It Was Supposed to Be a Routine Trial on Humans After Successful Animal Testing
By Investigations Editor Neil Mackay
EYE-WITNESSES describe it as being more like a clip from a David Cronenberg horror movie than a glimpse inside the normally dull and routine world of a suburban British drug testing centre. Instead of a sedate scene of tea and biscuits, flannel pyjamas, thermometers and clip-boards, men were screaming and holding their heads as if they were going to explode; others writhed on the floor, vomiting, hyperventilating and ripping their own clothes off. A room full of convulsing, hysterical, delirious human guinea pigs – their limbs swelling up and turning purple – begged staff to save their lives as doctors and nurses looked on helplessly.
That’s exactly what happened on Monday, moments after six healthy young men, all aged under 40, were injected with the cutting-edge trial drug TGN1412 – designed to tackle leukaemia and rheumatoid arthritis – at an independent research unit in London’s Northwick Park Hospital.
Almost a week later, two men are still in intensive care – one possibly trapped in a coma for at least a year – and the four others are showing a marginal improvement. Raste Khan, a test subject who escaped any of the terrible side-effects as he was given a harmless placebo, watched in horror as his six fellow subjects collapsed around him one by one.
"The test ward turned into a living hell minutes after we were injected, " he said. "The men went down like dominoes. First they began tearing their shirts off, complaining of fever, then some screamed that their heads felt like they were about to explode.
"After that they started fainting, vomiting and writhing around in their beds. It was terrifying because I kept expecting it to happen to me, but I felt fine and didn’t know why. An Asian guy next to me started screaming and his breathing went haywire as though he was having a terrible panic attack.
"They put an oxygen mask on him but he kept tearing it off, shouting ‘doctor, doctor, please help me!’. He started convulsing, shouting that he was getting shooting pains in his back."
Some of the victims have been described as resembling "the Elephant man" because of the grotesque swelling that the drug has caused to their bodies.
Myfanwy Marshall, the girlfriend of one of the six men, said she had been told that he needed "a miracle".
One of the most seriously ill is Ryan Wilson, a 21-year-old plumber. His head has swollen to more than three times its normal size, and his limbs have turned purple in colour. His family have been warned that he is expected to die from heart, kidney and lung failure.
Wilson’s sister-in-law, Jo Brown, who visited Ryan after the drug trials went wrong, said: "At first none of us recognised him. He looked nothing like the Ryan we know and love. His nose was spread across his face like it had been squashed. Ryan had tubes in his nose and mouth and was hooked up to a machine helping him breathe and to a kidney dialysis machine.
"His eyes had been sellotaped up and he had been sedated. The doctors told us Ryan begged them to put him to sleep because he was in so much pain. He was in agony. Our fear is that he may never wake up.
"They say they cannot give us any hope. They have no idea how to treat him because they know nothing abut the drug he’s been given. It doesn’t look good."
The American company running the tests, Parexel, has sent blood samples to the US for urgent tests. Its head of international clinical pharmacology, Herman Scholtz, said all "appropriate policies and procedures" had been followed during testing.
TeGenero, the makers of the drug, said it had shown no safety problems in previous trials. Chief scientific officer Thomas Hanke said he was "devastated" at the "shocking developments".
The British drug testing watchdog, the Medicines and Healthcare Products Regulatory Agency, is investigating what went on during the tests. Dr Ganesh Suntharalingam, clinical director of intensive care at the hospital where the men are being treated, says he has never seen a case like it in his career.
The men had been paid pounds-2000 apiece, and were to receive pounds-30 for each of the 11 follow-up examinations. Scotland Yard detectives are investigating to ensure no crime was committed, and lawyers for the victims are believed to be already preparing for legal action against the companies involved.
So why did this nightmarish event happen? There are three likely scenarios: human failure in the manufacturing process, human failure in the administration of the drug to the test subjects or – the most likely cause – a difference in the way humans react to the drug than how animals react to it. The drug had been successfully administered to animals, including rabbits and monkeys – genetically our closest relative.
TGN1412 is an MAB – a monoclonal antibody; a genetically engineered drug.
Ordinary antibodies are a protein in the blood which are made by white blood cells and part of the immune system.
Antibodies defend humans against infectious disease by binding themselves to invading germs and neutralising them.
The British Medical Research Council (BMRC) invented monoclonal antibodies back in the 1970s by genetically engineering antibodies from mice. One single white blood cell was taken from a mouse and cloned so it could be grown in industrial quantities – hence the name monoclonal antibodies, for an antibody cloned from a single cell.
But the problem remained that these MABs were from mice and human bodies rejected them. So the MRC then tinkered with the mouse antibodies, genetically modifying them into a hybrid human/mouse antibody.
Dr Roberto Solari is the chief executive of the MRC’s technology unit and one of the world’s leading experts on the science behind drugs like TGN1412. He said: "Think of an antibody as a spear, and the tip of the spear, the spearhead, is the mouse antibody. We took that and fitted it on to a human handle, so it became 95-per cent human and 5-per cent mouse. It became a humanised antibody."
There are 19 MAB products approved as drugs on the market, the most famous being Herceptin, used to fight breast cancer. Another 150 MAB drugs are currently undergoing clinical trials.
TGN1412 was meant to work by controlling the human body’s white blood cells. Solari said: "In rheumatoid arthritis the body’s immune system attacks itself. TGN1412 was intended to deactivate the immune system. In animal experiments, prior to the human tests, it worked just fine."
ALL drugs have to be tested on at least two mammalian species – usually a rat and a dog – before being trialled on humans. However, most antibody products, including TGN1412, are also tested on monkeys. "This drug went through all the normal procedures, " said Solari. It was approved by the Medicines and Healthcare Products Regulatory Agency for human testing after passing its animal test stage and was cleared by the ethics committee.
What was new and different about TGN1412 was what the drug was targeting. "The warhead loaded on the antibody was targeting a protein on the surface of white blood cells called CD28, " Solari said. "CD28 is like an on switch. When you hit it, it activates white blood cells to fight."
There are two types of white blood cells – ones that suppress inflammation of cells and ones that cause inflammation of cells. Both types are activated by CD28. TGN1412 was meant to activate the suppressant white blood cells to calm down the body’s immune system.
Instead, it appears, that TGN1412 activated the cells that inflame the body’s immune system. Solari said: "TGN1412 was meant to activate the fire brigade, but instead it activated the fire starters."
Most antibody drugs turn off parts of the body’s immune system. TGN1412 was different because it was turning things on. This attempt to use an old technology in a new way may well be what lies behind last week’s events.
Solari said: "One would have expected the same toxicity in the monkey experiments as there was in the human experiments, but it didn’t occur. There seems to be an exquisite difference in this function between humans and monkeys."
Solari said he thought it "incredibly unlikely" that there had been human error in either the administration of the drug or its manufacture, as all the companies and personnel taking part in the process were "extremely reputable".
"In all my experience it is unheard of that technicians and doctors would have made mistakes. I can only, therefore, come down on the side of believing that this must have been caused by some difference between us and monkeys that we did not know about before these tests."
Of course, this one "exquisite difference" in the make-up of humans and monkeys means that there may well be many other differences that we are currently not aware of that will only be revealed when future tests go similarly wrong. "It is a risk, and we need to recognise that, " Solari said.
"Live animal experiments are not perfect, no-one has ever claimed they are. But they are quite reliable and strongly reduce the risks to humans in testing. If we didn’t test, tragedies like this would happen more frequently. Animal testing is the best safeguard we have."
Huge safety margins are also built into human testing. For example, if a monkey is noted to suffer side effects when administered 1g of a specific drug, then humans, during testing, will receive 1/500th of 1g of the same drug. The TGN1412 test subjects were at the beginning of clinical trials so would have been receiving the very smallest doses of the drug. Later, in testing, the amount of the drug administered is slowly increased to observe effects at higher doses.
"The staff were being very careful. That is why these events are so surprising and shocking, " Solari added.
TeGenero, the makers of the drug TGN1412, did not use the pioneering technology known as the Winter Technique, developed by the MRC, to "humanise" the mouse antibody and fuse it with human tissue – most antibodies are "humanised" using this technique. If TeGenero had used the Winter Technique, they would have had to apply to the MRC for a licence, which they did not do.
But Solari said: "I don’t think this would be a risk. There are about half a dozen other ways to do it."
Despite the horror of the events, Solari remains positive about the future of human testing. "The message is that this is a very, very rare event, " he said.
"Clinical trials are very safe and highly regulated. Volunteers should not be put off from coming forward. To me, this is a unique, one-off and tragic event."
TeGenero, however, could be another casualty of the tragic events. The new start-up company says the terrible side effects were totally unexpected, and "did not reflect the results obtained from initial laboratory studies".
Dr Benedikte Hatz, TeGenero’s chief executive, insisted all guidelines had been followed and the drug had been proved safe in nonhuman tests.
The company was set up specifically to specialise in the development of monoclonal antibodies designed to target the CD28 protein on white blood cells. Therefore the collapse of the development of its flagship drug at the testing stage could deal a fatal blow to a thrusting young German drugs company which many thought was on the verge of rising to the top of the industry.