Daiichi Sankyo Presents Positive Results of the ENTRUST-AF PCI Study of LIXIANA® (edoxaban) in Patients with Atrial Fibrillation

- ENTRUST-AF PCI study achieved the primary safety endpoint of
non-inferiority in bleeding for edoxaban-based dual therapy compared
with VKA-based triple antithrombotic therapy (using a risk-based
duration of ASA for at least one month) in AF patients following
stent placement

- Data contributes to growing body of evidence supporting edoxaban
in combination with a P2Y12 inhibitor as an alternative to the
current VKA triple therapy

- Data presented during ESC Congress 2019 Hot Line Session and
simultaneously published in The Lancet

Munich (ots/PRNewswire) - Daiichi Sankyo Company, Limited,
(hereafter, Daiichi Sankyo) today announced results from ENTRUST-AF
PCI, the first large randomised study to evaluate the efficacy and
safety of once-daily edoxaban (known by the brand name LIXIANA®) plus
a P2Y12 inhibitor against a regimen of vitamin K antagonist (VKA)
plus P2Y12 inhibitor and acetyl salicylic acid (ASA) in atrial
fibrillation (AF) patients following successful percutaneous coronary
intervention (PCI). The study showed the edoxaban-based regimen is
non-inferior compared with the VKA-based triple therapy regimen on
the composite endpoint of major or clinically-relevant non-major
bleeding over 12 months.[1],[2] The results were presented in a
late-breaking presentation during the Hot Line Session yesterday at
ESC Congress 2019 in Paris, France, and published in The Lancet
(http://dx.doi.org/10.1016/S0140-6736(19)31872-0).

It is estimated that about 20% to 40% of patients with AF also
present with coronary artery disease (CAD), a sizeable proportion of
whom requires revascularisation using percutaneous coronary
intervention (PCI) and stent implantation.[3] Current treatment
guidelines for these patients recommend VKA-based triple therapy
including a P2Y12 inhibitor and ASA, however, triple therapy has been
associated with significantly increased risk of bleeding.[4]
ENTRUST-AF PCI was a multinational, multicenter, randomised,
open-label, blinded outcome evaluation Phase 3b study that evaluated
a 12-month antithrombotic regimen of edoxaban 60 mg once-daily in
combination with a P2Y12 inhibitor compared to a VKA in combination
with a P2Y12 inhibitor and 100 mg of ASA for a risk adapted duration
for one to 12 months in patients with AF following successful stent
placement for ACS or stable CAD. The primary safety outcome was the
composite of major or clinically relevant non-major bleeding, as
defined by the International Society of Thrombosis and Haemostasis
(ISTH).[1]

"For patients with atrial fibrillation receiving PCI, an
antithrombotic treatment strategy that prevents both bleeding and
potential coronary events is critical," said Andreas Goette, MD,
Chief Physician, St. Vincez-Hospital Paderborn, Germany, Department
of Cardiology and Intensive Care Medicine and principal study
investigator. "These results from the ENTRUST-AF PCI study support
the use of a dual antithrombotic therapy with edoxaban plus a P2Y12
inhibitor as an alternative option with an equivalent safety profile
compared to VKA-based triple therapy, including a P2Y12 inhibitor,
plus risk adapted ASA for a duration of one to 12 months."

The ENTRUST-AF PCI study enrolled 1,506 patients with AF following
successful stent placement for ACS (51.6%) or stable CAD (48.4%).[1]
Patients were randomised to receive once-daily edoxaban (60 mg or 30
mg per dose reduction criteria) plus a P2Y12 inhibitor for 12 months
or a VKA in combination with a P2Y12 inhibitor plus 100 mg of ASA.[1]
Major or clinically relevant non-major bleeding, the study's primary
endpoint, occurred in 128 (17.0%; annualised: 20.7%) patients in the
edoxaban group and 152 (20.1%; annualised: 25.6%) patients in the VKA
group (HR: 0.83, 95% CI: 0.654-1.047), demonstrating non-inferiority
of the edoxaban-based dual therapy for the 12 months post PCI
(p=0.001, pre-specific non-inferiority margin=1.2).[2] There was a
trend toward less bleeding with edoxaban, though, results did not
show statistical superiority (p=0.115). Similar rates of the main
efficacy composite outcome of cardiovascular death, stroke, systemic
embolic events, spontaneous myocardial infarction, and definite stent
thrombosis were observed for the edoxaban-based dual therapy regimen
and the VKA-based triple therapy regimen.[2]

"These results reinforce the value of the approved regimen of
edoxaban for AF treatment in post-PCI patients, providing the
potential for less bleeding compared to current standard-of-care
VKA-based triple therapies without significant differences in
ischemic events," said Hans Lanz, MD, Vice President, Global Medical
Affairs Specialty & Value Products, Daiichi Sankyo. "ENTRUST-AF PCI
is part of the Edoxaban Clinical Research Programme, which is
designed to address a broad range of cardiovascular conditions and
patient types including the elderly. We are encouraged by these
results which represent an important advancement in our understanding
of how to best manage AF patients post-PCI."

In the ENTRUST-AF PCI study, bleeding events were consistent
across all commonly applied bleeding definitions (ISTH, TIMI,
BARC).[2] Intracranial hemorrhage occurred in four (0.58% per year)
of edoxaban-treated patients and nine (1.32% per year) VKA-treated
patients.[2] Fatal bleeding occurred in one patient receiving
edoxaban and seven patients receiving VKA treatment.[2]

ENTRUST-AF PCI is one of more than 10 randomised, controlled
trials (RCTs), registries and non-randomised clinical studies that
comprise the Edoxaban Clinical Research Programme. More than 100,000
patients worldwide are expected to participate in the Edoxaban
Clinical Research Programme studies, with the goal of generating new
clinical and real-world data regarding edoxaban use in AF and venous
thromboembolism (VTE) populations, providing physicians and patients
worldwide with greater treatment confidence.

About ENTRUST-AF PCI

EdoxabaN TReatment VersUS Vitamin K Antagonist in PaTients With
Atrial Fibrillation Undergoing Percutaneous Coronary Intervention
(ENTRUST-AF PCI) is a prospective, multinational, multicenter,
randomised, open-label with blinded endpoint evaluation phase 3b
study. The ENTRUST-AF PCI trial was designed to evaluate the safety
and accrue exploratory information on the efficacy of an
edoxaban-based antithrombotic regimen compared to a VKA-based
antithrombotic regimen in patients with AF following successful PCI
with stent implantation. The primary objective of the ENTRUST-AF PCI
trial was to compare the incidence of major or clinically relevant
non-major International Society on Thrombosis and Haemostasis
(ISTH)-defined bleeding over a 12-month period of an edoxaban-based
antithrombotic regimen against a VKA-based regimen. 1,506 patients
were enrolled in ENTRUST-AF PCI from 186 clinical sites across Europe
and Asia. Participants were randomly allocated in a 1:1 ratio to a
12-month antithrombotic regimen of edoxaban and a P2Y12 inhibitor or
to a standard therapy with a vitamin K antagonist (VKA) and P2Y12
inhibitor plus ASA for one to 12 months.[1]

About Atrial Fibrillation

AF is a condition where the heart beats irregularly and rapidly.
When this happens, blood can pool and thicken in the chambers of the
heart causing an increased risk of blood clots. These blood clots can
break off and travel through the blood stream to the brain (or
sometimes to another part of the body), where they have the potential
to cause a stroke.[5]

AF is the most common type of heart rhythm disorder and is
associated with substantial morbidity and mortality.[6] More than six
million Europeans are diagnosed with AF, and this figure is expected
to at least double over the next 50 years.[7],[8] Compared to those
without AF, people with the arrhythmia have a 3-5 times higher risk
of stroke.[9] One in five of all strokes are a result of AF.[7]

About the Edoxaban Clinical Research Programme

More than 10 studies, more than 100,000 patients worldwide

Daiichi Sankyo is committed to expanding scientific knowledge
about edoxaban, as demonstrated through research programmes
evaluating its use in a broad range of cardiovascular conditions,
patient types and clinical settings in atrial fibrillation (AF) and
venous thromboembolism (VTE) designed to further build on the results
of the pivotal ENGAGE-AF and Hokusai-VTE studies. More than 100,000
patients worldwide are expected to participate in the Edoxaban
Clinical Research Programme, which is comprised of more than 10 RCTs
(randomised controlled trials), registries and non-randomised
clinical studies, including completed, ongoing and future research.
Our goal is to generate new edoxaban clinical and real-world-data
regarding its use in AF and VTE populations, providing physicians and
patients worldwide with greater treatment assurance.

The RCTs include:

- ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next
GEneration in Atrial Fibrillation), in AF patients at
moderate-to-high risk of thromboembolic events
- Hokusai VTE (Edoxaban in Venous Thromboembolism), in patients with
either acute symptomatic deep vein thrombosis (DVT), pulmonary
embolism (PE) or both
- ENSURE-AF (EdoxabaN vs. warfarin in subjectS UndeRgoing
cardiovErsion of Atrial Fibrillation), in AF patients undergoing
electrical cardioversion
- ENTRUST-AF PCI (EdoxabaN TReatment versUS VKA in paTients with AF
undergoing PCI), in AF patients undergoing percutaneous coronary
intervention
- Hokusai-VTE Cancer (Edoxaban in Venous Thromboembolism Associated
with Cancer), in patients with cancer and an acute VTE event
- ELDERCARE-AF (Edoxaban Low-Dose for EldeR CARE AF patients), in
elderly AF patients in Japan
- ELIMINATE-AF (EvaLuatIon of edoxaban coMpared with VKA IN subjects
undergoing cAThEter ablation of non-valvular Atrial Fibrillation)
- ENVISAGE-TAVI AF (EdoxabaN Versus standard of care and theIr
effectS on clinical outcomes in pAtients havinG undergonE
Transcatheter Aortic Valve Implantation (TAVI) - Atrial
Fibrillation)
- STABLED Study (STroke secondary prevention with catheter ABLation
and EDoxaban for patients with non-valvular atrial fibrillation) in
Japan
- ENRICH-AF (EdoxabaN foR IntraCranial Hemorrhage survivors with A
trial Fibrillation, an investigator initiated phase III study)

In addition, global and regional registry and non-randomised
clinical studies provide important real-world and clinical data about
the use of edoxaban and other oral anticoagulants in everyday
practice; these include:

- ETNA-AF (Edoxaban Treatment in routiNe clinical prActice in
patients with nonvalvular Atrial Fibrillation)
- ETNA-VTE (Edoxaban Treatment in routiNe clinical prActice in
patients with Venous ThromboEmbolism)
- EMIT-AF/VTE (Edoxaban Management In diagnostic and Therapeutic
procedures-AF/VTE)
- Prolongation PREFER in AF (PREvention oF thromboembolic events -
European Registry) in patients with AF
- ANAFIE (All Nippon AF In Elderly) Registry in Japan
- Cancer-VTE Registry in Japan
- RYOUMA (Real world ablation therapY with anti-cOagUlants in
Management of Atrial fibrillation) Registry in Japan
- KYU-RABLE (Multicenter study associated with KYU-shu to evaluate
the efficacy and safety of edoxaban in patients with non-valvulaR
Atrial fiBriLlation undergoing cathEter ablation) in Japan
- BPV-AF (Atrial Fibrillation with BioProsthetic valve) Registry in
Japan

Through the Edoxaban Clinical Research Programme, we are committed
to adding to the scientific body of knowledge around edoxaban in a
variety of AF and VTE patients, including those who are vulnerable.

About Edoxaban

Edoxaban is an oral, once-daily, direct factor Xa (pronounced "Ten
A") inhibitor. Factor Xa is one of the key components responsible for
blood clotting, so inhibiting this makes the blood thin and less
prone to clotting. Edoxaban is currently marketed by Daiichi Sankyo
and its partners in more than 30 countries and regions around the
world.

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of
innovative pharmaceutical therapies to improve standards of care and
address diversified, unmet medical needs of people globally by
leveraging our world-class science and technology. With more than 100
years of scientific expertise and a presence in more than 20
countries, Daiichi Sankyo and its 15,000 employees around the world
draw upon a rich legacy of innovation and a robust pipeline of
promising new medicines to help people. In addition to a strong
portfolio of medicines for cardiovascular diseases, under the Group's
2025 Vision to become a "Global Pharma Innovator with Competitive
Advantage in Oncology," Daiichi Sankyo is primarily focused on
providing novel therapies in oncology, as well as other research
areas centered around rare diseases and immune disorders. For more
information, please visit: www.daiichisankyo.com.

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.

Contact:
Lydia Worms (Europe)
Daiichi Sankyo Europe GmbH
Edoxaban Comm. & Product PR Europe
+49-(89)-7808751

References

1. Goette A, et al. Edoxaban-based versus
vitamin-K-antagonist-based anti-thrombotic regimen following
successful coronary stenting in atrial fibrillation patients. The
ENTRUST-AF PCI trial. Presented at ESC Congress 2019; September 03,
2019; Paris.

2. Vranckx P, et al. Edoxaban-based versus vitamin K
antagonist-based antithrombotic regimen after successful coronary
stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a
randomised, open-label, phase 3b trial. The Lancet, 2019. Available
at: http://dx.doi.org/10.1016/S0140-6736(19)31872-0. [Last accessed
September 2019].

3. Capodanno D, et al. Management of antithrombotic therapy in
atrial fibrillation patients undergoing PCI: JACC State-of-the-Art
Review. J Am Coll Cardiol 2019; 74(1): 83-99.

4. Steffel J, et al. The 2018 European Heart Rhythm Association
Practical Guide on the use of non-vitamin K antagonist oral
anticoagulants in patients with atrial fibrillation. Eur Heart J,
2018;39(16):1330-1393.

5. National Heart, Lung and Blood Institute - What is atrial
fibrillation. Available at:
http://www.nhlbi.nih.gov/health/dci/Diseases/af/af_diagnosis.html.
[Last accessed: September 2019].

6. Iqbal MB, et al. Recent developments in atrial fibrillation.
BMJ. 2005;330(7485):238-43.

7. Camm A, et al. Guidelines for the management of atrial
fibrillation: the Task Force for the Management of Atrial
Fibrillation of the European Society of Cardiology (ESC). Eur Heart
J. 2010;31(19):2369-2429.

8. Krijthe BP, et al. Projections on the number of individuals
with atrial fibrillation in the European Union, from+- 2000 to 2060.
Eur Heart J. 2013;34(35):2746-2751.

9. Ball J, et al. Atrial fibrillation: Profile and burden of an
evolving epidemic in the 21st century. Int J Card.
2013;167:1807-1824.

Date of preparation: September 2019, EDX/19/0506

ots Originaltext: Daiichi Sankyo Europe GmbH
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