Daiichi Sankyo`s Once-Daily Edoxaban Meets Primary Efficacy Endpoint for Stroke Prevention and Superiority for the Principal Safety Endpoint Compared to Warfarin for Patients with Atrial Fibrillation in a Phase 3 Clinical Trial

Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced results from the phase 3 ENGAGE AF-TIMI 48 study.(1) This clinical trial found that the investigational, oral, once-daily direct factor Xa-inhibitor edoxaban met the primary efficacy endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with non-valvular atrial fibrillation (NVAF). Once-daily edoxaban also demonstrated significant reductions in major bleeding compared to warfarin, achieving superiority for the principal safety endpoint. Results from ENGAGE AF-TIMI 48 were presented as a late-breaking clinical trial at the American Heart Association (AHA) Scientific Sessions 2013 in Dallas and published online in the New England Journal of Medicine.(2) ENGAGE AF-TIMI 48 compared two edoxaban treatment arms, 60 mg and 30 mg, with warfarin in 21,105 patients with NVAF for a median of 2.8 years. This represents the largest and longest trial with a novel anticoagulant in patients with atrial fibrillation performed to date. The edoxaban 60 mg treatment arm had an annual incidence of stroke or SEE of 1.18% versus 1.50% for warfarin (hazard ratio [HR], 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; pAbout ENGAGE AF-TIMI 48 ENGAGE AF-TIMI 48 (Effective aNticoaGulation with Factor XA next GEneration in Atrial Fibrillation) was a three-arm, randomized, double-blind, double-dummy, global phase 3 clinical trial comparing once-daily edoxaban with warfarin in 21,105 patients with NVAF at moderate-to-high risk of thromboembolic events at 1,393 centers in 46 countries.(2) Patients were randomized (1:1:1) to receive warfarin (n=7,036), edoxaban 60 mg (n=7,035) or edoxaban 30 mg (n=7,034). Edoxaban dosage was reduced by half if any of the following was present at randomization or during the course of the study: creatinine clearance 30-50 mL/min, body-weight About Atrial Fibrillation Atrial fibrillation (AF) is a condition in which the heartbeat is rapid and irregular, and can potentially lead to a stroke. AF is a common condition, affecting approximately 1-2% of people in developed nations.(3) Stroke is the second most common cause of death worldwide, responsible for approximately 6.2 million deaths each year.(4) Compared to those without AF, people with the arrhythmia have a 3-5 times higher risk of stroke.(3) Strokes due to AF are nearly twice as likely to be fatal than strokes in patients without AF5 and have poorer prognosis than non-AF related strokes with a 50% increased risk of remaining disabled at three months.(6) About Edoxaban Edoxaban is an investigational, oral, once-daily anticoagulant that specifically and reversibly inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting.(7) The global edoxaban clinical trial program includes two phase 3 clinical trials, Hokusai-VTE(8) and ENGAGE AF-TIMI 48 (Effective aNticoaGulation with Factor XA Next GEneration in Atrial Fibrillation),(1,2) which are evaluating edoxaban, administered once-daily, for treatment and prevention of recurrence of venous thromboembolism (VTE) in patients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and for the prevention of stroke and systemic embolic events (SEE) in patients with non-valvular atrial fibrillation, respectively.(1,2,8) Edoxaban is currently approved only in Japan, since April 2011, for the prevention of VTE after major orthopedic surgery, and was launched in July 2011 under the brand name Lixiana®. Elsewhere, including Europe and the U.S., edoxaban is currently in phase 3 clinical development and has not been approved in any indication.(9) Results from the Hokusai-VTE clinical trial were presented at the European Society of Cardiology Congress on September 1, 2013 and published in the New England Journal of Medicine.(8,9) About Daiichi Sankyo Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address the diversified, unmet medical needs of patients in both mature and emerging markets. While maintaining its portfolio of marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial infections, the Group is engaged in the development of treatments for thrombotic disorders and focused on the discovery of novel oncology and cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has created a "Hybrid Business Model," which will respond to market and customer diversity and optimize growth opportunities across the value chain. For more information, please visit: www.daiichisankyo.com. 1. Ruff, C et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635-41. 2. Giugliano, RP et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013. 3. Ball, J et al. Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century. Int J Cardiol. 2013;167:1807–24. 4. World Health Organization. The top 10 causes of death. July 2013. Available at: who.int/mediacentre/factsheets/fs310/en/. [Last accessed: October 2013]. 5. Lin, H et al. Stroke severity in atrial fibrillation. Stroke 1996;27:1760–1764. 6. Lamassa, M et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 2001;32:392–8. 7. Ogata, K et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010;50:743-753. 8. Buller, H et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15. 9. Daiichi Sankyo press release - Daiichi Sankyo launches LIXIANA® (edoxaban), a direct oral factor Xa inhibitor, in Japan for the prevention of venous thromboembolism after major orthopaedic surgery. 19 July 2011. Available at: https://www.daiichisankyo.com/news/detail/004123.html. [Last accessed: October 2013].