CHMP Issues a Positive Opinion for Daiichi Sankyo's Once-Daily LIXIANA®▾ (edoxaban) in Patients with Atrial Fibrillation Undergoing Cardioversion

Recommended label update for LIXIANA^® provides guidance on its use in patients undergoing transoesophageal echocardiography (TEE)-guided and delayed cardioversion

Update is based on data from ENSURE-AF, the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation (NVAF), to date^[1]

LIXIANA is now the only non-vitamin K oral anticoagulant (NOAC) with specific label guidance for early cardioversion within two hours after LIXIANA intake in the TEE-guided approach

MUNICH, GERMANY -- Daiichi Sankyo Europe GmbH (hereafter, "Daiichi Sankyo") today announced that the European Committee for Medicinal Products for Human Use (CHMP) has recommended approval of a label update for the company's oral, once-daily direct factor Xa-inhibitor LIXIANA^®, to provide guidance on its use in patients undergoing transoesophageal echocardiography (TEE)-guided and delayed cardioversion (treatment to restore a normal heart rhythm).

The label update is based on results from the ENSURE-AF study, the largest, prospective randomised clinical trial of an anticoagulant for cardioversion in patients with NVAF. The study enrolled 2,199 patients, and compared once-daily LIXIANA with enoxaparin/warfarin with a median time in therapeutic range (INR 2-3) of 70.8 %.^[1] These data support the use of LIXIANA as an effective and safe alternative to the best possible conventional treatment with enoxaparin and warfarin.^[1] LIXIANA's rapid onset of action allows for prompt cardioversion in the TEE-guided approach as early as two hours after LIXIANA intake, helping to avoid delays or postponements of the procedure.

"ENSURE-AF provides important insight into the use of LIXIANA in the setting of TEE-guided and delayed cardioversion in NVAF patients," said Wolfgang Zierhut, MD, Executive Director, EU Cardiovascular Medical Affairs. "We are pleased that the CHMP has recognised the importance of the ENSURE-AF data for LIXIANA in this common procedure, by recommending this label update. Daiichi Sankyo is committed to supporting patients and physicians by advancing understanding of the efficacy and safety of LIXIANA in different clinical settings, through studies such as ENSURE-AF."

Cardioversion is a procedure used to restore normal, regular heart rhythm in AF patients. Due to an associated risk of thrombotic events such as stroke, guidelines recommend anticoagulation before and after the procedure.^[2],[3],[4] The delayed onset of action and fluctuations in INR associated with VKA treatments such as warfarin, can result in costly and inconvenient delays to cardioversion in patients.^[5] Initial treatment with enoxaparin (followed by overlapping VKA treatment) until the VKA reaches the therapeutic range of INR 2-3, represents the best possible conventional treatment.^[5]

The primary efficacy endpoint of the ENSURE AF study was a composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality, which occurred in five patients in the LIXIANA 60/30 mg arm versus 11 in the enoxaparin-warfarin arm. The primary safety endpoint was major and clinically relevant non-major bleedings (CRNM), which occurred in 16 patients in the LIXIANA arm versus 11 patients in the enoxaparin-warfarin arm.^[1] The difference between the treatment arms was statistically non-significant.^[1]

Event rates of thromboembolism and major and CRNM bleedings were low in the LIXIANA and exceptionally well-controlled warfarin arms. There was no difference between the TEE-guided approach and the delayed cardioversion setting.^[1]

These data support the use of LIXIANA as an effective and safe alternative to the best possible conventional treatment with enoxaparin and warfarin, and allow for prompt cardioversion in the TEE-guided approach as early as two hours after LIXIANA intake.^[1]

This label update makes LIXIANA the only NOAC with specific label guidance for early cardioversion within two hours after LIXIANA intake in the TEE-guided approach.

About ENSURE-AF
(EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation)

ENSURE-AF is a Prospective, Randomised, Open-Label, Blinded Endpoint evaluation (PROBE), parallel-group phase 3b study, evaluating the efficacy and safety of once-daily edoxaban versus enoxaparin/warfarin in patients undergoing electrical cardioversion. The primary efficacy endpoint was the composite of stroke, systemic embolism, myocardial infarction and cardiovascular mortality. A total of 2,199 NVAF patients undergoing electrical cardioversion were enrolled at 239 clinical sites across North America and Europe. Patients were randomised to receive edoxaban 60 mg (or a reduced dose of edoxaban 30 mg for specific patients with renal impairment or low body weight or P-glycoprotein inhibitor use) or enoxaparin/warfarin for 28-49 days. Edoxaban demonstrated comparable efficacy and safety to well-managed enoxaparin/warfarin (mean time in therapeutic range on warfarin was 70.8%) for the prevention of stroke and other blood clot complications.^[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.^[6]

AF is the most common type of heart rhythm disorder, and is associated with substantial morbidity and mortality.^[7] An estimated 8.8 million Europeans suffered from AF in 2010, and this figure is expected to at least double over the next 50 years.^[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 as a result of AF.^[3]

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 20 countries around the world.

The edoxaban Summary of Product Characteristics can be viewed here:

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf

About Edoxaban Clinical Research Programme (ECRP)
Daiichi Sankyo is committed to expanding scientific knowledge about edoxaban, as demonstrated through our 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). The Edoxaban Clinical Research Programme includes multiple RCTs (randomised, controlled trials), registries and non-interventional studies, with the goal of generating new clinical and real-world-data regarding its use in AF and VTE populations. Daiichi Sankyo expects that more than 100,000 patients will participate in the Edoxaban Clinical Research Programme, including completed, ongoing and future research.

The RCTs include:

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)

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

ETNA-AF (Edoxaban Treatment in routiNe clinical prActice in patients with non valvular 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

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.

Daiichi Sankyo Fights Thrombosis

Daiichi Sankyo is your partner in antithrombotic therapy with the discovery and development of innovative products, to help patients with a wide range of cardiovascular conditions. These include EFIENT^® (prasugrel) for acute coronary syndromes^[10] and LIXIANA^® (edoxaban) for non-valvular atrial fibrillation, deep vein thrombosis and pulmonary embolism.^[11] Daiichi Sankyo's ongoing commitment in this field is demonstrated by their continued investment into patient-relevant clinical development activities that aim to advance the care and improve the lives of people suffering with these diseases. For more information, please visit: http://www.daiichi-sankyo.eu

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical products to address diversified, unmet medical needs of patients in both mature and emerging markets. With over 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 hypertension and thrombotic disorders, under the Group's 2025 Vision to become a "Global Pharma Innovator with Competitive Advantage in Oncology," Daiichi Sankyo research and development is primarily focused on bringing forth novel therapies in oncology, including immuno-oncology, with additional focus on new horizon areas, such as pain management, neurodegenerative diseases, heart and kidney diseases, and other rare diseases. For more information, please visit: http://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 Communications & Product PR Europe
+49(89)7808751

References

Goette, A, et al. Edoxaban versus enoxaparin / warfarin in subjects undergoing cardioversion of atrial fibrillation: the randomized (ENSURE-AF) study. The Lancet. Published online August 30, 2016: http://dx.doi.org/10.1016/S0140-6736(16)31474-X.
National Heart, Lung, and Blood Institute. What is Cardioversion. 2012. Available at: https://www.nhlbi.nih.gov/health/health-topics/topics/crv /. [Last accessed: June 2017].
Kirchhof P, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. European Heart Journal. 2016;37:2893-2962.
January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol. 2014;64:e1-76.
Lip GYH, et al. A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation: The EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study. Am Heart J. 2015 May;169(5):597-604.
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: June 2017].
Iqbal MB, et al. Recent developments in atrial fibrillation. BMJ. 2005;330(7485):238-43.
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.
Ball J, et al. Atrial fibrillation: Profile and burden of an evolving epidemic in the 21st century. Int J Card. 2013;167:1807-1824.
EFIENT Summary of Product Characteristics (SmPC), 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000984/WC500021971.pdf [Last accessed: June 2017].
LIXIANA. Summary of Product Characteristics (SmPC), 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf [Last accessed: June 2017].

SOURCE Daiichi Sankyo Company