The Scary Past Of Thalidomide And Understanding Its Teratogenic Mechanism

(RTTNews) - Thalidomide babies or Thalidomide disaster. Do these terms sound familiar?

Well, they are disabled children born in late 1950s and early 1960s to mothers who had been prescribed the drug Thalidomide during early pregnancy.

Under the brand name Contergan, Thalidomide was launched in Germany in 1957 as an over-the- counter medication to treat insomnia, and nausea associated with pregnancy. It was introduced in Britain in 1958 by Distillers Bio-chemical Ltd. under the brand name Distaval. By 1960, the drug was available in 46 countries, including Canada. But it was not introduced in the U.S. then as it failed to pass muster, courtesy of FDA inspector Frances Kelsey.

By 1959, reports of peripheral neuritis, a numbness that can lead to severe pain and even partial paralysis associated with Thalidomide were doing the rounds. But the worst came in 1961, with several cases of malformed children being born to women who took Thalidomide early in pregnancy.

According to reports, 100,000 babies died in the womb and 10,000 were born with serious disabilities like absence of limbs, deformed hands, facial disfigurement, absence of ears and eyes, and brain defects, to name a few.

The drug was withdrawn from the market in late 1961.

Understanding the mechanism of Thalidomide-induced birth defects has always been of interest to the scientific community.

Now, scientists at the Dana-Farber Cancer Institute have finally found an answer.

According to the researchers, Thalidomide degrades a lot of *transcription factors, including SALL4, eventually resulting in complete removal of SALL4 from cells. Sall4 plays a diverse role during early embryonic development, and its degradation is said to interfere with limb development and other aspects of fetal growth. (*transcription factors are cell proteins that help switch genes on or off).

The Thalidomide-induced birth defects are similar to the characteristics and associated anomalies in Duane Radial Ray Syndrome.

Duane-radial ray syndrome (DRRS), an inherited disorder that affects the eyes and causes abnormalities of bones in the arms and hands, is also caused by mutations in the SALL4 gene.

Commenting on the finding, the new study's senior author, Eric Fischer, said, "The similarities between the birth defects associated with Thalidomide and those in people with a mutated SALL4 gene are striking. They make the case even more strongly that disruption of SALL4 is at the root of the devastation produced by Thalidomide in the 1950s."

From Trouble To Triumph...

Though Thalidomide was banned in late 1961, researchers never lost interest in the drug. In 1975, the U.S. Public Health Service set up a compassionate use program to distribute Thalidomide to leprosy patients. Following reports of Thalidomide's efficacy, Celgene and other companies began investigating the various potential uses of the drug.

In July 1998, Celgene won the FDA approval to market Thalidomide for leprosy under the brand name Thalomid. The company was required to establish a System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program to ensure that fetal exposure to the drug does not occur as it has been associated with birth defects. The S.T.E.P.S program, renamed REMS, helps to control access to the drug, educate prescribers, pharmacists and patients about the risks of Thalidomide, and monitor compliance.

In its first full year of commercial sales, Thalomid generated revenues of $24.1 million. The drug proved to be effective in treating multiple myeloma also in clinical trials.

Celgene filed its supplemental New Drug Application seeking approval to market Thalomid for the treatment of multiple myeloma in 2004. Finally in May 2006, the FDA granted accelerated approval for Thalomid in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.

Thalidomide, which was withdrawn from the European market in late 1961, was re-introduced in April 2008 for treating newly diagnosed multiple myeloma.

The drug generated global sales of $132 million in 2017 and $59 million in the first half of 2018. This compares with global sales of $152 million and $70 million in the respective periods.

How important is understanding Thalidomide's birth-defect-causing mechanism? Here's Fisher's explanation...

"Knowing the mechanism by which Thalidomide produces birth defects will be critical as drug developers devise and test new drugs that use the same structural "scaffold" as Thalidomide. As new derivatives are tested, we'll be able to explore whether they have the same potentially damaging effects as Thalidomide. We know that the therapeutic effect of these drugs is based on their ability to degrade specific proteins. Our findings will help drug developers distinguish between proteins whose degradation is likely to be beneficial and whose may be harmful".

The study is published in the journal Elife.

(Teratogenic is a drug capable of interfering with the overall growth of a fetus, causing birth defect).