Biotech Values

[DewDiligence]

Apixaban ADVANCE-2 Study in VTE Prevention Published in The Lancet

[This is a repost of #msg-47419186 to correct the misstatement re qD vs BID dosing of Lovenox in the prior ADVANCE-1 study (thanks, genisi).

Refresher course: Apixaban is an oral FXa inhibitor from BMY/PFE is being tested in several indications including VTE prevention, VTE treatment, ACS, and stroke prevention in AF. The VTE-prevention program consists of three phase-3 studies testing apixaban vs Lovenox called ADVANCE-1, -2, and -3. ADVANCE-1, in patients undergoing knee surgery, failed by a hair to show non-inferior efficacy (#msg-31742223); ADVANCE-2, also in knee surgery, showed superior efficacy and comparable bleeding and is the subject of the PR below; ADVANCE-3, in hip surgery, has been completed but the data have not yet been disclosed (http://clinicaltrials.gov/ct2/show/NCT00423319 ).

Top-line results of ADVANCE-2 have been known since Jul 2009 (http://www.hemonctoday.com/article.aspx?rid=41557 ), so the PR below is not market-moving news.

BMY/PFE have committed to submitting an apixaban MAA in Europe during 1H10 based on ADVANCE-2 and ADVANCE-3 (#msg-44219816), but the companies have made no such commitment with respect to an FDA submission (#msg-46029245). To the contrary, the word from BMY’s investor presentation today was merely that an FDA submission is “possible.”

What is the problem vis-à-vis the FDA? The companies have not said, but I infer that the problem is the Lovenox dose used in the comparator arm. ADVANCE-1, the study that failed, used 30mg BID of subcutaneous Lovenox, while ADVANCE-2 and ADVANCE-3, the studies that succeeded, used 40mg qD of subcutaneous Lovenox. 30mg BID is the initial Lovenox dose specified in the FDA label for VTE prevention following knee and hip surgery (see #msg-47460573), although 40mg qD is commonly used in this indication and is the typical dose for this indication in most of the world. Thus, it would seem that the FDA is being unreasonable in disallowing the ADVANCE-2 and ADVANCE-3 studies because they used an off-label, although widely accepted, Lovenox dose.

Given the heavy competition in this arena from oral anticoagulants that are further advanced than apixaban, BMY/PFE may not be willing to expend additional resources on the VTE-prevention indication for the US market if the FDA continues to play hardball.]

http://finance.yahoo.com/news/ADVANCE2-Study-Results-bw-2456939698.html/print?x=0

›ADVANCE-2 Study Results Demonstrate Investigational Anticoagulant Apixaban Was Statistically Superior To Enoxaparin In The Prevention Of Venous Thromboembolism Following Knee Replacement Surgery

Phase III Data Published in The Lancet also Demonstrate Comparable Rates of Bleeding with Apixaban Versus Enoxaparin

Thursday March 4, 2010, 6:30 pm EST

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Apixaban, an oral anticoagulant being developed by Bristol-Myers Squibb Company (NYSE: BMY) and Pfizer Inc. (NYSE: PFE), was statistically superior to 40 mg once daily enoxaparin in reducing the incidence of venous thromboembolism in patients undergoing elective total knee replacement surgery, according to the ADVANCE-2 study results published today in The Lancet. The study results also showed numerically lower rates of major and clinically relevant non-major bleeding in patients treated with Apixaban compared with those treated with enoxaparin. These [bleeding, i.e. safety] results did not meet statistical significance.

Apixaban is a novel, oral, highly selective Factor Xa inhibitor, part of a class of agents being studied for their potential to prevent and treat blood clots in the veins and arteries. Results of ADVANCE-2 were first presented in July 2009 at the 22nd Congress of the International Society on Thrombosis and Haemostasis in Boston.

Patients undergoing major orthopedic surgery, including total knee replacement, are at high risk for venous thromboembolism. In fact, venous thromboembolism occurs in 40 to 60 percent of patients undergoing orthopedic surgery who do not receive preventive care. With an estimated 400,000 people worldwide undergoing total knee replacement surgery each year, the threat of venous thromboembolism and its associated morbidity and mortality risk represent a growing challenge to physicians.

“One of the major concerns for orthopedic surgeons using oral anticoagulants for venous thromboembolism prevention in knee surgery is the significant risk of bleeding,” said Michael Rud Lassen, M.D., Hoersholm Hospital in Copenhagen, Denmark, lead investigator for the study. “We are encouraged by the ADVANCE-2 data, which demonstrated better antithrombotic effect and comparable bleeding rates for apixaban compared with enoxaparin.”

About ADVANCE-2

ADVANCE-2, a randomized, double-blind, multicenter, head-to-head trial was designed to evaluate the efficacy and safety of oral, twice daily apixaban 2.5 mg compared with subcutaneous enoxaparin 40 mg once daily, over a 10-to-14 day treatment period for reducing the risk of venous thromboembolism in patients undergoing elective total knee replacement surgery. Of the 3,221 patients from 27 countries (Europe, Asia/Pacific, Latin America, Africa) enrolled in the study, 1,973 patients were eligible for the analysis of the primary efficacy endpoint defined as the composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause during study treatment. The statistical plan for the study required testing non-inferiority of apixaban before testing for superiority.

When apixaban was compared with enoxaparin, the primary efficacy endpoint occurred in 15.1 percent of patients in the apixaban group and 24.4 percent of patients in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 38 percent (p<0.0001).

The secondary efficacy outcome of major venous thromboembolism occurred in 1.1 percent of patients in the apixaban group compared with 2.2 percent in the enoxaparin group, demonstrating a statistically significant relative risk reduction for apixaban of 50 percent (one-sided p=0.02).

The primary safety measure of major bleeding occurred in 0.6 percent of patients who received apixaban, and in 0.9 percent of patients who received enoxaparin, not reaching statistical significance (p=0.30). The composite outcome of major bleeding and clinically relevant non-major bleeding occurred in 3.5 percent and 4.8 percent of patients in the apixaban and enoxaparin groups, respectively, and did not reach statistical significance (p=0.09).

The overall safety profiles of apixaban and enoxaparin were similar in ADVANCE-2. During the treatment and follow-up periods, liver alanine transaminase (ALT) and liver aspartate transaminase (AST) elevations greater than three times the upper limit of normal were reported in 2 percent of patients in the apixaban and enoxaparin groups. Discontinuations due to adverse events in the apixaban and enoxaparin patient groups were similar.

About Venous Thromboembolism

Venous thromboembolism encompasses two serious conditions: deep vein thrombosis, a blood clot in a vein, usually in the leg that partially or totally blocks the flow of blood; and pulmonary embolism, a blood clot blocking a vessel in the lungs. Deep vein thrombosis causes multiple symptoms including pain, swelling and redness and, more importantly, can progress to pulmonary embolism, which carries the risk of sudden death.

About the Apixaban Clinical Trial Program

Apixaban is being investigated within the EXPANSE Clinical Trials Program, which is projected to include nearly 60,000 patients worldwide across multiple indications and patient populations and includes a total of nine completed or ongoing, randomized, double-blind Phase III trials, including ADVANCE-2.

The dose and regimen for apixaban were informed by Phase I and II apixaban clinical trial data and data modeling results. Dosing apixaban twice daily appeared to reduce fluctuations in Factor Xa inhibition over the dosing interval and lower the peak-to-trough ratio for apixaban blood levels compared with once-daily dosing.

In addition to prevention of venous thromboembolism, apixaban is in Phase III trials studying the prevention of stroke and other thromboembolic events in patients with atrial fibrillation, the treatment of venous thromboembolism and in patients with acute coronary syndrome.

About the Bristol-Myers Squibb/Pfizer Collaboration

In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide collaboration to develop and commercialize apixaban, an investigational oral anticoagulant discovered by Bristol-Myers Squibb being studied for the prevention and treatment of a broad range of venous and arterial thrombotic conditions. This global alliance combines Bristol-Myers Squibb's long-standing strengths in cardiovascular drug development and commercialization with Pfizer’s global scale and expertise in this field to maximize the potential benefits of apixaban for patients.‹