Biotech Values

[DewDiligence]

Drugs to Treat or Prevent Blood Clots Have Big Potential

[This article from Monday’s WSJ is apropos to the recent posts on this board regarding the burgeoning anticoagulant market. (The title above is mine.)]

http://online.wsj.com/article/SB119725064671318856.html

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By RON WINSLOW and AVERY JOHNSON
December 10, 2007

Big-name pharmaceutical companies are hoping to find a new blockbuster drug in a market now dominated by one of the oldest mainstay pills in medicine: the blood thinner warfarin.

At least five next-generation blood thinners are in advanced testing to treat or prevent potentially debilitating or life-threatening blood clots in surgery and heart patients. First candidates could reach the market in 2009.

But important questions about their effectiveness and safety remain unanswered, and a clear picture about the scope of the clinical and economic potential for the drugs isn't likely to emerge for at least another two years. If major hurdles are cleared, some analysts believe the global market for the blood thinners could exceed $10 billion by the middle of the next decade.

Interest in new anticlotting treatments is being ratcheted up at a meeting of the American Society of Hematology under way in Atlanta, where Johnson & Johnson is presenting data showing that the experimental pill rivaroxaban is superior to another blood thinner -- in this case, Lovenox, an injectable treatment marketed by Sanofi-Aventis SA -- in preventing clots in patients undergoing hip- or knee-replacement surgery. Johnson & Johnson is co-developing rivaroxaban with Bayer AG of Germany, which discovered the compound.

Other contenders include Bristol-Myers Squibb Co., which is developing a pill called apixaban with Pfizer Inc.; Eli Lilly & Co.; Boehringer-Ingelheim GmbH of Germany; and closely held Portola Inc., South San Francisco, Calif. All are testing their drugs initially in hip and knee-replacement patients, who often receive Lovenox. Sanofi-Aventis says Lovenox is proven safe and effective for such patients and that safety of oral anticoagulant remedies remains unknown.

But the big opportunity is atrial fibrillation, a type of irregular heart beat that afflicts an estimated 2.2 million Americans and 5.5 million people world-wide. The condition is a major cause of stroke and patients need to be on daily preventive therapy. Warfarin, a half-century old drug marketed as Coumadin by Bristol-Myers and in generic versions by other companies, is the standard option but can be complicated for doctors and patients alike.

"Atrial fibrillation is really everyone's main target," says Jack Lawrence, vice president of development in charge of apixaban at Bristol-Myers. Several large late-stage trials of the new drugs vs. warfarin are under way, with initial results expected in 2009.

The flurry of interest reflects increasing understanding of what doctors call the coagulation cascade [#msg-23010615] -- the complex system that causes clots to form to stop bleeding in the face of injury, but which can lead to heart attacks, strokes and clots in the legs or lungs when triggered by disease processes in the body.

Four of the new blood thinners target an enzyme called factor Xa, one of several enzymes that play an important role in the cascade. Boehringer-Ingelheim's drug dabigatran blocks thrombin, another enzyme in clot formation.

A previous thrombin inhibitor called Exanta developed by AstraZeneca PLC showed promise in preventing clots, but it caused liver damage, killing its prospects. Observers say new treatments will also be watched closely for effects on the liver.

Doctors have long yearned for an alternative to warfarin. The drug requires frequent blood-test monitoring and can have serious side effects if it reacts adversely to other drugs a patient takes, a common occurrence, or even to a change in diet. Many patients struggle to stay on the drug and estimates are that doctors prescribe it for less than 50% of those who need it.

An effective drug for atrial fibrillation without warfarin-like baggage "will be an instant blockbuster," says William O'Neill, executive dean of clinical affairs at University of Miami's Miller School of Medicine. "People will switch on day one."

Johnson & Johnson and Bayer are hoping rivaroxaban can strike the right balance. In one study of 4,541 patients undergoing hip replacement presented Saturday at the hematology meeting, 1.1% of those given rivaroxaban either died or had a nonfatal blood clot in the legs or lungs compared to 3.7% of those given Lovenox, a reduction of 70%. Two other 2,500-patient studies -- one on hip replacements and one on knee replacements scheduled to be presented today -- yielded similar findings. Bleeding episodes were similar for both medicines.

"These are results that exceeded our expectations," says Peter DiBattiste, vice president and head of cardiovascular medicine at Johnson & Johnson.

Johnson & Johnson plans to file data from the three studies plus another nearing completion to the Food and Drug Administration by late next year. Bayer has already filed in Europe. Approval for hip and knee replacement could come in 2009, if all goes well.

More research is required to show whether the medicine is safe and effective in broader and more lucrative conditions, including atrial fibrillation and high-risk heart patients. Johnson & Johnson says it plans to enroll a total of 50,000 patients in studies to evaluate the drug's potential.

The new rivaroxaban data add "more credence to the mechanism but it doesn't tell us much for atrial fibrillation," says Steven Paul, research and development chief at Lilly, whose factor Xa program trails that of Johnson & Johnson and Bayer. "They, and we, need to do additional testing, because the long-term tolerance is critical. The example of Exanta is that people did great for a couple months but over time there was toxicity."
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