Replies to post #44894 on Biotech Values

[DewDiligence]

BMY, PFE Ink $1B Apixaban Collaboration

[Apixaban is one of a select group of drug candidates vying to replace the much-maligned warfarin as the standard anticoagulant in a wide range of indications (#msg-18759853). Its main competitors are rivaroxaban from Bayer/JNJ and LY517717 from LLY. All three drugs are Factor Xa inhibitors and thus have a different MoA from Lovenox and other LMW heparins (see graphic in #msg-16968590).

Apixaban is in phase-3 for prevention of DVT/PE and stroke in patients with AF. It is also in phase-2 for acute DVT and, separately, for prevention of MACE in patients with ACS. These are very large indications and hence whichever of the aforementioned drugs makes it to market has a good chance to become a blockbuster.

Given the potential upside, it’s not surprising that PFE is paying BMY $250M up-front and up to $750M in clinical and regulatory milestones for the rights to half of the worldwide profits while paying 60% of the development costs.

Separately, the companies announced a smaller collaboration to jointly develop PFE’s preclinical compounds in obesity and diabetes, but this reads almost as an afterthought given the magnitude of the apixaban deal.

BMY holds its 1Q07 CC today at 10:30 am and the apixaban deal figures to be a hot topic.]

http://biz.yahoo.com/bw/070426/20070426005515.html?.v=1

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Bristol-Myers Squibb and Pfizer Announce Worldwide Collaboration to Develop and Commercialize Anticoagulant and Metabolic Compounds

Thursday April 26, 7:00 am ET

Apixaban Currently in Phase III Trials for Prevention of Venous Thromboembolism and Prevention of Stroke Associated with Atrial Fibrillation

Early-Stage Compounds Being Studied in Treatment of Metabolic Disorders

PRINCETON, N.J. & NEW YORK--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY ) and Pfizer Inc (NYSE: PFE ) today announced a worldwide collaboration to develop and commercialize apixaban, an anticoagulant discovered by Bristol-Myers Squibb being studied for the prevention and treatment of a broad range of venous and arterial thrombotic conditions. In a separate agreement, the companies will also collaborate on the research, development and commercialization of a Pfizer discovery program which includes advanced preclinical compounds with potential applications for the treatment of metabolic disorders, including obesity and diabetes.

Phase III trials are currently underway investigating the potential use of apixaban in the prevention of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of stroke in patients with atrial fibrillation (AF). Phase II trials are studying apixaban in the treatment of acute symptomatic DVT and for the secondary prevention of cardiovascular events in patients with acute coronary syndrome.

Terms of the apixaban agreement include an upfront payment of $250 million by Pfizer to Bristol-Myers Squibb. Pfizer will fund 60% of all planned development costs effective January 1, 2007 going forward, and Bristol-Myers Squibb will fund 40%. Bristol-Myers Squibb may also receive additional payments of up to $750 million based on development and regulatory milestones. The companies will jointly develop the clinical and marketing strategy of apixaban, and will share commercialization expenses and profits/losses equally on a global basis.

Pfizer will be responsible for all research and early-stage development activities for the metabolic disorders program, and the companies will jointly conduct Phase III development and commercialization activities. Bristol-Myers Squibb will make an upfront payment of $50 million to Pfizer as part of this agreement. The companies will share all development and commercialization expenses along with profits/losses on a 60%-40% basis, with Pfizer assuming the larger share of both expenses and profit/losses.

"By combining our company's long-standing strengths in cardiovascular drug development and commercialization with Pfizer's global scale and expertise in this field, we can maximize the potential benefits of apixaban for patients. In addition, the metabolic disorders program complements existing research efforts in another area of significant unmet medical need where Bristol-Myers Squibb is quite active," said Jim Cornelius, chief executive officer, Bristol-Myers Squibb. "This collaboration supports our strategy to focus on serious diseases, maintain commercial emphasis on specialists and high-prescribing primary care physicians, and work with partners to offset the risks inherent with developing certain medicines."

"We're very pleased to collaborate with Bristol-Myers Squibb on the worldwide commercialization of apixaban, which has the potential to be a best-in-class product and would represent an excellent strategic fit with our global cardiovascular franchise," said Jeffrey B. Kindler, chairman and chief executive officer, Pfizer. "We see significant opportunities for an orally active anticoagulant with the clinical profile apixaban has demonstrated to date, particularly because of the clear need for new treatments to combat thrombosis and stroke. This agreement demonstrates our commitment to pursue revenue opportunities both through our business development and external alliances as well as our internal research and development pipeline."

About Venous Thromboembolism and Atrial Fibrillation

The process by which blood clots occur and travel through the veins is known as venous thromboembolism (VTE), the collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). In the U.S., it is estimated that 2 million people develop DVT each year. DVT is the formation of a thrombus (clot) in one of the deep, large veins of the body, such as in the leg or pelvis. A thrombus that breaks free and travels through the circulatory system is called an embolism. An embolism that lodges in a pulmonary artery in the lungs results in pulmonary embolism (PE). PE is a potentially fatal condition if not immediately diagnosed and treated.

Atrial fibrillation (AF) is an abnormal heart rhythm that affects approximately 2.3 million people in North American and 4.5 million people in Europe. The chief hazard of atrial fibrillation is the risk of stroke, which is five times higher in people with AF than in those without AF. AF is responsible for one out of every six ischemic strokes.

About Apixaban

Apixaban is a novel, oral, highly selective, direct factor Xa inhibitor currently in Phase III development. Factor Xa plays a pivotal role in the coagulation cascade and may represent a more targeted approach to anticoagulation therapy compared to current treatments that affect multiple factors in the coagulation pathway. The companies plan to file for U.S. regulatory approval of apixaban for prevention of VTE in the second half of 2009 assuming the successful completion of clinical trials, with filings planned for additional indications beginning in 2010.
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[DewDiligence]

BI Reports Phase-3 Results for Dabigatran

[Dabigatran is an oral inhibitor of thrombin that is among an array of drugs vying to supersede warfarin (#msg-18759853). What makes Dabigatran different from the other candidates is that it inhibits thrombin directly rather than via the Factor Xa feedback loop. BI hopes that Dabigatran can avoid the liver toxicity that doomed AZN’s Exanta, the last oral thrombin inhibitor to make it through phase-3. To date, Dabigatran’s safety profile has looked OK.]

http://biz.yahoo.com/prnews/070711/nyw078.html?.v=101

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Phase 3 Results for Dabigatran Etexilate, an Investigational Oral Anticoagulant, Presented Today at the XXIst Congress of the International Society on Thrombosis and Haemostasis
Wednesday July 11, 12:04 pm ET

RIDGEFIELD, Conn., July 11 /PRNewswire/ -- Phase 3 results from the RE-NOVATE™ trial demonstrated that oral dabigatran etexilate once daily, administered for an average of 33 days, was non-inferior to enoxaparin, also administered for an average of 33 days, in preventing venous thromboembolism (VTE) and all-cause mortality after total hip replacement surgery. In this trial, the rate of major bleeding associated with dabigatran etexilate was similar to enoxaparin. The incidence of liver enzyme elevations and acute coronary events during the treatment or during the follow-up period did not differ significantly between the treatment groups. These data were presented at the XXIst Congress of the International Society on Thrombosis and Haemostasis (ISTH) today. In clinical trials, dabigatran etexilate is given orally once daily and does not require titration or coagulation monitoring.

Results of the RE-NOVATE trial showed that both oral doses (220mg; 150 mg) of dabigatran etexilate were non-inferior to injected enoxaparin at reducing the risk of thromboembolic disease after primary elective total hip replacement surgery when given for the extended average time period of 33 days. The incidences for the primary efficacy composite endpoint of total VTE and all-cause mortality were 6.0% (dabigatran 220 mg), 8.6% (dabigatran 150 mg), and 6.7% (enoxaparin 40 mg). The incidences of total VTE and all-cause mortality in both dabigatran dose groups were within the pre-specified non- inferiority margin of 7.7%. Safety was evaluated for 3,463 patients receiving study treatment. The incidences of major bleeding events were similar in all treatment groups, 2.0% (dabigatran 220 mg), 1.3% (dabigatran 150 mg), and 1.6% (enoxaparin 40 mg).

Also presented at ISTH was a pooled analysis of major VTE and VTE-related mortality after primary elective knee and hip replacement surgery across more than 8,000 randomized patients that were included in the phase 3 primary VTE prevention program (RE-MODEL(TM), RE-MOBILIZE(TM) and RE-NOVATE studies). The pooled analysis concluded that dabigatran etexilate was non-inferior to enoxaparin in the prevention of major VTE and VTE-related mortality after both knee and hip replacement. Major VTE rates for both doses of dabigatran etexilate were similar to enoxaparin -- major VTE and VTE-related mortality occurred in 3.8% of the 150 mg dabigatran etexilate group and 3.0% of the 220 mg dabigatran etexilate group, versus 3.3% of the enoxaparin group. Major bleeding events were similar across all treatment groups (1.1%, 1.4% and 1.4% respectively). As part of the safety evaluation, patients were monitored frequently for liver enzyme elevations. Those patients with elevations of >3 x ULN (upper limit of normal) were infrequent and similar across all treatment groups. In addition, treatment emergent acute coronary syndrome (ACS) events were infrequent and similar across treatment groups.

Results from the European knee replacement trial (RE-MODEL) were previously presented in December 2006 at the Annual Meeting of the American Society of Hematology. The RE-MODEL study was a multi-national, randomized, double-blind, non-inferiority trial involving 2,076 patients comparing dabigatran etexilate with enoxaparin in the prevention of VTE in patients undergoing primary elective total knee replacement surgery. Patients were randomized to either oral dabigatran 150 mg or 220 mg once daily or 40 mg enoxaparin administered by subcutaneous injection once daily. In the U.S., the approved dose of enoxaparin for this indication is 30 mg, administered twice daily by subcutaneous injection.

Results from the North American knee replacement trial (RE-MOBILIZE) were also presented at ISTH. The RE-MOBILIZE study was a randomized, double- blind, non-inferiority trial involving 2,615 patients comparing 150 mg or 220 mg once-daily or 30 mg twice-daily enoxaparin administered by subcutaneous injection. The primary endpoint of a composite of total VTE, and all-cause mortality was not achieved (33.7% and 31.1% for 150 mg and 220 mg dabigatran etexilate respectively, versus 25.3% enoxaparin). The difference in these results was primarily due to the incidence of asymptomatic deep vein thrombosis (DVT) detected by protocol required venography at the end of therapy. Major VTE occurred at similar rates across all treatment groups (3.0% and 3.4% for 150 mg and 220 mg dabigatran etexilate respectively, versus 2.2% enoxaparin). Although major bleeding events were more common in the enoxaparin group (1.4%) compared to the dabigatran 220 mg group (0.6%) and the dabigatran 150 mg group (0.6%), these differences were not statistically significant.

About dabigatran etexilate

Dabigatran etexilate is an investigational oral direct thrombin inhibitor that specifically and reversibly inhibits thrombin, the key enzyme for blood clot formation, and is currently in phase 3 development. It is administered as a once daily oral dose that does not require titration or coagulation monitoring.

Further studies investigating dabigatran etexilate

Dabigatran etexilate is being investigated in multiple phase 3 trials that are designed to investigate the oral direct thrombin inhibitor as a potential treatment and prophylaxis for several thromboembolic disease conditions. The phase 3 clinical trial program is expected to involve more than 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa.

Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 137 affiliates in 47 countries and approximately 38,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2006, Boehringer Ingelheim posted net sales of US $13.3 billion (10.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development. For more information, please visit http://us.boehringer-ingelheim.com.
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[DewDiligence]

MNTA – Here’s an index to some recent posts on anti-
coagulant drugs. The longer it takes for the FDA to
approve generic Lovenox (assuming that they approve
it at all), the less consequential the approval is likely
to be. Newer and better drugs are soon going to take
market share from Lovenox, perhaps abruptly.

#msg-18759853 Overview of the new oral anti-coagulants
#msg-21044989 Rivaroxaban (BAY, JNJ) bests Lovenox in VTE prevention
#msg-19134406 PFE, BMY ink $1B Apixaban collaboration
#msg-21044973 Apixaban non-inferior to Warfarin (phase-2)
#msg-21155926 Dabigatran (BI) non-inferior to Lovenox in VTE prevention
#msg-10569101 Arixtra (GSK) bests Lovenox in ACS

[DewDiligence]

FDA Pushes Genetic Test Tied to Warfarin

[Doctors worry about malpractice liability if the test is not performed.]

http://online.wsj.com/article/SB118722561330199147.html

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By ANNA WILDE MATHEWS
August 16, 2007

In May, Karen Schmale was rushed to Barnes-Jewish Hospital in St. Louis, gasping for air. Diagnosed with blood clots in her lungs, she was given a powerful blood thinner called warfarin.

The medicine probably helped save her life. Then it almost killed her. About a week later, Ms. Schmale, 49 years old, noticed blood in her urine and soon became so weak she could barely climb the stairs to her second-floor apartment. The warfarin was causing the bleeding, and she had to go back to the hospital for an emergency blood transfusion.

A genetic test revealed Ms. Schmale was unusually sensitive to the drug and needed a smaller dose. Before the test, "nobody knew I was going to react like that," says Ms. Schmale, a data-entry coordinator at a university in St. Louis.

The case shows the advances in personalized medicine, where treatment is tailored to an individual's genetic makeup. But, in a possible harbinger of battles to come, the warfarin tests have also led to a clash between the Food and Drug Administration and some doctors.

The FDA is set to announce today that warfarin's label will carry new information describing the role of genetics in dosing. The label will say that a lower initial warfarin dose "should be considered for patients with certain genetic variations."

Some specialists say testing hasn't been proved to reduce the risks of the drug. They fear patients who don't get the tests and run into trouble will sue doctors, citing the drug's label. While Medicare covers the tests, which generally cost between $300 and $500, major insurers such as Aetna Inc., WellPoint Inc. and Cigna Corp. don't. The insurers say they need more evidence about the benefits.

"It would be irresponsible and potentially harmful to suggest that testing be used, or even mentioned, in the label," said University of Washington professor Ann Wittkowsky in an interview before the FDA's decision. "It is fascinating science, but it is not yet ready for prime time."

Larry Lesko, director of the clinical pharmacology office at the FDA, says the agency has "substantial" evidence to support the new label and hopes it will improve safety by informing doctors.

Dr. Lesko is part of a larger initiative at the FDA to promote the use of genetic factors to predict how individuals will react to medicines. It's a shift for the agency, which traditionally has more of a reactive role as the regulator of the drug industry. "If the potential wasn't huge, we wouldn't be doing it," he says. "We felt we had to be more outspoken."

The agency has already included information about genetic testing on the labels of less-frequently used drugs for colon cancer and leukemia, among others. One drug, Genentech Inc.'s Herceptin for breast cancer, is designed especially for women whose tumor cells have a genetic abnormality.

But warfarin is the largest case study to date of what happens when the new science of genetics runs up against the everyday practice of medicine. Originally marketed as a rat poison, the drug was prescribed more than 30 million times last year in the U.S., according to IMS Health. It's available as an inexpensive generic pill.

Its main problem is the narrow window for safety. An excessive dose leads to bleeding. Warfarin is the second-most-likely drug, after insulin, to send Americans to the emergency room. By one estimate, it accounts for 43,000 ER visits a year in the U.S..

If tests for warfarin-sensitivity genes become commonplace, it would encourage other efforts to develop genetic tests linked to popular drugs. Researchers are looking at how genes affect the action of such drugs as the antidepressant Prozac, the diabetes drug metformin and the asthma inhaler albuterol. A team of Harvard researchers has shown good results with a genetic test predicting who will fail to respond to albuterol and similar drugs, says Scott Weiss, a professor involved in the study.

"There's going to be a debate about every one of these tests," says Dr. Weiss.

Researchers began developing warfarin as a drug for people after an Army inductee during the Korean War tried to commit suicide by eating it. He survived, and doctors were struck by how effectively the poison had restricted his blood's clotting ability, or coagulation. President Eisenhower took it after a 1955 heart attack. The drug's generic name derives from the Wisconsin Alumni Research Foundation, or WARF, which originally held the patent on it. It is also known by the brand name Coumadin.

From the start, doctors struggled with how to give warfarin safely. In the 1990s, they began using a measure called International Normalized Ratio that compares the blood's clotting ability at a given moment to a standardized measure. Typically, doctors prescribe an initial warfarin dose based on factors including a patient's size, age and other medications. They check the patient's blood frequently -- every few days, at first -- and tweak the dose to bring the INR within the desired range.

Stephanie Davis, 58, a development director for a Johns Hopkins University cancer center in Baltimore, developed blood clots in both legs after a long flight home from California three years ago. As she was released from the hospital, she was prescribed warfarin to prevent new clots and told to visit a clinic two days later so her blood could be checked.

The test showed Ms. Davis's INR wasn't in the target range, so her dose was adjusted and she had to return two days later. In the end, she spent five months visiting the clinic every other morning before she went to work. Even after that, she still had to get checked twice a week. Eventually, she stopped taking warfarin. Her doctors felt she didn't need to be on a blood-thinner full-time. "It is so frustrating," says Ms. Davis, who is on the board of an organization for people with blood clots.

Without such scrutiny, warfarin can be deadly. Maria Tirado, a 79-year-old diabetic who suffered from an irregular heartbeat, was prescribed a high dose after a brief hospital visit. The doctor noted that if her INR went above a certain number, the drug should be halted. But staffers at the La Jolla Nursing and Rehabilitation Center in La Jolla, Calif., didn't check her INR, according to a state inspection report, and kept giving the high dose for at least three weeks.

Massive Bleeding

Ms. Tirado was eventually brought to an emergency room and died in January 2006 after "massive bleeding into the brain," the inspection report said. Ms. Tirado's family is suing the nursing center's owner and people involved in her care. Andrew Torok, the center's general counsel, declined to discuss specifics of the case but said the center is appealing the state's findings. He said the center is "dedicated to providing quality care" and is "committed to taking whatever corrective actions are warranted."

About a decade ago, research began to show that a gene known as CYP2C9 could affect how people's bodies process Warfarin. People with certain variants tended to break down the drug more slowly, meaning it stayed in the body longer in its potent form. A 2002 study in the Journal of the American Medical Association suggested these people were more likely to get too much warfarin and bleed.

A few years later, researchers discovered that a gene known as VKORC1 also plays a role. It affects how efficiently the body processes vitamin K. That is relevant because warfarin's anticlotting action comes from its ability to interfere with vitamin K. A 2005 study in the New England Journal of Medicine affirmed that patients with certain variants of VKORC1 appeared to need lower warfarin doses.

Doctors in the field say that traditional measurements such as size and age account for just 15% to 20% of the variability in responses to warfarin. Adding the genetic factors can raise that figure to 50% or higher, say advocates of genetic testing.

Ms. Schmale in St. Louis says she had a rare combination of both genes that made her highly sensitive to warfarin. Doctors had started her on a daily dose of 10 milligrams of the drug, but after the tests she ended up on a dose averaging less than one milligram a day.

For another patient, 60-year-old John D. Marlin, genetics pointed in the opposite direction. When he developed a clot in his lung this May, the retired biology teacher from Evansville, Ill., was told he would start with four milligrams of warfarin each day. But after the genetic test, doctors switched the dose to eight to nine milligrams daily. "I just don't absorb it very well, so it takes more of it to work," Mr. Marlin says.

Ms. Schmale and Mr. Martin were part of a study led by Brian Gage, an associate professor at Washington University. "There's clear agreement that variants of these genes affect the therapeutic dose of warfarin, so the product labeling ought to reflect that knowledge," says Dr. Gage.

Intriguing Studies

As studies on the genetic connections began to appear, the FDA's Dr. Lesko was intrigued. He is a 62-year-old pharmacologist and former University of Maryland researcher. The agency's database showed warfarin had one of the highest rates of reported side effects. The 50-year-old drug seemed like a perfect subject for a working group Dr. Lesko and others had formed to examine how emerging science could be translated into real-world safety improvements.

Dr. Lesko had a personal experience with the issue when his 82-year-old mother-in-law, prescribed warfarin after a hip replacement, struggled with the frequent blood checks. "Using genetic factors...not only improves safety -- that was my belief -- but it also was a way around the inconvenience," he says.

In November 2005, an outside FDA advisory committee, by a 8-2 vote, favored putting information about genetic tests on warfarin's label. "I think doctors need to know," says the panel's chairman, David Flockhart, a professor at Indiana University.

But the agency has encountered resistance from doctors who believe the tests' benefits are unproven. On May 4 of this year, Dr. Lesko addressed a medical group called the Anticoagulation Forum, which includes doctors, nurses and others who work at clinics focused on clot treatment. He said warfarin doses were being set by "trial and error," and described how genetic testing might help.

Dr. Lesko's talk "put a chill up many of our spines," says David Garcia of the University of New Mexico, the forum's president. Dr. Garcia notes that no one has conducted a clinical trial focused on bleeding rates that randomly assigns patients with clots to either the genetic-testing approach or the traditional way of prescribing warfarin. Unless such a trial proves that the tests lead to better safety, "it's all just theoretical," says Dr. Garcia.

The forum's board wrote a letter to Dr. Lesko warning that doctors might rely too heavily on the tests and fail to monitor patients closely enough. The letter said doctors might think they had to wait for test results to come back before giving patients any warfarin, although the FDA says that's not what it intends. The group asked that any new label "reflect the uncertainty" so doctors wouldn't be held liable in court for failing to do the tests.

In a nod to such concerns, the new warfarin label keeps the genetic factors out of a "black box" at the top of the label that warns of bleeding risk. It also refrains from directly recommending that doctors conduct the genetic tests when they prescribe warfarin.

However, a section of the label called "Precautions" says certain variations in the two key genes "may increase the need for more frequent INR monitoring and the use of lower warfarin doses." Another part of the label summarizes the genetic research on warfarin.

For doctors, the new label may create practical dilemmas. Experts are still developing guidelines for how to translate genetic results into a recommended dose. Washington University's Dr. Gage has one computer program, posted at warfarindosing.org, but there is no definitive model. The FDA is backing research to develop a guide.

Three FDA officials, including Deputy Commissioner Randall Lutter, released an economic analysis last November projecting that widespread use of the tests in the U.S. could avoid 85,000 serious-bleeding events and 17,000 strokes a year, and save about $1.1 billion annually.

'Very Optimistic'

David Matchar, director of the Center for Clinical Health Policy Research at Duke University, calls it a "very optimistic interpretation," and says there is "a disconnect between the clinical evidence...and the idea that the FDA should be advocating for this."

The FDA's Dr. Lutter, an economist, says the analysis was meant to "draw attention to the exciting opportunities" and is "consistent with our mission of protecting and promoting the public health," but wasn't intended as a treatment recommendation. Dr. Lesko says, "The evidence for updating this label was much more substantial than it has been for other label updates."

In the past year, a growing number of lab-testing companies including the for-profit unit of the Mayo Clinic and Laboratory Corp. of America Holdings have begun doing warfarin genetic tests. Quest Diagnostics Inc., another major testing company, plans to introduce one soon.

Because it takes time to get test results, doctors typically have to decide the initial dose using older methods. Some testing labs say they can deliver results in one to three days. LabCorp does its test only at a facility in North Carolina and it takes about 10 days to get results. A company official says it hasn't heard complaints about the turnaround time.

Medco Health Solutions Inc., which manages employers' drug-benefit plans, is doing a study with the Mayo Clinic to examine the effect of the genetic testing in a real-world setting. Robert Epstein, chief medical officer of Medco, says an FDA label change could have a big impact, but some insurers are "waiting for studies like the one we're doing to see what is the ultimate outcome."
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[DewDiligence]

A Blood-Thinner Best Seller?

[This article could be the “Cliff’s Notes” version of the anticoagulant overview in #msg-18759853. It barely scratches the surface.]

http://www.forbes.com/2007/12/06/10a-inhibitors-warfarin-biz-healthcare-cz_rl_1207thinner.html

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By Robert Langreth
12.07.07

The race to develop new blood thinners is going into overdrive.

Some of the biggest drug companies in the world are moving into final-stage trials of new anti-clotting drugs aiming to be safer and more convenient then existing remedies.

Johnson & Johnson, Bayer, Bristol-Myers Squibb and Eli Lilly are all rushing to test the new drugs, called factor Xa inhibitors. The pills aim to replace a finicky, fifty-year-old drug called warfarin.

While effective, warfarin is incredibly tricky for doctors to use because there is only a tiny margin between giving too little and giving too much, risking uncontrolled bleeding. It is slow to kick in and interacts with many foods and other drugs. The new drugs aim to avoid these problems. And unlike Sanofi-Aventis' big-selling injectable blood thinner, Lovenox, they can be given as pills.

Drug industry research firm Decision Resources predicts that, if successful, the new drugs could double the size of the anti-coagulant market from $3 billion last year to $7.4 billion in 2016. The factor Xa inhibitors have "home run potential," says Citigroup analyst Matthew Dodds in a recent report. The drugs work by blocking an enzyme called factor Xa that helps spur the production of a crucial clot-promoting protein called thrombin.

Anti-clotting drugs represent one of the few big sales opportunities at a time when the drug industry researchers are struggling to come up with new drugs. Genentech's bid to get its Avastin colon cancer drug approved in breast cancer was rejected by a Food and Drug Administration panel earlier this week. Drug approval numbers are at a multiyear trough.

Rivaroxaban, invented by Bayer and soon marketed by Johnson & Johnson in the U.S., is among the farthest along of the new clot-stoppers. At a big meeting of hematologists in Atlanta this coming weekend, Johnson & Johnson and Bayer are scheduled to present results of three big trials showing that rivaroxaban is better than Sanofi-Aventis' Lovenox at preventing leg vein clots in patients getting knee or hip replacement surgery.

The presence of such clots, a problem called deep vein thrombosis, is dangerous because they can eventually dislodge and end up causing fatal pulmonary embolisms, clots in the main artery leading from the heart to the lung. Abstracts of these trials were published a few weeks ago in advance of the meeting, but J&J and outside researchers who did the trial are prohibited from commenting in advance of the meeting.

Johnson & Johnson is finishing up a required U.S. trial and hopes to apply for approval for preventing leg clots in the second half of 2008. (Bayer has already filed for European approval.)

Meanwhile, J&J and Bayer have begun a giant 14,000-patient trial in a potentially far bigger market: preventing strokes in patients with a common heart rhythm problem, atrial fibrillation. Some 2.9 million Americans suffer from this problem, estimates Citigroup. But studies have found that only around half of the eligible patients end up on warfarin because of the hassles involved in using it.

Bristol-Myers, with partner Pfizer, is testing factor Xa blocker apixaban in a giant 15,000-patient trial on preventing stroke. Both of these trials directly compare the new drugs to warfarin. Meanwhile, at an analyst meeting in New York yesterday, Eli Lilly said it's also testing a factor Xa drug and plans to begin first final-stage trials in 2009.

All sorts of issues could still hold up approval of the new drugs, given an increasingly risk-averse FDA. One big concern: whether the drugs cause liver problems. A few years ago, AstraZeneca touted its new blood thinner drug Exanta as a breakthrough that could replace warfarin. But the FDA rejected it after regulators saw signs it could cause liver failure; the drug eventually was withdrawn in Europe as well. Expect scrutiny of the J&J/Bayer trials at this weekend's hematology meeting as Wall Street analysts look closely for any hint of liver problems. No signs of such problems have emerged in data released so far.
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