. Positive Benefit-Risk profile for Rivaroxaban Confirmed
. First Phase III Data in the Chronic Setting to be Presented as a Late-Breaker at the Annual Meeting of the American Society of Hematology
. Ongoing Discussions with FDA on Complete Response Letter for VTE Prevention After Total Knee and Hip Replacement Surgery
New Orleans, Louisiana (USA), December 6, 2009 – The novel oral anticoagulant rivaroxaban 20 mg once-daily significantly reduced the risk of recurrent symptomatic venous thromboembolism (VTE) compared to placebo in patients who have been treated for a previous deep vein thrombosis (DVT) or pulmonary embolism (PE). The rate of major bleeding was low. The results of the Phase III EINSTEIN-Extension (EXT) clinical study were presented today in the official press program of the 51st Annual Meeting of the American Society of Hematology (ASH) in New Orleans, LA.
Rivaroxaban showed an 82% relative risk reduction (RRR) in the recurrence of symptomatic VTE over patients treated with placebo [1.3% (n=8) vs. 7.1% (n=42), respectively] – an outcome that was highly statistically significant (p<0.0001).
“The results from EINSTEIN-EXT highlight the potential clinical benefit of extending prophylaxis for an additional 6 or 12 months beyond the currently recommended treatment duration,” said Harry R. Büller, M.D., Academic Medical Center in Amsterdam, Netherlands. “This study could help transform the way physicians treat patients who have previously suffered a DVT or PE. Currently, up to 10% of patients who are treated adequately, according to today’s recommended guidelines, still experience a recurrence within 12 months of the initial event.”
In the study, rivaroxaban was well tolerated and the rates of major bleeding, the primary safety endpoint, were low and not statistically significantly different (p=0.11) between the two groups [0.7% (n=4) vs. 0.0% (n=0), for the rivaroxaban and placebo arms, respectively]. A secondary endpoint measuring the composite of major and clinically relevant, but non-major bleeding, showed a statistically significant difference (p<0.001) between the two groups [6.0% (n=36) vs. 1.2% (n=7) in the rivaroxaban and placebo arms, respectively]. Liver safety results included: ALT >3x ULN: 1.9% in the rivaroxaban arm and 0.5% of patients in the placebo arm; ALT >3x ULN + Total Bilirubin >2x ULN: n=0 in both groups. No cases of serious liver injury were reported in either group. There were no differences in the incidence of cardiovascular-related events between the two treatment groups.
“We are delighted that rivaroxaban has now also shown benefit in a chronic setting. Rivaroxaban has previously demonstrated superior efficacy to the current standard treatment in the prevention of VTE after orthopedic surgery in all four RECORD trials. Therefore, this is the fifth study in a row in a total of more than 13,500 patients, in which rivaroxaban has shown consistent benefit in reducing the risk of VTE in patients,” said Kemal Malik, M.D., member of the Board of Management of Bayer Schering Pharma AG, Germany, responsible for Global Development.
To be eligible for enrollment in EINSTEIN-EXT, patients must have previously completed 6 or 12 months of treatment with a vitamin K antagonist (VKA) for an acute episode of VTE or had participated in the ongoing Phase III EINSTEIN-DVT or EINSTEIN-PE trials, in which patients were treated with either rivaroxaban or a VKA, for the same duration of time. Patients were then randomized to receive either 20 mg of rivaroxaban dosed once-daily, or a placebo, and were evaluated for an additional 6 or 12 months.
For further information, the abstract (lba-2) is available online at the ASH website: http://ash.confex.com/ash/2009/webprogram/Paper25669.html
About the EINSTEIN Program
EINSTEIN is a global clinical development program composed of three clinical studies in approximately 8,000 patients. Two of these studies enrolled patients with acute, symptomatic deep vein thrombosis (EINSTEIN-DVT, enrollment complete) or pulmonary embolism (EINSTEIN-PE). In these two trials, patients received oral rivaroxaban 15 mg twice-daily for the first three weeks, followed by oral rivaroxaban 20 mg once-daily, compared with initial enoxaparin treatment followed by a vitamin K antagonist. The third study, EINSTEIN-EXT, compared the efficacy and safety of rivaroxaban to placebo in the secondary prevention of recurrent symptomatic venous blood clots by extending preventative treatment by 6 or 12 months beyond a previously completed regimen of 6 or 12 months of therapy, and enrolled approximately 1,200 patients from 28 countries around the world with symptomatic DVT or PE. Approximately two million cases of deep vein thrombosis and nearly 600,000 pulmonary embolism cases are reported each year in the United States.
Update on FDA´s Complete Response Letter for VTE Prevention After Total Knee and Hip Replacement Surgery
Rivaroxaban is currently under review by the U.S. Food and Drug Administration (FDA) as one tablet, once-daily for the prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip or knee replacement surgery. The new drug application (NDA) for rivaroxaban was submitted by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., on behalf of Ortho-McNeil Inc., on July 28, 2008. In March 2009, an FDA Advisory Committee agreed by a vote of 15-2 that the available clinical data for rivaroxaban demonstrated a favorable benefit-risk profile. In May 2009, the FDA issued a Complete Response Letter for the NDA for rivaroxaban.
As previously announced, no new clinical or non-clinical studies to evaluate the efficacy or safety of rivaroxaban were requested by the FDA as a pre-requisite for approval. The Agency has asked the company to submit additional data from completed and ongoing studies of rivaroxaban, and from market surveillance from those countries outside the U.S. where the drug is currently sold to further assess the benefit-risk profile of the drug. The FDA also asked for additional information on RECORD study sites.
Following discussions with the FDA, Johnson & Johnson and Bayer are continuing to provide additional information to address the questions raised in the Complete Response Letter. Based on those discussions the companies have decided not to submit its Complete Response to the FDA for approval of rivaroxaban for the prevention of VTE after total knee and hip replacement surgery by the end of 2009. Postponing the complete response until these requirements are fully addressed provides the greatest opportunity for successfully bringing rivaroxaban through the regulatory process.
Bayer will communicate an updated filing strategy in its Annual Press Conference on February 28, 2010.
If approved by the FDA, Ortho-McNeil, a division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. (a Johnson & Johnson Company), will commercialize rivaroxaban in the U.S. The U.S. Bayer HealthCare sales force will support the Ortho-McNeil sales force by detailing rivaroxaban in designated hospital accounts. Bayer HealthCare is exclusively responsible for the marketing of rivaroxaban in countries outside the U.S.
Rivaroxaban is a novel oral anticoagulant that was invented in Bayer’s Wuppertal laboratories in Germany, and is being jointly developed by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. In clinical studies, rivaroxaban has shown a rapid onset of action with a predicable dose response and high bioavailability, no requirement for coagulation monitoring, and limited risk for food and drug interactions. Rivaroxaban is marketed under the brand name Xarelto®. Approvals have been granted for the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery in over 80 countries, including the EU, Australia, Canada, China and Mexico. To date, Xarelto® has been launched in more than 50 countries by Bayer HealthCare.
The extensive clinical trial program supporting rivaroxaban makes it the most studied oral, direct Factor Xa inhibitor in the world today. More than 65,000 patients are expected to be enrolled into the rivaroxaban clinical development program, which will evaluate the product in the prevention and treatment of a broad range of acute and chronic blood-clotting disorders, including VTE treatment, stroke prevention in patients with atrial fibrillation, secondary prevention of acute coronary syndrome, and VTE prevention in hospitalized, medically ill patients.
To learn more about thrombosis, please visit www.thrombosisadviser.com
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Bayer Schering Pharma, Consumer Care and Medical Care divisions. Bayer HealthCare’s aim is to discover, manufacture and market products that will improve human and animal health worldwide. Find more information at www.bayerhealthcare.com.
About Bayer Schering Pharma
Bayer Schering Pharma is a worldwide leading specialty pharmaceutical company. Its research and business activities are focused on the following areas: Diagnostic Imaging, General Medicine, Specialty Medicine and Women's Healthcare. With innovative products, Bayer Schering Pharma aims for leading positions in specialized markets worldwide. Using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life.
Find more information at www.bayerscheringpharma.de.
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