Dr. Andy

Reflections on medicine and biology among other things

Thursday, April 20, 2006

TGN1412

It was apparently the medicine itself, not a contaminant that caused the horrific reactions to TGN1412:
A preliminary investigation of a UK trial in which six healthy volunteers became critically ill said this was probably due to effects of the drug in humans not predicted by animal studies. But the report stopped short of questioning how the study was carried out.

The investigation into the phase I trial of the monoclonal antibody TGN1412, carried out by the Medicines and Healthcare Products Regulatory Agency (MHRA), the body that approves clinical trials in England, said the trial was run according to the agreed protocol, using the correct dose. It also found no evidence of a manufacturing problem or contamination of the product given to the trial volunteers.
One problem with animal testing for monoclonal antibodies against human proteins is that they are likely to be much more potent in humans than animals since they are specifically engineered for high affinity for a human protein and may have little or no binding to the homologous animal protein. This is unlike more classic small molecules which are likely to have similar potencies in animals and humans.

6 Comments:

At 5:07 AM, Anonymous Anonymous said...

Hi,

Have you thought that homeopaths have claimed that as certain substances are diluted they become more potent.

The dose of TGN1412 used in the human trial was diluted to 1/500th of its concentration when used in animals.

In the book "The emerging science of homeopathy" it is claimed that some cells have receptors that only respond to diluted concentrations and do not respond at all at high concentrations.

What is the effect of TGN1412 at the same concentrations in animals? No-one knows because that test has not been done.

 
At 12:08 PM, Blogger Michael said...

Changing the culture of research

See this week’s BMJ (August 5):
http://bmj.bmjjournals.com/

Editorial
Further lessons from the TGN1412 tragedy
New guidelines call for a change in the culture of research
BMJ 2006;333:270-271 (5 August), doi:10.1136/bmj.38929.647662.80

“As eight young men assembled at a London hospital on 13 March this year, they
had no idea that within an hour their lives would be changed irrevocably and
they would have contributed to a fundamental rethinking of the development and
testing of new drugs. The first trial of TeGenero's TGN1412 (a T cell agonist)
in humans took place at Parexel's clinical pharmacology research unit at
Northwick Park Hospital, London. The events that followed fuelled speculation
not only into the conduct of the trial and the nature of the drug, but also
into aspects of research as diverse as comparative molecular biology,
bioethics, and health economics.

The Medicines and Healthcare Products Regulatory Agency initiated an
investigation, but the BMJ and other journals called for a more far reaching
inquiry independent of the regulatory agency that had approved the trial. On 5
April the agency released its interim report, and the government announced that
an independent Expert Scientific Group, chaired by Professor Gordon Duff, would
be appointed "to learn from the Parexel clinical trials incident." On 25 July
this group released their interim report and recommendations. …..”

http://bmj.bmjjournals.com/cgi/content/full/333/7562/270?ijkey=whP3FyWKdYWdMvy&keytype=ref

 
At 7:02 AM, Anonymous Anonymous said...

The victims of the catastrophic 'Elephant Man' clinical trial were given the test drug at a 'reckless' rate, according to experts.


The drug TGN 1412, designed to fight leukaemia, rheumatoid arthritis and multiple sclerosis, was injected 15 times more quickly than when given to monkeys in animal studies, confidential documents have revealed.


Leading scientists believe this 'reckless' mistake could explain the horrendous reaction to the drug which left volunteers fighting for their lives.


The six young men - all fit and healthy before signing up for the March trial at Northwick Park Hospital in North-West London - suffered a host of side-effects, including pain, vomiting and organ failure.


Bar manager Mohamed 'Nino' Abdelhady, 28, was described as 'the Elephant Man' by his partner Myfanwy Marshall after his head swelled up.


Trainee plumber Ryan Wilson, 20, suffered heart, kidney and liver failure, pneumonia and blood poisoning and was in a coma for three weeks.


While in the coma, he suffered a frostbite-like reaction and has since lost parts of his fingers and had his toes amputated.


The volunteers, who are launching a multimillion pound damages claim against Parexel, the private research firm that ran the trial, face contracting cancer and other chronic and incurable diseases such as multiple sclerosis.


An investigation by the Government's drugs watchdog, the Medicines and Healthcare products Regulatory Agency, concluded no mistakes had been made in either making or testing the drug.


Instead, the horrific side-effects were down to an effect of the drug in the human body that could not have been predicted.


Now, documents obtained by the Channel 4 programme Dispatches reveal that the speed at which the drug was given could be to blame.


They show that Mr Wilson was given the drug - a cutting-edge medicine known as a monoclonal antibody - in just four minutes. The others were injected or infused with the solution over periods ranging from three to six minutes.


In contrast, monkeys used in earlier experiments were slowly infused with the drug over an hour.


Professor Terry Hamblin, a Southampton University expert on monoclonal antibodies, said: 'When you give an antibody, the quicker you put it in, the more likely you are to get a reaction.


'I usually give it over about six hours. If you give it in less than an hour you get horrific reactions.


'To quickly infuse it over three to six minutes in six individuals I think is reckless.'


Dr David Glover, former chief medical officer of drug developer Cambridge Antibody Technology, said: 'The drug was given too quickly.'


Parexel refused to comment on the Dispatches findings, while TeGenero, the German company which made the drug, said the trial was 'the right thing to do'.


The MHRA, which gave the human trial the go-ahead after looking at the results of animal experiments, said the men were given doses 500 times lower than those used in animals.


A spokesman said similar drugs have been given to people in the past at a faster rate without any problems.


He added: 'There was no reason to believe the administration rate proposed would present as a foreseeable hazard to the subjects.


* Watch Dispatches: The Drug Trial That Went Wrong on Channel 4 on Thursday at 9pm.

 
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