BBC Two, Thursday 12 February 2004, 9pm Thalidomide - A Second Coming Up Chance?

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Thalidomide - A Second Chance? - transcript

NARRATOR (VOICE OVER): Half a century ago, scientists made one of the biggest medical blunders in history. They created this drug. A drug that destroyed many lives, but now its saving them. NANCY TOUHEY: I was planning my own funeral but this drug gave me my life back. DR PAUL RICHARDSON: Certain cancers instead of being rapidly fatal will become more treatable. CHASE PETERSON: It is a wonder drug. DR KENNETH ANDERSON: Its really the gift of life for some patients and there really is no greater gift than that. NARRATOR (VOICE OVER): Sales of the drug are rocketing but can this drug ever be used safely. KEVIN DONELLEN (VOICE OVER): Life places fair, is with the drug being widely used on the market that its a tragedy waiting to happen again. KEVIN DONELLEN: Im living proof of how dangerous it is. NARRATOR (VOICE OVER): This is the extraordinary story of Thalidomide. A drug that even today no one fully understands. But which some now want to bring back. NARRATOR (VOICE OVER): Chase Peterson was looking forward to a long and happy retirement. CHASE PETERSON: I played tennis since I was five years old, it is part of the definition of lifecheerful, fun. CHASE PETERSON (VOICE OVER): I played tennis with my grandson, I taught him years

before and I can still beat him. NARRATOR (VOICE OVER): But Chase should have died three years ago. In 1997, he was diagnosed with multiple myeloma, a type of blood cancer which is always fatal. CHASE PETERSON (VOICE OVER): The diagnosis was clear, I would be dead in two to four or five years. CHASE PETERSON: My wife and I together, we prepared for me to die. Not in a morbid way, not really in a frightened way, but we made the necessary steps. NARRATOR (VOICE OVER): For two years he held the disease at bay with chemotherapy. But then the cancer came back. His only option was a painful and dangerous bone marrow transplant. CHASE PETERSON: Thats tough treatment- it rarely cures anybody and it gives you an extra year or two. Well if thats all you can have youre grateful for that. But er, it was not a very pleasant prospect. NARRATOR (VOICE OVER): As Chase was a doctor himself, he searched for an alternative treatment. He soon heard of a new wonder drug- a drug with a terrifying past. CHASE PETERSON (VOICE OVER): I had almost nothing to lose and the only question was how long would it take for us to know if it worked. CHASE PETERSON: And to our great joy within two weeks my levels had dropped, within 6 weeks they were down to normal. NARRATOR (VOICE OVER): The drug that saved Chases life was Thalidomide. CHASE PETERSON (VOICE OVER): The word wonder drug has probably been over-used. CHASE PETERSON: In this country we have a bread called Wonder-Bread and theres WonderWoman. Well Ill tell you Thalidomide is a wonder drug. NARRATOR (VOICE OVER): The claim that Thalidomide is a miracle drug could not be more shocking to someone like Kevin Donnellon. He is one of more than 4000 people around the world who know first hand this drugs ability to ruin lives. KEVIN DONNELLON (VOICE OVER): The only generation I think that realises the dangers of Thalidomide because it was in the 1960s I think it is largely forgotten. KEVIN DONNELLON: Doctors in the 1960s had one excuse, you know they didnt really know the effects of the drug, but you know all the doctors in the world know the effects of Thalidomide, or they should do. I mean you know Im living proof of the effects of Thalidomide. NARRATOR (VOICE OVER): The story of Thalidomide began in 1954 when the drug was

discovered by accident. Chemists at a pharmaceutical firm in Germany had been trying to produce an anti-allergy drug, it didnt work. Instead all the lab rats fell asleep. The scientists had discovered a new tranquilliser that was harmless even when overdosed. Thalidomide was hailed as a huge breakthrough, so safe that even if a toddler swallowed a whole bottle, it would do no harm. Marketed under the name Distaval it became so popular it was taken like aspirin. Doctors prescribed it for all kinds of minor symptoms that they thought were linked to anxiety including morning sickness. NARRATOR (VOICE OVER): And this was the use that was to have devastating consequences. Agnes Donnellon was one of millions of women who were prescribed Thalidomide. AGNES DONNELLON (VOICE OVER): I was about 6 weeks pregnant with Kevin and I had very bad morning sickness. I went to the doctors. AGNES DONELLON: He said oh we have some new tablets on the market, well try them and they were called Distaval which is Thalidomide. NARRATOR (VOICE OVER): Agnes took two tablets, months later she gave birth to her baby son, but for some mysterious reason she wasnt allowed to seem him for two days. AGNES DONNELLON (VOICE OVER): All the mums in my ward were let have their babies and I wasnt. AGNES DONNELLON: I kept looking round wondering why and so I asked the sister and she said, oh Ill see you tomorrow, she said your baby is not too well. AGNES DONNELLON (VOICE OVER): And I was taken down in a wheelchair, they pushed me over to the cot and then she left me. AGNES DONNELLON: She didnt tell me what was wrong with him or anything, she just left me by the cot and she said oh by the way she said, hes got very short arms and legs. My brain tore when she said he had short arms and legs, he had short complete arms and legs. She didnt tell me what was wrong with him at all completely,. So when I lifted him up and put the blanket around him I got the shock of my life. NARRATOR (VOICE OVER): No one had an explanation for Agnes and around the country more and more babies were being born with the same malformations. DR CLAUS NEWMAN (VOICE OVER): When I first saw one of these babies I was affably shaken. DR CLAUS NEWMAN: Perfect head, perfect trunk, perfect baby, just no arm and legs. DR CLAUS NEWMAN (VOICE OVER): None of us had ever seen anything like this. DR CLAUS NEWMAN: When this happens in ones or twos one can develop some kind of

response. But when this happens in considerable numbers I think people were overwhelmed and simply didnt know what to think or what to do. NARRATOR (VOICE OVER): It soon became clear that the same tragedy was unfolding in many other countries around the world but no one had any idea what was causing it. At first doctors though it might be a virus possibly linked to a new type of flu. Some thought it was caused by radioactivity, perhaps leakage from an atomic reactor. Even a new type of chemical washing up liquid came under suspicion. Without knowing the cause of the tragedy there was no hope of stopping it. DR CLAUS NEWMAN: One realised that a major disaster had occurred but we really had no idea what the cause was. NARRATOR (VOICE OVER): It remained a mystery for almost five years, until a young Australian obstetrician named William McBride made the connection. He examined the medical records of three disabled babies that he had delivered. McBride realised that early on in pregnancy before the foetus was fully formed the mothers had all taken the drug Distraval. His discovery was published in December 1961. DR CLAUS NEWMAN: My feeling was partly relief, part horror. relief that at last a cause had been found, that therefore one might be able to see the end of the epidemic. But horror that this was another example of a man made disaster. AGNES DONNELLON (VOICE OVER): When I heard what did it I thought well somebody somewhere has got to pay for this. AGNES DONNELLON: It wasnt a revenge thing at all because what had happened had happened. But someone has to be shown up about this because this can happen to other mums and this drug has got to be banned. NARRATOR (VOICE OVER): The drug was finally withdrawn in the summer of 1962. But by then over 8000 Thalidomide children had been born in 46 countries. Only half of them survived past the first month of life. What puzzled scientists was how could a drug that was so harmless to adults be capable of causing such damage to the body of these tiny babies. Until then it was thought that any drug that was safe for the mother had to be safe for the foetus. PROF NIGEL BROWN (VOICE OVER): It was an absolute shock. PROF NIGEL BROWN: to realise that chemicals that were apparently very safe and somewhat innocuous could have totally unexpected effects on the development of the embryo and that is the most significant feature of the whole Thalidomide episode. NARRATOR (VOICE OVER): Scientists tried to understand exactly how the drug stopped limbs from developing in the womb but they couldnt tell what was happening when Thalidomide entered the body.

PROF NIGEL BROWN (VOICE OVER): Thalidomide is not a very stable chemical. PROF NIGEL BROWN: As soon as you put it into the body or even into a solution in the laboratory PROF NIGEL BROWN (VOICE OVER): It immediately starts to break down and you get lots of breakdown products. Were never actually sure whether the effects weve seen are caused by Thalidomide itself or one of these many other breakdown products. NARRATOR (VOICE OVER): In the end only one thing became clear. The damage only occurred in the first 60 days of pregnancy. Even today Thalidomide remains a disturbing enigma. Scientists have still not managed to solve the riddle of how this chemical works. NARRATOR (VOICE OVER): Although the scientists were defeated, the Thalidomide children learnt to adapt. KEVIN DONNELLON (VOICE OVER): Were all like different shapes and sizes. The majority of Thalidomiders have actually got legs and theyre effective in their arms, theyve got shortened arms. But Im not the worse effected in the country, I mean one or two have got no hands at all. KEVIN DONNELLON: I cant imagine how Id cope independently if I didnt have any hands at all. That would be a total nightmare. NARRATOR (VOICE OVER): Medical science did try to make amends to the children who were living with the effects of Thalidomide. For years these children under went repeated and painful operations and were fitted with crude artificial limbs. KEVIN DONNELLON: I looked totally ridiculous in them, I looked like a robot. They were totally unfunctional, I mean you couldnt do anything in them. These are arms which are activated by gas cylinders which you move your shoulder and then the claws would open. Most of the time youd just drop things, I mean I can do more things with these hands than these. And theyre extremely heavy and I felt like really caged in. The gas wouldnt last that long and sometimes youd be picking up a cup say and theyd get it half way to your mouth and then the gas would run out. KEVIN DONNELLON: The legs in some ways were worse because they were far more dangerous. I mean these legs were extremely heavy you know the design hasnt been changed since the first world war. With having no arms I couldnt save myself if I fell over you know, fall to the ground like that. KEVIN DONELLEN (VOICE OVER): But it was a constant fear, any second I expected to fall forwards or backwards, you know straight on my face or on my head. Ive got loads of stitches in the back of my head. NARRATOR (VOICE OVER): There was no getting round the tragedy. Thalidomide was branded one of the biggest disasters in medical history. But only three years later it was

resurrected. NARRATOR (VOICE OVER): In 1965, opinions about Thalidomide began to change. This new chapter of its story began in Jerusalem where a disease thats been with us since biblical times was still rife- leprosy. NARRATOR (VOICE OVER): Around 5 percent of leprosy patients develop a painful and sometimes fatal side effect to their condition called ENL. ENL is the bodys immune response to the leprosy bacteria. It causes deep inflammatory skin nodules on the face, arms and thighs and can lead to deformities. So distressing was this constant pain to patients at one hospital that a doctor Jacob Cheskin was determined to find some way of relieving their suffering. NARRATOR (VOICE OVER): In the hospital pharmacy he stumbled across an old bottle of Thalidomide. Cheskin decided to give it to his patients so they could at least get some rest. What happened next was quite unexpected. NARRATOR (VOICE OVER): Literally over night their skin lesions cleared up. No one could understand why. Cheskin announced his results to an astonished world. DR CLAUS NEWMAN (VOICE OVER): I read Thalidomide was being used for leprosy. DR CLAUS NEWMAN: At first I was quite incredulous that this drug was being used for anything at all. I thought it had been sort of relegated completely. NARRATOR (VOICE OVER): In leprosy areas around the world, the demand for Thalidomide great as word spread about this novel treatment. New stocks of the drug were made in Brazil and exported to other countries. The discovery of the curative properties of Thalidomide was a milestone in its history. But still no one knew why it was working. PROF NIGEL BROWN: We do not understand how the birth defects are caused by Thalidomide. And we do not understand equally many of the beneficial effects of Thalidomide. It is always a surprise when a relatively simple molecule, a drug like Thalidomide, has such a range of biological effects. NARRATOR (VOICE OVER): It became clear that Thalidomide for some reason regulated the immune system of leprosy patients. So doctors tried it out on other diseases of the immune system. NARRATOR (VOICE OVER): One condition to benefit was Behcets disease. In Behcets disease, the immune system mistakenly attacks and harms the bodys own tissues. Among the major symptoms are sores and ulcers particularly in the mouth and on the genitals. A team of medical staff in Nottingham headed by Dr Richard Powell had started Thalidomide as a treatment for Behcets disease, despite the drug not being officially licensed. DR RICHARD POWELL (VOICE OVER): Behcets disease is very unpleasant because not only

do you get severe oral ulcers, but also severe genital ulcers. DR RICHARD POWELL: So when you pass urine Ive known ladies to bite on a towel, because they know how much pain theres going to be. SARAH CRAVEN (VOICE OVER): Ive suffered with genital ulcers the size of the palm of your hand. SARAH CRAVEN: I couldnt eat, I was eating compound meals through a straw. I had to take a rubber ring with me everywhere because I couldnt sit down from the severe pain of the ulcer. NARRATOR (VOICE OVER): Sarahs symptoms were so severe that Dr Powell decided he would have to try Thalidomide. SARAH CRAVEN: Within a matter of three weeks of taking Thalidomide, all my symptoms had gone. Its such a.. it worked so fast, it really is a miracle drug. DR RICHARD POWELL (VOICE OVER): The results were just outstanding, we just couldnt believe our eyes. The first three patients within 14 to 21 days, the ulcers that had troubled them for years just disappeared. DR RICHARD POWELL: Thalidomide blocks one of the inflammatory mediators in the body like nothing else that we currently have available. And therefore for those conditions where this particular mediators important, Thalidomide is unique, necessary and there are no substitutes. NARRATOR (VOICE OVER): But the dark side of Thalidomide was to re-emerge, this time in Brazil. Here the drug was widely available for the leprosy condition ENL. The results were heart breaking. NARRATOR (VOICE OVER): In the seventies and eighties a new generation of Thalidomide children were born in Brazil. These are the children born to mothers who took the drug during pregnancy. Mothers who did not speak English and couldnt read the warnings on the packets or never understood the risks they were taking. KEVIN DONNELLON (VOICE OVER): Theres one kid on the video, hes about 8 Id say and his impairments KEVIN DONNELLON: were more or less exactly the same as mine and hes getting around on the floor the same way as, that I do. And I was just very very angry and I had the sickening feeling inside when I realised that weve allowed this to happen yet again. DR CLAUS NEWMAN: I think there is a continuing ethical dilemma in this. I think that with all the precautions that one can set up there will continue inevitably to be a risk of it leaking into the population and causing yet more malformed babies. NARRATOR (VOICE OVER): It was this dark side of Thalidomide that Sarah Craven was forced

to confront in 1988. She had been using it to keep her ulcers at bay. In fact the drug had kept her so healthy that it was now possible for her to undergo a major change in her life. Sarah became pregnant. SARAH CRAVEN: Im 7 months pregnant now and I havent been taking Thalidomide during pregnancy but er, my symptoms have, Im suffering severe pain with a genital ulcer and mouth ulcers and I need really some consultation as to whether I can go back on Thalidomide during pregnancy. SARAH CRAVEN: Im not sure what the risks are at this late stage. NARRATOR (VOICE OVER): Sarah and her husband turned to Doctor David Heath of Selly Oak hospital for advice. SARAH CRAVEN: I just dont think for the next 5 or 6 weeks, that I could cope. DR DAVID HEATH: I think we can think of putting you back on the Thalidomide to get it healed up. Now Thalidomide as you know, its a drug we desperately try to avoid during pregnancy, but its the early stages of pregnancy. NARRATOR (VOICE OVER): Others fear that Thalidomide may not be safe at any stage in pregnancy. PROF NIGEL BROWN: I think we can not use the drug in pregnancy with absolute confidence at all. I think that there are still, well clearly we dont know how it works and therefore we cannot be absolutely sure of its safety in later stages. Perhaps there are aspects of the actions of Thalidomide that are as yet undiscovered and frankly we dont wasnt to discover them in humans. NARRATOR (VOICE OVER): The week after seeing her doctor, Sarah had some deeply worrying news. Thalidomide wouldnt affect the childs limbs at this late stage but nobody could be sure it wouldnt effect its brain. SARAH CRAVEN (VOICE OVER): On Saturday I was in excruciating pain with the genital ulcer, so I have taken two tablets. SARAH CRAVEN: Ive now just received a call from the hospital saying that there is some doubt whether I should have taken those tablets because of neurological problems it can cause to the baby. Im sort of in a state of shock at the moment, Im really devastated. Im feeling really guilty because Im sort of nervous that Ive done something to the baby. NARRATOR (VOICE OVER): So Sarah returned to Nottingham to seek the reassurance of Doctor Richard Powell, the man who had pioneered the used of Thalidomide in Behcets disease. SARAH CRAVEN: After Id taken them I was just distraught really. Because they said that it could bring neurological problems and I was just sort of like, well..

DR RICHARD POWELL: The baby will be fully formed now and that really isnt an issue. SARAH CRAVEN: Ok. Thank you . DR RICHARD POWELL: That was a horrendous consultation, I found that really difficult. I did reassure Sarah because I think she is at very low risk of foetal damage. The reality is that although Thalidomide is only meant to damage babies in the early part of pregnancy we dont know that it cant do it later on in pregnancy. The point is that she has now taken those tablets, any damage thats happened has happened, and theres really nothing we can do about it now, other than have a very difficult few weeks waiting for that baby to be delivered. NARRATOR (VOICE OVER): Sarah Cravens son Jake was born on the 10th September 1998. SARAH CRAVEN: We counted all your bits and youve been checked by a doctor and hes perfect. NARRATOR (VOICE OVER): Jake is now five. SARAH CRAVEN (VOICE OVER): Hes healthy, hes happy. SARAH CRAVEN: Hes a normal child. Just about to go to school so yeah theres no sign of brain damage whatsoever. NARRATOR (VOICE OVER): The irony of Sarahs story is that although Thalidomide can cause terrible birth defects, without it she wouldnt have been able to have Jake. SARAH CRAVEN (VOICE OVER): Im still taking Thalidomide. It relieves me from pain quickly and I wouldnt consider taking anything else. Without Thalidomide there would have been no Jake because I wouldnt have been well enough to have him. NARRATOR (VOICE OVER): Such was the success of Thalidomide that by the late nineties the drug was in great demand for other immune disorders. For multiple sclerosis to Aids. But the dangers to pregnant women and their unborn babies had not done away. So the question was: how could Thalidomide be controlled? This was the problem facing the America licensing authorities. They had to decide whether to take the momentous step of licensing this drug. The issue they faced was could they ever actually fulfil their responsibility of controlling the drug if they decided to sanction it. MAN AT MEETING: Every doc will get one of these folders, theyre expected to use one for each patient NARRATOR (VOICE OVER): The most extensive system of controls ever used was drawn up by the company hoping to market the drug. Among the controls patients had to sign a contract agreeing never to take Thalidomide without at least two forms of contraception. DR MURRAY LUMPKIN (VOICE OVER): We dont want a Thalidomide tragedy in this

country, DR MURRAY LUMPKIN: we know what this drug can do and its a really very very special side effect, it does not have to happen. Its not inevitable, it can be prevented if you dont expose a foetus to this drug you will to have a birth defect. NARRATOR (VOICE OVER): So in July 1998, Thalidomide was licensed but only for the treatment of the ENL lesions of leprosy. For other diseases and elsewhere in the world it remained unlicensed. But then came pressure to license the drug for a new condition because Thalidomide began to be used as a revolutionary treatment for one of our biggest and most feared diseasescancer. NARRATOR (VOICE OVER): Nancy Touhey was a flight attendant of a major airline, she met and married Mark in 1990, but two years later she was diagnosed with multiple myeloma, a type of blood cancer. NANCY TOUHEY: I was a 31 year old woman and I thought well how did this happen was did I ingest or eat or smell? What happened that I would have caught something like this? I just had, was really in shock. NARRATOR (VOICE OVER): In multiple myeloma, the cells produced in the bone marrow that normally fight infections are turned into malignant cells that ultimately destroy bone, damage kidneys and lower immunity to disease. NANCY TOUHEY (VOICE OVER): They showed a four and a half inch tumour on my NANCY TOUHRY: Iliac crest, outside tumours on my shoulders in my femur and erm, parts of my skull and my limbs. NARRATOR (VOICE OVER): Nancy knew nothing about multiple myeloma and her doctor at the time didnt give her much information. She didnt know that within two to four years it could kill her. NANCY TOUHEY: The doctor said theres no cure, but youll do ok kid and I remember thinking Im going to do ok, damn right Im going to do ok. I wanted so badly to not have this be my life. NARRATOR (VOICE OVER): Nancy started chemotherapy, after a year there was some progress. Then despite her cancer and against all the odds Nancy gave birth to two children. Shannon now ten and Erin now eight. With her family complete Nancy went through the painful process of a bone marrow transplant. NANCY TOUHEY: And who is that in the picture with me? NARRATOR (VOICE OVER): The donor was her sister, the operation was dangerous and her body was prey to numerous infections but it was Nancys only option.

NANCY TOUHEY (VOICE OVER): I did get something very severe, NANCY TOUHEY: I had a fever of four nights of 106 it was just horrible. I was on near near, near death. NARRATOR (VOICE OVER): But for two years everything seemed to be going well, then Nancy had a simple fall and fractured her back. It was the first sign that her disease had returned but Nancy had already had all the conventional treatment on offer. MARK TOUHEY: We were out of options and Ive got to tell you that was the time I was the most afraid of losing her. I mean I can remember having a conversation with her that this cannot happen because Im not prepared to raise two little girls on my own. NARRATOR (VOICE OVER): But then a completely new treatment for multiple myeloma was suggested - Thalidomide. NARRATOR (VOICE OVER): It was Doctor Judah Folkman who was the first to spot a radical new way to treat cancer. His new theory would make Thalidomide a key drug in fighting the disease. The traditional treatment was to use chemotherapy to attack cancer tumours directly. But Judah Folkman had the idea of attacking the tumours indirectly by starving them of blood. His theory was tumours send out signals that made it possible for them to create their own blood supply. A process he called Angio-genesis. JUDAH FOLKMAN (VOICE OVER): I came to the conclusion that tumours are angio-genesis dependant, they were dependant on recruiting their own blood supply JUDAH FOLKMAN: and in the early 1970s that was greeted with much scepticism and a certain amount of ridicule. NARRATOR (VOICE OVER): Folkman spent over ten years proving he was right and another ten years trying to create a new drug that could prevent angio-genesis. But then as a short cut a colleague suggested trying an existing drug like Thalidomide. NARRATOR (VOICE OVER): In their lab Thalidomide was tested on tumours and was shown to successfully limit the growth of blood vessels. It was then put into trials for a particularly lethal form of brain tumour and showed some success. JUDAH FOLKMAN: We do clearly have stabilisation which is the first step to a shrinkage of the tumour. NARRATOR (VOICE OVER): Then it was tried in other types of cancer with solid tumours but it had not occurred to anyone that Thalidomide could work against blood cancers. Cancers where the tumours grow in blood and are liquid. Cancers like multiple myeloma. JUDAH FOLKMAN: Thalidomide was being used for solid tumours but no one thought it could be used for any bone marrow or leukaemia type tumour until a phone call that I received from a

patient whose husband was very ill from multiple myeloma and he had failed all of the drugs. I suggested that they try Thalidomide. NARRATOR (VOICE OVER): Folkmans thinking was that just like all other cancers, blood cancers were still crucially dependant on building their own blood supply. His evidence was based on this simple observation. A normal bone looks like this but this is what it looks like when the patient has multiple myeloma. Although you cant see the cancer cells, the huge network of blood vessels they have built to bring oxygen and nutrients to help them grow is clearly visible just like with a solid tumour. So Thalidomide was tried on a group of patients who had failed all other therapy. It worked for about a third of them . JUDAH FOLKMAN (VOICE OVER): When those results were published it was very exciting because previously there had been no other drug when you failed the standard drugs for multiple myeloma. NARRATOR (VOICE OVER): Among the first to try Thalidomide was Nancy Touhey, it changed her life. MARK TOUHEY: To find a medicine that she could take for 60 days that completely turned our life right side up, the way it ought to be um was just a dream come true. NANCY TOUHEY: What do you think about these pictures girls huh? Yes that was my wig. NANCY TOUHEY (VOICE OVER): I definitely was on a path of spiralling downwards and Thalidomide gave me a great chance to watch my kids play and just grow up. NARRATOR (VOICE OVER): Unlike chemotherapy, Thalidomide is taken in pill form. For someone like Nancy it means no time has to be wasted travelling to and from hospital to take it intravenously. And because Thalidomide doesnt kill healthy cells, those taking it dont feel sick or lose their hair. Although its not a cure Thalidomide saved Nancys life. And it hasnt just helped Nancy. This success has been repeated in trials carried out by Dr Kenneth Anderson. DR KENNETH ANDERSON (VOICE OVER): Excitingly when we use Thalidomide together with other drugs DR KENNETH ANDERSON: as the very first patients receive for their new myeloma, about two thirds to three quarters of patients respond and they respond very quickly. NARRATOR (VOICE OVER): Some believe that the way it works against cancer could be a clue to why Thalidomide had damaged all those babies years before. JUDAH FOLKMAN (VOICE OVER): The birth defects that were caused by Thalidomide JUDAH FOLKMAN: could possibly now be explained as interruptions in blood supply in the early embryo or foetus by that drug.

NARRATOR (VOICE OVER): So was starving the limbs of blood the cause of all those terrible deformities. Even now it is very hard to tell. Lab work at the Dana Farber cancer institute shows that Thalidomide does much more myeloma tumours than just starving them of blood. DR PAUL RICHARDSON: We were able to show that Thalidomide worked directly on killing the myeloma. It also critically disrupted the way the myeloma adheres to the so-called bone marrow sproma, a bit like a plant and its root system in the soil. NARRATOR (VOICE OVER): It also appears to kick start the immune system to fight cancer. This multi-target approach makes Thalidomide a particularly effective anti-cancer drug. DR PAUL RICHARDSON: A lot of our newer drugs are very specific, they have one target and one of the advantages to me of Thalidomide is that it seems to hit several targets. DR PAUL RICHARDSON (VOICE OVER): It effects several different aspects of myeloma self growth and survival DR PAUL RICHARDSON: and in that respect its really quite unique. NARRATOR (VOICE OVER): This all adds to Thalidomides mystery. Just why no one is quite sure why it caused birth defects, so no one quite knows why it works so well against cancer. These uncertainties still surrounding the drug means that many doctors will remain wary about prescribing it, particularly to women of child bearing age. PROF NIGEL BROWN: Its a continuing to me and everybody else in our fields that we have not been able to find out how Thalidomide causes birth defects and it will remain for us a major goal for the future until we do. NARRATOR (VOICE OVER): And its not just pregnant women who might be at risk. Thalidomide can have other side effects as Chase Peterson discovered. CHASE PETERSON (VOICE OVER): Its quite a sleeping pill, I sleep like a baby after Ive taken it at night. CHASE PETERSON: It gives you a little constipation, I take more bran, I can do that. But the serious one for most people is a little perferak neuritis which is a fancy word for meaning you get tingling in your fingers and your toes. And I have some of that, its not really a bother in me, but some people go on to get rather serious affliction wt that and sort of shooting pains and things of this sort and I would like that not to happen to me. NARRATOR (VOICE OVER): That tingling feeling is what doctors call neuropathy. It can be debilitating and irreversible. Chase found a way of minimising it by taking the drug only when his myleoma is at its most severe. When his blood counts are normal he stops. CHASE PETERSON (VOICE OVER): Why treat something if I dont need to. My suggestion, I said lets watch it and we did and over 8 months the levels gradually rose up and we concluded a

certain level would be safe, CHASE PETERSON: maybe above that it might be doing damage to me, so at that level we treat it again for one month. Just one capsule a night- 50 milligrams. And sure enough, boom, the levels came right back down to normal. NARRATOR (VOICE OVER): Chases occasional use of Thalidomide works for him. But for most people the side effects mean that sooner or later they have to stop taking it. NANCY TOUHEY: There was a bit of neuropathy. I did feel a little bit of tingling around my mouth area. NARRATOR (VOICE OVER): After four years on Thalidomide, Nancy began to experience bone pain, a sign that the effect of the drug had weakened. Her cancer had come back again. DR PAUL RICHARDSON: Sometimes the side effects become such that you have to reduce the dose and when you reduce the dose the effect on the myeloma begins to weaken and the myeloma is able to grow. NARRATOR (VOICE OVER): This combination of the threat to women who might want to have children ad the side effects mean that scientists are now looking at an alternative to Thalidomide. A drug based on it but without the dangers. And there maybe one on the way. Developed by Celgene, the American manufactures of Thalidomide. They have spent ten years exploring socalled analogues of Thalidomide. Chemicals that are based on the Thalidomide molecules, but with subtle changes. DR DAVID STIRLING (VOICE OVER): As we learn more about the activity of the drug we can use that knowledge to make safer versions of Thalidomide DR DAVID STIRLING: and hopefully you end up with something that has accentuated the positive activities of the drug while at the same time minimising the side effects. DR DAVID STIRLING (VOICE OVER): So ultimately we would like to retire Thalidomide. NARRATOR (VOICE OVER): Finding an analogue of Thalidomide has proved immensely difficult. Precisely because no one really knows how it works. DR DAVID STIRLING (VOICE OVER): We still dont know the absolute molecular targets for this drug. DR DAVID STIRLING: So for that reason we couldnt do the normal drug development where you test compounds against the known target. DR DAVID STIRLING (VOICE OVER): So its trial and error. You make small changes on the molecule and then you go test them in the laboratory to find improved activity.

NARRATOR (VOICE OVER): But eventually sterling and his team made a breakthrough. They removed one particular oxygen atom and introduced a nitrogen atom. The precise placing of that atom was crucial. DR DAVID STIRLING: Now those simple chemical changes had to be at very specific sites on the molecule. When you make the same chemical changes on other parts of the molecule, the drug has no activity. NARRATOR (VOICE OVER): What they found was that when the nitrogen atom was in this position the drug is highly active. They called their new drug Revemid. And it seems to be far more effective than even Thalidomide. DR DAVID STIRLING: Benefits of Revemid are that the positive activities of the drug have been increased over the parent molecule from anyway from a hundred to a thousand, two thousand fold. NARRATOR (VOICE OVER): Then they had to find out, did it cause birth defects. They ran a series of tests. DR DAVID STIRLING (VOICE OVER): Its very difficult to prove a negative in these kinds of models but from all of the FDA requirements, DR DAVID STIRLING: Revemid has been shown to not cause any of the birth defects that Thalidomides shown. NARRATOR (VOICE OVER): Further trials seemed to show that revermid may not cause the other unpleasant side effects of Thalidomide such as neuropathy. DR PAUL RICHARDSON: Patients dont see the sort of side effects where they have numbness and tingling, constipation, sedation and the types of quality of life symptoms that are so much of an issue if you are on long term Thalidomide. NANCY TOUHEY (VOICE OVER): I feel good on Revemid. Ive been on Revemid for almost a year now and my blood statistics are higher than theyve ever been before. My red blood count, my white blood count, theyre all in the normal range NANCY TOUHEY: and Im really delighted that it works the way it does because I really wouldnt be here without it. DR PAUL RICHARDSON: Whats impressed us is that in patients who have either been intolerant of Thalidomide or have actually run out of benefit from Thalidomide, when they have been treated by Revemid and thats very exciting because it means you can use one after the other. NARRATOR (VOICE OVER): Revemid could be a major breakthrough in the fight against myeloma. And currently Thalidomide and its analogues are being used in over 150 clinical trials worldwide. The success with Thalidomide has led to a major re think in the battle against cancer.

The theory now is you dont just attack the tumour but its whole surrounding environment. DR KENNETH ANDERSON (VOICE OVER): Thalidomide has revolutionised the way we think and the way we will treat cancer in the future. Some day with targeted therapies DR KENNETH ANDERSON: like Revemid, like Thalidomide, together with other conventional and new agents, I strongly feel will result in a cure. For now at least patients should now that their prognosis is better than it ever has been and that we do have the opportunity to markedly extend their life span. NARRATOR (VOICE OVER): Thalidomide and Revemid are not cures, but they could turn some forms of cancer into long-term illnesses rather than fatal diseases. DR PAUL RICHARDSON: An important paradigm in our treatment of myeloma now is that as each of these new drugs comes along, er basically it buys hopefully patients time where their disease is controlled for long enough that they can then move on to these newer treatments and continue the benefit in the longer term. NANCY TOUHEY: When it is my time to go, I have to accept it, but I really dont want to. I want to keep living and I feel like theyre going to take me, theyre going to take me dragging by my toenails. NANCY TOUHEY (VOICE OVER): I have a hobby, scrap booking. And sometimes we do it together. Its a way of preserving our stories. NANCY TOUHEY: Look at the pages that Ive finished. There you are inside my tummy. NANCY TOUHEY: I feel very hopeful and I feel that Im in a good spot and I feel that theyre coming close to treating multiple myeloma as a chronic illness and thats really my hope. Of curse eventually for a cure, but as a chronic illness would be great. CHASE PETERSON (VOICE OVER): People have asked me am I cured? And the answer is CHASE PETERSON: almost certainly not. But who cares? CHASE PETERSON (VOICEOVER): If I have controlled the signs and symptoms of the disease so that its growing harmlessly in my bone marrow not dissolving my bones, not killing my kidneys, CHASE PETERSON: Then whats the harm in having cancer if it doesnt harm you. CHASE PETERSON (VOICE OVER): We have 11 grandchildren and 4 have been born since Thalidomide, its fun to grow up with those grandchildren and perhaps pass on some advice and wisdom, share their lives. Thats precious. NARRATOR (VOICE OVER): Thalidomide achieved notoriety because it ruined so many lives.

But there have so far been no reported cases of babies being born with birth defects as a result of its use against cancer. So, half a century after its discovery, provided a truly rigorous system of controls can be established, Thalidomide may start to achieve redemption.

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