Over the weekend Bristol-Myers Squibb and Pfizer announced that their blood-clot-preventing drug candidate, Eliquis (apixaban), bested the workhorse anticoagulant Coumadin (warfarin) in a large clinical trial. The results were announced at the European Society of Cardiology congress and simultaneously published in the New England Journal of Medicine. This is the first time that one of the cadre of anticoagulants seeking to replace warfarin has been shown to be superior to warfarin at preventing dangerous blood clots that can lead to strokes while also having a lower rate of bleeding compared to warfarin.
In the 18,201 patient Phase III clinical trial, called ARISTOTLE, apixaban reduced the risk of stroke in patients with an abnormal heart rhythm called atrial fibrillation by 21 percent, major bleeding by 31 percent, and mortality by 11 percent.
More statistics are available in the announcement, the journal article, and in this Forbes report, which plucks out these illustrative numbers:
The investigators calculated that for every 1000 patients treated with apixaban instead of warfarin for 1.8 years
•stroke would be avoided in 6 patients,
•major bleeding would be avoided in 15 patients, and
•death would be avoided in 8 patients.
Analysts reacted positively to the data, with Leerink Swann analyst Seamus Fernandez raising his 2017 sales estimate for apixaban by $1.1 billion to $4.1 billion in a note to investors.
We’ve previously explained how apixaban works– briefly, it blocks Factor Xa, a protease enzyme near the end of the complex biochemical pathway that regulates blood clotting. Another Factor Xa inhibitor, rivaroxaban, has been approved in Europe but awaits FDA approval. Pradaxa (dabigatran), which blocks the enzyme thrombin, has been approved by FDA for reducing the risk of stroke associated with atrial fibrillation.
So what’s the secret of apixaban’s success? In 2010, we spoke with Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb, who explained how apixaban was designed with pharmacokinetic properties (the properties that reflect how the body affects a drug’s fate after administration) in order to reduce the risk of off-target effects.
The extent to which an anticoagulant gets distributed through the body also matters, says Ruth R. Wexler, executive director of cardiovascular diseases chemistry at Bristol-Myers Squibb. “Coagulation factors are in the blood,” she says. So there’s no need for a drug candidate that blocks a coagulation factor, such as Factor Xa, to be distributed beyond the bloodstream and reach other tissues and organs. “Getting into other tissues and organs is frequently the reason why there are off-target safety issues,” she says. This was one of many concerns BMS had in mind as it developed its most advanced Factor Xa inhibitor, apixaban, which the company is developing with Pfizer. By making sure apixaban has what pharmacologists call a low volume of distribution, researchers hope to show that the drug stays in the bloodstream as much as possible, potentially reducing the risk of off-target safety issues, Wexler says.
While the new ARISTOTLE trial data represents a big boost for apixaban, we remind Haystack readers that last November, Terra Sigillata blogger David Kroll alerted us to a Wall Street Journal report about an apixaban trial that was halted. That trial was trying to determine whether apixaban reduced the incidence of strokes caused by coronary artery disease (a different condition from atrial fibrillation). An independent data-monitoring committee had determined apixaban was not effective at this task while also increasing the risk of bleeding.
Multiple clinical trials of apixaban are ongoing. Bristol-Myers said an application for apixaban’s approval will be filed with the U.S. Food and Drug Administration this year, according to the Wall Street Journal. And clinicians and researchers behind the scenes are no doubt carefully assessing what causes apixaban to increase the risk of bleeding in some settings while lowering it in others, whether it is dosage, patient population, or other as-yet-to-be-determined factors.
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