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 The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has withdrawn authorisation for the trial (obviously) and doctors in other countries have been sent a warning not test it.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.

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