-2 drugs are down. But they may not be out.

[Guest guest]

August 20, 2005

Battered but Unbowed: Can Painkillers Recover?

By STEPHANIE SAUL

-2 drugs are down. But they may not be out.

By deciding yesterday that the Merck drug Vioxx contributed to the

death of a Texas man, a jury dealt another punch to the battered class

of arthritis painkillers known as cox-2's. Merck withdrew Vioxx from

the market last fall over safety concerns, and Pfizer did the same

thing a few months later with one of its cox-2 drugs, Bextra.

So why are some companies, including Merck and Pfizer, still betting on

a big cox-2 comeback?

For one thing some analysts have said that sales of Celebrex, another

drug by Pfizer that is the only cox-2 remaining on the United States

market, are already rebounding after a big slump last winter. Celebrex

sales, they say, could reach as high as $2 billion this year, a decline

of 39 percent from last year. The rebound comes despite warnings that

Celebrex - like Vioxx and Bextra - can cause cardiovascular problems in

some patients. Merck has another cox-2 drug, Arcoxia, that is already

approved in 54 other countries and generated worldwide sales of $100

million in the first half of this year.

Meantime, GlaxoKline, Novartis and even Merck are investing

millions in clinical research to prove the safety of new cox-2's, which

must clear newly raised hurdles to gain Food and Drug Administration

approval, with submission of data to the F.D.A. still several years

away.

For all the clouds that hang over the class, cox-2's are still valued

by some physicians as a type of anti-inflammatory drug designed to be

safer on the stomach than some more conventional painkillers, like

aspirin. The drugs reduce the risk of gastrointestinal bleeding by

selectively inhibiting a specific enzyme, cyclooxygenase-2.

" There's still quite a lot of potential with these drugs, " said Gustav

Ando, an analyst for the business research firm Global Insight, in

Waltham, Mass. " It's just that the name has been tarnished and they

need to rebrand the therapeutic area. "

Mr. Ando said that the companies with cox-2's in development would be

closely watching yesterday's jury verdict and its aftermath to gauge

the potential risks of being associated with the class. But for many,

the potential rewards may lure them forward.

Many analysts and doctors predict that the dearth of effective

painkillers and the growing ranks of baby boomers suffering from aching

joints will drive growth in the market.

The worldwide market for cox-2's surpassed $7 billion in 2004, and had

been projected to reach $9 billion by 2010, before the Vioxx and Bextra

withdrawals sent the market tumbling. Mr. Ando predicts it will take

the industry several years to define the drugs' cardiovascular risks

and benefits clearly and to sort through a potential regulatory thicket

before the market begins to rebound.

Dr. Stanley Cohen, a rheumatologist in Dallas, said that the withdrawal

of Vioxx last September as well as Bextra in April had been devastating

to some of his patients, even though he has tried to substitute with

other drugs.

" We've all been trying to come up with our own type of game plan until

there's better evidence-based medicine to guide us, " said Dr. Cohen,

who has tried Mobic (a drug marketed jointly by Boehringer Ingelheim

and Abbott Laboratories), analgesics and older anti-inflammatories

combined with Tylenol on his patients. But not all users of those drugs

find relief.

Data compiled by Verispan, a company that tracks pharmaceutical

prescribing, shows that a variety of generic anti-inflammatories and

Mobic have been the big beneficiaries of the cox-2 controversy.

Prescriptions of Mobic, which is similar in some ways to the cox-2's,

went from 277,569 in August 2004, before Vioxx's withdrawal, to 698,145

this June.

" I had a number of patients who only responded to Bextra or only

responded to Vioxx, " Dr. Cohen said. " We had a terrible time giving

them comfort when those drugs were removed from the market. "

It is just those types of patients, suffering with pain, that Glaxo's

senior vice president for neuroscience medicines, Dr. J. Burch,

cited when discussing his company's as yet unnamed cox-2 drug, known

currently as 406381.

" There's really not much out there to treat patients who have chronic

pain, " Dr. Burch said. " The media has really scared a lot of people. A

lot of people are not taking pain medications because they're worried

about the cardiovascular risk. "

Glaxo, which is making a gigantic investment in drug 406381, announced

in May that it would go forward with Phase 3 clinical studies - the

last phase of patient trials before submitting a drug for F.D.A.

approval. Dr. Burch said the test would probably involve more than

20,000 patients. The company is currently in talks with the F.D.A. to

design the trial.

The cost of such large trials is high, often exceeding several thousand

dollars a patient. But in studying the cox-2's, the sample size is

extremely important. Because only 1 percent or 2 percent of patients

might be susceptible to cardiovascular risks, smaller samples may not

adequately reveal any risks.

" Really what we're talking about in our Phase 3 program is

demonstrating a compelling benefit that this drug will have, " Dr. Burch

said. " We're going to measure the risk unlike anyone has ever done

before. "

Glaxo was late to the cox-2 party. But Mr. Ando said that could work to

the company's advantage. " It's the only drug that's completely

disassociated from the crisis, " he said. " All the other drugs had brand

names given to them. "

Glaxo also says its drug is different from other cox-2's because it

works on the central nervous system in addition to peripheral nerves.

But even if all goes well with the drug, it will very likely be three

years before patients can use 406381.

A drug that could potentially be closer to market in this country is

Arcoxia from Merck. It is already the largest-selling painkiller in

Brazil, where Mr. Ando said it was benefiting from the withdrawal of

Vioxx and Bextra. Merck initially submitted Arcoxia for F.D.A. approval

in 2001 and received a letter last year indicating that it could

eventually be approved, with further data, the company said.

The company now has under way a 23,000-person clinical trial, called

Medal, to test Arcoxia's cardiovascular safety compared with

diclofenac, a nonsteroidal anti-inflammatory that is one of the world's

largest-selling painkillers, sold under a variety of generic and brand

names. The results of Medal, which will be available soon, are being

combined with data from two other trials to get a sample size of more

than 30,000 patients, according to Ogden, a Merck spokeswoman.

" Of course, having Medal under way and continuing shows our commitment

in exploring this product, " Ms. Ogden said.

Still, an investment report in May by Friedman Billings Ramsey said

Arcoxia's future was unclear. The report noted that members of an

F.D.A. panel were unenthusiastic in February about the design of the

Medal trial and it also compared Arcoxia's safety profile with that of

Vioxx.

Novartis, meanwhile, is pushing ahead with its cox-2 drug, Prexige,

already approved in 22 countries and on the market in Brazil. The

company submitted it for F.D.A. approval in November 2002, but the

agency said the next year that it could not approve the drug because

the company had submitted inadequate data. Novartis is continuing

clinical studies and hopes to resubmit data to the F.D.A in 2007, with

plans to request approval for patients with serious gastrointestinal

problems.

" Novartis believes that for the right patient, Prexige might prove the

pain relief needed, " the company said in a statement yesterday.

Dr. Garret A. FitzGerald of the University of Pennsylvania, who first

noticed problems with the cox-2's in 1998, said the new scrutiny the

drugs are receiving could provide an opportunity for the pharmaceutical

industry to develop an individualized approach to managing drug risks.

Such an approach would involve identifying and locating the genetic

biomarkers that make some people susceptible to cardiovascular risks

from cox-2's and, also, the markers that make some people's pain

respond to the drugs.

" It's a small risk, " Dr. FitzGerald said. " How do we detect that small

number of people who are getting into trouble so we can stop the drug? "

* Copyright 2005 The New York Times Company