Critical Trials TGN1412

The BBC reports today that six men are on the critical list after becoming seriously ill while taking part in a clinical trial of a new drug for treating leukemia and arthritis: BBC Report.

The previously healthy young men were being paid (up to £150, $330 a day) to take part in the early stages of a trial of the novel drug TGN1412. However, within hours of their first injection, they reacted adversely (suffering multiple organ failure) and were put in intensive care. The two men receiving placebo in the trial are fine.

The compound in question is biopharmaceutical company TeGenero’s humanized CD28-SuperMAB (TGN1412) which is in trials for rheumatoid arthritis and B-CLL (B-cell chronic lymphocytic leukemia). Following standard toxicity studies it was entered into initial clinical trials. “The drug was developed in accordance with all regulatory and clinical guidelines and standards,” explained Dr Thomas Hanke, Chief Scientific Officer of TeGenero AG, in a statement, “In pre-clinical studies, TGN1412 has been shown to be safe and the reactions which occurred in these volunteers were completely unexpected.”

Adverse reactions to drugs in clinical trials are exceedingly rare, but then TGN1412 is not your everyday small molecule type drug. TeGenero developed this drug, a superagonistic monoclonal antibody, with the aim of balancing T cell (a type of white blood cell) activation by triggering receptors on another group of white blood cells known as T lymphocytes. Today’s events are likely to provide animal rights activists with new fodder to push for animal testing to be banned, they will undoubtedly cite this unforeseen problem as further evidence that animal tests cannot show how a drug might act in people.

Ganesh Suntharalingam of Northwick Park Hospital told the BBC that, “The drug, which is untested and therefore unused by doctors, has caused an inflammatory response which affects some organs of the body.” Why this should be so is unclear. The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has withdrawn authorisation for the trial (obviously) and doctors in other countries have been sent a warning not test it.

Sciencebase will keep you posted on events as we hear them, in particular we’ll try to bring you the results of the ongoing investigation as soon as we can. It may emerge that a clinical error is to blame rather than there being a biological problem with the drug itself, we will have to wait and see.

This very unfortunate incident comes just one day after widely acclaimed findings were revealed showing how the totally unrelated statins could reverse atherosclerosis. Such positive results that inspire public confidence in the pharmaceutical industry are almost as rare as the present negative result!

Richard Ley of the Association of the British Pharmaceutical Industry was reported as saying “This is an absolutely exceptional occurrence.” and “cannot remember anything comparable.”

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18 thoughts on “Critical Trials TGN1412

  1. News just in (January 25, 2007) from a British Heart Foundation supported study at Imperial College London:

    A possible reason why the Northwick Park clinical trial of the drug TGN1412 caused multiple organ failure in human volunteers could be down to previous infection or illness. The Imperial reserachers suggest that stimulating the molecule CD28 on cells that mediate the immune response, known as T cells, (which is what TGN-1412 was designed to do) can have an adverse effect if these immune cells have been activated and altered by infection or illness in the past.

    The scientists found that when they artificially stimulated CD28 on these previously activated ‘memory’ T cells, this caused the cells to migrate from the blood stream into organs where there was no infection, causing significant tissue damage. CD28 is an important molecule for activating T cell responses and the TGN1412 drug tested on the human volunteers strongly activates CD28.

    More details appear online at IC soon.

  2. The BBC today reports that Professor Gordon Duff and his team investigating the TGN1412 drug trial that almost killed six volunteers have made 22 recommendations on avoiding a repeat of the tragedy.

    Perhaps the most interesting and potentially controversial is that “some drugs may be best given to people who are already ill” rather than testing cutting edge therapeutic approaches on healthy volunteers. This is something that many people with terminal and chronic diseases with little to lose and all to gain may welcome.

  3. There was a rather macabre follow-up to the TGN1412 story in the Herald Sun on Sunday November 12:

    “THE ELEPHANT Man drug trials scandal is all but forgotten. Yet for one 20-year-old the nightmare goes on. He has lost his girlfriend, is ravaged by gangrene and could be dead within a year.
    On Thursday, Ryan Wilson will go to hospital to have the third and fourth fingers of his left hand amputated at the second knuckle.

    They are blackened and shrivelled through blood poisoning, and he does not dare get them damp because wet gangrene, unlike dry gangrene, spreads and he doesn’t want to lose his whole hand. ”

    http://www.news.com.au/heraldsun/story/0,,20739759-663,00.html

  4. A detailed report from the doctors who treated the six men in the TGN1412 trial was published this month in the New England Journal of Medicine (NEJM).

    They confirmed that the volunteers received several injections of the drug in a short space of time, even though the drug had not been tested on people before. Ill effects were apparent within an hour to and hour and a half and all six volunteers were transferred to Northwick Park and St. Mark’s Hospital in London. Hospitals that saved the mens’ lives.

    The NEJM report says that the men appear to have recovered.

    However, a subsequent development suggests that one of the men has developed cancer, which is rather ironic given that TGN1412 was being developed as a treatment for leukemia.

    Paraxel, the company carrying out the trial, denies any wrongdoing.

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