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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
2013-11-20 01:09 1568

- Once-daily edoxaban, evaluated in two treatment arms (60 mg and 30 mg), achieved the primary endpoint of non-inferior efficacy versus warfarin in the prevention of stroke or systemic embolism

- Rates of major bleeding were significantly reduced with edoxaban compared to warfarin

- Efficacy and safety findings for patients who received a dose reduction for renal impairment or low body weight were consistent with the overall study results

- ENGAGE AF-TIMI 48, the largest and longest single comparative clinical trial of stroke prevention in atrial fibrillation, presented at a late-breaking clinical trials session at the American Heart Association Scientific Sessions 2013 and published in the New England Journal of Medicine

DALLAS and TOKYO, Nov. 20, 2013 /PRNewswire/ -- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced results today 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 today 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; p<0.001 for non-inferiority), and significantly reduced major bleeding by 20% (2.75% vs. 3.43% per year, respectively) (HR, 0.80; 95% CI, 0.71 to 0.91; p<0.001 for superiority). The edoxaban 30 mg treatment arm had an annual incidence of stroke or SEE of 1.61% versus 1.50% for warfarin (HR, 1.07; 97.5% CI, 0.87 to 1.31; p=0.005 for non-inferiority), and significantly reduced major bleeding by 53% (1.61% vs. 3.43% per year, respectively) (HR, 0.47; 95% CI, 0.41 to 0.55; p<0.001 for superiority).(2)

In ENGAGE AF-TIMI 48, patient-specific dosing was applied according to the study protocol. In both edoxaban treatment arms, the edoxaban dose was halved for patients with clinical factors that were known to increase the risk of bleeding (renal impairment, low body weight or concomitant use of certain P-glycoprotein inhibitors).(1, 2) Patients receiving a reduced edoxaban dose in the 60 mg treatment arm had an annual incidence of stroke or SEE of 2.32% versus 2.68% for warfarin and a significantly reduced major bleeding incidence of 3.05% versus 4.85%. Patients receiving a reduced edoxaban dose in the 30 mg treatment arm had an annual incidence of stroke or SEE of 3.14% versus 2.68% for warfarin and a significantly reduced major bleeding incidence of 1.50% versus 4.85%.(2)

"The results from the ENGAGE AF-TIMI 48 trial showed that edoxaban may provide a new treatment option for the prevention of stroke or systemic embolic events that demonstrates comparable efficacy to warfarin, while significantly reducing the risk of major bleeding. In addition, we identified an appropriate dose regimen for patients with clinical factors such as renal impairment and low body weight," said Robert Giugliano, MD, SM, FAHA, FACC, Senior Investigator with the TIMI Study Group, Physician Cardiovascular Medicine, Brigham and Women's Hospital, Associate Professor of Medicine, Harvard Medical School, and Co-Global Lead Investigator of the ENGAGE AF-TIMI 48 trial. "In conducting this landmark trial we sought to provide clinicians with robust data, evident by the trial size and follow-up, high percentage of time in therapeutic range for the warfarin treatment arm, and very low rate of missing data. In addition, we specifically designed a comprehensive transition plan to protect patients from the undue risk of stroke and bleeding when switching to open-label anticoagulation at the end of the trial."

"The edoxaban clinical trial program, the largest in the history of Daiichi Sankyo, has now yielded positive data for edoxaban in two major diseases, stroke prevention in atrial fibrillation and treatment of acute venous thromboembolism," said Glenn Gormley, MD, PhD, Global Head of Research and Development and Senior Executive Officer, Daiichi Sankyo Company, Ltd. and Executive Chairman of Daiichi Sankyo, Inc. in the United States (US). "Based on the findings from ENGAGE AF-TIMI 48 and Hokusai-VTE, we look forward to submitting New Drug Applications for edoxaban in both indications by the first quarter of 2014 in the US, Japan and Europe."

The annual incidence of hemorrhagic stroke was 0.47% for warfarin compared to 0.26% for edoxaban 60 mg (HR, 0.54; 95% CI, 0.38 to 0.77; p<0.001) and 0.16% for edoxaban 30 mg (HR, 0.33; 95% CI, 0.22 to 0.50; p<0.001). The annual incidence of ischemic stroke was 1.25% for warfarin compared to 1.25% in the edoxaban 60 mg treatment arm (HR, 1.00; 95% CI, 0.83 to 1.19; p=0.97) and 1.77% per year for the edoxaban 30 mg treatment arm (HR, 1.41; 95% CI, 1.19 to 1.67; p<0.001).(2)

The annual incidence of intracranial hemorrhage was 0.39% for patients in the edoxaban 60 mg treatment arm (HR, 0.47; 95% CI, 0.34 to 0.63; p<0.001) and 0.26% for the edoxaban 30 mg treatment arm (HR, 0.30; 95% CI, 0.21 to 0.43; p<0.001) compared to 0.85% for warfarin. Fatal bleeds occurred at an annual rate of 0.21% in the edoxaban 60 mg treatment arm (HR, 0.55; 95% CI, 0.36 to 0.84; p=0.006) and 0.13% for the edoxaban 30 mg treatment arm (HR, 0.35; 95% CI, 0.21 to 0.57; p<0.001) compared to 0.38% for warfarin.(2)

Annualized rates for the key secondary composite endpoint of stroke, SEE and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban 60 mg (p=0.005) and 4.23% with edoxaban 30 mg (p=0.32). Edoxaban was also associated with reduced annualized cardiovascular mortality rates versus warfarin: the incidence was 3.17% for warfarin, 2.74% (p=0.013) for the edoxaban 60 mg treatment arm and 2.71% (p=0.008) for the edoxaban 30 mg treatment arm. The primary net clinical outcome (defined in the study protocol as the composite of death, stroke, SEE or major bleeding) was 8.11% per year for warfarin, 7.26% per year for the edoxaban 60 mg treatment arm (p=0.003) and 6.79% per year for the edoxaban 30 mg treatment arm (p<0.001).(2)

Source: Daiichi Sankyo
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