-clinical studies indicate idarucizumab binds specifically to and inhibits dabigatran with no other expected interactions.

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

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

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.

Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulants are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. To reduce potential risk of bleeding with concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran. Placement/removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low but exact timing to reach a sufficiently low anticoagulant effect in each patient is unknown. If anticoagulation is administered with epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently for signs/symptoms of neurological impairment, i.e., midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs/symptoms. If spinal hematoma is suspected, initiate urgent diagnosis and treatment; consider spinal cord decompression even though it may not prevent or reverse neurological sequelae.

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

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.

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

* Idarucizumab is the proposed International Nonproprietary Name (pINN).

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.