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Cover Story

August 16, 2010
Volume 88, Number 33
pp. 15-22

To Clot, Or Not

Anticoagulants in the pipeline may overcome the drawbacks of well-entrenched drugs

Carmen Drahl

NECESSITY Dialysis patients are just one of many groups who rely on anticoagulants.
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Karen Rossi/Bristol-Myers Squibb View Enlarged Image
SWEET SPOT In this X-ray structure, apixaban is shown binding to Factor Xa’s active site.

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When Lisa Deck was in high school, she played defense on the varsity soccer team. In college, she took the field for intramural games. But these days, the last time she saw a soccer ball was on TV, when she watched the occasional World Cup game.

“I was 21 when I suffered my first stroke,” Deck says. A rare brain disease led to inflammation of the blood vessels in her brain, ultimately causing the stroke. As part of her therapy, her doctor prescribed coumadin, a drug that keeps blood clots from forming. But shortly after she was off coumadin, another stroke hit. Deck, now in her mid-thirties, has recovered from three strokes in all. And she’s become one of millions of people for whom coumadin is a part of everyday life.

For Deck, now a patient advocate for the American Heart Association, it’s the little things that matter, such as having to be extra careful when brushing her teeth in the morning. Coumadin alters the body’s balance between clotting and bleeding, so a nick to the gums is bloodier and more annoying than it used to be. Worse is the constant monitoring. Many drugs and foods affect coumadin’s activity, so Deck goes to a lab for a blood test once a month. That way, her doctor can keep tabs on how well her blood is clotting and adjust her coumadin dose accordingly. “Over the holidays, there was some fluctuation—we’re not sure why—but I was going once a week,” Deck says. With her two small children, only one and three years old, in tow, getting tested is a major production.

But what’s most frustrating is that being on coumadin means no contact sports, including soccer, Deck says. “Now that I’m feeling better, that would be an activity I would love to do, but it’s just something I’m not able to do.”

Coumadin, or warfarin, is one of an arsenal of medications already available to control blood clotting. Patients at risk of a stroke or a heart attack rely on these drugs. But cardiovascular disease remains the most common cause of death in the developed world, according to the World Health Organization. Companies are racing to get safer and more effective blood thinners to market. They’ve homed in on two targets—the protease enzymes Factor Xa (pronounced ten-ay) and thrombin—that they say will deliver those drugs.

A blood clot, or thrombus, is at its most dangerous when it cuts off blood flow to a vital organ, such as the brain. But not every clot is created equal. Depending on what type of clotting a patient has, physicians use different drugs to prevent or reduce it. For example, a heart attack is most often caused by a platelet-rich blood clot in an artery. So platelet-targeted drugs such as aspirin and Plavix (clopidogrel) are most effective at combating those clots. Plavix is the second-best-selling drug in the world, ringing up $6.1 billion in sales in 2009, according to comarketer Bristol-Myers Squibb. Plavix will go off-patent in 2011, and researchers have been eagerly debating what the next platelet-targeted blockbuster might be.

But another type of clot, one that is low in platelets and held together by a mesh made from the protein fibrin, can also cause trouble. For instance, in a condition called deep vein thrombosis, these clots form in leg veins, leading to pain and swelling. If these clots break away from where they formed, they can cut off blood flow in the lungs. Such clots can also form in patients with an abnormal heart rhythm called atrial fibrillation, ultimately leading to a stroke.

Courtesy of Lisa Deck

For controlling fibrin-rich clots, researchers have had to rely on warfarin and a family of drugs called heparins. These drugs are older than Plavix, and they have hassles that make them ripe for replacement. It’s these medications that drug companies hope to supplant with new Factor Xa- and thrombin-targeted drugs.

Both warfarin and the heparins are known as anticoagulant drugs. They affect the coagulation cascade, the complex biochemical pathway that produces fibrin. Both Factor Xa and thrombin are enzymes in this cascade. By far the most commonly used drug in its class, warfarin inhibits vitamin K epoxide reductase, which uses vitamin K to modify four different coagulation proteins. The heparins are complex polysaccharides that bind to the protein antithrombin III, affecting Factor Xa and thrombin. Synthetic pentasaccharides based on a key portion of heparin have also been introduced. These medications affect only Factor Xa.

But heparins and their pentasaccharide cousins all need to be given by injection, says Jeffrey I. Weitz, a physician who specializes in thrombosis at McMaster University, in Hamilton, Ontario. “Nobody wants to take an injection if they can help it,” he says. Some patients develop antibodies against heparin and cannot use it. And cases of adulterated heparin have led to worries about the reliability of the supply (C&EN, May 12, 2008, page 38).

Unlike the heparins, warfarin is a pill, which makes it more convenient for the long-term anticoagulation that patients at risk of stroke need. But that’s close to the only thing the drug has going for it. “Warfarin’s a very effective drug, but it’s hard to give it well,” explains Weitz, who disclosed consulting relationships with several companies developing new blood thinners, including Pfizer and Takeda. The drug takes a few days to kick in, and once it does, it has unpredictable behavior in the body because of its many interactions with other drugs and foods such as leafy greens. People respond differently to warfarin, depending on variations in their genes for vitamin K epoxide reductase and certain metabolic enzymes in the cytochrome P450 family. To top it all off, there is a small margin between giving too little warfarin and giving too much. These factors combine to make warfarin dosing more of a constant tinkering process than a one-time decision. It’s why patients such as Deck have to have regular blood tests.

Warfarin is far from an ideal blood thinner, agrees Raj Kasthuri, a physician and thrombosis specialist at the University of North Carolina, Chapel Hill. But if you want an orally active anticoagulant in the U.S., “warfarin is all we’ve got, and it’s all we’ve had for decades,” he says.

Finally, anticoagulant drugs have a built-in trade-off. “The more potent a drug is at preventing clots from forming, the greater the risk of bleeding,” says Elliott M. Antman, a senior faculty member in the cardiovascular division of Brigham & Women’s Hospital, in Boston. Excessive bleeding can be dangerous, so what drugmakers would like to be able to do is manage the trade-off, says Antman, who is leading studies evaluating potential new drugs from companies such as Sanofi-Aventis, Daiichi Sankyo, and Eli Lilly & Co. Drugmakers would like a pill that is more efficient than warfarin at controlling clotting but that has a lower risk of bleeding, Antman says. “Much of what we’re doing with the clinical trials you hear about is trying to define that sweet spot.”

To make a safer oral drug, companies have turned away from the vitamin K-mediated mechanism and are blocking one protein in the coagulation pathway at a time. The coagulation cascade is loaded with potential targets, but Factor Xa and thrombin are particularly promising, says Nigel Mackman, an expert in the biochemistry of coagulation at UNC Chapel Hill.

“From a drug development perspective, you could imagine designing a drug that prevents clotting or that treats an ongoing clot. The preference is a drug that can do both,” Mackman says. Factor Xa and thrombin sit near the end of the cascade, at a point called the final common pathway. It’s impossible to get to fibrin without going through Factor Xa and thrombin first, he explains. “If you work further up the cascade, you may have a really good prevention drug, but it’s not going to do much good when you’re clotting actively,” as is the case in deep vein thrombosis.

Promising though the targets may be, finding the right molecules to inhibit them hasn’t been easy. The toughest part of making new oral anticoagulants has been finding molecules with the right combination of pharmacokinetic properties. Every molecule has a slightly different fate inside the body, and fine-tuning that fate could make all the difference in a drug’s efficacy and safety.

“The lack of Food & Drug Administration-approved agents since warfarin just speaks to how difficult this drug discovery effort is.”

To compete with warfarin, any new drug must be able to be absorbed when taken orally. And the first Factor Xa inhibitors couldn’t do that, says Peter Wildgoose, cardiovascular therapeutic area lead at Ortho-McNeil Pharmaceutical. “They were fine intravenously, but they didn’t have any oral activity,” he says. “These early compounds were actually positively charged, and because of that they couldn’t get across the gut.” But in time, companies figured out how to replace the charged groups, usually with heterocyclic rings. That largely solved the oral activity issues, Wildgoose says. For instance, Bayer’s most advanced Factor Xa inhibitor, rivaroxaban, features a chlorothiophene moiety where a cationic group once was. Rivaroxaban is being developed jointly by Ortho-McNeil and Bayer HealthCare.

Chemists at Boehringer Ingelheim, where the lead anticoagulant drug is a thrombin inhibitor, took a different approach to improve oral availability. They developed a prodrug, says Andreas Clemens, a physician and corporate director of medical affairs at the company. Medicinal chemists discovered a potent thrombin blocker, dabigatran, but the compound was not orally active. Adding a hydrophobic side chain, which could later be cleaved by enzymes in the body, improved oral absorption and led to dabigatran etexilate, the company’s most advanced blood-clot preventer.

Absorption in the gut is just the beginning of an oral anticoagulant’s journey in the body. Scientists had to think hard about how much drug the body is exposed to at any given time, says Andrew S. Plump, a physician-scientist and head of worldwide discovery for cardiovascular disease at Merck & Co. The company is developing a Factor Xa inhibitor, betrixaban, that was licensed from Portola Pharmaceuticals. With most oral medications, the amount of drug in the bloodstream fluctuates throughout the day, Plump says. “If we think the risk of bleeding is related to the level of inhibition of the enzyme, you don’t want to go to extremes in drug exposure,” because too much Factor Xa inhibition could lead to bleeding, he says. The idea is to keep the amount of drug in the body as level as possible for as long as possible, and the company believes betrixaban does that well, Plump says.

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.

It’s hard to pack all those properties into one molecule, Wexler emphasizes. When it comes to oral anticoagulants, “the lack of Food & Drug Administration-approved agents since warfarin just speaks to how difficult this drug discovery effort is,” she says.

With so many anticoagulants in the pipeline, scientists are eager to know whether one target—Factor Xa or thrombin—is better. “People have spent many meetings trying to answer that question,” Mackman laughs.

Factor Xa is the first protease enzyme in the final common pathway, a feature that might be handy for controlling coagulation, Wildgoose says. “The key thing about the coagulation cascade is that it’s sort of a waterfall,” he says. “You activate a couple molecules at the top and you have a massive response at the end.” He likens coagulation control to shutting down water flow with a spigot. It’s easier to fine-tune things upstream in the cascade, he says. “You can control things better than at the bottom when you have the whole waterfall going.”

Animal tests with Factor Xa inhibitors suggest that the molecules might provide a lower risk of bleeding compared with thrombin inhibitors, Wexler says. “And unlike thrombin, Factor Xa has few roles outside the coagulation cascade.”

Blocking thrombin also has advantages, Clemens says. Thrombin, he says, is the central enzyme in the coagulation cascade. So blocking thrombin directly might be a rapid treatment for a patient at higher risk of excessive clotting, such as a person with atrial fibrillation. “There’s a hypothesis that these patients may already have elevated thrombin levels,” he says. Blocking higher up in the cascade only stops the generation of new thrombin molecules—it isn’t effective against the thrombin already present. So patients might have to wait until their thrombin levels drop naturally before seeing the drug’s full effect.

But the short answer is that nobody has all the data they need to determine which target is better. The gold-standard study would be a head-to-head clinical trial comparing a thrombin inhibitor with a Factor Xa inhibitor. No such trials are in the works.

The target might not be the most important thing in real-world settings anyhow, Weitz says. “My take is that both targets are good. A lot will depend on the pharmacologic properties of the different drugs. Each one is a little bit different and has its own quirks.”

For example, whether the new drugs get cleared by the kidneys matters to dialysis patients or others with impaired kidney function—a big segment of anticoagulant drug users, Kasthuri says. He consults for Baxter and Bayer on hemophilia products, but not on anticoagulants. Dialysis patients regularly receive standard heparin to prevent their blood from clotting in the dialysis machine’s tubing. “That’s okay, because the vast majority of it is not eliminated in the kidney,” Kasthuri says. But that’s not the case with most of the next-generation drugs, he notes. So far, the exception seems to be betrixaban, which is reported to have very little clearance via the kidney.

If approved in the U.S., the new drugs will mean new choices for controlling clotting, Weitz says. “They can be given in fixed doses, without the need for routine monitoring,” he says. With few if any interactions with foods and other drugs, the drugs would be much simpler to administer than existing ones, he says. Rivaroxaban and dabigatran etexilate are both approved in many countries outside the U.S. But so far, they are only approved for short-term use, for preventing blood clots in the legs that can arise after hip- or knee-replacement surgery. Multiple clinical trials on all the potential new drugs are ongoing. FDA will be looking at a number of factors very carefully before it approves anything, particularly for long-term applications such as stroke prevention.

A special priority is liver toxicity. In 2006, an orally active thrombin inhibitor approved in Europe, AstraZeneca’s ximelagatran, was pulled from the market for that reason. Clemens says dabigatran shows no signs of liver toxicity, which suggests that the toxicity problem is related to ximelagatran itself and not to all thrombin inhibitors. But drugmakers are taking liver toxicity seriously. And it’s not just thrombin inhibitors that will be under the regulatory microscope, Clemens says. “Authorities are looking at all the anticoagulants under development. They are being very careful.”

If the new drugs make the cut, their cost will also be an important issue, Kasthuri says. “Warfarin is dirt cheap,” he says. But it has hidden costs, such as monitoring and the occasional emergency room visit if a patient’s blood-clotting balance spirals out of control. Insurance providers will be weighing cost, efficacy, and safety for each new drug that’s approved, he says.

And there are still opportunities for improvement, particularly in the bleeding-clotting trade-off, as a major clinical trial of dabigatran suggests. In that trial, a Phase III study called RE-LY, Boehringer Ingelheim pitted dabigatran against warfarin in more than 18,000 atrial fibrillation patients. The company tried two different dabigatran doses. The low dose was as effective as warfarin at preventing stroke with less risk of bleeding. And the high dose was more effective than warfarin, with an equal risk of bleeding. That was an exciting and tantalizing result, Merck’s Plump says. “The opportunity that dabigatran is suggesting to us is that it’s possible to get more efficacy and less bleeding” together, he says. It’s up to researchers to figure out how to get there, whether by target selection or pharmacokinetic tweaks, he adds.

“The main challenge right now is to show efficacy and safety in all the different clinical-trial programs.”

Another area that needs work is the new drugs’ reversibility, Weitz says. Doctors must quickly stop an anticoagulant from working if a patient needs emergency surgery, he explains. Warfarin has a very long half-life in the body, but it can be reversed by giving a patient vitamin K or a cocktail of clotting factors. And heparin’s activity can be reversed with the drug protamine sulfate. But “we cannot reverse these new agents easily,” he says.

“This is where some of the differences among the agents may become important,” Weitz adds. And pharmacokinetics may once again be key. Because dabigatran doesn’t bind to plasma proteins, it can be removed with dialysis in critical situations, he says. But that’s not possible for anticoagulants that have higher protein binding, he says.

Clemens says that scientists at Boehringer Ingelheim have conducted animal tests on another potential reversal option for dabigatran—activated charcoal. But it is too early to know whether this is a viable approach in people.

“The whole anticoagulant field is really evolving,” Wildgoose says. “The main challenge right now is to show efficacy and safety in all the different clinical-trial programs.”

As for Deck, she’s not sure it’ll ever be safe for her to play soccer again. “It looks as though it will be for the rest of my life that I will be on coumadin,” she says. She’s tried to get her health insurance to pay for a blood-monitoring system that she can use at home but hasn’t had any luck. So for now, she’s still loading her kids into the car for the monthly trek to the blood lab. “A drug that wouldn’t make that an issue would be very nice,” she says.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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