Biotech Values

[DewDiligence]

BMY, PFE Report Tepid Phase-2 Results for Apixaban in ACS

[Unlike the phase-3 trial that recently failed to show non-inferiority of Apixaban to Lovenox in VTE prevention (#msg-31742223), the phase-2 study reported here was in ACS; i.e. anticoagulation was intended to avert thromboses in the arterial rather than the venous system.

The trial design was SoC ± Apixaban, where SoC was defined as mandatory aspirin and optional Plavix at the clinician’s discretion. Notably, the primary endpoint was a safety metric: the rate of clinically-relevant bleeding; the 2.5mg BID Apixaban arm and the 10mg qD Apixaban arm both fared considerably *worse* than the control arm on this endpoint. Moreover, the 10mg BID and 20mg qD Apixaban arms were discontinued prematurely due to excessive bleeding risk.

On the efficacy endpoint of MACE—defined as a composite of cardiovascular death, non-fatal heart attack, severe recurrent ischemia, and non-hemorrhagic stroke—the Apixaban arms were better than the control arm but the difference failed to achieve statistical significance.

All told, this phase-2 trial was merely a dose-finding exercise; it hardly provides much confidence that Apixaban will ever be successful in ACS.

Bad news for Apixaban is good news for MNTA, whose proprietary anticoagulant, M118, is squarely aimed at the ACS market (#msg-29698599, #msg-26900300). It is also a positive for Bayer/JNJ and BI, who own the competing anticoagulants Xarelto and Pradaxa, respectively.]

http://biz.yahoo.com/bw/080902/20080902005425.html

›September 2, 2008

Dose-Ranging Study Examined Apixaban in Patients Taking Commonly Used Anti-Platelet Therapies

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--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. [It would be helpful to state the p-value.]

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). [In other words, the Apixaban arms were considerably worse than the control arm on the primary endpoint of bleeding risk; they may even have been statsig worse, but this PR does not give p-values.] 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 <=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.‹