The 50 million Americans suffering from chronic pain got a little bit of good news in December -- but just a little. Amid a flood of reports linking existing painkillers with cardiovascular problems, the Food & Drug Administration greenlighted two new medications -- Prialt, from Elan Corp. (ELN ), and Lyrica, from Pfizer Inc. (PFE ) -- that attack pain in completely novel ways.
Unfortunately, neither drug is designed to help millions of patients, as was the blockbuster painkiller Vioxx, which Merck & Co. (MRK ) withdrew from the market in September. And neither will bring the same rich rewards to its manufacturer.
The lack of a giant payoff could be a problem for future analgesics, given that both Prialt and Lyrica went through a far lengthier and costlier development process than originally expected. The struggles by Elan and Pfizer to get these two medicines on the market highlight the immense difficulties that beset the entire field of pain research and treatment.
Both drugs are in the vanguard of a new generation of analgesics that act as precision bombs, targeting cellular mechanisms responsible for certain kinds of agony. The hope is that because these drugs are so precise, they won't cause side effects that would endanger broad groups of patients, as occurred with the widely prescribed COX-2 inhibitors such as Vioxx. But the fact that they address a smaller market could discourage drugmakers from taking costly risks on similar, targeted therapies in the future.
Prialt, derived from the poisonous venom of the tiny cone snail, was first developed in the mid-1990s, and Elan filed for FDA approval in the fall of 2000. But to satisfy the agency's safety concerns, Elan had to redo Prialt's clinical trial. Four years later, on Dec. 28, the drug finally got the go-ahead -- but only for patients with severe pain who cannot tolerate morphine.
Lyrica, Pfizer's successor to its epilepsy drug Neurontin, also ran into several years of delays as the company fine-tuned its clinical trials. Pfizer had hoped to market the drug for epilepsy, anxiety, and pain, but the FDA approved it only for nerve pain associated with diabetes and shingles. Worse, the agency classified Lyrica as a controlled substance under the purview of the Drug Enforcement Administration, which could limit its market. Standard & Poor's (MHP ) analysts say the drug eventually could reach $1 billion in annual sales -- less than half the $2.4 billion that Neurontin pulled in last year.
Medical specialists do not want drug researchers to give up the quest, despite the difficulties. "New drugs are desperately needed," says Dr. Allen W. Burton, an anesthesiologist at M.D. Anderson Cancer Center in Houston. "We are not covering groups of patients with very resistant pain."
Virtually every drug approved for pain today blocks one of just two cellular mechanisms. Nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, as well as the COX-2 drugs that include Vioxx and Celebrex, all block pain-causing COX enzymes that incite inflammation around joints. For more serious pain there are narcotics such as morphine, codeine, and OxyContin, which block opioid receptors in the brain that sense pain. These are the primary treatment for debilitating neuropathic pain caused by damaged nerves, which afflicts some 10 million people in the U.S.
The opioid drugs are considered the gold standard of pain treatment, because they can relieve just about any kind of suffering. But their downside -- severe side effects and possible addiction -- is too huge for many patients. The NSAIDs too, have side effects, particularly gastric bleeding. On top of all the safety concerns, pain drugs often simply do not work. A recent national survey sponsored by Purdue Pharma LP, maker of Oxycontin, found that two-thirds of pain patients considered their over-the-counter pain medication ineffective, and 52% of those on prescription drugs said the same.
A LONG SLOG
The subjective nature of pain also complicates the administration of any drug. No blood test can determine how badly patients are suffering, and many are loath to complain. Doctors often don't ask, either. It's only in the past five years that pain treatment guidelines have become commonplace in hospitals. As a result, medical studies routinely find that at least 40% to 50% of patients are undertreated for chronic pain, defined as pain that lasts more than three months. This, despite the fact that Americans spent some $18 billion last year on prescription pain drugs.
The vast market, combined with the poor profile of existing drugs, got Big Pharma to seek better treatments in the 1990s. Since then, researchers have been able to identify several cell receptors and nerve channels involved in pain transmission. Developing drugs to moderate the sensation has been a long slog, however. "It's very, very difficult to find targets in the central nervous system that are both safe and effective," says Dr. Clifford J. Woolf, professor of anesthesia research at Massachusetts General Hospital in Boston. In addition, Woolf notes, any pain drug must be tested for its potential for abuse and addiction, a problem most other classes of drugs don't face.
Elan's Prialt shows no signs of being addictive, a big advantage over opioids. The drug blocks a calcium channel found at the end of nerve fibers that transmits the pain signal up the spinal cord to the brain. Researchers estimate that it is hundreds of times more potent than morphine, but far more toxic as well, making Prialt an unacceptable candidate for a pill or injection.
Instead, small quantities are pumped directly to the fluid surrounding the spinal cord via an implanted catheter and pump. The FDA restricted Prialt's use to patients with severe pain who no longer get relief from morphine, not a blockbuster-size market. Elan, which has yet to announce pricing, estimates that about 120,000 patients in the U.S. are candidates for Prialt.
Nevertheless, Prialt's approval may pave the way for other pain treatments derived from poisons. Wex Pharmaceuticals Inc., a Vancouver startup, is in clinical trials with a drug called Tectin, derived from the deadly toxin of the puffer fish, whose flesh is a risky delicacy known as fugu in Japan. Delivered by injection, Tectin blocks sodium channels that play a role in transmitting many types of pain signals. Another startup, AlgoRx Pharmaceuticals Inc., is testing a drug based on capsaicin -- not a poison, but the substance in chili peppers that burns the skin. Capsaicin inhibits C neurons, the nerve cells responsible for dull, throbbing, continuous pain (as opposed to sharp, acute temporary pain).
Nicotine, the poisonous chemical found in tobacco, has also been shown to soothe pain in animals, but it is far too addictive for use in humans. As an alternative, Abbott Laboratories (ABT ) has spent a decade looking for drugs that target subsets of the nicotinic receptors, the nerve- cell proteins that suck up nicotine. The hope is that by homing in on just those receptors involved in pain, a drug will quiet overexcited nerve endings without risk of addiction.
After several attempts, Abbott has a nicotinic receptor pill, ABT-894, in early human trials. James P. Sullivan, head of the company's neuroscience discovery research, says 894 seems to work against a spectrum of neuropathic pain. And it's well-tolerated. "We still need to get it into (larger) trials to determine its best use, but we believe this is an innovative new mechanism for pain relief," says Sullivan.
It will be a few years, however, before 894 -- or any of the novel pain drugs in development -- are ready for FDA review. Winning that approval is sure to be difficult in the wake of the safety issues swirling around the COX-2s. Still, the approvals of Prialt and Lyrica show that it can be done and are encouraging pain researchers. "They open people's eyes to other categories of drugs beyond opioids," says M.D. Anderson's Burton. Now drug companies just have to figure out how to develop those categories in a cost-effective way.
By Catherine Arnst in New York