Final Phase III Study Results Confirm Benefit of Praxbind® as Reversal Agent for Pradaxa® Patients in Emergency Situations

Boehringer Ingelheim today announced final results from RE-VERSE AD^™.^1,2 The study shows that Praxbind^® (idarucizumab) was able to immediately and completely reverse the anticoagulant effect of Pradaxa^® (dabigatran etexilate) in patients in emergency situations. The effects were consistent both in patients requiring an urgent surgery or intervention, and in patients presenting with uncontrollable or life-threatening bleeding. The reversal of the anticoagulant effect of Pradaxa^® allowed physicians to quickly initiate necessary emergency interventions.^1,2 The findings were presented at the International Society on Thrombosis and Haemostasis (ISTH) 26th Biennial Congress in Berlin, Germany and simultaneously published in the New England Journal of Medicine.^1,2

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The primary endpoint of RE-VERSE AD^™ was reversal of the anticoagulant effect of Pradaxa^® within four hours as measured by diluted thrombin time (dTT) and ecarin clotting time (ECT), and was observed in 100 percent of patients (95 percent CI, 100-100). Reversal became evident immediately after administration of Praxbind^® and was maintained for 24 hours in most patients. Reversal was independent of age, sex, kidney function or dabigatran concentration at baseline.^1,2 A single 5 g dose of Praxbind^® was sufficient in 98 percent of patients.

The clinical outcomes captured as secondary endpoints provide insights into the clinical relevance of anticoagulation reversal:^1,2 in patients enrolled with acute bleeding (Group A), who could be assessed for time to cessation of bleeding, it took a median of 2.5 hours until the bleeding had stopped; in patients enrolled with a need for urgent surgery or intervention (Group B), the required procedures could be initiated after a median of 1.6 hours. In 93.4 percent of patients requiring procedures, haemostasis during the procedure was described as normal.^1,2

“Emergencies or accidents can happen to anyone. Patients with atrial fibrillation on an anticoagulant may feel anxious about how they might be managed in an emergency,” Professor Charles Pollack, lead investigator of RE-VERSE AD^™, Professor of Emergency Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, USA commented. “RE-VERSE AD^™ has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes and provides immediate, complete and sustained reversal of dabigatran, so that treating physicians can fully focus on dealing with the emergency at hand.”

There were no serious adverse safety signals related to Praxbind^® observed in the study. Patients in this study were elderly, had numerous comorbidities and presented with serious index events such as intracranial hemorrhage, multiple trauma or sepsis. Mortality rates at 90 days were 18.8 percent (Group A) and 18.9 percent (Group B). At 90 days, thrombotic events had occurred in 6.3 percent of Group A patients and 7.4 percent of Group B patients, which is consistent with rates reported after major surgical procedures or hospitalisation for uncontrolled bleeding in patients who had taken a vitamin K antagonist.^1,2

“These final data from RE-VERSE AD^™ fully confirm our interim insights,” Professor Jörg Kreuzer, Vice President Medicine, Therapeutic Area Cardiovascular, Boehringer Ingelheim commented. “The good news for patients and physicians is that Praxbind^® is already approved in 61 countries and is available in more than 8,200 sites worldwide, where it can be used to treat patients when urgently needed.”

Praxbind^® is the first and only approved specific reversal agent for a non-vitamin K antagonist oral anticoagulant currently available. Boehringer Ingelheim continues to study Praxbind^® in the RE-VECTO^™ programme, which evaluates usage patterns in a clinical practice setting. Expected completion of the RE-VECTO^™ programme is the end of 2018.⁵

~ENDS~

NOTES TO THE EDITORS

About RE-VERSE AD ^™

RE-VERSE AD^™ is a Phase III global study of patients taking dabigatran who require urgent procedures or have uncontrolled bleeding.^1,2,6 The final analysis from RE-VERSE AD^™ included data from patients requiring urgent procedures/emergency surgery, e.g. surgery for an open fracture after a fall, or patients with either uncontrolled or life-threatening bleeding complications, e.g. intracranial hemorrhage or severe trauma after a car accident.^1,2 The primary endpoint, the degree of reversal of the anticoagulant effect of dabigatran (Pradaxa^®) achieved by idarucizumab (Praxbind^®) within four hours, was measured by dTT and ECT.^1,2

The study, which began in May 2014, is the largest study to investigate a reversal agent for a non-vitamin K antagonist oral anticoagulant (NOAC) in real-world emergency settings. It enrolled a total of 503 patients at 173 sites in 39 countries, which were included in one of two groups:^1,2,6

• Group A: 301 patients (60 percent) presenting with uncontrolled or life-threatening bleeding (e.g. gastrointestinal [GI] and intracranial [ICH] bleeds)
• Group B: 202 patients (40 percent) requiring an invasive procedure or an emergency surgery or intervention (e.g. because of a hip fracture)

About Praxbind ^® (idarucizumab)

Praxbind^® (idarucizumab) is a humanised antibody fragment, or Fab, designed as a specific reversal agent to dabigatran.⁷ Idarucizumab binds specifically to dabigatran molecules only, neutralising their anticoagulant effect without interfering with the coagulation cascade.^6,7

In 61countries around the world, Praxbind^® is now indicated for patients treated with dabigatran when reversal of the anticoagulant effects of Pradaxa^® is needed:^3,4

• For urgent procedure/emergency surgery
• In life-threatening or uncontrolled bleeding

Regulatory reviews and submissions in other countries are ongoing. Boehringer Ingelheim plans to make Praxbind^® available in all countries where Pradaxa^® is licensed.⁸

About Pradaxa ^® (dabigatran etexilate)

Clinical experience of Pradaxa^® equates to over 6.9 million patient-years in all licensed indications worldwide. Pradaxa^® has been in the market for more than eight years and is approved in over 100 countries.⁸

Currently approved indications for Pradaxa^® are:^9,10

• 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.^9-11 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.¹² 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.^11,13

Pradaxa^® is the only novel oral anticoagulant with an approved reversal agent. Praxbind^® is approved in the European Union and United States for adult patients treated with Pradaxa^® who require rapid reversal of its anticoagulant effects prior to urgent procedures/emergency surgery or in life threatening or uncontrolled bleeding.^3,4

About Boehringer Ingelheim

Innovative medicines for people and animals have for more than 130 years been what the research-driven pharmaceutical company Boehringer Ingelheim stands for. Boehringer Ingelheim is one of the pharmaceutical industry’s top 20 companies and to this day remains family-owned. Day by day, some 50,000 employees create value through innovation for the three business areas human pharmaceuticals, animal health and biopharmaceutical contract manufacturing. In 2016, Boehringer Ingelheim achieved net sales of around 15.9 billion euros. With more than three billion euros, R&D expenditure corresponds to 19.6 percent of net sales.

Social responsibility comes naturally to Boehringer Ingelheim. That is why the company is involved in social projects such as the “Making More Health” initiative. Boehringer Ingelheim also actively promotes workforce diversity and benefits from its employees’ different experiences and skills. Furthermore, the focus is on environmental protection and sustainability in everything the company does.

More information about Boehringer Ingelheim can be found on www.boehringer-ingelheim.com or in our annual report: http://annualreport.boehringer-ingelheim.com.

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References
1. Pollack, C.V. et al. Final Results of RE-VERSE AD Study: Reversal of Dabigatran by its Specific Reversal Agent Idarucizumab in Patients with Uncontrolled Bleeding or Requiring Urgent Surgery/Procedures. International Society on Thrombosis and Haemostasis (ISTH) 26th Biennial Congress and 63rd Annual Scientific and Standardization Committee (SSC), Berlin, July 2017, Late-breaking abstract 01.4.
2. Pollack, C.V. et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. New Engl J Med. 2017; DOI: 10.1056/NEJMoa1707278. www.nejm.org/doi/full/10.1056/NEJMoa1707278
3. Idarucizumab European Summary of Product Characteristics, 2016.
4. Idarucizumab US Prescribing Information 2015.
5. https://www.boehringer-ingelheim.com/press-release/boehringer-ingelheim-launches-re-vecto-global-program
6. Pollack C.V. et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198-205.
7. Schiele, F. et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121(18):3554-62.
8. Boehringer Ingelheim. Data on File.
9. Pradaxa^® US Prescribing Information, 2015.
10. Pradaxa^® European Summary of Product Characteristics, 2016.
11. Stangier, J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
12. Di Nisio, M. et al. Direct thrombin inhibitors. N Engl J Med.2005;353:1028–40.
13. Stangier, J. et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.

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