New Uses For Thalidomide Yielding Valuable Lessons

Sidebar: Researchers Explore Thalidomide's Therapeutic Potential Firms are focusing on getting the teratogen to market to treat serious diseases; if successful, it may inspire fresh looks at other compounds. Thirty-five years after the effects of thalidomide horrified the world, the drug is teaching researchers a whole new set of lessons. This time, though, the message is positive: Working together, companies and the Food and Drug Administration (FDA) can indeed pursue important new compounds

Feb 3, 1997
Kathryn Brown

Sidebar: Researchers Explore Thalidomide's Therapeutic Potential

Firms are focusing on getting the teratogen to market to treat serious diseases; if successful, it may inspire fresh looks at other compounds.
Thirty-five years after the effects of thalidomide horrified the world, the drug is teaching researchers a whole new set of lessons. This time, though, the message is positive: Working together, companies and the Food and Drug Administration (FDA) can indeed pursue important new compounds-even when those substances cause birth defects. Today's thalidomide research-if successful-could motivate pharmaceutical firms to consider expanding research on other dangerous, yet badly needed, drugs.

Sold outside the United States as a sedative and morning sickness treatment in the 1950s and 1960s, thalidomide caused thousands of babies to be born with malformed arms and legs. In the wake of the disaster, FDA created guidelines for preclinical animal tests to learn if a new compound causes birth defects before it ever enters humans. Today, most companies abandon would-be pharmaceuticals at the first sign of birth defects in animal models.

But that could change-at least for drugs that treat serious disease. Ironically, thalidomide is now helping to open research opportunities for teratogenic (birth-defect-causing) drugs that fill a true market need. Several companies are pursuing thalidomide because it appears to moderate immune system reactions that characterize diseases like cancer and AIDS (see story on page 8).

MARKET NICHE: Celgene president Sol Barer says "the balance is in favor of" having thalidomide available to treat AIDS and leprosy.
In December, Celgene Corp. of Warren, N.J., asked FDA to approve thalidomide for treatment of an inflammatory disorder associated with leprosy, which is still prevelant in many countries. FDA could make a ruling this spring. Andrulis Inc. of Beltsville, Md., soon plans to ask FDA to approve thalidomide to treat mouth, throat, and rectal ulcers in people with AIDS. And Entremed Inc. of Rockville, Md., is conducting clinical trials of the drug to treat brain tumors.

Despite the thalidomide crisis in the 1960s, scientists have long appreciated the drug's important therapeutic potential. In 1965, researchers first reported that thalidomide's anti-inflammatory effect could ease erythema nodosum leprosum (ENL), a painful condition in leprosy patients. More than 2 million people suffer from leprosy worldwide. Outside the United States, thalidomide is commonly sold to treat ENL.

Until recently, however, researchers were uncertain how thalidomide works to tone down inflammatory reactions. Intrigued, Gilla Kaplan, an associate professor of cellular physiology and immunology at Rockefeller University, began exploring thalidomide's effect on tumor necrosis factor-alpha (TNF-alpha), a key cytokine that surges during inflammation. In 1991, Kaplan's lab reported that thalidomide selectively inhibits TNF-alpha production, thus stifling harmful immune reaction (E.P. Sampaio et al., Journal of Experimental Medicine, 173:699-703, 1991).

"We then realized we had a drug that could reduce inflammatory response," Kaplan says. "That means it might be useful for patients with HIV, tuberculosis, cancer, or rheumatoid arthritis, for example." That's where Celgene Corp. of Warren, N.J., came in. Collaborating with Kaplan's research group, the company has been developing thalidomide to treat symptoms of those diseases.

Now that researchers have a grip on thalidomide's biochemical mechanism, they hope to improve on it by creating more potent-and perhaps less teratogenic-drugs. "We're zeroing in on thalidomide's TNF-alpha inhibiting properties," says George Muller, group leader for medicinal chemistry at Celgene.

Muller and colleagues have developed several series of thalidomide analogs, or relatives. Starting with thalidomide, the scientists have added and removed various molecular groups and tested the resulting compounds for their ability to inhibit TNF-alpha in human blood cells.

In preclinical tests, some of the new compounds have appeared less teratogenic than thalidomide. But it's too soon to tell whether any of the drugs would actually be safer, Muller says.


Working on thalidomide, researchers and FDA regulators have held a host of meetings to grapple with challenges unique to teratogenic drugs-for example, how to teach doctors and patients about birth defect dangers. What makes this situation unusual, observers say, is that scientists have been considering these issues earlier in the development process than usual-long before the drug ever neared the market.

"Thalidomide has become a first-rate example of how to handle a drug that has a clear risk to the fetus," remarks Mark Novitch, who recently retired as vice chairman for the Upjohn Co., which recently merged with Pharmacia Inc. to form Pharmacia & Upjohn Inc., based in Kalamazoo, Mich. "What we're learning is that these drugs may in fact be channeled and used." Regulations that work for thalidomide might set new standards for badly needed drugs that have dangerous side effects.

According to Debra Birnkrant, a medical officer at FDA, the thalidomide effort sends a number of messages to drug developers. "One message is that if there's a promising therapy for a life- threatening disease-even if it is a teratogen-it should be developed," Birnkrant says. "If the benefits are greater than the risk, then it's clearly worthwhile to study the drug in a controlled manner. And if the data are good, it's probably going to be approved."

Every year, between 3 percent and 5 percent of babies are born with birth defects. No one knows exactly how many of those defects are due to recreational or prescribed drugs taken by the mother during pregnancy.

UNKNOWN CAUSES: William Scott of the Children’s Hospital Research Foundation in Cincinnati cites congenital malformations of unknown origin.
"The surveys we have would suggest that of all congenital malformations, 5 percent or less are induced by specific drugs," reports William Scott, Jr., a veterinarian who does animal research on teratogenic drugs at the Children's Hospital Research Foundation in Cincinnati. "What worries us isn't that 5 percent, though. It's that in 65 percent of kids with congenital malformations, we don't know what the cause is." Some of these poorly understood defects may be related to drugs, Scott says.

Today, doctors generally do not give pregnant women any drugs. But some women take potentially harmful medications-for example, anticonvulsants-before they realize they're pregnant. Unfortunately, it is in these early weeks of pregnancy that an embryo is most susceptible to teratogens, or substances that cause birth defects.

Such drugs are marketed with warning labels to alert pregnant women to the danger. Even so, a woman who gives birth to a malformed child sometimes sues the manufacturer. That's one reason pharmaceutical companies avoid developing teratogenic drugs. "It's a liability issue, an ethical issue, and a monetary issue," says Judy Buelke-Sam, a developmental toxicologist at Lilly Research Laboratories in Greenfield, Ind.

FDA and the National Institutes of Health require that women be included in clinical trials, regardless of whether the drug being tested is a known teratogen. During trials of teratogens, a company typically must go to the trouble of getting informed consent from women of childbearing age, performing routine pregnancy tests, and requiring that these women maintain two forms of birth control while taking the drug being tested.

LIMITATION: Jefferson’s Robert Brent notes that "animal models are far from perfect" in determining a drug’s teratogenicity.
An even more basic challenge for companies is figuring out which drugs are teratogenic in the first place. Forty years ago, thalidomide appeared safe in studies with rats and mice. It was only later, when scientists tried the drug in rabbits and primates, that they found the telltale signs of birth defects. "Animal models are far from perfect," says Robert L. Brent, a professor of radiology at Jefferson Medical College in Philadelphia.

Today, Buelke-Sam adds, researchers use two species of animal to check a drug's teratogenicity-for example, rodents and rabbits. Testing has been much more complete since the thalidomide crisis, she notes.

Despite the intensive effort required to develop and test teratogenic drugs, many companies have put them on the market for severe conditions. For example, most chemotherapeutic drugs can cause birth defects. Some anticonvulsants and antibiotics can, too.

'A GOOD FIRST STEP': Boston University’s Allen Mitchell studied pregnancy prevention by users of Accutane.
For thalidomide researchers, one teratogenic drug in particular offers a model for educational efforts that can persuade FDA to allow such substances on the market: Accutane, a vitamin A analog to treat severe acne.

From the beginning, animal studies suggested Accutane-a blockbuster drug produced by Hoffmann-LaRoche Inc. of Nutley, N.J.-was teratogenic. Roche Laboratories, a division of Hoffmann-LaRoche, released the drug in 1982, along with warnings to physicians and package inserts that explained its negative effects.

Despite the warnings, about 78 babies were reported with Accutane-related birth defects by the late 1980s (W.S. Dai et al., Journal of the American Academy of Dermatology, 26:599-606, 1992). FDA asked an advisory committee to review the drug. Rather than pull Accutane from the market, Roche proposed an intense public education campaign. Convinced of the drug's therapeutic usefulness, FDA agreed.

What followed is what many researchers consider one of the best education efforts for any drug. In 1988, as part of its "Pregnancy Prevention Program for Women on Accutane," Roche began sending drug information-including basic patient qualification and counseling literature-to every dermatologist in the U.S., as well as other doctors who had prescribed Accutane. In addition, the company revised patient booklets and self-evaluation forms. The general theme: Women should take a pregnancy test before receiving Accutane and take two forms of contraception while on it.

Boston University epidemiologist Allen Mitchell and colleagues conducted a patient follow-up survey to see whether women taking Accutane were following Roche's pregnancy-prevention advice. The team found just 3.4 pregnancies per 1,000 courses of Accutane medication, significantly lower than the normal pregnancy rate (A.A. Mitchell et al., New England Journal of Medicine, 333:101-6, 1995). "The pregnancy-prevention program and follow-up survey were the first-and to my knowledge, the only-efforts of their kind," Mitchell says. "We observed rates of pregnancy that are comparable with effective pregnancy-prevention efforts. Most observers view it as a good first step."

Sizing up Roche's effort, Sol Barer, president of Celgene, says: "Roche has a very effective program to counsel physicians and patients on Accutane. We have watched what they've done. There is nothing that can be more important than the education process in distributing a [teratogenic] drug."

Still, even Roche's massive campaign leaves some researchers concerned about birth defects from Accutane. "The results of the [Accutane] study were encouraging," states James Mills, chief of pediatric epidemiology at the National Institute of Child Health and Human Development. "But I'm concerned that because participation in the survey was voluntary, we're getting the best-case scenario in terms of results."

What about all the women who were not motivated to take part in the survey?, Mills asks. Were they motivated enough to carefully avoid getting pregnant while on the drug? "Remember, over half the people who get pregnant each year were not planning to get pregnant," he cautions.

CAUTIOUS: NCI's James Pluda, who is conducting thalidomide trials, plans to monitor pregnancy prevention.
As with Accutane, thalidomide researchers must decide the best way to protect women who might become pregnant while taking the drug. It's not an easy decision. At the University of Pennsylvania, researchers doing thalidomide trials have sought out women who cannot bear children. At the National Cancer Institute (NCI), scientists are less limiting but equally cautious. "We are putting in place significant admonitions [against getting pregnant]," says James Pluda, a senior investigator at NCI involved in clinical trials of thalidomide. "We're also planning to carefully follow up with physicians."

INFORMED CONSENT: Peter Andrulis aims to protect his company as well as clinical trial patients.
At Andrulis, women in clinical trials get weekly doses of thalidomide. Before receiving a dose, the women must obtain a negative result from a pregnancy test. Patients also use two forms of contraceptives while taking the drug.

FDA's Birnkrant says the agency might like to conduct similar pregnancy testing of patients if thalidomide does get approved. "You might take a monthly pregnancy test, and those results get sent to the pharmacy where drugs are being dispensed," she suggests. "Then you get your next two- or four-week supply."

Peter Andrulis, president of Andrulis, says the company will create what he calls an 'onion skin' approach -a layer of pregnancy protection, under another layer, under another. He hopes to protect both the women and the company itself. "We're thinking about unusual informed consent," he explains. "I don't want to be in a position where a patient says she was under stress or felt compelled to sign away consent, which opens us to a lawsuit [if she gets pregnant]."

One concern for both Accutane and thalidomide manufacturers is that doctors might prescribe the drugs outside their intended market. "We also are looking at thalidomide in Alzheimer's disease and myasthenia gravis," Andrulis says. "That just amplifies the [pregnancy protection] problem. If a drug is effective against just one disease, you could focus on just one market. But with this drug, you're likely to get doctors prescribing it for other conditions based on what they've read in the literature."

Even more worrisome, some people will likely take thalidomide without ever seeing a doctor, Mitchell says. "Women may get this drug without full benefit of a physician's advice. There are ways of getting the drug right now via the Internet."

Despite those concerns, Barer and others say, thalidomide definitely belongs on the market. "Given the critical nature of [AIDS and leprosy], the balance is clearly in favor of having a drug like this available," Barer says. If researchers and regulators can steer the drug to patients who need it and away from those it might hurt, thalidomide could have a major impact on the pharmaceutical community-again.

Kathryn S. Brown is a freelance science writer based in Columbia, Mo.