National Anti-vivisection Society

 

National Antivisection Society

The failed trial of TGN1412

Posted: 5 December 2006

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The unreliable nature of animal testing shot into the media in March when the trial of test drug TGN1412 went disastrously wrong.

The drug was given to healthy volunteers in doses 500 times weaker than that given to lab monkeys, but in an hour the volunteers were so seriously ill that they had to be transferred to intensive care at London’s Northwick Park Hospital.

TGN1412 was in Phase 1 of three phases of human trials, to test for safety and see whether there are any side effects. As a result of the devastating effects on the volunteers the Medicines and Healthcare Products Regulatory Agency (MHRA) suspended the trial and investigated the case. The investigation concluded that the horrifying effects suffered by the volunteers were caused by an unexpected biological reaction, which did not affect the animals the drug had been tested on. There was no evidence that incorrect doses were given or that contamination had occurred.

The drug

TGN1412 is an anti-inflammatory drug designed to treat conditions including rheumatoid arthritis, leukaemia and multiple sclerosis. It is in a class of drugs known as monoclonal antibodies – genetically engineered versions of antibodies, the body’s natural defences.
TGN1412 is a new type of monoclonal antibody which stimulates certain types of cells in the immune system. The drug was being developed by the German biotech company TeGenero.

Animal tests

According to TeGenero, the drug has been tested extensively in laboratory animals including rabbits, dogs and monkeys with no drug-related adverse events.
However, several studies have pointed out crucial species differences between humans and monkeys in the particular function of the immune system. Moreover, this drug stimulates a protein only found in humans, which increases the risk of falsely reassuring results from animal tests. This was the first time the drug had been tested on humans.

It has been reported that some monkeys in pre-clinical tests experienced an increase in the size of lymph nodes. This is not a side-effect, but is due to the way in which TGN1412 works on the immune system. According to TeGenero,
“this is evidence of the mode of action of the drug rather than a ‘drug related side effect’.” TeGenero says the symptoms also differed from those in the human volunteers.

Human side effects

In the clinical trial the volunteers suffered multiple organ failure caused by a massive immune reaction, as the drug triggered an uncontrollable response from antibodies. The worst affected volunteer was hospitalised for three months. They appear to have suffered permanent damage to their immune systems, and one has had fingers and toes amputated. Two of the men now have early (potential) signs of cancer while another has early stage lupus.

The side effects experienced included soaring body temperatures, dilated blood vessels; plasma leaking into surrounding tissue and dramatically falling blood pressure. One man’s head and neck were said to have swollen massively and his limbs turned purple. Another was said to resemble the “Elephant Man”.

Safer alternatives

Accelerator mass spectrometry (AMS) is an analytical tool of unprecedented sensitivity. It can be used to study samples from human volunteers given ultra-low, harmless, doses of new drugs (called micro-dosing).

Obtaining early metabolism data from the relevant species (humans) can avoid the unnecessary exposure of volunteers in Phase 1 clinical trials to potentially toxic drug candidates.

Emerging technologies like AMS have many advantages, including speeding the development process and improving safety. In 2003 scientists sponsored by our scientific research wing, the Lord Dowding Fund, called for greater promotion of AMS as a safe, effective way forward for drug testing – pointing out at the time that countries such as Japan already had many AMS units whilst the UK had just one.

Following TGN1412 it was widely reported that that micro-dosing would have avoided the horrific consequences.

Refs:
Villinger F et al (2001). Cloning, sequencing, and homology analysis of nonhuman
primate Fas/Fas-ligand and co-stimulatory molecules. Immunogenetics 53:315-
328.
Bhogal N & Combes R (2006). TGN1412: Time to change the paradigm for the
testing of new pharmaceuticals. ATLA 34:225-239.
Kenter MJH & Cohen AF (2006) Establishing risk of human experimentation with
drugs: lessons from TGN1412. The Lancet 368:1387-1391.

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