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TeGenero's TGN1412 drug trial

The Sunday Times

Monkey business

He is the worst afflicted of the victims from the tests on March 13, but all suffered life-threatening injuries. For development of new medicines, it was the worst calamity since the 1960s Thalidomide disaster.

In the space of one hour, Wilson and five other healthy young men, aged from 19 to 34, were all infused with the drug through tubes. All were soon in agony. Their blood pressure collapsed. Their hearts raced. They struggled to breathe. Their bodies and heads swelled to grotesque proportions and [redacted 9/16], the girlfriend of one victim, [redacted 9/16], 28, described him as looking like “the Elephant Man”.

“It started off with a lower back pain,” Wilson recalls. “I just remember it getting worse and worse, and then I remember vomiting, and then just too much pain and I just blacked out. And that was it. Gone.”

Wilson’s deterioration is shown in the documents obtained by The Sunday Times. They include adverse event forms filled in at Wilson’s bedside: “09.38 feeling cold”, “09.40 headache”, “10.00 lower back pain”, “10.10 nausea and vomiting”, “10.16 pressure on chest”, “10.22 vomiting (two episodes)”, “10.40 breathing difficulty”, “10.50 diarrhoea”, “11.40 vomiting”, “12.48 pyrexia” (fever).

“Between 7.30 and 7.40 in the evening, the phone went,” said Wilson’s mother, Marion Flanagan. “Somebody said, ‘Your son took part in a drug trial today.’ I just knew. It might be a mother’s sixth sense but the hairs on the back of my neck stood up and, before he could say another word, I was screaming down the phone at him, ‘Is my son all right?’”

At 9.30pm Wilson was admitted to intensive care, vital organs all supported by machines. For 16 days he was on a ventilator and in hospital until the end of June. “It’s like I took a bungee jump into hell,” Wilson said. “All of them thought I’d die.”

The TGN1412 trials had been vital for TeGenero, based in Würzburg, near Frankfurt. The firm had no other products and its fortunes depended on this drug. It was being tested in Britain because in 2001, in response to lobbying, Tony Blair backed moves to encourage foreign drug trials and attract “big pharma” investment.

The MHRA is regarded as Europe’s most business-friendly regulator. It gave TeGenero the green light on January 27, just six weeks before the trial began. Its target, announced last year, is to approve projects in just 14 days.

TeGenero’s plan was for TGN1412 to boost part of the immune system, and so be useful in Aids or radiation therapy for cancer. If this did not work, plan B was for it to damp down a different part and so be good for rheumatoid arthritis or leukaemia.

Professor Jürgen Drews, former chairman of TeGenero, said the trial was “the right thing to do”.

A legally required dossier submitted to the MHRA describes the firm’s tests on monkeys. Ten cynomolgus macaques were infused with 50mg of TGN1412 per kilo of body weight, and another six with one-tenth of this. Their blood levels were then measured for six cytokines, a kind of protein. Some levels remained unaltered, while others rose noticeably. These included IL-6, a key inflammatory protein.

“The results weren’t dramatic,” said a senior immunologist who knows Dr Thomas Hünig, TeGenero’s chief scientist. “They showed some kind of effect but it didn’t forewarn in any way of what followed.”

What followed was the disaster: a “cytokine storm” in the human volunteers. In the monkeys, the IL-6 was measured at 390. In Wilson it touched 5,000.

The MHRA was baffled. “The adverse incidents did not involve errors in the manufacture of TGN1412 or in its formulation, dilution or administration to trial participants,” was its verdict. “An unpredicted biological action of the drug in humans is the most likely cause.”

Documents, however, suggest the reactions might have been foreseeable. They do not set out clearly the speed at which the drug was to be administered but this came to light when Hamblin performed calculations based on papers submitted to the agency and later released under the Freedom of Information Act. His calculations have since been confirmed in a confidential Parexel document.

Experts believe MHRA assessors could have spotted the difference if they had taken more time to scrutinise the project.

“I usually give it over about six hours,” said Hamblin. “If you give it in less than an hour you get horrific reactions.”

The MHRA denies it missed warning signs. “There was no reason to believe that the administration rate proposed for TGN1412 would present as a foreseeable hazard to the subjects,” it stated.

The case has highlighted concerns over biotechnology. “Clinical trials in general have an excellent safety record,” said Professor Gordon Duff, head of molecular medicine at Sheffield University, who chairs a government inquiry into the Northwick Park incident. “But in light of the TGN1412 incident there is a need to look at future safety of clinical trials with novel and potentially higher-risk drugs.”

Some observers are worried that, if the MHRA gave the go-ahead in the absence of important information, there may be room for future mistakes. “It’s a wake-up call,” said Glover. “We need to redouble efforts to ensure we don’t have the same disaster in the future.”

Brian Deer investigates the TGN1412 incident in Dispatches, Channel 4, Thursday at 9pm.

TeGenero's TGN1412 drug trial
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This report is copyright, Brian Deer. No portion of this article on Ryan Wilson and the TGN1412 drug trial may be copied, retransmitted, reposted, duplicated or otherwise used without the express permission of the author. Responses, information and other feedback are appreciated