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Clinical trials for this notorious drug suggest uses against cancer and autoimmune diseases.
Since the 1960s, physicians have prescribed thalidomide to patients, but because it was manufactured overseas, there was very little quality control, says David Stirling, chief scientific officer of Celgene Corp. (Warren, NJ). In the 1990s, Gilla Kaplan at Rockefeller University (New York, NY) began studying the mechanism behind thalidomide’s effect on ENL and a similar autoimmune response to the related tuberculosis bacteria. The work showed that thalidomide’s clinical benefits mirrored a decline in tumor necrosis factor alpha (TNF- More news poured in. Judah Folkman, a researcher at Harvard Medical School whose work was sponsored by EntreMed, Inc. (Rockville, MD), announced that thalidomide had potent activity as an angiogenesis inhibitor and thus held promise as an anticancer therapeutic. EntreMed decided not to take on the molecule’s troubled history, choosing instead to focus on other angiogenesis inhibitors, and Celgene licensed the molecule in December 1998. Today, thalidomide shows promise in a variety of therapeutic areas, although its side effects range from discomforting to frightening. It can result in peripheral neuropathy, although that can be managed by monitoring patients closely. Taken in the first trimester of pregnancy, it can cause a disruption or cessation of limb development in the fetus. It is also a subtle regulator of TNF- “Whatever it does, thalidomide seems to be particularly good at it—for good or bad,” says Stirling Clinical trials and tribulations As daunting as those concerns may seem, they haven’t really posed a major roadblock to clinical development, says Stirling. “You would think it would be more difficult because of the baggage, but actually if anything it has been beneficial, because . . . FDA probably has more information on this molecule than all of the other drugs it oversees. They know the safety issues, so as long as they’re managed in clinical studies, it’s clear that the agency is comfortable with the drug being used in serious or life-threatening diseases.” And besides, it’s not as if danger to developing embryos is unique to thalidomide. “Any of the antineoplastics would have devastating effects on an embryo. Thalidomide . . . seems to have a time window of the first trimester of pregnancy, whereas other compounds can be embryotoxic throughout development,” says Stirling. That knowledge could smooth the road for clinical trials. “We can look for thalidomide’s known toxicity [in clinical trials]. We shouldn’t be surprised by anything else,” says Stirling. Representatives of the FDA agree. “The issue has moved somewhat away from [monitoring]. Now we have some trials to do to demonstrate that the drug does something,” says Mark Goldberger, director of the FDA’s division of special pathogen and immunologic drug products. The next generation Along with its clinical development program, Celgene began a drug discovery effort in 1992 to work out thalidomide’s mechanism of action and develop analogues, and the effort has produced two new classes of molecules that have entered the clinic. The selective cytokine inhibitory drugs (SelCIDs) target phosphodiesterase type 4 (PDE 4), which is a well-studied anti-inflammatory target and has been shown to down-regulate TNF- The second class of molecules, called immunomodulatory drugs (IMiDs), better reflects the parent, at least insofar as company researchers have yet to identify the molecular target. The IMiDs too are structurally similar to thalidomide. Indirect biological evidence suggests that they affect the same targets, and the drugs are up to 10,000 times as potent as TNF- Applications The National Cancer Institute (Bethesda, MD) has a large number of ongoing trials to investigate thalidomide’s use in breast, prostate, lung, and renal cell cancer, and in multiple myeloma, Kaposi’s sarcoma, and brain tumors, says James M. Pluda, senior investigator in the investigational drug branch of the institute. Many of the trials use thalidomide in combination with other angiogenesis inhibitors. The lung cancer trials have advanced to Phase III. Thalidomide is also the first real therapy available for multiple myeloma in almost 20 years, says Stirling, and the FDA has approved it for that indication. Mechanism of action Early on, it was thought that thalidomide acted as an immune suppressor. “But it clearly doesn’t do that. It can switch off the overproduction of TNF, but it doesn’t inhibit the basal level needed for a normal cellular immune response. It’s not like an antibody or [a soluble] receptor where you’re going in and mopping it up [an overexpressed molecule]. You’re going after the actual upregulation of TNF whether it’s caused by an infection or a tumor, without interfering with the basic immune response,” says Stirling. In cancer, the drug’s effects could be twofold. The antiangiogenesis may be due to an effect on growth factors or other cytokines besides TNF, and it could boost the immune response in combination with existing chemotherapy, says Stirling. “It could mobilize the immune system to take advantage of what the primary chemotherapy is doing. Hopefully, it will be synergistic.” How thalidomide produces its toxic side effects is even less understood. The peripheral neuropathy is a mystery and is often masked because diseases that thalidomide is used to treat—like AIDS and leprosy—can also result in the condition, as can some of the other drugs used in treatment. “There’s no a priori way to predict it. We just manage it clinically,” says Stirling. How it produces its notorious effects on a growing fetus also remain unexplained. “Enigmatolide” Regardless of the outcome of its investigations, Celgene vows to make its clinical data widely available, “good or bad”, according to Stirling. Given thalidomide’s history, there’s sure to be both.
Jim Kling is a science writer living in Bellingham, WA. Comments and questions for the author can be addressed to the Editorial Office by e-mail at mdd@acs.org, by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036. Top || Modern Drug Discovery Home Page
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You know about the nerve degeneration, gangrene, and tissue destruction that accompany advanced cases of leprosy, but you might never have heard of the autoimmune response induced by Mycobacterium leprae. That side effect, called erythema nodosum leprosum (ENL), can cause deep nodules on the face, arms, and thighs that are so painful that patients cannot sleep. This side effect severely affects quality of life. In the 1960s, in an effort to comfort leprosy patients, an Israeli physician gave them doses of thalidomide, the well-known antinausea medication and sedative that caused tens of thousands of birth defects in the late 1950s and early 1960s. To his astonishment, the ENL nodules cleared up within a few days. Further studies showed the drug helped 90% of ENL sufferers, and thus thalidomide was reborn. It would surprise many to know that thalidomide, the drug whose chilling side effects prompted the FDA to overhaul its drug approval process, has been used since the 1960s inside and outside the United States to treat ENL.
). That molecule’s broad role in autoimmune diseases, the general immune response, and cancer prompted Celgene to pursue official approval of thalidomide for ENL, which it accomplished in July 1998.