50 years after Thalidomide was discovered, the name is still synonymous with one of the greatest disasters in medicine. Just as the public are shocked by the extreme side effects, the pharmaceutical industry fear producing another drug capable of doing such harm. Yet, even as a result of its own notoriety, Thalidomide has had many positive effects upon the world. From making us think twice about how we produce our medicines, to the information we have derived from its many biological effects, Thalidomide has much in its favour. In this, the year of the anniversary of its discovery, let us hear the evidence and sit in judgement upon Thalidomide: Is it really a reformed character?
After its original synthesis by Swiss company Ciba in 1953, Germany’s Chemie Grunenthal developed Thalidomide and brought it to market in 1957. It was soon used widely as a sedative across Europe and Australasia. In its native Germany Thalidomide attained an almost cure-all status, through its ability to induce a natural all-night sleep without a hangover, and with apparently complete safety. It was added to treatments for colds, migraines, nervousness, asthma and particularly for pregnant women, providing them with a good nights sleep, and suppressing morning sickness. As Thalidomide continued its slow progress across the world, reports of nerve damage in long-term users surfaced, making West Germany reclassify it as a prescription-only medicine. In the US, suspicions were raised at the Federal Drug Agency. Dr. Francis Kelsey, who had previously worked on identifying birth defects associated with quinine, was assigned to the approval of Thalidomide. Her principal concern was the reported nerve damage, however the recommendation that it be prescribed to pregnant women made Dr. Kelsey ask for more evidence of the safety of the drug during pregnancy. This was to prove a key moment in the history of the regulation of medicines.
In the following years, thousands of babies were diagnosed with the inherited disorder phocomelia, which prevents limbs from developing completely, instead leaving hands and feet attached directly to the body or an absence of limbs completely. As genes being passed on from parent to child both cause and limit such inherited disorders, increases in frequency are rare. This explosion of cases required an alternative explanation. In the early 1960s reports linking the use of Thalidomide to the proliferation of birth defects was supported by a series of animal tests. When taken between 3rd and 5th week of pregnancy a range of malformations of the foetus was observed, very similar to those in phocomelia. The drug was subsequently removed from the market and labelled “teratogenic”, literally meaning “tending to produce anomalies of formation”. In the USA, one of the few countries to avoid the tragedy of Thalidomide, the reputation of the FDA was greatly enhanced.
For some months previous to this discovery a US bill enhancing safety regulations affecting drugs had been languishing in committee through lack of support, but the bill was resurrected when the media attention surrounding Thalidomide made drug safety a hot topic. New laws were pushed through requiring that the FDA must know intimately all the details surrounding safety studies for drugs, before, during and after the study, and that any infringements of the process would allow the FDA to terminate the research. The UK government followed closely behind with the British Medicines Act of 1968, and to this day governments’ regulation of the pharmaceutical industry remains prudently strict.
Many consider this to be where the story of Thalidomide ends. As the controversy surrounding the drug grew, however, a serendipitous observation made a strong case for its continued use. In 1964, a physician named Jacob Sheskin was treating patients in Israel for a condition known as erythema nodosum leprosum (ENL), a complication of leprosy. He prescribed Thalidomide to his patients as a sedative to allow sleep despite the painful skin nodules and fever resulting from the disease. Very quickly Sheskin observed his patients’ ENL symptoms abating, and then reversing. These findings have made Thalidomide the therapy of choice for ENL, and it is currently designated for use globally by the World Health Organization – including in the USA.
Given a legitimate reason for its existence, Thalidomide has continued to interest the medical fraternity. In attempting to answer the most obviously important question – the origin of the drug’s “teratogenicity” – another landmark discovery was made, which would alter the pharmaceutical industry’s outlook permanently.
Carbon atoms, which are largely responsible for the framework upon which you, I, and drug molecules are built, link together in such a way that they can yield “isomers” of the same molecule, identical, except that they are mirror images of each other. A simple example of this relationship is the difference between your left and right hands. Compounds produced in biological systems, like our bodies, are almost exclusively present as one isomer, for example the ‘right handed’ isomer. Prior to Thalidomide, it was assumed either that in drugs the ‘right handed’ isomer was also responsible for all the biological activity, and the ‘left’ was inactive, or that there was little difference between the two. As such, drugs tended to be made without discriminating between the two isomers, and prescribed in a mixed form. In Thalidomide, the sedative activity was traced to one isomer, and the teratogenicity was traced to the other. This suggested that the tragedy may have been avoided by producing only the sedative isomer, however since this discovery was made Thalidomide has also been found to interconvert between the two forms in the body, negating any such effort. Even so, one-third of all marketed drugs are now sold as a single isomeric form, and all forms of a drug now have to be tested rigorously for possible side effects and for stability in biological systems before approval. The FDA also insists on switching to one pure isomer for older drugs, and will only approve single isomers of new drugs. Through the influence of Thalidomide, the pharmaceutical industry has had its assumptions questioned, and has been regulated to prevent history repeating. Thalidomide has, in a sense, made us all a little safer.
Other crucial questions – that of how Thalidomide works, and why it is toxic – remain matters of great controversy. Metabolism breaks the drug down to many different chemical structures, to each of which may be attributed a different effect. An overall explanation of its activity is therefore likely to be extremely complex, and as such no universally accepted biochemical explanation for Thalidomide’s effects has been put forward. Instead, many of the different parts of Thalidomide’s biological character have been studied, and are giving scientists pointers to better, safer, ways of treating diseases.
For examples, Thalidomide has been widely shown to exhibit anti-inflammatory properties, and effects upon the immune system of patients suffering from a variety of diseases, including rheumatoid arthritis, inflammatory bowel disease, asthma and AIDS.
Studies suggest that Thalidomide’s anti-inflammatory activity, responsible for its efficacy in ENL, is derived from its ability to suppress levels of hormone-like chemical messengers in the blood known as cytokines. Thalidomide mainly suppresses levels of two specific cytokines, known as Tumour Necrosis Factor-α (TNF-α) and interferon-γ, and may also be able to reduce the amount of locations on cells within the immune system, for example white blood cells, that TNF-α interacts with. The overall effect is that of decreasing the strength of the message, and reducing the number of ways it can get the message to the immune cells, reducing the intensity with which they attack and cause inflammation in the affected tissue.
Leading the way in such studies are Celgene, a US company who have been manufacturing Thalidomide since its approval by the FDA. They now hope to use it as a lead from which to develop new medicines, the key hope being a series of new anti-inflammatory drugs, IMiDs and SelCIDs, aimed at suppressing TNF-α in the same way as Thalidomide. The new compounds are up to 50000 times as effective and lack teratogenicity according to early studies.
Another explanation of Thalidomide’s anti-inflammatory activity could be its effect on phosphodiesterase-4 (PDE-4), an enzyme found in monocytes, the white blood cells responsible for producing TNF-α. This enzyme is responsible for signalling to the monocytes whether or not to produce TNF-α. Thalidomide’s breakdown products may interact with PDE-4 so that a signal telling the monocytes to stop producing TNF-α is sent, adding to the overall effect of the drug.
Interestingly, the more potent compounds Celgene have produced do not interact with PDE-4. They have, however, also developed different compounds that show an anti-inflammatory effect specifically through this enzyme, with chemical structures similar to Thalidomide, but this time only 1500 times more effective.
Celgene’s research has shown that Thalidomide derivatives also interact with another enzyme involved in inflammation, called cyclooxgenase-2 (COX-2). COX-2 is involved in the production of different compounds that transfer signals resulting in inflammation, known as prostaglandins. Their IMiDs have been shown to reduce the amount of COX-2 made by certain cells, in turn reducing the amount of prostaglandin signals, hence Thalidomide may have the ability to reduce the amount of signalling that leads to inflammation in yet another way.
Much of the work in establishing causes of Thalidomide’s anti-inflammatory effects has been performed over the past decade, driven by its recognition as a valid treatment for ENL. Even within the last year findings have been published lending more weight to the ability of Thalidomide to inhibit the production of cytokines. A team led by Dr. David Grainger working at the University of Cambridge were researching a protein native to the human body, Peptide 3, responsible for the suppression of production of a number of cytokines. Through a series of studies they were able to identify a small fragment within the overall structure responsible for the bulk of Peptide 3’s activity. A final small modification to this fragment gave a compound, NR58,4, approximately 1000 times more effective than Peptide 3 at suppressing cytokine production, with a structure somewhat analogous to Thalidomide.
“Certainly they have structural similarity,” explains Dr. Grainger. “The key question is whether the structural similarity underlies functional analogy. The answer in this case, is tantalising. That NR58,4 and Thalidomide are analogues is supported by studies that show that Thalidomide is a weak cytokine inhibitor. If that is true, then it may suppress TNF-α by the same mechanism as NR58,4,”
So, by approaching the generation of anti-inflammatory drugs from the opposite end of the drug discovery spectrum to Celgene, Dr. Grainger and his team appear to have unearthed further clues to how Thalidomide works – that is, in a way similar to Peptide 3. In addition, by modifying compounds that already exist in the body, as opposed to trying to design the toxicity out of an existing drug, the Cambridge team seem to have achieved similar potent, and safe, drugs as those that Celgene have developed – although perhaps unintentionally.
“My colleagues and I chose the modification route to our target not because we felt it was intrinsically safer, but because the traditional drug discovery machine in large pharma had been very ineffectual,” says Grainger. “I don’t really think we had any expectations of what we would find. This class of molecules, collectively called Chemotides, are under active pharmaceutical development for a range of inflammatory diseases. Certainly, they appear safe. Toxicological testing is relatively well advanced and no specific toxicities have been exhibited. The molecules are remarkably well tolerated.”
Beyond inflammation, Thalidomide’s revival continues further, as it lends its weight to the ongoing fight against cancer. In 1994, Thalidomide was shown to prevent angiogenesis – the process which tumours use to convince blood vessels to form to link them to the body’s blood supply and allow them to grow. As well as holding promise for people suffering from cancer, this discovery may help explain some of Thalidomide’s teratogenic effects. In particular, the growth of limbs in the foetus depends greatly upon the formation of new blood vessels – and so if Thalidomide can stop blood vessels growing in cancer, it may be able to stop them growing in foetuses too, hence affecting limb growth.
Multiple myeloma, the second most common cancer of the blood, is a particular case where Thalidomide has shown promise in stopping progression of the disease, which is notoriously unresponsive to chemotherapy. In multiple myeloma carcinogenic blood plasma cells replace the bone marrow, damaging the bone with the formation of tumours and the extra capillaries that support them. Studies in Arkansas and Minnesota showed that treatment with Thalidomide stopped progression of the condition in a third of cases.
Subsequently, Celgene, and another company, Entremed, have investigated Thalidomide and its derivatives to help treat cancers via angiogenesis. In healthy adults angiogenesis only occurs in wound healing, so compounds that stop this process are relatively non-toxic and therefore attractive as potential new medicines.
Entremed were the first company to patent Thalidomide and its analogues for this purpose, and also claim to be the first to study which exact properties are required for those analogues in stopping angiogenesis. Once alerted to the possibilities in this research area, Celgene’s expertise allowed them to use one of their IMiDs to similarly explore the use of Thalidomide analogues, whilst paying Entremed for the rights to further research and sell Thalidomide for treatment of cancer. Any goodwill this arrangement may have established was soon undermined, however, as the two companies clashed over the prospective cancer treatments they were developing. Both Celgene and Entremed had patented Thalidomide-analogue drugs to inhibit angiogenesis and induce cell death in multiple myeloma cells, and in November 2002 each issued legal challenges to the other’s patents. Both were studying these potential new drugs in clinical trials, but through its sales of Thalidomide, Celgene had more money in the bank. Needing funds for other studies, Entremed sold the rights for its candidate to Celgene in December of the same year, avoiding both companies a long, costly litigation process and allowing research in this promising area to progress once more.
Thalidomide’s potential to treat cancer is not limited to multiple myeloma, or suppressing angiogenesis. Celgene have patented the use of Thalidomide in conjunction with the chemotherapy drug Irinotecan used to treat cancers of the colon and rectum. Other approaches use Thalidomide and its derivatives to attempt to stop the process by which tumour cells break down tissue barriers to allow their migration. It seems likely that a range of cancers may be able to benefit from the inhibition of angiogenesis, and given the wide range of effects that Thalidomide has on the body, there may well be much more to say about its use in treating cancer over the coming years.
Although Thalidomide is no longer headline news, it has left a legacy engraved deeply in the statute books to help make sure history is never repeated. Thalidomide continues to be of benefit to people around the world, and is still available on prescription, albeit under a program named S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety) that only allows prescription to women if they use two highly effective forms of contraception or are past the age of reproduction. Research into Thalidomide also continues to bring benefits in the form of a pipeline of future medicines, which have isolated one of the biological effects of their parent and improved upon it. So perhaps Thalidomide has reformed, to become a drug that currently does more good than harm. Is this enough to counterbalance the damage caused to so many unborn children? Maybe not. However, the sense of caution with which scientists now develop medicines, instilled by Thalidomide, could come close to making amends.
“Frighteningly, I think we know the precise target of action of very few of our drugs,” admits Dr. Grainger, “in many cases, it is almost certainly not the target which the drug was designed to hit. I think we should all be a lot more humble and accept that we understand a biological network of interacting signalling pathways very poorly, and that we are still feeling our way in the dark when we begin to interfere with those pathways with drugs like Thalidomide. Our best protection against harmful side-effects remains thorough empirical testing and a realisation that we do NOT really understand what we are doing.”
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