FDA Approves Apixaban to Prevent Stroke in Nonvalvular AF
Dec 28, 2012
Rockville, MD — The US Food and Drug Administration (FDA) has approved apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).
Apixaban is the third anticoagulant to be approved in the US for this indication, following the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) and the factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson). Like rivaroxaban, apixaban is a factor Xa inhibitor.
The US approval is based on the positive results from the ARISTOTLE trial — first reported at the European Society of Cardiology meeting in 2011 and published simultaneously in the New England Journal of Medicine — and the AVERROES trial. In a press release accompanying the US approval, the FDA states that patients taking apixaban had significant fewer strokes than patients who took warfarin.
Apixaban was approved in Europe for the prevention of stroke and systemic embolism in nonvalvular AF in late November and was approved by Health Canada just a few weeks ago. The US delay occurred as the FDA requested more information from Bristol-Myers Squibb and Pfizer this past June. No new studies were required, but additional information on data management and verification was requested from the ARISTOTLE trial.
The agency warned today that patients with a prosthetic heart valve or AF caused by a heart valve problem should not take apixaban. The FDA and European Medicines Agency (EMA) recently warned that dabigatran should not be used in patients with mechanical prosthetic heart valves.
What is Apixaban??
Apixaban (BMS-562247-01) is a compound being investigated as an anticoagulant. Apixaban molecule is developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban, a coagulation factor Xa inhibitor, approved in the E.U. in 2011 for the prevention of venous thromboembolic events in adult patients, who have undergone elective hip or knee replacement. The Apixaban based drug will be marketed under the brand name Eliquis® and is expected to rack up annual sales of over $2.5 billion. Apixaban is expected to provide stiff competition to warfarin, a popular blood thinner used in Europe. Warfarin is known to cause some serious side effects in patients. Apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism in patients experiencing atrial fibrillation by more than 50% (from 3.7% per annum with aspirin to 1.6% per annum with apixaban). Apixaban exhibits superiority to enoxaparin in preventing thrombosis in patients undergoing elective hip replacement surgery with similar bleeding rates. Apixaban is a highly selective and potent Factor Xa Inhibitor with Ki=0 8nM to both free as well as prothrombinase bound FXa. In X-ray crystal structure studies indicate that the pyrazole N-2 nitrogen atom interacts with backbone of Gln192 and the carbonyl oxygen of carboxamide interacts with NH of Gly216. The orientation of phenyllactum in the S4 region indiacates an edge to face interaction with Trp215, which is positioned between the Tyr99 and Phe174. In the present review, we have tried to cover comparative study of various FXa-inhibitors and point out apixaban in the various aspect including molecular chemistry, physical properties, commercial synthesis, current patent status, crystalline polymorphic forms, molecular receptor interaction, pharmacophore rational, mechanism of action, clinical studies, preclinical, adverse effect, available formulation, dose regimen and co-therapy, thus giving emphasis on medicinal chemistry aspects
