The European Committee for Medicinal Products for Human Use (CHMP) has recommended approval of Daiichi Sankyo's Lixiana (edoxaban), an oral, once-daily selective factor Xa inhibitor, for the prevention of stroke and systemic embolism (SE) in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors.

The CHMP also recommended approval of Lixiana for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. The two related conditions DVT and PE are collectively referred to as venous thromboembolism (VTE).

“The CHMP recommendation to approve once-daily edoxaban for the NVAF and VTE indications is an important milestone for our company,” said Glenn Gormley, MD, PhD, senior executive officer and global head of R&D, Daiichi Sankyo Company, Limited and executive chairman and president, Daiichi Sankyo, Inc.

“The European regulatory committee has recognised the positive benefit-risk profile of the 60 mg dosing regimen with a dose reduction to 30 mg in selected patients with creatinine clearance (CrCL) 15-50 mL/min, body weight = 60 kg, or concomitant use of certain P-glycoprotein (P-gp) inhibitors.”

The CHMP opinion to approve once-daily edoxaban for the prevention of stroke and SE in adult patients with NVAF with one or more risk factors and for the treatment and prevention of recurrent VTE (DVT and PE) is based on the data of the phase 3 ENGAGE AF-TIMI 48 and Hokusai-VTE studies, respectively.

In the ENGAGE AF-TIMI 48 study, once-daily edoxaban 60 mg demonstrated non-inferiority to well-managed warfarin for the primary efficacy endpoint of occurrence of stroke or SE in patients with NVAF (1.18 per cent vs. 1.50 per cent per year, respectively; hazard ratio, 0.79; 97.5 per cent confidence interval, 0.63 to 0.99, p<0.001). In addition, once-daily edoxaban 60 mg demonstrated a significant 20 per cent risk reduction of major bleeding in patients with NVAF compared to warfarin (2.75 per cent vs. 3.43 per cent per year, respectively; HR, 0.80; 95 per cent CI, 0.71 to 0.91, p<0.001).

In the Hokusai-VTE study, once-daily edoxaban 60 mg was non-inferior to warfarin for the primary efficacy endpoint of recurrence of symptomatic VTE (3.2 per cent vs 3.5 per cent of patients, respectively; HR, 0.89; 95 per cent CI, 0.70 to 1.13, p<0.001). In addition, edoxaban demonstrated a significant 19 per cent risk reduction of clinically relevant bleeding in patients with VTE compared to warfarin (8.5 per cent vs 10.3 per cent of patients, respectively; HR, 0.81; 95 per cent CI, 0.71 to 0.94, p=0.004).

Atrial fibrillation (AF) is the most common type of heart rhythm disorder, and is associated with substantial morbidity and mortality. More than six million Europeans suffer from AF and this figure is expected to at least double over the next 50 years. One in five of all strokes is as a result of AF.

VTE is a major cause of morbidity and mortality. VTE is a major health problem in Europe, with more than one million VTE events or deaths per year (France, Germany, Italy, Spain, Sweden, UK), including more than 370,000 VTE-related deaths.

ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation) was a three-arm, randomised, double-blind, double-dummy, global phase 3 clinical trial comparing once-daily edoxaban with well-managed warfarin in 21,105 patients with NVAF at moderate-to-high risk of thromboembolic events at 1,393 centers in 46 countries. ENGAGE AF-TIMI 48 compared two edoxaban treatment strategies, a higher dose arm (60 mg or 30 mg dose reduced) once-daily and a lower dose arm (30 mg or 15 mg dose reduced) once-daily, with warfarin in patients with NVAF for a median of 2.8 years follow-up.

Patients were dose reduced for CrCL 30 to 50 mL/min, body weight of 60 kg or less or certain P-gp inhibitor use. ENGAGE AF-TIMI 48 represents the largest and longest single comparative global trial with a novel anticoagulant in patients with NVAF performed to date. The full results were presented at the AHA scientific sessions 2013 in Dallas and published in the New England Journal of Medicine.

Hokusai-VTE was a global, event-driven, randomised, double-blind, double-dummy, parallel-group phase 3 clinical study involving 8,292 patients in 439 clinical sites across 37 countries to evaluate once-daily edoxaban in patients with either acute symptomatic DVT, PE or both. The Hokusai-VTE study was designed to reflect clinical practice using a flexible treatment duration of 3-12 months in a broad spectrum of VTE patients, including initial use of parenteral anticoagulant (heparin) for 5-10 days, the proven global standard of care.

Patients were randomised to receive edoxaban 60 mg once-daily (dose reduced to 30 mg for CrCL 30 to 50 mL/min, body weight of 60 kg or less, or certain P-gp inhibitor use) or the comparator, warfarin, following initial open-label enoxaparin or unfractionated heparin therapy. In the comparator arm, patients received initial heparin therapy concurrently with warfarin, titrated to a target INR of 2.0 to 3.0, followed by warfarin alone. The treatment duration was from 3 months and up to a maximum of one year. The duration of study treatment was determined by the investigator based on the patient’s clinical features. The full results were presented at the ESC Congress 2013 in Amsterdam and published in the New England Journal of Medicine.

Edoxaban is an investigational, oral, once-daily anticoagulant that specifically inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting. The global edoxaban clinical trial programme includes two phase 3 clinical studies, Hokusai-VTE and ENGAGE AF-TIMI 48, which included nearly 30,000 patients combined. The results from these trials form the basis of regulatory filings for edoxaban for symptomatic VTE in patients with DVT and/or PE, and for the prevention of stroke and SE in NVAF, respectively.

Edoxaban is currently marketed in Japan and the US and has received approval in Switzerland. In other countries, regulatory review is ongoing.