By Ransdell Pierson
NEW YORK, April 13 A new crop of medicines to prevent stroke and blood clots could emerge within several years, easing dangers and hardships for patients and creating blockbuster sales for drugmakers.
The oral drugs could prove better and safer than injectable medicines such as heparin now widely used to cut the risk of dangerous blood clots in the legs and lungs after major surgery.
But makers of the new drugs say their biggest use would be as an alternative to warfarin, a pill used for decades by people with atrial fibrillation -- or irregular heartbeat -- to prevent strokes. An estimated two million Americans have been diagnosed with the heartbeat problem and the number is expected to double in the next 20 years.
Warfarin, sold by Bristol-Myers Squibb Co. (BMY.N) under the brand name Coumadin but now widely available as a generic, is notoriously difficult to tolerate because of its interactions with food and other medicines.
Patients taking warfarin must undergo constant blood tests to ensure that warfarin levels are sufficient to prevent strokes, but not so high that they increase the risk of dangerous bleeding or brain hemorrhages. Moreover, patients scheduled for surgery must stop taking warfarin days ahead of time, to avoid serious bleeding.
"With all these disadvantages, an alternative to warfarin is direly needed, particularly since our aging population is becoming more vulnerable to atrial fibrillation and other conditions that can cause dangerous blood clots," said Dr. Stephen Winters, an associate professor of medicine at New Jersey Medical School.
"Replacement drugs for warfarin would be blockbusters because of the critical need," he said.
Among the replacement candidates, a once-daily pill called rivaroxaban, being developed jointly by Bayer AG BAYG.DE and Johnson & Johnson (JNJ.N), is the farthest along in clinical trials and could fetch annual sales of more than $2.5 billion, analysts say.
Bayer aims in 2010 to seek approval to market the compound for stroke prevention related to atrial fibrillation. It plans later this year to unveil data from studies testing the drug's ability to prevent blood clots after orthopedic surgery, a less lucrative indication.
Like several rival pills under development, rivaroxaban blocks the Factor Xa protein, which plays an early role in the chemical process by which blood clots are formed.
"It potentially could replace Coumadin," said Frank Misselwitz, Bayer's head of cardiovascular clinical development.
Bayer has tested a wide range of doses and "has not had to stop any of them due to increased bleeding," a worrisome common side effect of Coumadin, heparin and other anti-clotting medicines, Misselwitz said. "And we've had good efficacy even at the lowest doses."
"Because of its predictability, unlike warfarin, you don't need monitoring, and the same dose is used despite gender and body weight," Misselwitz said.
Bristol-Myers' Factor Xa inhibitor, called apixaban, is believed to be just behind rivaroxaban in a similar range of late-stage trials.
Apixaban has reduced rates of death and clots in legs and lungs of patients that have undergone orthopedic surgery, compared with Lovenox, an improved form of heparin sold by Sanofi-Aventis (SASY.PA). Late-stage trials of apixaban began last year for prevention of strokes associated with atrial fibrillation.
"Clearly, for patients who are hard to maintain on warfarin because of dietary restrictions and interactions with other medicines, there could be clear advantages to switching" to newer drugs like apixaban, said Jack Lawrence, who leads the apixaban program for Bristol-Myers.
Lawrence said that apixaban will likely require two doses a day. That could give a marketing advantage to Bayer's rivaroxaban because "the first once-daily drug will gain the lion's share" of sales, Bayer's Misselwitz said.
The brokerage Cowen and Co. predicts an oral Factor Xa inhibitor being developed by Eli Lilly and Co. (LLY.N) could post annual sales of $600 million by 2012, based in part on its apparent equivalence to Lovenox in mid-stage trials to prevent dangerous clots among patients undergoing knee and hip replacements.
"It was safe and well tolerated and there was no difference in bleeding risk, which was the exciting thing," said Holger Ilske, a senior Lilly research executive. He said the drug, called LY517717, has once-a-day potential, and Lilly is gearing up for Phase III stroke-prevention trials.
Researchers are placing high hopes on Factor Xa inhibitors following AstraZeneca's (AZN.L) decision last year to halt development of Exanta, a blood thinner once deemed a likely replacement for warfarin.
Exanta, which worked by directly blocking another clotting protein called thrombin, was scrapped due to concerns that it could harm the liver.
Privately held German drugmaker Boehringer Ingelheim is conducting late-stage trials of its own thrombin inhibitor, called dabigatran, to prevent blood clots following surgery.
Manfred Haehl, senior medical vice president of Boehringer, said the company "is substantially ahead of plan" in a stroke-prevention trial involving 15,000 patients with atrial fibrillation.
"If things continue well, we could also seek marketing approval ahead of plans, maybe by the end of 2009" for stroke prevention, he said.
Haehl said it remains unclear how long it will take his drug and the Factor Xa medicines to supplant warfarin, if they are approved.
"The more convincing the results are in terms of establishing better safety than warfarin, the faster it will happen. But with all these developments taking place, I think they will take over," he said.
((Reporting by Ransdell Pierson; editing by John Wallace; Reuters Messaging: firstname.lastname@example.org; 646-223-6034; email@example.com))
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