Daiichi Sankyo's Once-Daily Edoxaban Meets Primary Efficacy Endpoint for Stroke Prevention and Superiority for the Principal

   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

  PR Newswire

  DALLAS and TOKYO, Nov. 19, 2013

- 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. 19, 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

About ENGAGE AF-TIMI 48

ENGAGE AF-TIMI 48 ( E ffective a N ticoa G ulation with Factor X A next GE
neration in A trial F ibrillation) 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 < or = 60 kg, or
concomitant verapamil, quinidine or dronedarone (standard dosing was resumed
if the concomitant drug was discontinued and no other dose reduction factors
were present). The primary efficacy outcome was the time to first adjudicated
stroke or SEE. The principal safety outcome was adjudicated major bleeding.
Complete information on the primary endpoint was ascertained for 99.5% of the
total 56,346 patient-years of potential follow-up, with only one patient lost
to follow-up. Warfarin therapy was proactively monitored throughout the trial,
resulting in a median time within therapeutic range (TTR) of 68.4%. Adverse
event (excluding bleeding) and discontinuation rates were similar among the
three treatment groups. ^2

ENGAGE AF-TIMI 48 implemented a unique, pre-specified plan to transition
patients to open-label anticoagulation at the end of the trial, which resulted
in a low and evenly distributed number of events post-discontinuation of study
therapy. In the 30 days following the transition, the number of patients
experiencing stroke or SEE was the same in all three treatment groups (n=7),
while major bleeding occurred in 11 patients in the warfarin group compared to
10 and 18 patients in the edoxaban 60 mg and 30 mg treatment arms,
respectively. ^ These results demonstrate that the transition plan was
effective in preventing undue risk of excessive stroke / SEE for
edoxaban-treated subjects transitioning to a vitamin K antagonist (VKA) or a
novel oral anticoagulant. ^2

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 AF ^5 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 ( E ffective a N ticoa G ulation with Factor X A Next GE
neration in A trial F ibrillation) ^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 US,
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 .

Contact Michaela Paudler-Debus, PhD Daiichi Sankyo Europe
michaela.paudler-debus@daiichi-sankyo.eu +49-89-7808-685 (office)
+49-176-11780966 (mobile)

Forward-looking statements

This press release contains forward-looking statements and information about
future developments in the sector, and the legal and business conditions of
DAIICHI SANKYO, Co. Ltd. Such forward-looking statements are uncertain and are
subject at all times to the risks of change, particularly to the usual risks
faced by a global pharmaceutical company, including the impact of the prices
for products and raw materials, medication safety, changes in exchange rates,
government regulations, employee relations, taxes, political instability and
terrorism as well as the results of independent demands and governmental
inquiries that affect the affairs of the company. All forward-looking
statements contained in this release hold true as of the date of publication.
They do not represent any guarantee of future performance. Actual events and
developments could differ materially from the forward-looking statements that
are explicitly expressed or implied in these statements. DAIICHI SANKYO, Co.
Ltd. assume no responsibility for the updating of such forward-looking
statements about future developments of the sector, legal and business
conditions and the company.

References

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: http://www.daiichisankyo.com/news/detail/004123.html . [Last
accessed: October 2013].

Website: http://www.daiichisankyo.com