By: Kevin J. Choi, PharmD Candidate c/o 2016

–

“Morning Sickness” – we have all heard of this term being associated with thalidomide, a drug particularly recognized for its antiemetic effect, but also for its notorious teratogenicity. However, it is worth re-familiarizing ourselves with the nature of the drug itself (and the clinical threats that it presented to the pharmaceutical world), as we mourn the loss of former Food and Drug Administration (FDA) medical officer Dr. Frances Oldham Kelsey (who passed away on August 7, 2015).¹ In short, Dr. Kelsey became a 20th-century heroine for sparing the United States from widespread birth deformities by questioning thalidomide’s safety data after its release in Europe.¹

Thalidomide contains a chiral carbon in its structure, yielding two enantiomers, R(+) and S(-), and the former enantiomer was responsible for the drug’s sedative effects, whereas the latter and its derivatives were teratogenic.² Pharmacologically, thalidomide possesses immunomodulatory, anti-inflammatory, and anti-angiogenic properties.³ The first property (immunomodulation) is due to a suppression of excessive tumor necrosis factor-alpha (TNF-a) production and a down-regulation of certain cell surface adhesion molecules involved in white blood cell (WBC) migration.⁴ The second property (anti-inflammation) is due to a suppression of macrophage involvement in prostaglandin synthesis, along with modulation of interleukin (IL)-10 and IL-12 production by monocytes and lymphocytes. The last property (anti-angiogenesis) involves an inhibition of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor.⁴ Despite these properties, the discovery of thalidomide’s teratogenicity shed doubt on the benefits of the drug, and led it to be closely monitored and under major scrutiny.

The doubts about thalidomide trace back to the 1950s, when Chemie-Grunenthal (a German pharmaceutical company) produced the drug as a non-addictive, non-barbiturate sedative. Thalidomide was an effective anti-emetic agent in pregnant women — hence its additional use for “morning sickness.”⁵ Until it was banned in 1961, thalidomide was one of the world’s highest selling drugs and it was advertised as safe for use.⁶ However, reports of patients developing peripheral neuropathy became inevitable upon the drug’s release, and there were multiple reports of severe birth defects that affected various systems of the human body. In 1961, these detrimental effects were linked to thalidomide use, and FDA officer Dr. Kelsey expressed great concerns over the drug’s safety profile.^1,7,8

Yet exactly how severe were the consequences of thalidomide that this chapter in the pharmaceutical world warrants the label, “worldwide disaster”? Based on the wide range of birth defects caused by drug exposure, the thalidomide disaster is sometimes referred to as the “thalidomide embryopathy.” The drug affects limbs or extremities (upper and especially lower), but it can also affect the eyes, ears, and internal organs (heart and kidneys).⁵ Infant mortality due to thalidomide embryopathy has been reported to be as high as 40%. Moreover, it is very probable that babies with malformations may die in utero and be either miscarried or stillborn.⁹

Thalidomide causes damage to the developing embryo during a short time (“critical period”) that occurs during day 20 to day 36 after fertilization. Exposure to the drug within this timeframe causes the teratogenic effects, as evidenced by reports that involved significant birth defects in up to 50% of pregnancies from a single dose of 50 mg during the critical period.⁵

The time-sensitive window of exposure to thalidomide was an essential discovery in understanding the severity of its teratogenicity. Interviews were conducted worldwide with parents of thalidomide-affected children and their physicians.^10-12 Dates of maternal drug intake and exposure were collected as data for establishing at least an association (and eventually a direct relationship) between the magnitude of the damage seen in the infants and the timing relative to embryonic development.

Through careful analysis, it was concluded that the time-sensitive window coincided with the period during which there is rapid embryonic development of cell growth, movement, and organogenesis. This process begins at week 4 and progresses until week 10 or 11, when the embryo is fully developed. Since morning sickness also occurs during this timeframe, many women inadvertently used thalidomide during the critical period and thereby had major birth defects in their children.⁵ All of the information obtained from interviews and other relevant findings was the bulk of the content in Dr. Kelsey’s articles.⁵ Furthermore, Dr. Kelsey persistently requested for more information from the manufacturer (William S. Merrell Company of Cincinnati) to better support her concerns.¹ It was through her determination that she prevented the marketing of the drug in the United States and subsequently disapproved its use for morning sickness during this time. Had she not played such a role, this disaster would have taken quite a toll on the lives of children in America.

Thalidomide is still in use today, but not for morning sickness. Back in 1964, Israeli scientists made the discovery that this drug could control leprosy by reducing the inflammation caused by the disease. Then, in 1998, the FDA approved it for multiple myeloma (MM), a cancer of plasma cells in the blood.¹³ The first clinical trial that was done to test thalidomide for MM included 169 patients who received an initial dose of 200 mg/day with dose increases of 200 mg every two weeks, up to 800 mg/day. In long-term follow-up studies (median follow-up of 9.2 years), 17 patients were still alive as of that article’s publication (10 of whom were event-free, meaning that they had no recurrence of any complications since the initiation of the trial).¹⁴ In patients with cytogenetic abnormalities (seen in 47% of the patients within three months of study enrollment) and a lambda (l) light chain isotype, 48% (n=58) of patients who lacked both features survived at least 6 years, as opposed to fewer than 5% who had either or both of the features (P < 0.001).¹⁴

Although patients who received a cumulative thalidomide dose greater than 42 grams in the first three months experienced superior overall and event-free survival, thalidomide was under extensive investigation.¹⁴ In fact, a recently published study from 2010 claimed that the treatment of newly diagnosed MM was more effective with lenalidomide (Revlimid®, Celgene), a molecular derivative of thalidomide introduced in 2004.¹⁵ In a study of 411 MM patients, participants were given either lenalidomide with dexamethasone (RD) or thalidomide with dexamethasone (TD). The former group (RD) yielded higher response rates with higher partial responses, as well as longer time-to-progression and progression-free survival (PFS).¹⁵ Dr. Rajkumar, an investigator of the study, stated that lenalidomide was “the superior immunomodulatory drug compared with thalidomide for treatment of multiple myeloma,” but he also admitted that the results needed to be confirmed through randomized controlled trials that the drugs to other treatment regimens (in order to establish the optimal initial therapy).¹⁵

Thalidomide is currently a subject of research testing in trials for Crohn’s disease as well, a condition affecting 219 per 100,000 adults; for children younger than 20 years of age, the estimated prevalence is 43 per 100,000.16 The numbers seem less daunting for children, but more concerns are directed towards them because pediatric Crohn’s disease is more aggressive than the adult-onset disease, with higher rates of drug resistance.¹⁷ A multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted between 2008 and 2012, involving children with active Crohn’s disease. There were 28 randomized to receive thalidomide and the remaining 26 were in the placebo group. The objective was to evaluate the therapeutic efficacy of thalidomide for remission in refractory pediatric Crohn’s disease.¹⁷ The primary efficacy endpoints were clinical remission at week 8, determined with the Pediatric Crohn’s Disease Activity Index (PCDAI) and defined by a score of 10 or less, as well as a reduction in the score of at least 25% (at week 4) or at least 75% (at week 8).^17,18  Non-responders to placebo were permitted to cross over and receive thalidomide.¹⁷ Overall, approximately 63.3% (n=49) of children treated with thalidomide achieved clinical remission, and 65.3% (n=49) achieved a 75% response.¹⁷ Essentially, the conclusion from the study was that thalidomide improved both clinical remission at 8 weeks of treatment and longer-term maintenance of remission; however, further investigation is needed in order to additionally validate the findings.¹⁷

Thalidomide may serve as a therapeutically useful agent, but it has an unspeakable adverse drug reaction that has haunted the pharmaceutical world for the past several decades. However, a major asset gained from the thalidomide disaster was the development of modern day drug testing, which could not have been possible without the late Dr. Kelsey.⁵ Healthcare providers should commemorate Dr. Kelsey’s crucial efforts of ensuring that our world could be a safer place.

 

SOURCES:

1. McFadden R. Frances Oldham Kelsey, who saved U.S. babies from thalidomide, dies at 101. New York Times. http://www.nytimes.com/2015/08/08/science/frances-oldham-kelsey-fda-doctor-who-exposed-danger-of-thalidomide-dies-at-101.html
2. Smith SW. Chiral toxicology: it’s the same thing…only different. Toxicol Sci. 2009;110(1):4-30. doi: 10.1093/toxsci/kfp097
3. Eriksson T, Bjorkman S, Roth B, Hoglund P. Intravenous formulations of the enantiomers of thalidomide: Pharmacokinetic and initial pharmacodynamic characterization in man. J. Pharm. Pharmacol. 2000;52:807-817.
4. Jones C. Thalidomide: New Cancer Uses for an Old Drug. U.S. Pharmacist. 2008;33(7)(Oncology suppl):3-13.
5. Vargesson N. Thalidomide-induced teratogenesis: History and mechanisms. Birth Defects Res C Embryo Today. 2015;105(2):140-56. doi: 10.1002/bdrc.21096
6. Vargesson N. Thalidomide-induced limb defects: resolving a 50-year-old puzzle. Bioessays. 2009;31(12):1327-36. doi: 10.1002/bies.200900103.
7. McBride W. 1961. Thalidomide and congenital malformations. Lancet1:358
8. Lenz W. 1962. Thalidomide and congenital abnormalities. Lancet1:271–272
9. Smithells RW, Newman CGH. 1992. Recognition of thalidomide defects. J Med Genet 29:716–723. doi: 10.1136/jmg.29.10.716
10. Nowack E. 1965. The sensitive phase in thalidomide embryopathy. Humangenetik 1:516-536. (article in German).
11. Ruffing L. 1977. Evaluation of thalidomide children. Birth defects Orig Artic Ser 13:287-300.
12. Lenz W. 1988. A short history of thalidomide embryopathy. Teratology 28:203-215.
13. Zimmer C. Answers begin to emerge on how Thalidomide caused defects. The New York Times. http://www.nytimes.com/2010/03/16/science/16limb.html. Published 03/15/2010.
14. van Rhee F, Dhodapkar M, Shaughnessy JD Jr, et al. First thalidomide clinical trial in multiple myeloma: a decade. Blood. 2008;112(4): 1035–1038. doi: 10.1182/blood-2008-02-140954
15. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood. 2010;115(7):1343-50. doi:10.1182/blood-2009-08-239046
16. Kappelman MD, Moore KR, Allen JK, Cook SF. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Dig Dis Sci. 2013;58(2):519-25. doi: 10.1007/s10620-012-2371-5
17. Lazzerini M, Martelossi S, Magazzù G, et al. Effect of thalidomide on clinical remission in children and adolescents with refractory Crohn disease: a randomized clinical trial. JAMA. 2013;310(20):2164-73. doi: 10.1001/jama.2013.280777.
18. Kundhal  PS, Critch  JN, Zachos  M, Otley  AR, Stephens  D, Griffiths  AM.  Pediatric Crohn Disease Activity Index: responsive to short-term change. J Pediatr Gastroenterol Nutr. 2003;36(1):83-89.

Published by Rho Chi Post