GENET archive


1-Proteins: Volunteers collapsed in GE monoclonal antibody test

                                 PART I
------------------------------- GENET-news -------------------------------

TITLE:  Doctors call for worldwide help in race to save lives of men who
        collapsed 'like dominoes' in drug trial
SOURCE: The Guardian, UK, by Sarah Boseley, Jacqueline Maley and
        Suzanne Goldenberg in Washington,,1732972,00.html?gusrc=rss
DATE:   17 Mar 2006

------------------ archive: ------------------

Doctors call for worldwide help in race to save lives of men who
collapsed 'like dominoes' in drug trial

- Seriously ill volunteers on organ support machines
- Questions over why six people were dosed at once

Doctors treating six young men who have become seriously ill after taking
part in a drug trial are consulting experts around the world to try to
save their lives, it emerged yesterday.

The novel nature of the drug TGN1412, which was being given to people for
the first time and which provoked massive inflammation in their tissues
and internal organs, means that no one has any direct medical experience
to call on.

"The exact sequence of what's happening here is unique," said Ganesh
Suntharalingam, clinical director of intensive care at Northwick Park
hospital, in Harrow, north London, where the men are being treated.

The US company which conducted the testing, Paraxel, said it followed the
rules for drug research. But last night a former executive expressed
surprise at the simultaneous application of the drug. "The issue of six
people getting this at once is troublesome to me," said the former
executive in the company's clinical research services, who asked to
remain anonymous. "It is common sense not to dose six individuals with
the drug at once where there is no prior human experience."

The men are on organ support machines and receiving steroids to dampen
down their immune systems.

The drug was being developed to treat immunological diseases "such as
multiple sclerosis, rheumatoid arthritis and certain cancers", said the
makers, the German biotech firm TeGenero.

One of the two participants given a placebo instead of the drug,
yesterday gave a graphic account of the distress caused. "The test ward
turned into a living hell minutes after we were injected," said Raste
Khan, 23, a television technician who had signed up for the 2,330 fee
for the trial. "The men went down like dominoes. They began tearing their
shirts off complaining of fever, then some screamed that their heads were
going to explode. After that they started fainting, vomiting and writhing
around in their beds."

Myfanwy Marshall, 35, the girlfriend of one of two men in a critical
condition, appealed for international medical help through Ann Alexander,
a solicitor.

Ms Alexander said: "Our client's family is sickened by what has happened
... it is their intention to seek widest possible attention to this
tragedy in the hope that ... the scientific and medical community around
the world will come forward with suggestions for treatment." She said
that there was family concern not just about the lack of information but
also the "inconsistency" of what was available. "While the doctors are
doing everything they can to treat the symptoms they actually don't know
what's gone wrong."

She added: "I don't feel [the drugs firm] have issued a proper apology.
The words 'I'm sorry' mean an enormous amount to someone who has suffered
like this."

The investigation by the Medicines and Healthcare Products Regulatory
Authority could take weeks but scientists believe the drug itself caused
the disaster, and that its potential to have such a damaging effect in
humans did not show up in trials carried out on mice and monkeys.

Human error was a possibility, but the drug was made up and shipped to
London by the large German pharmaceutical firm Boehringer Ingelheim. The
human volunteers were given one five-hundredth of the dose that had
proved toxic in other animals. "That's a very large safety margin," said
Roberto Solari, chief executive of Medical Research Council Technology.

He said it was "very unlikely" the volunteers got an overdose 500 times
what it should have been. It was more likely, though this was
speculative, that the drug had provoked a reaction in humans that was
different to that in animals.

TGN1412 is a humanised monoclonal antibody, a genetically engineered
protein that is part mouse but mostly human. Almost all monoclonal
antibody drugs aim to suppress an immune system reaction - but this does
the opposite. "It is designed to turn on white blood cells, particularly
a sub-set called regulatory cells," Dr Solari said. Inflammatory
reactions in rheumatoid arthritis are caused by too many cells in the
immune system being turned on. This drug tries to turn on other cells
which have the power to switch off the trouble makers.

It is possible, Dr Solari said, that "instead of switching on the
regulators, we have switched on the activators and super-induced the
immune system".

                                 PART II
------------------------------- GENET-news -------------------------------

TITLE:  Relatives' fury over calamitous drug trial
SOURCE: The Guardian, UK, by Sarah Boseley,,1731921,00.html
DATE:   16 Mar 2006

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Relatives' fury over calamitous drug trial

Investigators began an urgent inquiry yesterday into the clinical trial
that has left six healthy volunteers in intensive care, as scientists
voiced fears the disaster could prove a major setback to developing cures
for life-threatening diseases.

Nothing had been ruled out, said the Medicines and Healthcare Products
Regulatory Agency (MHRA), leading the investigation. But although the
police were still nominally involved, it was clear that a criminal act,
such as deliberate tampering with the experimental medication, was
unlikely. Scientists were left contemplating the possibility that the
dangerous side effects of this drug in humans had not been, and perhaps
could not be, detected in the normal animal trials.

Human error - the possibility that somebody on the trial staff gave the
volunteers too high a dose of the experimental drug - is still being
looked into, even though Parexel, the US-based contract company running
the trial unit at Northwick Park hospital in Harrow, north London, denied
it and insisted that everything had gone according to protocol.

The health secretary, Patricia Hewitt, described what happened as
"shocking", but said she was confident everything was being done to look
after the men and to discover what went wrong.

Last night, two of the men remained in a critical condition at Northwick
Park hospital while four others were serious but showing some signs of
improvement, according to a hospital spokeswoman.

The girlfriend of one of the men, Myfanwy Marshall, said her 28-year-old
boyfriend had swollen beyond recognition. She said his doctors had told
her: "He needs a miracle; those were their words, he needs a miracle."

Ann Alexander, a solicitor representing a 29-year-old man who is on a
life support machine, said his family had complained of receiving "mixed
messages" during their two meetings with the drug firm.

In the first meeting, they were told the drug had been tested on monkeys
and dogs, and that one of the dogs had died. In the second, they were
told it had been tested on monkeys and rabbits. Ms Alexander said she
believed the drugs firm had pledged to give her client's family all the
financial support they required, and added it was unclear what legal
action might be taken."It has been a devastating tragedy, and these mixed
messages cause great concern," she said.

The company said in a statement: "Parexel administered the appropriate
dosage to the volunteers based on the protocols designed by the sponsor,
TeGenero, and which were approved by the ethics committee and UK
regulatory authority." TeGenero's chief scientific officer, Thomas Hanke,
said last night that the company had apologised to the men's families,
adding that the firm was "devastated" at the "shocking developments".

It is increasingly likely that the drug itself, given at the right dose,
was to blame - an explanation that could have very serious consequences
for research into the biological drugs called monoclonal antibodies which
are the bright hope for better treatments in the future.

The trial drug is not a chemical but a biological product, a genetically
engineered "humanised" protein. Unlike the old chemical entities, these
monoclonal antibodies are designed to be accepted by the human body,
which experts say makes it difficult to work out by animal testing what
dose would be toxic to humans.

The volunteers took the drug on Monday - the first time that humans had
been exposed to it. Within hours they were critically ill. Yet the MHRA
and the regulatory authorities in Germany, where the biotech company
TeGenero is based, had both examined the data from the animal tests and
allowed the human trial to proceed.

When drugs are first tested on humans, doctors do not expect any response
at all. But the six men who had taken the drug suffered a massive
inflammatory reaction. Scientists are concerned that the incident may
deter people from volunteering to take part in clinical trials.

Richard Gray, director of the University of Birmingham clinical trials
unit, said: "It must have been a huge surprise to the people running the
trial that something like this should happen. It is very, very rare
indeed for something as catastrophic as this to happen."

                                 PART III
------------------------------- GENET-news -------------------------------

TITLE:  The follow-up of animal tests
SOURCE: Equivita, Italy, Press Release
DATE:   17 Mar 2006

------------------ archive: ------------------

The follow-up of animal tests

The dramatic turn of events involving six young English men now at
death's door for accepting 2000 to be experimental subjects of the drug
TGN1412, a drug already tested on animals without any adverse effects,
demonstrates once again the truth behind the claims of Fabrizia Pratesi,
director of the antivivisection committee EQUIVITA:

- Animal experimentation does not provide a reliable prediction of human risk

- Animal experimentation is an alibi for subsequent human experimentation
with no guarantees

- That, as asserted in the world renowned scientific journal Nature (10/
11/05), reliable scientific methods, like Toxicogenomics already, exist
that can be reliably predictive for man. These must as quickley as
possible substitute animal-based experiments.

The pharmaceutical companies that continue to refute this evidence are
declaring an intention to persist with fallacious methods for the sake of

Comitato Scientifico Antivivisezionista
Via P. A. Micheli, 62
00197 Roma
Tel. +39.06.3220720
Fax +39.06.3225370

European NGO Network on Genetic Engineering

Hartmut MEYER (Mr)
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