Daiichi Sankyo Initiates Hokusai-VTE Cancer Study to Evaluate the Role of Edoxaban in Patients with Venous Thromboembolism Associated with Cancer

PARSIPPANY, N.J., June 18, 2015 /PRNewswire/ -- Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced the initiation of Hokusai-VTE Cancer, a multinational study, which will investigate the efficacy and safety of edoxaban, marketed in the U.S. as SAVAYSA^®, an oral, once-daily selective factor Xa inhibitor, versus dalteparin for the treatment of VTE associated with cancer (other than basal-cell or squamous-cell carcinoma of the skin) for whom long-term treatment with a low molecular weight heparin (LMWH) is intended.¹ The purpose of the study is to evaluate edoxaban in comparison with dalteparin in preventing the combined outcome of VTE recurrence or major bleeding following an acute deep vein thrombosis (DVT) or pulmonary embolism (PE) event in patients with cancer. The recruitment has started, and approximately 1,000 patients are expected to be enrolled in the study at clinical sites across 13 countries.¹

"VTE is a major cause of morbidity and mortality in patients with cancer, with an annual incidence that can be as high as 20 percent depending on the cancer type, background risk and time since diagnosis.^2,3 Compared to those without cancer, patients with cancer who receive chemotherapy treatment have a 4- to 7-fold risk of developing VTE," said Professor Gary Raskob, PhD, Dean, College of Public Health and Regents Professor, Epidemiology and Medicine, University of Oklahoma Health Sciences Center in Oklahoma City, Oklahoma.^2,3,4 "This trial will allow us to gain further understanding of the efficacy and safety of edoxaban in comparison to current standards of care for these patients."

"The initiation of the Hokusai-VTE Cancer study marks an important next step in our clinical research of edoxaban," 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 Hokusai-VTE Cancer study, along with the ongoing ENSURE-AF study, demonstrate the commitment of Daiichi Sankyo research and development to improve outcomes for patients at risk due to thrombosis."

Edoxaban is currently marketed in Japan, the U.S., and Switzerland, and has also been recommended for approval in the EU by the European Committee for Medicinal Products for Human Use (CHMP).^5,6,7,8 In other countries, regulatory review is ongoing.

About the Hokusai-VTE Cancer study
Hokusai-VTE Cancer is a multinational, prospective, randomized, open-label, blinded endpoint evaluation (PROBE) study, evaluating the efficacy and safety of once-daily edoxaban compared to dalteparin for the treatment of VTE associated with cancer. The purpose of the study is to evaluate edoxaban in comparison with dalteparin in preventing the combined outcome of VTE recurrence or major bleeding in patients with VTE associated with cancer. Other objectives include assessing the effects of treatment on VTE recurrence, clinically relevant bleeding and event-free survival, defined as the proportion of subjects over time free of recurrent VTE, major bleeding events and death. Approximately 1,000 patients are expected to be enrolled across 13 countries in North America, Europe, Australia and New Zealand. Patients will be randomized to receive edoxaban 60 mg once-daily (reduced to 30 mg edoxaban for patients with creatinine clearance [CrCL] 30-50 mL/min, body weight ≤ 60 kg, or concomitant use of P-glycoprotein [P-gp] inhibitors), following treatment with LMWH for at least five days; or dalteparin SC 200 IU/kg once-daily for 30 days, then 150 IU/kg once-daily for the remainder of the 12-month study.¹

For more information please visit: https://www.clinicaltrials.gov/ct2/show/NCT02073682.

About VTE and Cancer
VTE is an umbrella term for two conditions, DVT and PE.⁹ DVT is a disease caused by a blood clot found in deep veins, usually within the leg, thigh or pelvis, although they can occur in other parts of the body as well.¹⁰ PE occurs when part of a clot detaches and lodges in the pulmonary arteries, causing a potentially fatal condition.⁹ VTE is a major cause of morbidity and mortality worldwide.¹¹ VTE is a major cause of morbidity and mortality in patients with cancer, with an annual incidence that can be as high as 20 percent depending on the cancer type, background risk and time since diagnosis.^2,3 Patients with cancer have multiple risk factors for VTE and the risk of VTE events increases in patients with cancer receiving chemotherapy.¹² In addition, patients with cancer and VTE have a lower survival rate than those without VTE.^12,13

About SAVAYSA^® (edoxaban)
Edoxaban, also known as SAVAYSA in the U.S., is an oral, once-daily anticoagulant that specifically inhibits factor Xa, which is an important factor in the coagulation system that leads to blood clotting.¹⁴ The global edoxaban clinical trial program included two phase 3 clinical studies, Hokusai-VTE and ENGAGE AF-TIMI 48, with nearly 30,000 patients combined. The results from these trials formed the basis of the regulatory filing in the U.S. for SAVAYSA for the reduction in risk of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF), as well as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5-10 days of initial therapy with a parenteral anticoagulant. According to the U.S. label, SAVAYSA should not be used in NVAF patients with creatinine clearance (CrCL) levels greater than 95 mL/min because in that population there is an increased risk of ischemic stroke compared to warfarin.^6,15,16

INDICATIONS
SAVAYSA^® (edoxaban) is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).  SAVAYSA should not be used in patients with creatinine clearance (CrCL) > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.

SAVAYSA is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.

IMPORTANT SAFETY INFORMATION FOR SAVAYSA
BOXED WARNINGS:

• REDUCED EFFICACY IN NVAF PATIENTS WITH CRCL > 95 ML/MIN
  SAVAYSA should not be used in patients with CrCL > 95 mL/min.  In the ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to patients treated with warfarin.  In these patients another anticoagulant should be used.
  
  
• PREMATURE DISCONTINUATION OF SAVAYSA INCREASES THE RISK OF ISCHEMIC EVENTS
  Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If SAVAYSA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance in the Prescribing Information.
  
  
• SPINAL/EPIDURAL HEMATOMA
  • Epidural or spinal hematomas may occur in patients treated with SAVAYSA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures
  • ­Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery
  • ­Optimal timing between the administration of SAVAYSA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.  Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

CONTRAINDICATIONS
SAVAYSA is contraindicated in patients with active pathological bleeding.

WARNINGS AND PRECAUTIONS
Bleeding Risk
SAVAYSA increases the risk of bleeding and can cause serious and potentially fatal bleeding.  Promptly evaluate any signs or symptoms of blood loss.  Concomitant use of drugs affecting hemostasis may increase the risk of bleeding.  These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, and chronic use of nonsteroidal anti-inflammatory drugs.  Discontinue SAVAYSA in patients with active pathological bleeding.  There is no established way to reverse the anticoagulant effects of SAVAYSA, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of SAVAYSA cannot be reliably monitored with standard laboratory testing.  A specific reversal agent for edoxaban is not available.  Hemodialysis does not significantly contribute to edoxaban clearance.  Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse its anticoagulant activity.

Mechanical Heart Valves or Moderate to Severe Mitral Stenosis
The safety and efficacy of SAVAYSA has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis.  SAVAYSA is not recommended in these patients.

ADVERSE REACTIONS

• NVAF: The most common adverse reactions (≥ 5%) are bleeding and anemia
• DVT/PE: The most common adverse reactions (≥ 1%) are bleeding, rash, abnormal liver function tests and anemia

DISCONTINUATION FOR SURGERY AND OTHER INTERVENTIONS
Discontinue SAVAYSA at least 24 hours before invasive or surgical procedures because of the risk of bleeding.  SAVAYSA can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established.

DRUG INTERACTIONS

• Anticoagulants, Antiplatelets, and Thrombolytics: Coadministration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding
• P-gp Inducers: Avoid concomitant use of SAVAYSA with rifampin
• P-gp Inhibitors (DVT/PE only): Co-administration of certain P-gp inhibitor medications requires a dose reduction of Savaysa to 30 mg once daily

SPECIAL POPULATIONS

• Nursing mothers: Discontinue drug or discontinue nursing
• Impaired renal function (CrCL 15 to 50 mL/min): Reduce SAVAYSA dose to 30 mg once daily
• Moderate or severe hepatic impairment: Not recommended
• Pregnancy Category C

Please see full Prescribing Information, including boxed WARNINGS and Medication Guide.

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 17,000 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 its strong portfolio of medicines for hypertension, dyslipidemia, bacterial infections, and thrombotic disorders, the Group's research and development is focused on bringing forth novel therapies in cardiovascular-metabolic diseases, pain management, and oncology, including biologics. For more information, please visit: www.daiichisankyo.com.

Contact
Jennifer Silvent (US Media)
Daiichi Sankyo, Inc.
[email protected]
+1 973 944 2160 (office)
+1 973 479 9845 (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. ClinicalTrials.gov. Cancer Venous Thromboembolism (VTE). Available at: https://clinicaltrials.gov/ct2/show/NCT02073682. [Last accessed: June 2015].
2. Ay C, et al. Prediction of venous thromboembolism in cancer patients. Blood. 2010;116:5377-5382.
3. Khorana AA, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634.
4. Mandala M, et al. Management of Venous Thromboembolism (VTE) in Cancer Patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011:22(6):vi85-vi92.
5. Daiichi Sankyo press release - Daiichi Sankyo Launches New Formulation of LIXIANA® 60 mg Tablets (edoxaban) in Japan. 8 Dec 2014. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006226.html. [Last accessed: June 2015].
6. Daiichi Sankyo press release - SAVAYSA^®(edoxaban) Now Available in U.S. Pharmacies. 9 February 2015. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006247.html. [Last accessed: June 2015].
7. Daiichi Sankyo press release - Daiichi Sankyo's Once-Daily LIXIANA® (edoxaban) Approved for the Prevention of Stroke and Systemic Embolism in Non-Valvular Atrial Fibrillation and for the Treatment and Prevention of Recurrent Venous Thromboembolism in Switzerland. 15 April 2015. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006269.html. [Last accessed: June 2015].
8. Daiichi Sankyo press release - Daiichi Sankyo's Once-Daily Lixiana® (edoxaban) Receives Positive CHMP Opinion for the Prevention of Stroke and Systemic Embolism in Non-Valvular Atrial Fibrillation and for the Treatment and Prevention of Recurrent Venous Thromboembolism in Europe. 27 April 2015. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006278.html. [Last accessed: June 2015].
9. Deep Vein Thrombosis (DVT) / Pulmonary Embolism (PE) — Blood Clot Forming in a Vein. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/ncbddd/dvt/facts.html. [Last accessed: June 2015].
10. Van Beek E, et al. Deep Vein Thrombosis and Pulmonary Embolism. New York: John Wiley & Sons, 2009. Print.
11. Cohen A, et al. Venous thromboembolism (VTE) in Europe. Thromb Haemost. 2007;98(4):756-764.
12. Lee AYY, Levine MN. Venous thromboembolism and cancer: Risks and outcomes. Circulation. 2003;107:I-17-I-21.
13. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28:370-372.
14. 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(7):743-753.
15. Giugliano R, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.
16. Büller H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.

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