The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development

Abstract

Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses.

Keywords: anti-angiogenic; anti-apoptosis; graft-versus-host disease; plasma cell myeloma; teratogenic.

Figure 1.

(a) Single views of upper extremities in a patient exposed to thalidomide in utero. White arrow: fusion at the elbow joint and absence of fingers; Yellow arrow: absence of radius and shortening of ulna. (Reproduced with permission from LearningRadiology.com.) (b) Phocomelia in a baby.

Figure 2.

Dr Frances Kelsey is awarded the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy in 1962.

Figure 3.

Thalidomide interconverts between (R)- and (S)-enantiomers with protein binding of 55% and 65%, respectively. The (R)-form is responsible for sedative effects and the (S)-form is responsible for immunomodulatory effects.

Figure 4.

Proposed mechanisms of action of thalidomide upon tumorous plasma cell and surrounding microenvironment. In addition to direct inhibitory effects on the malignant plasma cell, thalidomide enhances the immune system effector cells, suppresses angiogenesis, inhibits various cytokine mediators and interferes with the bone marrow stromal cell-malignant plasma cell interaction (adhesion molecule interference, yellow circle). NK, natural killer; TNF, tumor necrosis factor; IL-6, interleukin-6; VEGF, vascular endothelial growth factor. The circular ‘plus sign’ indicates stimulation and the circular ‘minus sign’ indicates inhibition. Illustration courtesy of Alessandro Baliani © [2011].

Figure 5.

Timeline of events in thalidomide and immunomodulatory drug (IMiD) development.