Boehringer Ingelheim Pharmaceuticals, Inc. Release: New Data Show Idarucizumab* Reverses Anticoagulant Effects Of Dabigatran (PRADAXA) In Middle-Aged, Elderly And Renally Impaired Volunteers

RIDGEFIELD, Conn., Dec. 8, 2014 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced phase I data that showed administration of investigational idarucizumab in healthy volunteers who were middle-aged (45 to 64 years) or elderly (65 to 80 years), or volunteers with mild or moderate kidney impairment, resulted in immediate, complete and sustained reversal of the anticoagulation effects of dabigatran (PRADAXA®) (ClinicalTrials.gov Identifier: NCT01955720). Further, anticoagulation was restored when volunteers were re-dosed with dabigatran 24 hours after idarucizumab was administered. A second administration of idarucizumab also showed that anticoagulation reversal was comparable to the results observed in the first administration. The data were presented today in an oral session at the 56th American Society of Hematology (ASH) Annual Meeting and were selected for inclusion in the 2015 Highlights of ASH "Thrombosis and Anticoagulation" presentation.

"These data in adults of various age, gender and kidney function status complement previously reported data in younger, healthy volunteers, showing that idarucizumab reversed the anticoagulant effects of dabigatran," said lead investigator Stephan Glund, PhD, senior clinical pharmacokineticist, Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. "Our findings are also important because they provide insights on the timing to restore dabigatran's anticoagulant effects after idarucizumab is given, and information on the antidote's effect following a second administration."

The randomized, double-blind, placebo-controlled cross-over study included 46 male and female volunteers ranging from 45 to 80 years of age. For three days, investigators gave a high dose of dabigatran (220 mg twice daily**) to healthy participants, 45 to 64 years of age or 65 to 80 years of age, and 150 mg twice daily to those with mild or moderate kidney impairment (creatinine clearance [CrCl] 60 to < 90 mL/min or 30 to < 60 mL/min, respectively), with one final dose given on the fourth day. On the fourth day, two hours after taking dabigatran, volunteers received a five-minute intravenous infusion of 5 g of idarucizumab or, for volunteers with moderate kidney impairment, two doses of 2.5 g idarucizumab.

Pharmacodynamic measurements showed that idarucizumab reversed the anticoagulant effect of dabigatran immediately after the infusion. Prolonged blood clotting time induced by dabigatran was restored to baseline levels by the end of the antidote infusion. In healthy volunteers aged 45 to 64, restarting dabigatran 24 hours after an idarucizumab infusion of 5 g restored the anticoagulation effects, as shown by prolonged blood clotting time. Similar results were seen after administration of 2.5 g idarucizumab dose. A second infusion of idarucizumab also resulted in immediate, complete and sustained reversal of dabigatran-induced anticoagulation.

In this study, there were no clinically relevant idarucizumab-related adverse events, although idarucizumab was associated with a dose-related, transient increase in urinary protein levels. Adverse events and tolerability reactions were similar with idarucizumab and placebo. No adverse events were indicative of immunogenic reactions.

"These newest data are important because this study included volunteers who were older and who had impaired kidney function characteristics that are different from those of volunteers in our earlier phase I study," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "While research is ongoing, these findings add to the growing evidence supporting our development of idarucizumab as an innovative therapeutic option for use in PRADAXA patients in emergency situations."

Boehringer Ingelheim is continuing to evaluate idarucizumab in RE-VERSE AD, a phase III global study investigating idarucizumab in actual clinical settings where PRADAXA patients may require emergency intervention or experience an uncontrolled or life-threatening bleeding event. This is the first-ever trial to investigate a specific antidote in patients actively being treated with a newer oral anticoagulant.

About Idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific antidote for the anticoagulant effect of dabigatran. Pre-clinical studies indicate idarucizumab binds specifically to and inhibits dabigatran.

Phase I data in healthy volunteers demonstrated the potential of idarucizumab to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation. In that placebo-controlled study, idarucizumab did not cause any clinically relevant side effects. No pro-thrombotic effect was observed after the administration of idarucizumab and no return of anticoagulant activity of dabigatran over time at adequate doses. Other phase I data in healthy volunteers show that idarucizumab restores wound-site formation of fibrin, the main component of a blood clot.

In June, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to idarucizumab.

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

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.

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

• 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).

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

*  Idarucizumab is the proposed International Nonproprietary Name (pINN).
** The approved dosing for PRADAXA in the United States for non-valvular atrial fibrillation is 150 mg twice daily for patients with CrCl >30 mL/min, and 75 mg twice daily for patients with CrCl 15-30 mL/min.  

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