Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against

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Thalidomide*, a white, crystalline, odorless and tasteless powder which is a synthetic derivative of glutamic acid (alpha-phthalimido glutarimide), now recognized as the cause of an epidemic of infant malformations, was, as the story is told, originally developed in 1952 as a tranquilizer by Swiss pharmaceutical company Ciba AG (now part of Novartis)[1][2][3]. The drug was one of the many chemical compounds discovered in the post-World War II decade, and was thought to have many potential uses.

However, after briefly testing the drug for efficacy, scientists at Ciba did not observed marketable pharmacological potential for thalidomide. As a result, the company abandoned further product development inlieu of glutethimide (Doriden®). Over time, glutethimide became well known as the first barbiturate-free hypnotic to treat insomnia. In the late 1950s the drug was sold in direct competition to thalidomide.[4][5]

The generally accepted narrative goes on to describe that, despite Ciba’s decision not to commercially develop the chemical compound, the German company Chemie Grünenthal GmbH, based in Stolberg near Aachen (Germany) – in 1954 – re-synthesized phthalimido glutarimide (soon abbreviated to thalidomide), and acquired a twenty-year patent for the drug. In April 1954, immediately following patent application Chemie Grünenthal started clinical trials. However, there was no clear indication for, or a treatment including the new compound.

Thalidomide was now a drug in search of a disease and was tested as a spasmolytic, a local anesthetic and an anticonvulsant for the treatment of epileptics. The drug did not show efficacy. A subsequent trial included its use as an antihistamine, which also failed to show efficacy.#However, other trials unexpectedly demonstrated that the drug was well tolerated and was effective as a sedative and helped to induce sleep.

Thalidomide appeared to be exceptionally well tolerated, was not habit-forming, and had little potential for misuse for suicidal purposes. An overdoses did not cause any notable drug related adverse events, but simply resulted in prolonged sleep, not death, at least so it seemed. [5]

Inadequate trials
Unfortunately, the drug trials conducted by Chemie Grünenthal where not a scientific and methodical investigation of thalidomide. Instead, judging from little historical evidence that remains, the extend of the trials was that the drug was distributed as free samples through doctors, without any monitoring or follow-up. Chemie Grünenthal even handed it out to their own employees. As a result, thalidomide was introduced by the method of Russian roulette and practically nothing was known about the drug effects at the time of its marketing.

In November 1956 the the drug was marketed for the treatment of respiratory infections in Hamburg, Germany under the trade name Grippex®, a combination drug that contained thalidomide, quinine, vitamin C, phenactin and acetylsalicylic-acid or Asperin® [6]

Photo 1.0: The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd., which became part of Diageo plc in 1997, marketed thalidomide under the brand name Distavel® as a remedy for morning sickness throughout the United Kingdom, Australia and New Zealand. This advertisement appeared in the June 24, 1961 edition of British Medical Journal (BMJ).

Morning Sickness
Researchers at Chemie Grünenthal also found that the drug was particularly effective for pregnant women suffering from morning sickness. [7][8] At the time of the commercial development of the drug, the medical community did not believe that any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus. Hence, in 1957, Chemie Grünenthal began aggressively marketing thalidomide – now recognized as a powerful synthetic tranquilizer and antiemetic – in West-Germany as an over-the-counter drug for nausea and morning sickness.[9]

The drug was see as a safe sedative, a perfect alternative to the growing abuse and accidental death from barbiturates. The company even made a liquid formula designed to help fuzzy children. Within a relatively short time, thalidomide quickly became a drug of choicefor pregnant women.

Safety and lack of toxicity?
A study published in the the March 1960 issue of the British Journal of Pharmacology and Chemotherapy further confirmed the efficacy of thalidomide as “a new sedative hypnotic drug…” that was “was safe, and produces no toxic effects when administered orally to animals in massive doses.”

According to the author of the study, “this lack of toxicity could be the result of limited absorption.” The author further noted, “the drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep.”[7]

A very successful drug
Thalidomide became one of the most successful prescription drugs in the history of medicine. In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd., which became part of Diageo plc in 1997, marketed thalidomide under the brand name Distavel® as a remedy for morning sickness throughout the United Kingdom, Australia and New Zealand. Their advertisement claimed that “Distavel can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child…Outstandingly safe Distavel has been prescribed for nearly three years in this country.”

Following the same strategy Chemie Grünenthalhad used when it developed Grippex®, The Distillers Company (Biochemicals) Ltdalso started to market products that combined thalidomide with other drugs under a number of trade names including Tensival (hypertension), Valgraine (migraine) and Asmavel (asthma), while stressing the safety of thalidomide.

Photo 2.0: This advertisement for Distavel® appeared in the August 15, 1959 edition of British Medical Journal (BMJ). The drug was promoted as safe… ‘free from untoward side effects…’

Conquering North America
Around the world, more and more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid 1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under 37 (some reports suggest 51) different trade names. The only major market not yet conquered was the United States. [6]

Eager to crack the enormous potential of this market, representatives from Chemie Grünenthal approached Smith, Kline & French (SKF), now GlaxoSmithKline (GSK) with a request to market and distribute the drug in North America.

A newly discovered FDA memorandum (found hidden in the federal archives in 2011) shows that, as part of their in licensing approach, the Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women, in 1956–57.

In 1956 researchers at SKF involved in clinical trials, noted that even when used in very high doses thalidomide could not induce sleep in mice. And when administered at doses 50 to 650 (!) times larger than that claimed by Chemie Grunenthal to be “sleep inducing” the researchers could still not achieve the hypnotic effect in animals that it had on man.

After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug.

Following the decline by SKF, Chemie Grünenthal offered the drug, without a lot of success, to a number of other pharmaceutical companies. Ultimately, in 1958, the company reached an agreement with William S Merrell Company in Cincinnati, Ohio (later Richardson-Merrell)to market and distribute thalidomide throughout the United States [6]. In 1960, separate from their agreement with William S Merrell Company, Chemie Grünenthal obtained a US trademark for their thalidomide drug product Softenon®.

In September 1960, William S Merrell Company and National Drug Company (later Richardson-Merrell, now part of Sanofi) submitted a New Drug Application (NDA) to the U.S. FDA (United States Food and Drug Administration)with a request to approve the drug, to be marketed as Kevadon®,for distribution throughout the United States.[6][8]

Polyneuropathy
Soon after launching thalidomide (Contergan® and Contergan Forte®; Chemie Grünenthal) in West Germany, reports began to be published that polyneuropathy, a painful tingling of the arms, hand and feet resulting in nerve damage and partial paralysis, was one of the toxic adverse drug reactions observed in elderly patients using the drug.

In October 1959, after observing that one of his patients, a 68-year old man, had developed ployneuropathy after taking the thalidomide for 18 months, the neurologist Ralf Voss M.D., based in Düsseldorf, Germany, wrote a letter to Chemie Grünenthal, asking thecompany if the observed symptoms could be among the side effects of the drug. The answer was a resounding and straightforward “No!” Suspicion and and observed ill-effects – especially reports of polyneuropathy and (later) teratogenecity associated with thalidomide – were minimized by representatives of the company, ascribing them as the result of overdosage and prolonged usage. [8]

Photo 3.0: Packaging of Distaval, distributed by The Distillers Company (Biochemicals) Ltd.

In private, however, representatives of Chemie Grünenthal had discussions with the company’s lawyers about compensation claims, a fact that would ultimately hurt them legally.

In December 1959 and January 1960,soon after Voss stressed his concerns, George F. Somers, Ph.D, a scientists at The Distillers Company (Biochemicals) Ltd wrote internal memos to his superiors stating the apparant high toxicity of the drug. Following further scrutiny, The Distillers Company (Biochemicals) Ltd broke with Chemie Grünenthal in the late 1960s by placing a warning on the label for their thalidomide brands. It was months later, in spring 1961 that Chemie Grünenthal decided to add similar warnings on their own label. By then ployneuropathy was already affecting up to 40,000 people around the world. [8]

U.S. FDA does not approve
However,  the reports of adverse drug reactions were cause enough for Frances O. Kelsey, Ph.D., M.D, the Medical Officer of the U.S. Food and Drug Administration (FDA) to recommended rejecting the application to market thalidomide in the United States. Kelsey – who had learned from her own research that drugs could pass through the placental barrier between mother and unborn child – was not satisfied that the drug would be safe during pregnancy.[9]

At the same time, on the other side of the world, the authorities in the German Democratic Republic, as former Communist East Germany was called, reviewed the drug but did not approve its distribution and use, because, they concluded, the scientific rationale for the drug was wanting and…this drug “cannot be considered as an indispensable drug.”[6]

Photo 4.0: Frances O. Kelsey, Ph.D., M.D, the Medical Officer of the U.S. Food and Drug Administration (FDA).

Growing concern
Kelsey’s suspicion was not without reason. In an interview in 2001 published in the FDA Consumer a publication from the U.S. FDA, Kelsey said that the chronic toxicity studies, absorption and excretion data were inadequate. “We were concerned about the non-absorption,” she noted in that interview, “That you could give enormous amounts [of the drug], both to animals and humans, without toxicity. We felt that there might be conditions, illnesses, or other drugs that might change the absorption, and toxic effects might appear.” [9]

In December of 1960, Leslie Florence, MD, confirmed Kelsey’s reason for suspicions and concerns when he wrote to the British Medical Journal. Florence, who had prescribed thalidomide to his patients, reported seeing cases of peripheral neuritis (ployneuropathy), in patients who had taken the drug over a prolonged period of time.

He wondered in thalidomide was to blame. The observation was eerily similar to the observations in Germany by Ralf Voss a year earlier. [10]

Florence’s reports coincided with the observation, presented a pediatric meeting in Kassel, Germany, by the German physician Kosenowand Pfeiffer, MD in October 1960, of multiple cases of severe limb defects. Another German physician, H.R. Wiedemann, MD, confirmed the observations and linked the limb defects in children with a number of associated malformations, including congenital heart disease, microphthalmos and coloborna, intestinal atresis, renal malformations, abnormal pinnae, and facial nacvus. [11]Given the large number of children involved Wiedemann called this the beginning of an epidemic.

With mounting pressure and a growing number of reported adverse drug reactions, Chemie Grünenthal revised the package insert and applied for prescription-only status for thalidomide in 1961. Then, on 16 November of that year, the Hamburg-based pediatrician and geneticist, Widukind Lenz, MD, finally confirmed his suspicion that an increase in deformities in unborn children could be related to thalidomide.

He had observed that in 50% of patients cases, their mothers had taken thalidomide. As part of his research, Lenz had also reviewed more than 212,000 birth records from babies being born in hamburg, Germany, between 1930 and 1955. To his amazement, he only discovered one case of a baby born with similar birth defects as the one observed in births of babies born to mothers who had taken thalidomide. [6][12]

The babies born to these mothers were not the first victims of thalidomide. Five years earlier, on Christmas Day 1956, a little girl was born without ears. She was the daughter of one of Chemie Grünenthal’s employees who had given samples of the drug to his pregnant wife when the drug was being tested as part of the company’s clinical trial program. Later, their child became the first baby of record recognized as having disabilities caused by thalidomide.

Lenz’ observations were not unique. Other physicians, including the Australian gynecologist and obstetrician William G. McBride, MD, expressed concern about the safety of the drug. In a letter published inThe Lancet, McBride noted that the drugcaused many cases of a rare birth defect involving shortened or absent limbs in babies whose mothers had used thalidomide in the first trimester of pregnancy.[6][9][10][11]The same year, in November 1961, the drug was withdrawn from market and a letter were sent to doctors, pharmacists and hospitals in West Germany and around the world informing them of the withdrawal and reports of the side effects.[6][14]


Photo 5.0: Children with phocomelia of the arms. Phocomelia is a congenital disorder that presents with a reduction in length of the long bones of the legs and/or arms. In some cases, the hand or foot is attached to the end of the shortened appendage, but in other cases there is no hand or foot at all. Two most common causes of Phocomelia are genetic inheritance and drug use. This article discussed the effects of thalidomide. In the 1950s this drug was prescribed to fight anxiety and stress related problems. The drug was also used in pregnant women who had trouble controlling morning sickness and nausea.

Even after the drug was withdrawn from the market, pregnant women were still taking the drug. Many of them did not realize what they were using. And while almost everyone knew that thalidomide caused birth defects, most people were unaware that they were taking combinations therapies containing thalidomide. And in many cases, thalidomide was not included on the label of these drugs.

The World Health Organization (WHO) banned the in 1962. However, research continued. Today, the interest in and use of thalidomide is increasing due to its potential as an immunomodulating and antiangiogenic agent. [5][16][18]

Following the market withdrawal of the drug it became clear that between 8,000 – 12,000 so called thalidomide babies had been born in Latin America, Europe, Australia and New Zealand to women who had taken thalidomide as a morning sickness remedy in the first trimester of pregnancy. [6] These babies presented with a common pattern of limb deformities called phocomelia (from the Greek word for ‘seal limbs’), which includes shortened limbs and other severe, which often fatal birth defects, as reported by Pfeiffer and Wiedemann. The drug also caused abnormalities in the eyes, ears, heart, genitals, kidneys, digestive tract (including the lips and mouth), and nervous system. While many of these babies died in infancy (it is estimated that 40% died before their first birthday), quite a few survived into adulthood. Now in their early 50s, most of these thalidomide survivors continue suffering from a variety of chronic health problems which are directly related to their condition.[14]

Lessons learned
While the the thalidomide tragedy is probably one of the greatest therapeutic disasters of all time, it can be said that one of the positive effects directlyresulting from it was a tightening of laws and preventative measure designed to improve drugsafety and testing, leading to stricter regulations governing drug development and clinical trials around the world. In the United States, for example, the thalidomide tragedy is generally credited with helping to win passage of the 1962 Kefauver-Harris Amendment to theFederal Food, Drug, and Cosmetic Act, which introduced or strengthened requirements for drug manufacturers to demonstrate the safety and efficacy of their drugs prior to market approval. Drug legislation in Canada was tightened in accordance with the stricter laws and regulations in the United States. [16]

Regulation introduced in The Netherlands (‘Wet op de Geneesmiddelenvoorziening’ of 1963), in Western Germany (the Pharmaceutical Law of 1976) and in Japan (Drug Side-Effect Injury Relief Fund Act of 1979) are also considered indirect products of the thalidomide disaster. Furthermore, drug manufacturers in Sweden and a number of other countries adopted voluntary regulations governing drug safety and efficacy.

It can be said that the thalidomide tragedy resulted in a safer pharmaceutical market. However, the pressures that have led to the thalidomide disaster still exist today. Most experts readily agree that management and shareholder pressures, parallel worldwide marketing, increased outsourcing maypossiblylead to future breakdowns in the regulatory system of checks and balances created by the regulatory authorities. Furthermore, based on the scientific understanding, as well as trial standards and practices at the time, many experts doubt that the thalidomide tragedy could have been averted.[17]

A reversal of fortune
But despite this tragic legacy of causing birth defects 50 years ago, thalidomide never disappeared. A reversal of fortune resulted in a resurrection of thalidomide. In 1964, an Israeli dermatologist, Jacob Sheskin, MD, observed that thalidomide was effective in treating a particularly disfiguring form of leprosy called erythema nodosum leprosum (ENL), a disease known to cause diffuse red nodular lesions along with fever, weight loss, arthritis, and general malaise. [18]Although thalidomide proved to be beneficial in the treatment of ENL, the U.S. FDA had many serious concerns about the risks related to drug’s use in women of childbearing age and pregnant women.

Photo 6.0: Thalomid® (Cellgene) packaging

Ultimately the agency approved thalidomide for the treatment of ENL on July 16, 1998. To ensure safe use of the drug, the FDA required Celgene Corporation, that markets the drug under the brand name Thalomid®, to establish a System for Thalidomide Education and Prescribing Safety orSTEPS.

This comprehensive oversight program was designed for patients, physicians, and pharmacists by experts in public and women’s health to providing extensive patient education about the risks associated with thalidomide. The program also included a 100% patient registry, to ensure a zero tolerance policy for thalidomide exposure during pregnancy.

HIV/AIDS and Cancer
But the reversal of fortune did not stop there. Thalidomide was found to have immunomodulatory and anti-inflammatory properties. [22]In 1991, working as a researcher at New York’s Rockefeller University, Gilla Kaplan, Ph.D, Professor of Medicine in the Laboratory of Mycobacterial Immunity and Pathogenesis at the Public Health Research Institute Center of the University of Medicine and Dentistry of New Jersey, demonstrated that thalidomide inhibited an important cytokine called tumor necrosis factor-alpha or TNF-?, which has multiple immunologic functions involving apoptosis, inflammation, tumorigenesis, and viral replication, by inducing TNF-? mRNA degradation. [19]This discovery provided a theoretical framework for the development of thalidomide as a treatment option for people with HIV/AIDS. Kaplan partnered with Celgene Corporation to further develop the potential therapeutic use of thalidomide.

Angiogenesis
Subsequent research has shown that thalidomide is effective in the treatment of multiple myeloma. The drug also induced partial or complete responses in ?30% of patients withrefractory myeloma. [19]Moreover, in 1994 Robert J. D’Amato, MD, PhD, Professor, Department of Ophthalmology, Harvard Medical School Research Associate, Surgical Research, Boston Children’s Hospital, but at that time working in the lab of Judah Folkman, MD, found that thalidomide inhibits angiogenesis by interrupting processes mediated by bFGF (basic fibro­blast growth factor)and vascular endothelial growth factor or VEGF. [19]Since angiogenesis is critical during limb development of the fetus, this was understood to be one of the possible mechanisms of thalidomide’s teratogenic action. But angiogenesis also plays a critical role in the growth and spread of cancer. Inhibiting angiogenesis is therefore an important cancer-fightings strategy in the treatment of cancer because these drugs tend to inhibit the growth of blood vessels rather than tumor cells.

How does thalidomide slows cancer?
Today, thalidomide- and a number of newer drugs derived from it – is considered an effective drug for improving the survival rate in bone-marrow-transplant patients and various forms of cancers. However, while thousands of research papers have been written – so far – scientists have not been able to find the real mechanism of action of thalidomide and similar drugs in slowing the spread of cancer.[20][21][24]

Photo 7.0: William G. Kaelin Jr., MD, Professor of Medicine, Harvard Medical School Chair, Executive Committee for Research. Photo Courtesy: Dana-Farber Cancer Institute

In a new report, scientists at Dana-Farber Cancer Institute say, for the first time, that they have discovered that thalidomide kill multiple myeloma cells by a mechanism that’s different from the way that they cause birth defects. As a result, explains William G. Kaelin, Jr., MD, senior author of the report in Science Express: “It may be possible to develop better thalidomide-like drugs that retain the anticancer activity but not the activity that causes birth defects.” [23][24]

In 2006 the combination of thalidomide and dexamethasone was approved for treating multiple myeloma. More powerful and safer derivatives including lenalidomide (Revlimid®; Celgene Corporation) and pomalidomide (Pomalyst®; Celgene Corporation), are now also approved, albeit under strict regulations, for use in multiple myeloma patients.

“Safer drugs of this type,” Kaelin further explained, “would be useful not only for multiple myeloma, but could be explored for treating other B-cell malignancies such as certain types of lymphoma, some of which affect young women.” The thalidomide and thalidomide-like drugs can also dampen immune system activity and new versions could be tried in women with autoimmune diseases like lupus.

Other important implication
These findings may have another important implication for cancer treatment. The researchers demonstrated that lenalidomide killed multiple myeloma cells by disabling overactive switches called transcription factors that drive the cells’ excessive growth. Transcription factors are proteins that bind to genes and increase their activity, and cancers are often driven by overactivity of these molecular switches. For example, a transcription factor called c-Myc appears to be overactive in many different types of cancer. “It has proved difficult to target or drug transcription factors,” Kaelin said, “but the new study suggests that lenalidomide’s ability to disable transcription factors could be a template for targeting other transcription factors linked to cancer.”

Mechanism of Action
For decades the mechanism of action of thalidomide remained a mystery. But in 2010, scientists in Japan reported that thalidomide binds to and inactivates a protein, cereblon, which is important in normal development of limbs. Cereblon is a component of a protein complex called an E3 ubiquitin ligase, which tags proteins that need to be destroyed for the cell’s health, and is a key to embryonic development. The researchers found that thalidomide’s inactivation of cereblon disrupted development and explained the drug’s tendency to cause birth defects, but not its ability to block cancer growth.

The new report describes research by Kaelin, along with first author Gang Lu and other Dana-Farber investigators, showing that when lenalidomide binds to cereblon, it can trigger the destruction of two transcription factors, IKZF1 and IKZF3, that are overactive in multiple myeloma cells. The immediate result is that cancer growth is shut down, halting the progress of the disease.

“The anticancer mechanism is that lenalidomide binds cereblon and allows the ubiquitin complex to degrade the transcription factors,” Kaelin explained. “This is a different mechanism from the way lenalidomide binds and inactivates cereblon, leading to birth defects.”[24]


Notes
* Thalidomide was original marketed under brand names including Contergan®, Contergan® Forte, Distaval®, Enterosediv®, Noctosediv® and Softenon®. Around the world the drug was marketed under a variety of 37 brand names (Some reports suggest that the drug was sold under 51 different brand names). [Overview]
**Under the terms of the agreement, the company shared the Canadian Market with Frank W. Horner Ltd, based in Montreal. This company sold the drug under the brand name Talimol
*** Because in the United States thalidomide was only distributed on an investigational basis, damage was small by comparison. In total 17 children were born with thalidomide-associated deformities. However, a recent legal case suggest that this number is underestimated.
# The German trade name Contergan® suggest that Thalidomide was supposed to have antihistamine and antiergotropic activity.
## Today, Grippex® is marketed in Russia by Unipharm, Inc., is a combination of 325 mg paracetamol, 30 mg pseudoephedrine, and 10 mg dextromethorphan designed to temporarily reduce fever and relieve symptoms of the common cold such as runny nose, sneezing, cough, headache, minor aches and pains, nasal congestion, and sore throat. In Germany, “Grippex Brausetabletten” is a brand name for paracetamol (acetaminophen).

Also see:
Thalidomide: In the Shadow of Death – Onco’Zine – The International Oncology Network [Video/Article]

Last editorial review: November 30, 2013

Featured Image: Contragan Packaging, 1960.

Historical photos used with permission based on a fair use as provided for in section 107 of the US Copyright Law. Reproduction in accordance with Title 17 U.S.C. Section 107, for educational purposes only.

Copyright © 2013 Sunvalley Communication. All rights reserved. Republication or redistribution of InPress Media Group/Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group/Sunvalley Communication. InPress Media Group/Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco’Zine and Oncozine are registered trademarks and trademarks of Sunvalley Communication around the world.

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