FDA Approves the New Thalidomide

By Angelo DePalma

FDA announced on July 16 that it has cleared thalidomide for marketing as a treatment for erythema nodosum leprosum (ENL), a serious inflammatory condition in patients with Hansen's disease (also known as leprosy). While allowing the drug to be used in this narrow indication, the agency simultaneously imposed unprecedented restrictions on thalidomide's distribution. Because of its well-known potential for causing birth defects, thalidomide will be among the most tightly restricted drugs ever to be marketed in the United States.

Thalidomide was first distributed in Europe and Canada in the late 1950s but by 1961, having been linked with about 10,000 serious birth defects (and many times that many spontaneous abortions), it was withdrawn from the market. It turns out that only one of the isomers of thalidomide (the drug has one chiral center, hence two stereoisomers) is teratogenic; the other isomer is quite safe. In addition to causing serious fetal deformities, thalidomide has been associated with other adverse reactions, including peripheral neuropathy, a disorder that, in some patients, has resulted in permanent nerve damage. Little known fact: Thalidomide was never approved for use in the United States until now.

Over the past decade the benign isomer has been tested for various conditions and found effective for a remarkably diverse set of conditions, including blindness, multiple sclerosis, and autoimmune diseases. In AIDS patients the drug has been shown effective for oral and esophageal ulcers, wasting, and Kaposi's sarcoma. Thalidomide is also known to be a potent inhibitor of angiogenesis (blood vessel growth), which makes it a potential anticancer drug.

What's fascinating about thalidomide's resurgence is that drug companies are treating it as a new entity. More than 20 racemic (mixture of both chiral forms) analogues of thalidomide have been synthesized and tested against various illnesses. Some of these analogs have potencies 400 to 500 times greater than the original thalidomide. Celgene has synthesized and patented many of these analogs.

Think about it: With million-compound libraries and high-througput screening at their disposal, drug companies in 1998 are turning to a 40-year-old drug that was developed, as drugs were in those days, by trial and error.

Thalidomide and Hansen's Disease

In fact, interest in thalidomide has ebbed and waned but never totally evaporated. Research over the past decade led the FDA's Dermatologic and Dental Drugs Advisory Committee to recommend, back in September, 1997, that thalidomide be approved based on analysis of historical data collected over 30 years. The agency specifically cited experiments demonstrating thalidomide's efficacy in treating skin lesions associated with ENL. In clinical trials at least 70-80% of patients with ENL responded to thalidomide therapy with improvements in skin lesions as assessed in double blind, controlled clinical trials. Improvement in patients given placebo was about 25%.

To prevent fetal exposure to thalidomide, the drug's manufacturer, Celgene Corp. (Warren, NJ), has developed the System for Thalidomide Education and Prescribing Safety (STEPS) program. Only physicians registered in the STEPS program may prescribe thalidomide to patients, and those patients -- both female and male -- must comply with mandatory contraceptive measures, patient registration and patient surveys.

Additionally, female patients' prescriptions will not be filled without a physician's written report of a negative pregnancy test that has been conducted within 24 hours of starting thalidomide therapy. Pregnancy testing will continue to be required weekly during the first month of use, then monthly thereafter in women with regular cycles, or every two weeks if menstrual cycles are irregular. Prescriptions are only for one month's supply. Women must use two reliable forms of contraception simultaneously while taking the drug.

Male patients will receive written and oral warnings of the risk of possible contraception failure and of the need to use condoms when having intercourse with women of childbearing age. It is unknown whether thalidomide is present in sperm or semen or whether its presence in sperm or semen would affect fetal development.

While birth defects are the most widely known side effect of thalidomide, this drug also can cause a potentially irreversible kind of nerve damage known as peripheral neuropathy, particularly when it is used chronically over a period of months. More information is needed to determine how dose and use of the drug affects onset of this side effect and irreversibility.

Additionally, thalidomide is known to cause drowsiness and dizziness.

Marketing thalidomide, an old drug for a new indication, represents an unusual turn for Celgene, a discovery-stage company focusing on innovative chiral chemistry and immunotherapeutics. The firm will market thalidomide as Thalomid.

For more information: John W. Jackson, CEO, Celgene Corp., 7 Powder Horn Dr., Warren, NJ 07059. Tel: 732-271-1001.

To learn more about thalidomide and the FDA's position on new indications for this drug, check the FDA's thalidomide site at http://www.fda.gov/cder/news/thalinfo/default.htm