NEWS

Despite Checkered Past, Thalidomide and Its Analogues Show Potential

M. J. Friedrich

Available in Europe in the late 1950s as a sedative, thalidomide was also used by pregnant women to ameliorate morning sickness. Within a few years, however, its use during pregnancy was linked to severe birth defects in infants, and more than 10,000 children were born with underdeveloped limbs before the drug was withdrawn from the market in 1961.

But thalidomide did not disappear. Not long after its removal from clinical use, it was shown to be effective in treating an inflammatory skin disease that is a complication of leprosy, and in 1998 it was approved for the treatment of this condition.

Curious as to why a drug developed as a sedative had anti-inflammatory effects, researchers were eager to better understand thalidomide’s biologic behavior. Investigations have revealed a broad range of physiologic effects, including immunomodulatory and antiangiogenic activity. Researchers are investigating potentially less toxic versions of thalidomide and are exploring the drug’s clinical benefits in various malignancies and immunologic and autoimmune disorders as they continue to elucidate the drug’s precise mechanism of action.

Antiangiogenic Properties

Thalidomide’s ability to halt angiogenesis by inhibiting angiogenic and growth-promoting factors prompted studies of the drug as an antitumor agent. Initial studies in the late 1990s examined its use in treating patients with refractory, relapsed multiple myeloma. Since that time, thalidomide has been shown to achieve responses—reductions in the level of myeloma protein markers in serum or urine—in roughly 30% of patients, with the duration of response being about 1 year, said Kenneth Anderson, M.D., director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, Boston.



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Dr. Kenneth Anderson

 
Anderson pointed out that thalidomide—and the new more potent thalidomide analogues called immunomodulatory drugs—seems to act against myeloma in a variety of ways. It induces apoptosis in myeloma cell lines and in patients’ tumor cells that are resistant to conventional treatment, it stops myeloma cells from binding to bone marrow stromal cells, and stimulates an autologous natural killer cell response against myeloma.

Toxicities and New Analogues

In spite of its action against tumors, thalidomide is still haunted by its harsh side effect profile. When used as a single agent, thalidomide may cause adverse effects such as sedation, constipation, and peripheral neuropathy. In general, these side effects can be controlled by dose reduction. Patients who develop neuropathies must be monitored to prevent permanent nerve damage.

Thalidomide’s most notorious side effect—teratogenicity—gave rise to a system to prevent fetal exposure to the drug from occurring. Celgene Corp., Warren, N.J., the maker of thalidomide (marketed as Thalomid®) and the U.S. Food and Drug Administration created the System for Thalidomide Education and Prescribing Safety (STEPS) program, which requires registration of those who prescribe or dispense the drug, and it requires pregnancy testing of all female patients of child-bearing age.



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Thalomid® is made by Celgene Corp. The company is also developing immuno-modulatory drugs based on the biologic activity and structure of thalidomide.

 
The side effects of thalidomide have provided the impetus for coming up with a less toxic and more effective form of the drug. Biochemists at Celgene Corp., Warren, N.J., have developed a new class of thalidomide analogues, called immunomodulatory drugs (IMiDsTM). These drugs appear to have a similar if not identical target to that of the parent molecule, said David Stirling, Ph.D., executive vice president and chief scientific officer at Celgene. Stirling explained that, because the molecular target of thalidomide remains elusive, researchers have relied on functional characteristics of analogues to assess their similarities to the parent compound. "Essentially if you look at all the positive biology of thalidomide—downregulation of tumor necrosis factor-{alpha}, antiangiogenesis activity, the ability to stimulate the immune system, etc.—these compounds [the IMiDs] do all that and they do it all more potently."

The drug farthest along in clinical trials, CC-5013 (RevimidTM), has been shown to have antitumor activity in multiple myeloma and metastatic malignant melanoma. It is being evaluated in a number of trials, including two phase II trials for multiple myeloma and two phase I/II trials for all types of solid tumors.

Stirling said that CC-5013 has a much greater ability to alter immune system responses than does thalidomide. It does not appear to be teratogenic in animal models, and so far CC-5013 does not seem to cause the adverse effects that thalidomide does, although he pointed out that too few patients have gone through trials to say that this is unequivocally the case.

Dana-Farber’s Anderson, who has been involved in myeloma studies with CC-5013, said that the best dose and schedule for CC-5013 still need to be worked out, as do questions about which conventional and novel treatments should be used with the drug to optimize its clinical utility. But so far, said Anderson, the results look promising.

"Because it is active in refractory, relapsed myeloma and has a very favorable side effect profile and it is an oral agent, it is being tested in protocols for newly diagnosed patients with myeloma, for patients in first relapse, and soon it will begin testing as a maintenance medication, in particular in patients who undergo high-dose chemotherapy and stem-cell transplant for myeloma who have prolonged overall and event-free survival but are not cured," he said.

Thalidomide Trials

Alternatives such as CC-5013 are showing promise, but because of the success of thalidomide itself it is still being tested. Because thalidomide has shown benefit in studies of patients with advanced myeloma, researchers are studying the drug in patients with early-stage disease. S. Vincent Rajkumar, M.D., assistant professor of medicine at the Mayo Clinic and Mayo Foundation, Rochester, Minn., has worked on a number of these studies, including the first published study to use thalidomide for untreated patients with asymptomatic disease. Currently such patients are not treated until symptoms appear. Rajkumar’s group reported a reduction in myeloma protein markers in the serum or urine of 35% to 40% of patients, but he said randomized trials are needed to determine whether low doses of thalidomide delay disease progression in asymptomatic patients.

Researchers have also examined the benefits of combining thalidomide with other anticancer agents to combat myeloma. Rajkumar said that results soon to be published by his group show that the use of thalidomide with the oral agent dexamethasone to treat newly diagnosed, symptomatic myeloma patients yielded a response rate of 64%. He said the hope is that this oral regimen could replace the standard intravenous regimens for myeloma, which present risks of catheter-associated thrombosis and infection. An ongoing randomized study at the Mayo Clinic and elsewhere will compare whether the thalidomide/dexamethasone combination is more effective than dexamethasone alone in newly diagnosed patients.

Based on the promising results with thalidomide in myeloma, researchers are evaluating the drug in a wide range of solid malignancies. A number of early studies suggest that thalidomide has activity against such tumors as Kaposi’s sarcoma, renal cell carcinoma, prostate cancer, and gliomas. Further studies in these and other malignancies will help identify in which cancers thalidomide would be most beneficial.

Timothy Eisen, Ph.D., a medical oncologist at Royal Marsden Hospital, Sutton, Surrey, England, pointed out that, because thalidomide appears to be more effective against myeloma when used in a multidrug regimen, such an approach will most likely be most effective against solid malignancies as well.

Possibly More Side Effects

However, combining thalidomide with other active agents can give rise to different or more severe side effects than seen with thalidomide alone. In a recent study that Eisen and his colleagues conducted in patients with advanced renal cell carcinoma, thalidomide combined with interferon alfa proved to be highly neurotoxic.

However, using a lower dose of interferon alfa with thalidomide, as other researchers are doing, seems to be less problematic, he said. Serious side effects have also been noted when thalidomide is combined with other chemotherapy drugs.

But given the preliminary success observed with thalidomide analogues, the parent drug and its side effects may once again fade into history. The studies with thalidomide are blazing a trail in the treatment of oncologic conditions, said Stirling, that researchers can follow when using the new analogues. "To replace thalidomide completely will take some time, but it’s certainly our long-term goal," he said.



             
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