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## Cardiovascular Disease 

In late 2012, Bristol-Myers Squibb received regulatory approvals for Eliquis  (apixaban) in the U.S., EU, Japan and Canada. Tested in one of the largest clinical trial programs ever undertaken, it was approved to reduce the risk of stroke and systemic embo- lism in patients with nonvalvular atrial fibrillation, the most common cardiac arrhythmia. Without lifelong treat- ments, these patients are at serious risk of developing strokes. 

Clinical studies comparing Eliquis (a Factor Xa inhibitor) to warfarin, the standard of care for almost 60 years, found that Eliquis  was superior in reducing stroke and systemic embo- lism, major bleeding and mortality. In a trial comparing Eliquis  to aspirin in patients who could not take warfarin, Eliquis  showed a substantial reduc- tion in stroke risk, without a significant increase in major bleeding compared to aspirin. 

“While it took more than a decade to bring Eliquis  to patients, it remains the only drug in its class that shows superiority against warfarin in patients with atrial fibrillation in all three mea- sures: stroke and systemic embolism, major bleeding and mortality,” says Jack Lawrence, M.D., Eliquis  full devel- opment lead. Scientists at DuPont Pharmaceuticals, which we acquired in 2001, provided the first clinical proof that direct Factor Xa inhibition with a small molecule was an effective approach to preventing clots. 

In addition to recent approvals for stroke risk reduction in atrial fibrillation, in 2011 Eliquis  received clearance in the EU to prevent venous thromboem- bolic events (VTEs) following elective 

hip and knee replacement surgeries. 

Beyond VTE prevention in the ortho- pedic setting, the company is studying Eliquis  for VTE treatment, with the first of two large studies finding that Eliquis was superior to placebo in preventing recurrent VTEs in patients who had completed a standard anticoagula- tion course of therapy. Treatment with Eliquis  for an additional year reduced the risk of the combined endpoint of recurrent VTEs and total mortality. Although patients on Eliquis  are at risk for bleeding, in this study Eliquis  did not show an increase in major bleeding. A second trial is studying whether Eliquis can replace the current standard of care as an initial course of treatment. 

Eliquis  joins other company efforts to reduce potentially debilitating and sometimes deadly cardiovascular events. After all, even with multiple interventions available, heart dis- 

ease remains the leading cause of death worldwide. That’s why we are developing both our cardiovascular and metabolic disease portfolios to focus on cardiovascular event reduc- tion. Several of our novel diabetes agents – Byetta  (exenatide), Bydureon (exenatide extended-release for injectable suspension) and Forxiga (dapagliflozin) – have demonstrated reductions in weight and blood pres- sure, two major risk factors for heart disease, while helping to control glucose levels, a third major risk factor. Onglyza  (saxagliptin), Bydureon  and Forxiga  are being studied for their potential to be cardio-protective (also see pages 16-17). 

New approaches are in earlier devel- 

opment. For example, along with Pfizer, our development and commercializa- tion partner for Eliquis , Bristol-Myers Squibb is collaborating with Portola Pharmaceuticals to develop a novel reversal agent for urgent clinical situa- tions where reversing the anticoagula- tion effects of certain blood thinners, including Eliquis , is needed. 

Other R&D efforts are focused on heart failure, for which there are few new effective treatments, with a long-acting version of relaxin, a naturally occurring peptide that has the potential to improve cardiac function and patient survival. Also being studied is a next-generation anticoagulant to treat strokes as well as a compound that may be able to normalize the rhythms of atrial fibrillation. Therapeutic approaches for atherosclerosis include a novel therapy to remove cholesterol from plaque and a robust approach to lowering LDL (bad) cholesterol that, 

when combined with statins, poten- tially would allow patients to achieve their cholesterol-lowering goals. 

Lawrence believes the attributes that helped bring Eliquis  to market will also aid in developing a robust cardiovascu- lar pipeline. “Our success with Eliquis speaks to the successful efforts of our global clinical development program that tested Eliquis  at 4,000 sites, exploring five potential indications con- currently in nine large Phase III studies involving more than 60,000 patients,” he says. “And it speaks to the talent and dedication of biologists, chemists and clinicians, who were involved in this pioneering Factor Xa program starting in 1994 and those who have stayed with this effort to this day.” r 

