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Saturday, August 05, 2006

TGN1412

I'm late to the ball here. Even so, as it was all over the news when I was in England in March, I thought I'd provide a summary post.

In case you don't know what I'm talking about, this is one of the worst modern Phase I trial disasters of all time. Six test subjects injected with an immunomodulatory drug called TGN1412, suffered severe excessive immune reactions reactions, swelled up like "elephant" men from inflammation associated with excessive cytokines, suffered gangrene, and possibly face severe long term consequences.
NRI student Nav Modi, one of the "Elephant Men" who nearly died in March during a botched drugs trial in a London hospital, fears he may have only two more years to live.

"It's a really bizarre feeling when you discover you might be dead in a couple of years or even in a couple of months," 24-year-old Modi who has just graduated from university and was looking forward to a career in his family's electrical business told The Sunday Times.

The botched drug test has been one of Health Care Renewal's category coverage issues. From their first post to the most recent, it's a good resource.

The broad idea was for the drug to work as an immunosupressant for B Cell leukemia patients by activating regulatory T Cells. An odd idea to say the least, seeing as the drug worked as a superantigen, activating T Cells independent of the T Cells specificity or of the antigen being presented by an antigen presenting cell. The Telegraph provides a description of what might have gone wrong.
The drug, called TGN1412, is an antibody treatment designed for some forms of leukemia and rheumatoid arthritis. It stimulates the production of T-cells with the aim of improving control of a malfunctioning immune system.

"This is a different sort of antibody and I don't know of another antibody that is on the market that works in the same way," Sir Gregory said. "It is a different and very potent process and very difficult to predict in advance how mild or severe the clinical response might be."

Not all explanations of what went wrong have been so kind as to claim that this effect was impossible to predict or judge. In New Scientist,
An immunologist contacted by New Scientist, but who asked not to be named, says: "You don'’t need to be a rocket scientist to work out what will happen if you non-specifically activate every T cell in the body."
Even so, the company that carried out the testing was found to have followed all procedures, and cleared of wrong doing in both an interim report and final report by the Medical and Helathcare products Regulatory Agency of the UK.

The manufacturer (not the same company as the one who carried out the test), TeGenero, filed for bankruptcy limiting the financial compensation available to the six victims. They did have these kind words.

Meanwhile, the future of drug testing and the future health of the TNG1412 victims remains in the air.

1 Comments:

Anonymous Anonymous said...

Drug 'injected too quickly' in trial that left volunteers ill
By Amy Iggulden


(Filed: 25/09/2006)



A drug trial that left six healthy men seriously ill was caused by a "reckless" mistake that meant the substance was injected too fast, an investigation will claim this week.

Documents obtained by the Channel 4 programme Dispatches allegedly show that the drug TGN1412 was administered 15 times more quickly to the volunteers than to monkeys in safety studies.

The volunteers suffered massive organ failure, with two men fighting for their lives in Northwick Park Hospital, London, an hour after the injection in March. Four others also experienced internal damage.

advertisementThe girlfriend of one of the men described him as looking like "the Elephant Man".

The worst affected victim, Ryan Wilson, 20, has since lost his toes, parts of his feet and sections of his fingers.

After the trial, for which the men were paid £2,000, the Medicines and Healthcare products Regulatory Agency described the reaction as the result of "an unexpected biological effect". But Dispatches claims that the outcome could have been foreseen, and says the mistake of injecting the drug too rapidly was overlooked by the MHRA.

Prof Terry Hamblin, of the University of Southampton, an expert in the monoclonal antibody family to which the drug belonged, tells the programme: "When you give an antibody … the quicker you put it in, the more likely you are to get an infusion reaction. To quickly infuse it over three to six minutes in six individuals, I think, is … reckless."

He said yesterday: "The odd thing was that when they put the antibody into the monkeys it took over an hour. Even with an antibody that is very safe it seems odd to have put it in [to the men] so quickly."

The volunteers, aged from 19 to 34, were given the drug, manufactured by the German firm TeGenero, in three to six minutes.

Parexel International, a contract research company, told the MHRA how quickly the drug had been given to monkeys when it applied for permission to hold the trial. The programme-maker, Brian Deer, said this paperwork did not include details of the speed at which humans would be given the drug.

But he said the MHRA could have worked it out from the information given.

A spokesman for the MHRA denied that the reaction could have been foreseen, citing results from another monoclonal antibody that suggested injection was safe.

"It should be noted that the monoclonal antibody Orthoclone OKT3, which is known to produce a cytokine release syndrome [of the type affecting the men] and which was stated as such in the CTA documentation, is administered … over a period of less than one minute.

"So you can see from this example … that there was no reason to believe that the administration rate proposed for TGN1412 would present a foreseeable hazard to the subjects."

Parexel International could not be reached for comment.

The programme will be shown at 9pm on Thursday.

amy.iggulden@telegraph.co.uk



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