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 The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has withdrawn authorisation for the trial (obviously) and doctors in other countries have been sent a warning not test it.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. It’s worth pointing out that the final report of the Expert Scientific Group on Clinical trials published in November 2006
    (http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_063117)
    found that the pre-clinical animal tests done by TeGenero were not adequate.

    In particular they assumed that their superagonistic monoclonal antibody, designed to bind specifically to human CD28, would cause the same degree of activation and proliferation in macaque lymphocytes as it did in human lymphocytes. Had they done adequate in vitro comparisons of TGN1412 in human and macaque lymphocytes before starting pre-clinical testing they would have found that TGN1412 did not stimulate proliferation in macaque lymphocytes while it induced strong proliferation in human lymphocytes.

    Knowing that TGN1412 did not have the same effect on monkeys at a cellular level as it had on humans would have ensured that TeGenero looked at alternative strategies for in vivo pre-clinical testing. Animal testing would still be necessary though, since TeGenero believed the induction of lymphocyte proliferation and cytokine release that their in vitro tests had demonstrated was exactly what they wanted to see happen. It was necessary to determine what the effect of this stimulation would be on the whole organism.

    This problem of how to adequately test “human specific” monoclonal antibodies before human trials has been successfully addressed by the use of surrogate antibodies and transgenic animals in the development of other drugs (e.g. Infliximab and Keliximab). In future these may well replace testing on monkeys for most evaluation of monoclonal antibodies.

  2. The issue of the safety of clinical trials cuts deep. A report in FierceBiotech (which you can get for free via daily email through Sciencebase) says that: “the FDA does little to protect the safety of patients who participate in clinical trials. Daniel R. Levinson, inspector general of the Department of Health and Human Services, has released a report slamming the FDA’s oversight of the trials. The FDA has 350,000 testing sites but only 200 inspectors, some of whom work part time.”

  3. The Polonium-210 incident, which resulted in the death of Alexander Litvinenko, was an unprecedented event in the UK, making headlines across the globe. Today, John Croft of the Health Protection Agency present a report at Keele University in which he discussed the potential risks to members of the public who might have been exposed to radiation.

    He discussed how the Agency’s radiation scientists rapidly developed a mass urine testing process, supplied and co-ordinated teams to monitor a wide range of locations, and deployed scientific expertise in the public health investigation.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. The last of the six men who collapsed during the trial with multiple organ failure has been taken off the critical care list at Northwick Hospital, thankfully. He remains an in-patient, while the five others have been discharged.

    The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has tightened the regulations on future trials involving similar products to the monoclonal antibody TGN1412 given the seriously adverse reaction seen in this trial.

    In its preliminary report, the MHRA said, it “has found no evidence to suggest that there was any problem with the manufacturing of the product which was given to the trial volunteers – it appears not to have been contaminated, or to have contained anything other than the correct ingredients. Neither have we found anything in the way the trial was run which contributed to the adverse reactions experienced by the volunteers – it was run according to the agreed protocol, and the correct dose of the product was given to the patients.”

  9. The BBC today reports that “Two of the six men who took part in the TGN-1412 trial and suffered the consequences have been discharged from Northwick ParkHospital, although they will continue to be monitored closely as out-patients. One man remains critically ill while the other three are making progress, according to a Hospital spokesman.

  10. Tegenero are keeping a very tight rein indeed on this trial. The only news since last week was reported by the BBC on Sunday to say that, “One of the two men left critically ill by a drugs trial almost two weeks ago is reported to be making good progress.”

    There is still no hard report on what went wrong in the trial, whether or not the swollen monkey glands was a serious issue, or whether there were any error in administering the drug.

  11. While two men remain in a coma and four are on the road to recovery (three of whom are now off organ support), it emerges that the drug caused temporarily swollen lymph nodes (glands) in the earlier animal testing phase of it’s development. However, the company developing the drug Tegenero says this was a different side-effect to that seen in the trial volunteers. More importantly, the side-effect was noted in regulatory submissions and the volunteers were warned that they might suffer swollen glands during the trial. However, this swelling, says Tegenero, was actually a sign that TGN1412 was working as it stimulated extra regulatory T-cell production.

    The company claims no one could have predicted the seriously adverse effects that occurred in the volunteers.

  12. Four of the men left critical ill in the Phase I clinical trial of TGN1412 have thankfully regained consciousness. Two remain in a critical condition under sedation.

  13. In totally unrelated clinical news. Daily biotech industry newsletter FierceBiotech reports that eleven people have died in a clinical trial of Eisai’s Alzheimer’s therapy Aricept. There were no deaths in the control group, although Eisai says that it is not unusual for a few deaths in any Alzheimer’s trial.

  14. Lord Robert Winston, professor of fertility research at Imperial College London and vice-chairman of the Parliamentary Office for Science and Technology, told BBC Radio 4’s “The World Tonight” that the UK’s clinical trial system has “lots of safeguards” and echoed my earlier thought concerning animal experiments.

    “I wonder really whether in fact there’s increasing reluctance to do the preliminary trials on animals because of the difficulties generally in doing animal research,” he told the program, “”That I think is a disaster for humans.”

    That said, the current debacle with six men critically ill, four of whom are recovering slowly, occurred despite successful toxicity testing. The ongoing investigation of events is yet to discover whether there was a drug administering error, a toxic contaminant, or whether this really was simply a devastating but unexpected adverse drug reaction (ADR).

  15. In typical sensationalist tabloid style, the UK’s Sun newspaper has been flaunting the interview it did with one of the “placebo” members of the TGN1412. Even the BBC aired the interview. In it, volunteer Raste Khan (who let’s remind ourselves was allegedly being paid £150 a day to take part in the trial) described the ordeal as being like playing Russian Roulette. I’m pretty sure it was indeed an ordeal, but without wishing to sound like an apologist for the pharma industry, the media is once again making a huge deal out of this isolated incident while dozens, if not hundreds of trials countless other drugs are carrying on elsewhere with no such incidents.

    It seems like an increasingly suspicious coincidence that these adverse reactions occurred the day after the positive announcements regarding the statins and their potential for reversing atherosclerosis. It’s almost as if…

    …I shan’t say.

  16. Quite a timely article in The Onion:

    “The Food and Drug Administration today approved the sale of the drug PharmAmorin, a prescription tablet developed by Pfizer to treat chronic distrust of large prescription-drug manufacturers.

    Pfizer executives characterized the FDA’s approval as a “godsend” for sufferers of independent-thinking-related mental-health disorders.”

  17. The BBC today reports that the US drugs company, Parexel, which was running the TGN1412 clinical trial has apologised to the families of two critically ill men and four others.

    The six are still in intensive care with no word of a reason for the adverse drug reactio they have experienced, which was characterised by feelings of fever, swelling, and problems with most organs

    One of the trial participants has been named as student Ryan Wilson, 21, of Highbury, North London and another has been confirmed as a New Zealander.

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