Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off
Aug29

Bristol-Myers, Pfizer’s Apixaban Tops Warfarin In Anticoagulant Face-Off

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,...

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Blood Thinner Blog Posts Worth Reading
Nov19

Blood Thinner Blog Posts Worth Reading

What you’re looking at is an overview of the complex biochemical pathway behind blood clotting, and a smattering of the drugs researchers are developing to control clotting for preventing strokes and more. Over at Terra Sigillata, David Kroll has two back-to-back posts about some of these drugs that are worth reading. In the first post, Kroll discusses news out of the American Heart Association’s annual meeting: Rivaroxaban (Xarelto), a blood clot preventing drug from Bayer and J&J, has been shown to be about as efficacious as the established medication warfarin (coumadin) and better with regard to spontanous bleeding complications. He also dishes on some of the fascinating historical context behind the drugs. In the second, he brings attention to Pfizer and BMS’s announcement that they are halting a trial of apixaban, their investigational blood clot preventing medication. Eight other apixaban trials are ongoing. We covered some apixaban news last June, when a different apixaban clinical trial was stopped early because an independent analysis concluded that the drug candidate was more effective than aspirin at reducing strokes and blood clots in patients with a common abnormal heart rhythm. As we’ve written in C&EN, many factors will determine whether patients at risk of strokes or other dangerous blood clots will end up taking warfarin or will take one of the new drugs. Boehringer-Ingelheim’s Pradaxa (dabigatran), which acts at a different target from apixaban and rivaroxaban, is already approved by FDA. Rivaroxaban and Pradaxa are already approved in a number of other countries for short-term use. Each drug is slightly different, from how many times a day it must be taken, to how much of it is cleared via the kidneys (a potential issue for patients on dialysis or other kidney conditions), and much more. And of course, a big question is what the difference in cost is going to be- warfarin pills are cheap but the quality of life costs- incessant testing and diet monitoring- can be steep. Image:...

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BMS and Pfizer’s blood thinner beats aspirin- now, what can it really do?

Yesterday, Bristol Myers Squibb and Pfizer agreed to stop AVERROES, a late-stage clinical trial of an experimental blood thinner, early. It’s relatively rare for a trial to be stopped for positive reasons, but that is what happened here. An independent analysis concluded that the blood thinner, called apixaban, was more effective than aspirin at reducing strokes and blood clots anywhere outside of the brain in patients with atrial fibrillation, a common abnormal heart rhythm. Stroke is a major complication for patients that have this heart problem, and drug companies would like to find a more manageable way to reduce patients’ chances of having one. Apixaban is one of a slew of potential new blood thinners in the pipeline that is an oral inhibitor of Factor Xa, a protease enzyme that sits at a key point in the body’s complicated blood coagulation cascade. Matthew Herper at Forbes recently broke down how another drug in this same class, Merck’s betrixaban, works. One thing to keep in mind is that none of the 5600 patients in this study were taking warfarin, a decades-old blood thinner that’s still one of the gold standards for preventing stroke. For patients with atrial fibrillation, warfarin, a vitamin K antagonist that interferes with the coagulation cascade, is generally considered to be a more effective option than aspirin, which prevents blood platelet activation. The patients in the AVERROES trial, BMS’s press release explains, were either unable to take or chose not to take warfarin. I can understand the perspective of the folks choosing not to go that route. Warfarin works, it’s cheap, and it’s also an oral medication, but it’s far from perfect. People who take it must be very carefully monitored by a physician, because other drugs and even foods in the diet can alter its effects in the body. And with blood thinners, you’re always walking a tightrope- too high a dose can lead to excessive bleeding. Also, some genetic differences can affect how well warfarin will work. Patients who have that genetic makeup might want to have another option that they can take in the form of a pill. But apixaban is still an investigational agent- FDA has yet to approve it. The news in this trial was good news, but given the relative effectiveness of aspirin I’m not sure how surprising it really was to those following this field closely. To get a complete picture of what apixaban can do, it will be good to see what comes of the ongoing ARISTOTLE trial. That trial, like AVERROES, is a Phase III, randomized, double blind clinical trial in patients with atrial fibrillation. But instead of...

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