Idarucizumab* reverses the anticoagulant effect of dabigatran within minutes in patient study

• First patient study data show that idarucizumab* immediately reverses dabigatran within minutes in patients requiring urgent procedures or with serious bleeding complications^1,2
• Interim analysis from RE-VERSE AD™, the first study investigating the effect of a specific reversal agent to a NOAC with patients in a real-world setting
• Data are published in the New England Journal of Medicine and presented at the ISTH 2015 Congress^1,2

Ingelheim, Germany, 22 June 2015 – Results from an interim analysis of the Phase III RE-VERSE AD™ patient study demonstrate that 5 g of idarucizumab* immediately reversed the anticoagulant effect of dabigatran (Pradaxa®) in patients requiring urgent anticoagulant reversal. No safety concerns relating to idarucizumab* were identified. The results have been simultaneously published in the New England Journal of Medicine (NEJM) and presented today at the International Society of Thrombosis and Haemostasis 2015 Congress in Toronto, Canada.^1,2

"The interim analysis from RE-VERSE AD™ is important for healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non-vitamin K antagonist oral anticoagulant during real-world emergency situations," said Dr. Charles Pollack, Professor of Emergency Medicine at the Perelman School of Medicine, University of Pennsylvania in Philadelphia, USA, and lead investigator of the patient study. "As observed in earlier research in volunteers, idarucizumab* reversed the anticoagulant effect of dabigatran in patients completely within minutes, even in those rare critical care situations studied in RE-VERSE AD™. These data demonstrate that use of idarucizumab* can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients."

RE-VERSE AD™ is designed to evaluate the types of patients and real-world situations healthcare professionals may see in emergency settings.^1,3 The broad inclusion criteria ensure that even the most severely ill or injured patients (e.g. patients with sepsis or a severe intracranial haemorrhage), who require urgent reversal of dabigatran, may be enrolled in the study.^1,3 Patients were categorised into two groups – (A) patients with uncontrolled or life-threatening bleeding complications, e.g. intracranial haemorrhage or severe trauma after a car accident (Group A, n= 51), or (B) patients requiring emergency surgery or an invasive procedure, e.g. surgery for an open fracture after a fall (Group B, n=39).^1,3 The primary endpoint of the study is the degree of reversal of the anticoagulant effect of dabigatran achieved by 5 g idarucizumab* within 4 hours measured by diluted thrombin time (dTT) and ecarin clotting time (ECT).³

The interim analysis from RE-VERSE AD™ included data from 90 patients in emergency settings who were taking dabigatran and required reversal. Of the 81 patients that presented with elevated anticoagulation levels at baseline as measured with ECT, results showed:¹

• The study met its primary endpoint, achieving 100 per cent maximum reversal as median value across all patients
• Reversal was evident immediately after administration of the first vial of idarucizumab* and was complete in all but 1 patient
• After 4 and 12 hours, laboratory tests showed normal coagulation levels in almost 90 per cent of patients
• Normal blood clotting (haemostasis) during surgery was reported in 92 per cent of the patients that required surgery or invasive procedures
• There was no signal of a pro-coagulant effect following administration of idarucizumab
• Thrombotic events occurred in five patients, none of whom were receiving antithrombotic therapy at the time of the event
• There were 18 deaths overall. Mortality within 96 hours of study enrolment appeared to be related to the original reason for emergency admission to the hospital, while all later events appeared to be related to co-morbidities.

"The real-world results from RE-VERSE AD™ are extremely encouraging and demonstrate how idarucizumab* can support patient management during emergency situations," said Professor Jörg Kreuzer, Vice President Medicine Therapeutic Area Cardiovascular, Boehringer Ingelheim . "The study is ongoing. We look forward to gaining further understanding of the potential of idarucizumab* as yet another breakthrough in anticoagulant therapy for advancing care of patients who require urgent reversal of the anticoagulant effect of dabigatran."

NOTES TO THE EDITORS

About idarucizumab*
Idarucizumab* is a humanized antibody fragment, or Fab, designed as a specific reversal agent to dabigatran.³ Idarucizumab* binds specifically to dabigatran molecules only, neutralizing their anticoagulant effect without interfering with the coagulation cascade.³ Boehringer Ingelheim began research on idarucizumab* in 2009, before the first marketing authorisation of Pradaxa® for stroke prevention in atrial fibrillation in 2010.^4,5

In February and March 2015 idarucizumab* was submitted under an accelerated approval pathway to the U.S. Food and Drug Administration, European Medicines Agency and Health Canada for use in patients who require urgent reversal of dabigatran.⁶ The FDA granted idarucizumab both Orphan Drug and Breakthrough Therapy Designation.^4,7 Idarucizumab* is currently the only specific reversal agent for a NOAC in regulatory review.⁴ Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.⁴ Further submissions are ongoing and accelerated processes will be pursued with regulatory authorities where available.⁴

Submissions included data from studies in healthy volunteers as well as in elderly and renally-impaired individuals.^4,8,9 These data showed that a 5 minute infusion of idarucizumab* (>2 g) led to immediate, complete and sustained reversal of dabigatran, with no clinically relevant side effects or over activation of clot production (i.e. pro-coagulant effect).^4,8,9 The submissions also included first data from the RE-VERSE ADTM study.^1,2,4

About RE-VERSE AD™ (NCT02104947)
RE-VERSE AD™ is an ongoing, global Phase III patient study initiated by Boehringer Ingelheim in 2014 to investigate idarucizumab* in emergency settings.^3,10 Up to 300 patients taking dabigatran, aged 18 years or over are expected to be enrolled from more than 400 centres in 38 countries worldwide.^3,11 Group A includes patients with uncontrollable or life-threatening bleeding deemed to require reversal, whereas Group B includes patients who needed surgery or an invasive procedure within 8 hours for which normal blood clotting (haemostasis) were required.³

The broad inclusion criteria reflect the types of patients that would require urgent anticoagulant reversal in the real-world emergency setting.^1,3 These include severely ill or injured patients, (e.g. patients with sepsis, a severe intracranial haemorrhage or a large vessel injury).^1,3 Furthermore, the study investigators are also allowed to administer any other type of therapies for patient management (including other blood products), as demanded by the clinical situation.³

Patients received 5 g of intravenous idarucizumab* administered as two 50 ml bolus infusions, each containing 2.5 g of idarucizumab*, no more than 15 minutes apart.³ Blood was collected and assessed for anticoagulant effect at baseline, after administration of the first vial of idarucizumab*, and then between 10 and 30 minutes and 1,2,4,12 and 24 hours after administration of the second vial.³

The primary endpoint was the maximum degree of reversal of the anticoagulant effect of dabigatran, determined using different laboratory tests (including the coagulations tests diluted thrombin time (dTT) and ecarin clotting time (ECT)) at any point from the end of the first idarucizumab* infusion, up to 4 hours after administration of the second infusion.^1,3

Secondary endpoints include the proportion of patients achieving complete normalisation of the dTT or ECT in 4 hours, the reduction in unbound dabigatran concentration, and clinical outcomes as assessed by the treating clinician.^1,3 In Group A patients, clinical outcomes included the extent of bleeding, severity of bleeding and haemodynamic stability.^1,3 In Group B patients, haemostasis was classified as normal or as mildly, moderately or severely abnormal.^1,3 Adverse events were monitored from the time of idarucizumab* infusion to 90 days post-infusion including suspected thrombotic events or deaths (classified as vascular or non-vascular in origin).^1,3

About dabigatran etexilate
Clinical experience of dabigatran equates to over 4 million patient-years in all licensed indications worldwide. Dabigatran has been in the market for more than 6 years and is approved in over 100 countries.⁴

Currently approved indications for dabigatran are:^5,12

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and a risk factor for stroke
• Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery or total knee replacement surgery
• Treatment of DVT and PE and the prevention of recurrent DVT and recurrent PE in adults

Dabigatran, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.^12,13 Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation.¹⁴ In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or mandatory dose adjustment.^13,15

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 146 affiliates and a total of more than 47,700 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

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