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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Boehringer’s Blood Thinner Dabigatran (Pradaxa) Unanimously Endorsed
Sep22

Boehringer’s Blood Thinner Dabigatran (Pradaxa) Unanimously Endorsed

After last week's Meridia and Lorqess drama, I could've really used some good news from an FDA panel. And on Monday, I got it- in the form of a unanimous endorsement for a new blood thinner. The drug getting the love is dabigatran etexilate, which was developed by family-owned Boehringer Ingelheim and will be marketed as Pradaxa if approved. It's one of a cadre of drugs trying to replace warfarin (also known as coumadin), a medication that has been on the market for over 50 years and is among the most difficult to manage. Warfarin prevents formation of blood clots and can reduce ongoing clots. Doctors prescribe it to prevent painful leg clots in patients getting hip or knee replacements, to prevent stroke in patients with an abnormal heart rhythm called atrial fibrillation, and more. We recently wrote about how warfarin is a dirt cheap and effective medication, but it interacts with a plethora of foods, herbal supplements, and other drugs. Pradaxa is already approved in several countries outside the U.S. for short-term use, preventing leg clots in patients getting hip or knee replacements. The drug blocks thrombin, a protease enzyme that sits near the end of the complex biochemical pathway known as the coagulation cascade. Just about all of the drugs being developed to replace warfarin, at least the ones toward the end of the pipeline, target either thrombin or Factor Xa, the protein immediately before thrombin in the pathway. FDA's cardiovascular and renal drugs advisory committee voted 9-0 in favor of approving Pradaxa for preventing stroke in patients with atrial fibrillation. (Boehringer-Ingelheim press release) This will be a longer-term stint on Pradaxa than post-hip or knee surgery patients typically experience. So the most important part of the panel's discussion, to me, was their assessment of the drug's effects on the liver. That's because in 2006, another thrombin blocker called ximelagatran, developed by AstraZeneca, was pulled from the market because of liver toxicity. When you dig into the briefing documents that FDA provided to the panel, you find this blurb on page 103: Based on these data, the risk of severe drug induced liver injury from dabigatran appears to be low. Because the perceived risk is low and frequent liver monitoring may not prevent serious cases from occurring (even if an association did exist), regular monitoring of liver tests is not recommended. So it seems that ximelagatran's liver issues may not be a class-wide problem. Still to be determined is what doses of the drug might be approved- read this post by Pharmalot for an assessment of why doses matter. FDA is expected to make its call on...

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On Blood Thinners And Rat Poison
Aug16

On Blood Thinners And Rat Poison

C&EN's cover story this week is about finding replacements for the blood thinner warfarin, something that hasn't happened in the more than fifty years since the drug went on the market. Warfarin prevents blood clots from forming and reduces active clots as well. When it works, it's great for preventing strokes. As a bonus, it's a dirt cheap pill, costing on the order of a couple of cents a day. But the trouble is that warfarin doesn't always work well. It is extremely unpredictable in the body. Foods and other drugs affect its activity, as do certain genetic traits. The last thing you want to do is to take too much or too little warfarin. Too much warfarin could lead to uncontrolled bleeding, something that can be deadly in a place like the brain. And of course too little warfarin won't be effective at preventing clots. So patients on warfarin must constantly monitor how well their blood is clotting, so their doctor can get their dose just right. The fact that it's easy to overdose on warfarin is a pain for doctors and patients. But it comes in pretty handy in warfarin's other, perhaps less well-known application: rat poison. It seems that messing with rodents' blood clotting pathways is a very efficient way to off them. My cursory research indicates that we've got many rodenticide options, and warfarin isn't the most common one. I couldn't find warfarin at three different D.C. hardware stores. But it's still available online. YOUR KEYWORD FOR THIS BLOG IS: COMING As an aside: medical websites seem to use the name "coumadin", but the rat poison boxes read "warfarin". I'd love to know the history behind this name divergence. It could be another instance of name-changing to assuage patient fears. I can certainly understand how a patient would find it disconcerting to see a giant box of their blood thinner in the pest control aisle at Home Depot. Think of how a nuclear magnetic resonance spectrometer uses essentially the same technology as a magnetic resonance imaging instrument. But the name you see used in the health field drops the...

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