September 2, 2008
New Data is Presented on Investigational Oral Anticoagulant Apixaban in Acute Coronary Syndrome Patients
Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc (NYSE: PFE) announced today the results of a Phase 2 dose-ranging study (APPRAISE-1) involving the investigational compound apixaban in patients with acute coronary syndrome (ACS, commonly known as heart attack or severe chest pain). The study compared the current standard of care for ACS, including aspirin and clopidogrel, with apixaban on top of the standard of care. The study results were presented during a late-breaking session at the annual European Society of Cardiology (ESC) meeting in Munich, Germany.
Apixaban, which is currently being developed by the two companies, is an investigational oral, highly selective factor Xa inhibitor, a new class of agents with therapeutic potential to prevent and treat blood clots in the veins and arteries.
"The APPRAISE-1 study provided encouraging trends suggesting that anticoagulation with apixaban on top of current standards of care and continued beyond the initial hospitalization period may reduce the risk of a second heart attack, stroke or death. As with all effective anticoagulants, there was a trade off with some increase in bleeding for reduction in risk. We look forward to further studies of apixaban in patients with ACS to fully understand its potential beyond current therapies in this population," said John H. Alexander, M.D., Principal Investigator of the APPRAISE-1 study, Duke Clinical Research Institute and Duke Heart Center in Durham, North Carolina.
The six-month APPRAISE-1 study was not powered to demonstrate significance on the composite efficacy endpoint of cardiovascular death, non-fatal heart attack, severe recurrent ischemia and non-hemorrhagic stroke. However, there was a non-significant relative risk reduction compared to placebo (n=611) of 27 percent for 2.5 mg twice daily (n=317) and 39 percent for 10 mg once daily (n= 318) doses.
The incidence of the primary endpoint of this safety study, major bleeding plus clinically relevant non-major bleeding, was 5.7 percent for apixaban patients who took the 2.5 mg twice daily dose (n=315), 7.9 percent for patients who took the 10 mg once daily dose (n=315), and 3.0 percent for patients who took placebo (n=599). The bleeding scale used in the APPRAISE-1 trial was the comprehensive International Society of Thrombosis and Haemostasis (ISTH) standard. The incidence of major ISTH bleeding was 0.8 percent with placebo (n=599) versus 1.6 and 1.9 percent with the 2.5 mg twice daily (n=315) and 10 mg once daily (n=315) doses, respectively. Results for major bleeding measured using the more commonly used TIMI scale, in a post-hoc assessment, were 0.3 percent (n=599) for placebo, 0.0 percent (n=315) for the 2.5 mg twice daily apixaban dose and 1.0 percent (n= 315) for the 10 mg once daily apixaban dose. Two additional arms of the study that examined higher doses, 10 mg twice daily and 20 mg once daily, were stopped early due to increased total bleeding.
The incidence of adverse events, serious adverse events and discontinuations due to adverse events was similar for all treatment groups. The discontinuation rates for bleeding events were 1.2 percent with placebo, 1.9 percent with the 2.5 mg twice daily dose and 2.9 percent with the 10 mg once daily dose. The incidence of liver function test abnormalities following six-month dosing was similar with apixaban and placebo. The frequencies of alanine aminotransferase (ALT) elevations above 3-fold the upper limit of normal were 2.7, 0, and 1.0 percent for the placebo, 2.5 mg twice daily apixaban, and 10 mg once daily apixaban groups, respectively.
"This important study helps to identify appropriate apixaban dosing for future studies, with the goal of balancing potential efficacy benefit while minimizing the risk of bleeding for ACS patients," said Jack Lawrence, vice president, Research and Development, Bristol-Myers Squibb. "The objective is to identify whether apixaban can reduce the risk of secondary cardiovascular events, offering significant improvements for patient lives, as well as reducing the economic burden of cardiovascular disease around the world."
About the APPRAISE-1 Study
The study was a double-blind, placebo-controlled, dose-ranging study to evaluate the safety and efficacy of apixaban (2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, or 20 mg once daily) over a 26-week treatment period in 1715 patients presenting with acute coronary syndrome (ACS). All patients received aspirin less than or equal to 165 mg/day. The use of clopidogrel was left to the discretion of the treating physician. The primary endpoint of the study was the incidence of ISTH-defined major bleeding and clinically relevant non-major bleeding. The composite efficacy endpoint was the amount of time from patient randomization to the first occurrence of a combination of cardiovascular events including cardiovascular death, non-fatal heart attack, severe recurrent ischemia and non-hemorrhagic stroke.
Acute Coronary Syndrome (ACS)
Acute coronary syndrome (ACS) is a life-threatening form of coronary heart disease (CHD) that occurs when the heart muscle does not receive enough oxygen-rich blood. ACS includes myocardial infarction (MI), also known as a heart attack, and unstable angina, or sudden, severe chest pain that typically occurs when a person is at rest. Every year, ACS affects an estimated 1.4 million people in the United States and an estimated 1.40 million people in Europe. Even though patients are treated with intense management of ACS in the hospital setting, there still remains an unmet need for new treatments that can reduce the significant residual risk of acute MI, stroke and cardiovascular death. Patients with an ACS event are often given IV or injectable anticoagulants but, due to the route of administration, the use of these agents is limited to the hospital.
About the Apixaban Clinical Trial Program
Apixaban is currently being explored in the EXPANSE clinical trial program which includes eight Phase III clinical studies involving approximately 45,000 patients worldwide. The ADVANCE-2 and 3 trials are investigating the safety and efficacy of apixaban 2.5 mg twice daily compared to enoxaparin 40 mg once daily in patients undergoing major orthopedic surgery. The ADOPT study is investigating apixaban for one month compared to standard of care (enoxaparin 40 mg once daily for at least 6 days followed by placebo) for the prevention of VTE in hospitalized patients who are medically ill and at risk of VTE.
Apixaban is also in Phase III trials studying the prevention of stroke and other thromboembolic events in patients with atrial fibrillation (AF) and studying the treatment of VTE. The AF program consists of two trials. The ARISTOTLE trial is investigating apixaban compared to warfarin in approximately 15,000 patients with atrial fibrillation. The AVERROES trial is investigating apixaban compared to aspirin in approximately 5,600 patients with atrial fibrillation who are ineligible for vitamin K antagonists (VKA) treatment or haven't tolerated previous VKA treatment.
The VTE treatment program consists of two trials. The AMPLIFY trial is a 6-month trial investigating apixaban compared to enoxaparin plus warfarin in approximately 4,800 patients with acute DVT or PE. The AMPLIFY-EXT trial is a 12-month trial investigating apixaban compared to placebo for extended treatment to prevent recurrent VTE in approximately 2,400 patients who have completed 6 to 12 months of treatment for DVT or PE.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information visit www.bms.com.
Founded in 1849, Pfizer is the world's largest research-based pharmaceutical company. Pfizer is taking new approaches to advancing better health as it discovers, develops, manufactures and delivers quality, safe and effective prescription medicines to treat and help prevent disease for both people and animals. For more information visit www.pfizer.com.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the clinical trials described in this release will support a regulatory filing or that the product will receive regulatory approval. There can be no assurance that if approved, the products described in this release will be commercially successful. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2007, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.
Pfizer Forward-Looking Statement
The information contained in this release is as of August 26, 2008. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.
This release contains forward-looking information about a product candidate, apixaban, including its potential benefits that involves substantial risks and uncertainties. Such risks and uncertainties include, among other things, the uncertainties inherent in research and development; decisions by regulatory authorities regarding whether and when to approve any drug applications that may be filed for such product candidate as well as their decisions regarding labeling and other matters that could affect its availability or commercial potential; and competitive developments.
A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2007 and in its reports on Form 10-Q and Form 8-K.