Nearly four decades ago, a new sedative brought the golden age of pharmaceuticals to a tragic end. The drug debuted in Europe in 1957 as a treatment for nausea, and within a few years it was being sold in more than a dozen countries to relieve morning sickness in pregnant women. At the time, nobody suspected that drugs could pass from a mother's bloodstream to the fetus. But by 1962, reports of flipperlike limbs and other deformities in more than 10,000 newborns worldwide were linked to use of the drug among expectant mothers. The most notorious debacle in the history of drug development would become synonymous with the sedative's generic name: thalidomide.
Reports of the birth defects reached the U.S. Food and Drug Administration before the drug could be approved for sale in this country. But in July 1998, thalidomide came to the market. A New Jersey biotech company gained the right to sell it for the treatment of a debilitating complication of leprosy. Now, due to FDA regulations that permit "off label" use of approved drugs, thalidomide can be prescribed for any medical condition within a physician's discretion. And the possibility of its widespread use is more than theoretical: While it's unlikely to resume its former role as either tranquilizer or antiemetic, thalidomide has already demonstrated therapeutic potential against dozens of serious diseases, including cancer, rheumatoid arthritis, and AIDS. Its own manufacturer has called it "the most reviled drug in history," yet thalidomide may be primed for a surprising comeback.
In groundbreaking studies at the Rockefeller University in New York, for example, thalidomide has shown promise in treating symptoms of AIDS, tuberculosis, and utoimmune diseases, such as scleroderma, a life-threatening condition in which fibrous tissue grows in the skin and internal organs. Scientists still don't know why the drug causes birth defects. But as they discover more of its benefits, many are deciding that thalidomide therapy is worth the risk--as long as a patient isn't pregnant.
The rehabilitation of thalidomide began soon after its global fall from grace. In the mid-1960s an Israeli doctor reported that the drug not only eased discomfort in leprosy patients but also alleviated the symptoms of erythema nodosum leprosum, an otherwise intractable complication of leprosy that causes painful skin lesions. Thalidomide soon became the international drug of choice for that condition; in the United States, the Public Health Service distributed it at its leprosarium in Carville, Louisiana, beginning in the early 1970s. But it wasn't until the 1990s that work on the drug revealed its versatility. Led by immunologist Gilla Kaplan, the Rockefeller investigators found that thalidomide inhibits the production of a substance called tumor necrosis factor-alpha (tnf-alpha) that stimulates the immune system. In patients battling tuberculosis, AIDS, or leprosy, overproduction of TNF-alpha causes such systemic changes as fever, wasting, and night sweats. Too much TNF-alpha may also be associated with a host of diseases, including multiple sclerosis, some forms of lupus, asthma, Crohn's disease, and Alzheimer's disease. Studies are now under way to explore the drug's potential in all these areas.
Most thalidomide research, however, is focused on combating cancer. In the mid-1990s, scientists at Harvard Medical School and Children's Hospital in Boston announced that thalidomide belongs to a family of substances that curb the growth of blood vessels needed to nourish tumors. These so-called antiangiogenic agents have become a cottage industry in cancer research, and about 90 percent of thalidomide prescriptions now go to cancer patients. So far, the drug has proved most effective in treating multiple myeloma, a bone-marrow cancer that is especially resistant to traditional therapies. Results released last November from the University of Arkansas for Medical Sciences in Little Rock showed that thalidomide could boost survival rates even in patients who had relapsed after high-dose chemotherapy and bone-marrow transplants.
"We're talking about the first drug with solid activity against multiple myeloma in more than 35 years," says Elias Anaissie, clinical director of the Arkansas program. And because thalidomide doesn't work by the same mechanisms as standard cancer treatments, he says, "it's going to open new doors for scientists to discover other agents."
But Anaissie also cautions that thalidomide is no magic bullet. While encouraging, its success in cancer treatment has been limited, and some patients complain of side effects such as drowsiness, constipation, and nerve damage (which may be permanent) in the hands and feet. Victoria Freedman, a researcher in Kaplan's lab, says thalidomide's effects are varied and complex enough to be almost unpredictable. In addition to its activity against TNF-alpha and blood-vessel growth, the drug is now known to stimulate immune-system cells and other immunoregulators, sometimes with unexpected results.
"Thalidomide turns out to be a much more complicated drug than anybody ever thought," says Freedman. "You have to be really sure of what the pathogenesis of the disease is before you give a drug like thalidomide, because you could be aiding the disease instead of eliminating it." In two separate studies thalidomide therapy has been linked to the unexplained deaths of patients suffering from graft-versus-host disease--a condition in which immune cells from transplanted bone marrow attack host tissue--and a severe skin disorder called toxic epidermal necrolysis.
And many observers outside the medical community remain concerned about possible abuse of the drug. Distribution of thalidomide to physicians and pharmacists is strictly controlled and monitored by the FDA and Celgene Corporation, the drug's manufacturer. Thalidomide users are required to undergo counseling on the drug's risks and to use reliable contraception while taking it. Because thalidomide's disastrous effects on fetuses are known to occur during the first trimester, preventing conception among women taking the drug is crucial. The drug's packaging includes printed warnings and a picture of a thalidomide baby, and the pills themselves are stamped with the silhouette of a pregnant woman bisected by a diagonal--the universal do-not-take-while-pregnant symbol that marks a drug as a teratogen, a chemical that causes fetal deformities. Even so, a repeat of the 1960s tragedy is inevitable as long as thalidomide is readily available, says Randy Warren, founder of the Thalidomide Victims Association of Canada.
"The longer thalidomide is on the market, the lazier people will become about the warnings," says Warren. "They're going to start to feel safe with it again. Mark my words: Another thalidomide baby will be born."
"Our objective is to prevent any tragedies," counters Celgene president Sol Barer, who worked closely with the thalidomide victims association in designing both the distribution program and the drug's packaging. "Our trade name is Thalomid, which is very close to Ôthalidomide,' for obvious reasons. There should be no mistake that this is a teratogenic agent. And people aren't taking it for minor ailments. They're taking it for serious things for which there is very little alternative."
Warren's group and Celgene both support the development of thalidomide analogues that would preserve the drug's beneficial effects while eliminating its unfortunate ones. Celgene already has two families of such agents in clinical trials, says Barer, and the first product of these studies could arrive on the market within five years. It's unlikely, however, that any single compound will match thalidomide's broad spectrum of activity, he says; instead, different drugs will probably be designed to target each of thalidomide's mechanisms of action. That might be the most appropriate fate for a drug with a checkered past: to retire the paterfamilias with the foul reputation and divide the best of its legacy among a more benevolent generation.