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Thalidomide: An Unexpcted Odyssey

John Amendall

    Thalidomide is a drug developed by a Swiss pharmaceutical company (1953). After testing in rodent models the drug was generally believed to be non-toxic to humans. It was introduced in 1956 by a German firm. The drug became popular as a sedative for pregnant women experiencing morning sickness. Since it was accessible with out a prescription and was relatively inexpensive, it quickly became a top-selling sedative.
    However, in 1961 an Australian obstetrician and a German pediatrician and geneticist independently linked thalidomide use during pregnancy to limb and bone abnormalities as well as cardiac ones. These findings were confirmed by multiple worldwide studies. Approximately 40% of affected infants died within a year. Accordingly, thalidomide was withdrawn from the marketplace.
    Thalidomide was briefly available as an investigational agent in the U.S.A. FDA officer (physician and pharmacologist) assigned to review the drug application denied approval based on a lack of safety data. Her efforts prevented thalidomide entry to marketing averting a major tragedy in the U.S. She was honored with the President’s Award for Distinguished Federal Civilian Service in 1962. In the author’s opinion she did not receive the wide spread public recognition she deserved for such an important role. An estimated 10,000 infants were affected globally with more uncounted still born or miscarried pregnancies. Thalidomide was marketed in 40 countries and was licensed in Canada from April 1961 until March 1962.
    For decades thalidomide was cursed as a nightmare drug of irrefutable tragedy.
    Sic transit gloria thalidomide. And then the impossible occurred.
    On one hand we had the conscientious FDA officer preventing a serious wide spread disaster in the U.S. at least. And on the other another medical scientist provided a truly unexpected breakthrough.
    In 1964 a dermatologist working with leprosy patients in Jerusalem observed the following. Some patients developed a painful condition which caused diffuse red nodal skin lesions together with fever, weight loss, arthritis and general malaise. In an attempt to relieve one of his patients cruel symptoms the scientist sedated him with some thalidomide. Recall it was originally developed as a sedative for pregnant women. In view of its terrible, horrific history, it is almost unimaginable how a scientist saw any redeeming feature of thalidomide justifying its application in medicine. After 4 tablets the patient experienced a dramatic positive response. The dermatologist then treated 6 other patients recording similar results. What scintilla of intellect could’ve driven this application? The prepared mind benefits from serendipity. Additional studies involving much larger number of patients showed significant response of relief. The World Health Organization (WHO) then conducted a study (1971) showing significant superiority of thalidomide in the treatment of skin lesions compared to other commonly applied medication.
    In 1991 a researcher at New York Rockefeller University demonstrated that thalidomide inhibited the growth of a special tumor necrosis factor. Since people with HIV/AIDS may have elevated levels of the necrosis factor, this provided a theoretical framework for using thalidomide for this condition.
    Further studies showed that thalidomide was superior to standard therapies applied to the wasting syndrome of HIV/AIDS. At this time the FDA sought to control the supply and distribution of thalidomide to prevent readmission of the prior terrible occurrence. With time and more stringent testing patent approval was received to produce it.
    Meanwhile (1994) another researcher studying cancer growth demonstrated experimentally that the combination of thalidomide and sulindac an anti-inflammatory inhibited the growth of carcinoma in rabbits by 75%.
    In 1997 a cardiologist was extremely ill with multiple myeloma, an incurable plasma cell cancer which had failed to respond to usual treatments. As a last hope try another doctor was prompted to treat the cardiologist with thalidomide, but the effort failed. However, another patient with myeloma responded positively which encouraged a group of researchers at the University of Arkansas to establish a therapy trial with 84 previously treated but refactory multiple myeloma patients. After 12 months 58 patients were still alive. These numbers were not impressive but refactory multiple myeloma at that time was fatal in a matter of months.
    The above survivorship encouraged additional application of thalidomide. Accordingly thalidomide was the first chemotherapeutic drug demonstrating against myeloma in more than 30 years. The dreaded drug of the 50s and 60s designed for an entirely different medical profile was unimaginably resuscitated and successfully applied in the war against cancer.
    In 2004 a U.S. pharmaceutical firm developed a structural analogue of thalidomide called lenalidomide (Revlimid) with improved anti-tumor efficacy and a reduced toxicity profile. It deserves and indeed requires emphasizing that Revlimid can produce side effects. Some very slight. Some more challenging. The response of patients to Revlimid varies significantly depending on personal physiology and degree of myeloma. And still researchers are working to reduce side effects of Revlimid.
    “Detailed information about contraception is provided to both female and male patients. This program is designed to minimize fatal exposure to these drugs and maintain tight control over their use. But the biggest concern is the need to prevent any recurrence of the tragic teratogenicity of the 1960s.”
    The author of this piece wonders at the inspiration of researchers to take a clearly dreaded drug of the 50s and 60s converting it to such a positive medication for good. I owe a great deal to the above scientists.
    Finally this piece was based on two technical scientific papers (BC Medical Journal Vol. 53 no.5, June 2011 and Therapeutic Advances in Hematology (2011), 2151, 291-308).

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