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

August 20, 2005
Battered but Unbowed: Can Painkillers Recover?
By STEPHANIE SAUL
Cox-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, GlaxoSmithKline, 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. Daniel 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 Tracy 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?"