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Secondary Prevention in Acute Coronary Syndrome (ACS):
Phase II Data Presented as Late-Breaker at American Heart Association Meeting / Phase III Study to be Initiated in December 2008
Leverkusen, November 10, 2008 - Findings from the ATLAS ACS TIMI 46 study - a
Phase II study of the novel oral anticoagulant Xarelto® (rivaroxaban) - were
presented today as a late-breaking clinical trial at the American Heart
Association's Scientific Sessions 2008 in New Orleans by C. Michael Gibson,
M.D., Director of the TIMI Data Coordinating Center, Harvard Medical School,
Boston, Massachusetts, USA. Results from this Phase II study support moving
rivaroxaban into a pivotal Phase III trial for the secondary prevention of
acute coronary syndrome (ACS) later this year.
As a Phase II dose-finding study, the ATLAS ACS TIMI 46 trial was designed to
test the safety and efficacy of rivaroxaban at escalating total daily doses,
ranging from 5 mg up to 20 mg. Rivaroxaban was administered at once-daily and
twice-daily intervals, assessing eight different dosing regimens in total.
Nearly 3,500 patients were enrolled in the study and received standard
antiplatelet therapy of low-dose aspirin with or without a thienopyridine, such
as clopidogrel. Patients were then randomized to additionally receive either
rivaroxaban or a placebo for six months.
"This was a robust study that achieved its main objective of establishing the
preferred dosing scenario for further evaluating rivaroxaban in a large Phase
III clinical trial of ACS patients," said Dr. Gibson. "The additional benefit
of rivaroxaban over placebo in this study, given on a background of standard
antiplatelet therapy, highlights the unmet medical need of this patient
population."
The primary efficacy endpoint was death, myocardiaI infarction (MI), stroke, or
severe recurrent ischemia requiring revascularization. Rivaroxaban was
associated with an observed 21% Relative Risk Reduction (RRR) for the primary
efficacy endpoint (p=0.1) and a statistically significant 31% RRR against the
secondary endpoint of death, MI, or stroke (p=0.028), demonstrating a
consistent trend for efficacy across doses.
Safety was evaluated by measuring clinically significant bleeding, defined as a
composite of TIMI major bleeding, TIMI minor bleeding and any reported bleeding
event requiring medical attention. This very sensitive bleeding measure
represents a broader definition compared to other standard definitions. As
expected, rivaroxaban-treated patients exhibited higher rates of bleeding vs.
placebo when administered on a background of antiplatelet therapy, and there
was a significant dose trend (p<0.001). However, no study arm was halted due to
increased bleeding. Rates of clinically significant bleeding were: Placebo:
3.3%, rivaroxaban 5 mg: 6.1%, 10 mg: 10.9 %, 15 mg: 12.7%, 20 mg: 15.3%. Most
bleeding (82%) was classified as bleeding requiring medical attention, rather
than TIMI major or TIMI minor. No evidence of drug-induced hepatotoxicity was
seen in the study.
Though not statistically significant due to the small sample size, the two
doses selected for further evaluation in the pivotal Phase III program - 2.5 mg
and 5 mg dosed twice daily - showed the best balance between efficacy and
safety with an observed 46% RRR in the composite efficacy endpoint of death, MI
or stroke when dosed in addition to aspirin, and an observed 45% RRR when dosed
in combination with aspirin and a thienopyridine. Rates of TIMI major bleeding
were 1.2% for each stratum.
ATLAS ACS TIMI 51
The global Phase III study, ATLAS ACS TIMI 51, is planned to be initiated in
December 2008 with a potential enrollment of up to 16,000 patients. As in the
Phase II study, all patients will receive standard antiplatelet therapy and
will then be randomly assigned to take either rivaroxaban at doses of 2.5 mg or
5 mg, or placebo, twice daily for at least six months. The primary efficacy
endpoint will be a composite of cardiovascular death, MI or stroke. TIMI major
bleeding events not associated with coronary artery bypass graft (CABG) surgery
will be the primary safety endpoint. A study overview will be accessible at
www.clinicaltrials.gov.
"Given the encouraging response rates we saw in the ATLAS ACS TIMI 46 trial, we
feel very confident in the two doses selected for evaluation in the Phase III
study, and we are excited to progress Xarelto to the next level in our clinical
development program for this important indication," said Dr. Kemal Malik, Head
of Global Development and member of the Board of Management of Bayer Schering
Pharma AG.
About ACS
ACS occurs when a coronary artery is blocked by a blood clot, reducing blood
supply to the heart. ACS events include MI, commonly known as heart attack, and
unstable angina (a very serious condition that indicates a heart attack could
soon occur). ACS is a common and life-threatening result of coronary heart
disease (CHD), which kills approximately 7.2 million people worldwide each
year.
"ACS is a chronic, life-threatening condition requiring daily therapy," said
Study Chairman Eugene Braunwald, M.D., Distinguished Hersey Professor of
Medicine at Harvard Medical School and Chairman of the TIMI Study Group. "While
well-established therapies exist, there is a need for additional treatment
options that could help improve patient outcomes. We look forward to initiating
this pivotal study."
About Xarelto® (rivaroxaban)
Xarelto® is approved for use in the European Union for the prevention of VTE in
adult patients who have undergone elective total hip or knee replacement
surgery. Additional filings are under review with regulatory agencies in more
than 10 other countries worldwide, including the United States.
The extensive clinical trial program supporting Xarelto® makes it the most
studied oral, direct Factor Xa inhibitor in the world today. With the addition
of up to 16,000 patients in the Phase III ATLAS ACS TIMI 51 trial, over 60,000
patients are now expected to be enrolled into the Xarelto® 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 and VTE
prevention in hospitalized, medically ill patients.
Xarelto® 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.
To learn more about thrombosis please visit www.thrombosisadviser.com and to
learn more about Xarelto® please visit www.xarelto.com
The complete ATLAS ACS TIMI 46 presentation can be accessed at www.timi.org.
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, Consumer Care,
Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business
operates under the name Bayer Schering Pharma. Bayer HealthCare's aim is to
discover and manufacture products that will improve human and animal health
worldwide. Find more information at www.bayerhealthcare.com.
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.
