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A New Painkiller's Painful Path

By Catherine Arnst Pain treatment is very much in the news lately, with reports that Merck's (MRK) Vioxx, Pfizer's (PFE) Celebrex, and now Bayer's (BAY) Aleve may all increase the risk of heart attacks. It's ironic that Celebrex and Vioxx were originally developed to remove the risk of bleeding ulcers associated with ibuprofen, aspirin, and other over-the-counter pain medications. That both turned out to have their own worrisome side effects demonstrates how extremely difficult it is to develop new pain treatments. Given that some 50 million Americans are partially or totally disabled by chronic pain, the need couldn't be more dire.

Right now, almost all painkillers fall into two categories: aspirin and other nonsteroidal anti-inflammatories such as Aleve, and the so-called Cox-2 inhibitors that include Vioxx and Celebrex, all block pain-causing Cox enzymes that flood the body when a joint or muscle is inflamed. For very severe pain there are the opioids, such as morphine, codeine, and Oxycontin, which can cause extreme drowsiness and are open to being abused. There has been some success treating pain with antidepressants and epilepsy drugs, but their record is spotty. Consequently, drug researchers have been working for over a decade to come up with more effective treatments.

GASTROPOD JUICE. One of the first, called Prialt, is slated to receive a yea or nay from the Food & Drug Administration by the end of December. The product, made by Irish drug company Elan (ELN), will be used only by the most severely debilitated pain victims, who have found no relief with morphine. Still, it's a breakthrough drug, and particularly interesting because of its source -- the poisonous venom of the tiny cone snail.

Prialt is also a cautionary tale of how difficult it can be to develop a new pain treatment. Researchers first discovered in the early 1980s that a protein in cone-snail venom was 1,000 times more effective than morphine at relieving pain and had the added benefit of not having any addictive potential.

By the mid-1990s a tiny biotech outfit, Neurex, had come up with a drug based on that protein. Originally called Ziconotide, it's the first of a new class of analgesics known as N-type calcium channel blockers, so-called because they block the calcium channels found at the end of nerve fibers. These channels facilitate the passage of the electrical pain signal from one nerve to another and up the spinal column to the brain. If the channel is blocked, the pain signal can't reach the brain.

THREE-YEAR DELAY. Because Ziconotide is so potent, it can't be taken as a pill or even a shot. Instead, it is pumped with a surgically implanted catheter directly into the fluid surrounding the spinal cord, a delivery method known as intrathecal infusion. The drug looked so promising in initial clinical trials that Elan acquired Neurex in 1998 for $741 million in stock. Elan filed for FDA approval in 2000, but there were some major problems with the design of the clinical trials. In particular, the FDA said the data weren't sufficient to determine what the proper dosage should be, a key issue with pain drugs.

Still, the FDA considered Ziconotide promising enough to grant it an "approvable letter," meaning the chance was strong that the agency would issue a formal approval if it got the requested data. "Once we worked through all the questions with the FDA, we realized there was no other way forward than to redo" the final, Phase 3 trial, says Dr. Lars Ekman, Elan's president for research and development. And that took another three years.

Last January, Elan was finally ready to reveal those Phase 3 results. In an article in the Journal of the American Medical Assn. (JAMA), researchers reported the drug achieved statistically significant pain relief for patients with cancer and AIDS, two diseases associated with intense pain. The company changed the drug's name to Prialt and resubmitted its application to the FDA in June. It also sought approval from the European Union. An EU advisory committee recommended approval in November, raising expectations that the FDA would give the drug a green light.

"DESPERATELY NEEDED." Prialt will likely never match the blockbuster sales of Celebrex, however. Dr. Michael H. Levy, director of the pain-management center at Fox Chase Cancer Center in Philadelphia, notes that it's meant for a very small group of patients for whom morphine is no longer effective and who can tolerate the intrathecal-delivery method. "In general, that's 1 in 100 or 1 in 1,000 patients who can't get good comfort and function with existing drugs," he points out.

Still, Prialt does end the long drought of new pain treatments that take aim at novel cellular targets. "I think this medication opens people's eyes to other categories of analgesics beyond the opioids," says Dr. Allen W. Burton, associate professor of pain medicine at M.D. Anderson Cancer Center in Houston. "New drugs are desperately needed." Certainly the millions of people worried about Vioxx, Celebrex, and Aleve can attest to that. Arnst is a senior writer for BusinessWeek in New York

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