Boehringer Ingelheim Pharmaceuticals, Inc. Release: Positive Phase 3 Results For New Fixed Oral Dose Anticoagulant Presented At 48th Annual Meeting Of The American Society of Hematology
ORLANDO, Fla., Dec. 11 /PRNewswire/ -- Positive results from RE-MODEL(TM), a phase 3, randomized, parallel-group, double-blind, active controlled study investigating the efficacy and safety of two different dosing strengths of orally administered dabigatran etexilate capsules compared to subcutaneous injection of the low molecular weight heparin, enoxaparin, in the prevention of venous thromboembolism in patients with primary elective total knee replacement surgery were presented today at the 48th Annual Meeting of the American Society of Hematology(1).
Dabigatran etexilate was discovered through internal research programs at Boehringer Ingelheim and is being investigated for the prevention and treatment of thromboembolic disease. In clinical trials, dabigatran etexilate is given in a fixed oral dose form and does not require coagulation monitoring. Results from the RE-MODEL study, which was conducted throughout the European Union, South Africa and Australia, demonstrate that dabigatran etexilate met the pre-specified primary endpoint of non-inferiority versus enoxaparin with no difference in bleeding rates in patients undergoing elective knee replacement surgery(1).
The primary efficacy endpoint results from the 2,076 patient RE-MODEL study comparing fixed oral dose dabigatran etexilate and subcutaneously administered enoxaparin demonstrated non-inferiority for both dabigatran doses. Total venous thromboembolism (VTE) and all-cause mortality occurred in 40.5 percent of patients receiving 150 mg and 36.4 percent of patients receiving 220 mg dabigatran etexilate once daily, as compared to 37.7 percent of patients receiving 40 mg of enoxaparin. Secondary efficacy endpoint results showed that proximal deep vein thrombosis (DVT) and/or pulmonary embolism (the collective term for DVT and PE is VTE) occurred at similar rates across treatment arms. VTE occurred in 3.8 percent of patients receiving 150 mg, 2.6 percent of patients receiving 220 mg of dabigatran etexilate, and 3.5 percent of patients receiving 40 mg of enoxaparin.
Safety evaluation results for all 2,076 patients receiving study treatment showed that similar bleeding rates were observed between the treatment groups. The rate of major bleeding was 1.3 percent of patients receiving 150 mg, 1.5 percent of patients receiving 220 mg of dabigatran etexilate, and 1.3 percent of patients receiving enoxaparin. Elevated liver function tests (LFTs) (ALT > 3xULN) were observed in 3.7 percent of patients receiving 150 mg and 2.8 percent receiving 220 mg of dabigatran etexilate, as compared to 4.0 percent of the patients treated with enoxaparin during the study(1).
RE-MODEL was a multinational, randomized, double-blind, non-inferiority, placebo-controlled trial involving 2,076 patients and compared dabigatran etexilate with enoxaparin in the prevention of VTE in patients undergoing total knee replacement surgery. Patients were randomized to either oral dabigatran 150 mg or 220 mg once daily (half dose given on day of surgery, 1-4 hours post-operatively) or enoxaparin 40 mg once daily by subcutaneous injection (started 12 hours before surgery). The study treatment period was 6-10 days with follow up 3 months after surgery. Presence of VTE was determined by centrally adjudicated objective clinical tests for symptomatic events, and centrally adjudicated bilateral venograms on the last day of treatment for asymptomatic events.
"A new thromboprophylaxis agent which is given as a pill rather than the standard injection has great potential to decrease demands on hospital time and resources," said Bengt Eriksson, MD, PhD, Department of Orthopaedic Surgery, University Hospital Sahlgrenska / Ostra, Gothenburg, Sweden.
Patients undergoing hip and knee replacement surgery are at particularly high risk of developing VTE(2). In fact, VTE is the most common cause of hospital readmission following orthopedic surgery(2). Currently, the therapeutic options for preventing thromboembolic diseases are limited. Most anticoagulants are only available in an injectable form, which limits their long-term use. The most commonly used oral product is warfarin, which has been on the market for more than 50 years and is associated with numerous limitations. Notably, warfarin has a narrow therapeutic window, which means that there is little difference in the dose that provides effective protection against thrombosis and the dose that leads to bleeding. As a result of this narrow therapeutic window, patients must undergo time consuming and costly monitoring that can significantly impact patient quality of life. Managing this narrow therapeutic window is complicated by frequent drug-drug and drug- food interactions with warfarin. An ideal therapy would provide predictable and reliable protection for patients at risk of thromboembolic events, be suitable for long-term use with a low risk of bleeding, have no interactions with food or other drugs, and not require coagulation monitoring.
About dabigatran etexilate
Dabigatran etexilate is a promising new oral direct thrombin inhibitor that specifically and reversibly inhibits thrombin, the key enzyme for blood clot formation and is currently in phase 3 development. It is administered orally in a fixed dose and has a rapid onset of action. Published data shows that dabigatran etexilate provides a predictable and consistent anticoagulant effect, which suggests that coagulation monitoring will not be required. Published data also suggest that CYP450 isoenzymes are not involved in dabigatran etexilate metabolism and dabigatran etexilate has no inhibitory or inductory effect on CYP450 isoenzymes, which metabolizes many drugs, indicating low interaction potential. In pharmacokinetic studies, no food effect was observed with dabigatran etexilate.
Further studies investigating dabigatran etexilate
The RE-MODEL trial is part of a multi-center, randomized global trial program designed to investigate the novel oral direct thrombin inhibitor dabigatran etexilate as a potential treatment for several thromboembolic medical conditions. The trials are expected to involve more than 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa. Patients will be divided into different treatment arms involving dabigatran etexilate compared with warfarin or enoxaparin.
RE-LY(TM), a phase 3 study, is investigating dabigatran etexilate as a potential treatment for stroke prevention in atrial fibrillation. Total enrollment for this study is targeted at 15,000 patients from almost 1,000 study centers worldwide.
RE-MODEL(TM) investigated thromboembolism prevention after knee surgery in 2,000 patients throughout the European Union, South Africa and Australia. RE-MOBILIZE(TM) investigated dabigatran etexilate for the same indication in a similar patient population in North America.
RE-NOVATE(TM) conducted in the European Union, South Africa, and Australia, investigated approximately 3,300 hip surgery patients. RE-COVER and RE-MEDY are investigating dabigatran etexilate for acute treatment and secondary prevention of venous thromboembolism.
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 143 affiliates in 47 countries and approximately 37,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
In 2005, Boehringer Ingelheim posted net sales of US $11.8 billion (9.5 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.
For more information, please visit http://us.boehringer-ingelheim.com. REFERENCES: (1) Eriksson BI, Dahl OE, van Dijk CN, et al. A new oral anticoagulant, dabigatran etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (The RE-MODEL Trial). Abstract #573 presented at the 48th Annual Meeting of the American Society of Hematology in Orlando, Fl, 2006 (2) Blanchard J, Meuwly J-Y, Leyvraz P-F, et al. Prevention of deep-vein thrombosis after total knee replacement. J Bone Joint Durg Br 1999; 81-B; 654-9Boehringer Ingelheim Pharmaceuticals, Inc.
CONTACT: Mark R. Vincent of Boehringer Ingelheim Pharmaceuticals, Inc.,+1-203-798-4412
Web site: http://us.boehringer-ingelheim.