Let Bygones Be Bygones

COX-2 inhibitors may have fallen from grace in the eyes of patients and doctors, but companies that once dominated the market are still big believers.

An FDA advisory committee last week gave its blessing to Pfizer's well known osteoarthritis drug, Celebrex (celecoxib), to treat juvenile rheumatoid arthritis. Novartis has released additional safety data on Prexige (lumiracoxib), which is awaiting FDA review. And even Merck, still nursing its wounds from the Vioxx debacle, is pursuing another COX-2, Arcoxia (etoricoxib), also awaiting FDA review.

Companies are forging ahead with COX-2 innovation, despite skepticism. Even if FDA green lights the pending applications, analysts balk at the idea that the category will ever return to its former glory. Some observers also suggest that the drugs could become test cases for new post-marketing safety initiatives that the agency has been trying to put in place--but has had trouble enforcing.

"The public is scared of them," said Mary Anne Crandall, an analyst at market research firm Kalorama Information. "I think they're still going to question their doctors, and physicians are going to be much more conservative about prescribing these drugs."

Yet at the same time, she said she was surprised that Celebrex's financial performance managed to exceed expectations. In the third quarter alone, Celebrex had sales of $537 million, a 20 percent increase over the same period in 2005. The drug has recaptured about three-quarters of the sales it had before the withdrawal of Merck's Vioxx (rofecoxib) cast the category into a tumult.

Nevertheless, new COX-2s still face regulatory hurdles, as well as a number of public relations challenges. Outspoken COX-2 critics like Drs. Steven Nissen, who heads cardiology at the Cleveland Clinic, and David Graham, the FDA whistleblower, have pushed for FDA to accept more authority for monitoring these drugs post-approval.

FDA, for instance, might question Merck's use of diclofenac to benchmark the heart risks of Arcoxia; the decision sparked controversy since the NSAID isn't what's known as a "first path" treatment in the United States.

"They have a long uphill battle," said Ed Vawter, president of consultancy QD Information Services, of drug makers pursuing COX-2 development programs. "Is it worth continuing to push [an R&D platform] forward?"

New clinical data, however, might be the saving grace for the class. More evidence has come to light about why COX-2 inhibitors pose heart risks. In the journal Biochemistry, researchers write that the drugs reduce production of prostacyclin and increase thromboxane--which dilate and constrict blood vessels, respectively. The findings could usher in the next generation of COX-2 drugs that have the same anti-inflammatory benefits but fewer side effects.

"That's going to be the key issue to keep an eye on: Is it all COX-2 inhibitors or just some COX-2 inhibitors" that pose heart risks? Vawter noted. "The jury's still out on that."