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1-Proteins: Trial drug TGN1412 had affected monkey glands in previous tests



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

TITLE:  Trial drug had affected monkey glands
SOURCE: The Guardian, UK
        http://society.guardian.co.uk/health/news/0,,1735131,00.html
DATE:   20 Mar 2006

------------------ archive:  http://www.genet-info.org/ ------------------


Trial drug had affected monkey glands

The drug that left six men seriously ill after its first tests on humans
had caused the glands of two monkeys to swell in previous experiments,
the company behind it said today.

However, TeGenero said the monkeys' symptoms were completely different to
those suffered by the men being treated at Northwick Park hospital, in
north-west London.

The company said two of the 20 monkeys used in pre-clinical tests of the
TGN1412 drug - designed to treat rheumatoid arthritis, leukaemia and
multiple sclerosis - had experienced a "transient increase in size of
lymph nodes".

In a statement, it said information that there was a small chance of
temporary swelling as the drug worked on the immune system had been
included in details submitted to UK regulators. The information was also
on the consent form signed by the volunteers before the trial began.

"We are encouraged by the progress being made by the volunteers, but
remain deeply concerned for all of them as they continue their
treatment," Thomas Hanke, the TeGenero chief scientific officer, said.

"Once again we would like to thank the excellent work by the doctors at
Northwick Park hospital. We are continuing to do all we can to ensure
that the investigations into what went wrong proceed as quickly as possible."

The condition of four of the men is continuing to improve after almost a
week in intensive care, their doctors said yesterday.

Three of the four had now been removed from organ support, Ganesh
Suntharalingam, the clinical director of intensive care at the hospital,
added.

However, he said two other patients remained in a critical condition and
said it was still too early to comment on their prognosis despite some
early signs of improvement.

The six patients who became ill after being injected with the drug last
Monday were continuing to receive specialist anti-inflammatory treatment.

They "went down like dominoes", when given the drug, vomiting and
screaming in pain, according to a witness who was given a placebo in the
tests. The partner of one volunteer said his face had swollen up "like
the Elephant Man".

Parexel, the medical research company responsible for the drug trial,
insisted it had followed the correct procedures.

TeGenero said TGN1412 was a monoclonal antibody stimulating the
production of more white blood cells, known as T-lymphocytes.

While immunologists throughout the world know drugs targeting molecules
on T-cells should be developed with care, pre-clinical evidence suggested
TGN1412 was a safe and important development in this area, the company added.

The trial drug, a biological rather than chemical product, is a
genetically engineered "humanised" protein that is part mouse but mostly
human.

Unlike old chemical entities, monoclonal antibodies are designed to be
accepted by the human body, which experts say makes it difficult to
determine through animal testing what dose would be toxic to humans.

Almost all monoclonal antibody drugs aim to suppress an immune system
reaction, but TGN1412 does the opposite.

"It is designed to turn on white blood cells, particularly a sub-set
called regulatory cells," Roberto Solari, the chief executive of Medical
Research Council Technology, said last week.

Inflammatory reactions in rheumatoid arthritis are caused by too many
cells in the immune system being turned on, and the drug is an attempt to
turn on other cells with the power to switch off troublemakers.

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


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

TITLE:  Trial and Terror
SOURCE: The Observer, UK, by Robin McKie and Jo Revill
        http://society.guardian.co.uk/health/story/0,,1734447,00.html
DATE:   19 Mar 2006

------------------ archive:  http://www.genet-info.org/ ------------------


Trial and Terror

It was the stuff of nightmares. Six men volunteered for a clinical trial
to test a new drug and within minutes were fighting for their lives.
Robin McKie and Jo Revill report on the race to develop life-saving
medicines ... and the grave risks that can be involved

The first inkling that doctors were facing an unprecedented medical
crisis began with a call to the critical care unit at Northwick Park
Hospital last Monday afternoon. Patients on the seventh floor were having
strange reactions to a new drug, they were told. Some were having
breathing difficulties, others were losing consciousness.

The news triggered alarm, but nothing more. The unit's six beds were
already occupied by patients who were too ill to be moved. So a separate
bay was taken over and the first patients rushed down. It was then that
staff realised the nature of the calamity they were up against. Within
minutes, the bay was filled with the writhing bodies of young men
screaming for help.

Consultants were summoned from their homes. All were baffled. Even the
team who had administered the test drugs could not explain why the men
were slipping in and out of comas, why their heads had puffed up to twice
their normal sizes, why some were vomiting, or why some were in such
pain. Their only real comfort was provided by an experienced nurse who
supervised the installation of drips and ventilators.

By the time Ganesh Suntharalingam, director of intensive care, arrived at
the unit in the sprawling, windswept Northwick campus in Harrow, north-
west London, the scene was horrific. Six healthy young men - including
British Asians, an Australian, a New Zealander, and a South African -
were now in the throes of massive inflammatory reactions.

The men, who had been contracted by the US drug testing company Parexel
to test the anti-cancer drug TGN1412, were put on ventilators. Then some
began showing signs of kidney failure. Blood filtration units were
brought it to clean out their veins and arteries. Relatives were called
and told to expect the worst. Only a miracle would see them through, one
was told.

By any standards, it is a shocking story. How could a carefully
controlled medical trial have produced such mayhem in such a short space
of time? What exactly happened to those six healthy young men? Why did
the rigorous rules laid down by the Medicines and Healthcare Products
Regulatory Agency (MHRA) fail to halt last week's dreadful events? And
what are the implications for the chaos triggered by the drug-trial disaster?

The MHRA has announced it has begun an investigation into the calamity of
Parexel's trial, one that should provide answers to these questions.
'This was completely unexpected,' said Simon Gregor, spokesman for the
MHRA. 'There are a number of possibilities which we have to consider: was
there a manufacturing problem or some form of contamination or was there
something about this product that could not have shown up at an earlier
stage?' He predicted it would take several weeks, possibly months, before
any inquiries would produce results.

Few expect a whitewash. This country is one of the world's biotechnology
leaders but that reputation will be seriously tarnished if it is found
there were significant regulatory errors involved in the medical disaster
at Northwick Park.

Consider the simple issue of timing. It is now clear the doses of TGN1412
used in the trial were given with extraordinary rapidity, with an
interval of only minutes separating each patient's injection. Normally,
doses would be interspersed with waits of hours to give researchers time
to study volunteers for side-effects. Indeed, sometimes doses are given
at intervals of days, even weeks, as Dr Kate Law, of Cancer Research UK, said.

'We usually give one person a small dose. Then weeks later we give
another volunteer an equally small dose,' she said. That precaution was
clearly not enforced last week.

Within minutes of the last volunteer getting his TGN1412, the first
injected recruit had begun to complain of a severe headache, backache,
fever and pain. He tore his shirt off and yelled he was burning. 'An
Asian guy next to me started screaming and his breathing went haywire as
though he was having a terrible panic attack,' said one of the
volunteers, Raste Khan, who had been given a placebo.

'They put an oxygen mask on him but he kept tearing it off. He was
shouting "Doctor, doctor, please help me!" He started convulsing,
shouting that he was getting shooting pains in his back. People were
fainting and coming back to consciousness. It was terrifying. I kept
expecting it to happen to me at any moment. But I felt fine and didn't
know why.'

The whole affair 'is shocking because it is unprecedented,' said Simon
Best, chair of the UK Bioindustry Association. 'If you think about the
number of Phase I trials carried out in this country, you've never heard
of anything having such a terrible impact.'

In fact, Phase 1 trials - which are carried out merely to determine a
drug's toxicity, its efficacy being assessed at subsequent Phase 2 and 3
trials - can all too frequently sound the death knell for a new medicine.
'Between 20 to 30 per cent of drug developments go no further than this
stage because of ill-effects suffered by volunteers,' Ray Noble, a UK
medical ethicist, pointed out. However, no drug has ever seen such an
abrupt termination as that of TGN1412.

Not that Parexel are newcomers to the business. The company made more
than $100m last year carrying out clinical trials for researchers and has
plenty of experience in the field, with more than 5,000 employees in 39
countries. All the doctors and nurses at its Northwick Park unit are
employees and the company takes great care in getting participants to
sign full consent forms and to be given medical examinations. The company
also provides pool tables, digital TVs and computer games for volunteers.

And that leads us to another vexed issue: money. Khan, like the other
volunteers taking part in the trial of TGN1412, had joined up because of
the fee he would receive: £2,000. Last week, medical ethicists and trial
experts raised serious worries about payments of this level. 'People
should be recompensed for the time they take out of their lives to become
involved in a trial but that is a different matter from paying
inducements,' said Janet Derbyshire, of the Medical Research Council (MRC).

This point was backed by Ray Noble, a UK medical ethicist. 'People who
are designing these trials have to make sure they do not offer so much
money that young people simply ignore the boxes about their medical
conditions in their consent forms in order to make sure they get the
thousands of pounds they need to pay off their student loans.'

Indeed, it emerged last week that Parexel - which launched the trial on
behalf of the German drug company TeGenero, the manufacturers of TGN1412
- had breached guidelines laid down by the Association of British
Pharmaceutical Industries, the drug industry's main trade body, over the
offering of inducements. 'Neither payment, nor the level thereof, should
be mentioned in a public notice,' these state. Yet Parexel's web site for
enrolling volunteers to its TGN1412 trials clearly states that recruits
would be 'paid for your time and inconvenience'.

These issues are serious enough. However, of all the concerns raised by
scientists last week, it was the decision by Parexel to use healthy
volunteers, not cancer patients, as guinea pigs that has caused most
unease. The issue takes us to the very heart of the crisis that has
engulfed Northwick Park and to the nature of TGN1412, a drug known as a
monoclonal antibody or mab.

Mabs were first developed in Britain by Cesar Milstein and George Köhler,
who shared the 1984 Nobel Prize for Physiology for the achievement. They
are artificial versions of natural chemicals called antibodies, proteins
that are made in the body and which latch on to the surfaces of cells.
Herceptin, the breast cancer drug, is a monoclonal antibody. It fits on
to a site on a tumour cell, like a key sliding into a lock, initiating a
chemical reaction inside the cell that causes it to stop dividing. Thus
the spread of breast cancer is halted. It is this specificity, this
ability to use mabs as tiny biological guided missiles that makes them so
powerful, and dangerous.

Today, sales of antibody drugs now stand at more than £7bn a year and
there are 17 of them on the market. Most work by stopping a cell from
dividing. But one or two do the opposite. They stimulate a cell into
action. And crucially, TGN1412 is one of these.

The drug targets a site called CD28 which lies on the surfaces of white
blood cells called T-cells, key components of the body's immune system.
In effect, the drug latches on to the T-cell and initiates a chemical
reaction that should fire the body's immune system into action. Thus it
was hoped TGN1412 could be used to treat a disease called B-cell chronic
lymphatic leukaemia (B-CLL), and also auto-immune diseases which include
rheumatoid arthritis and multiple sclerosis.

'The aim would be to kick the body's defences into a highly active state
so that they could mount a more effective attack on the proliferating B-
cells that were causing a patient's leukaemia,' said Dr David Chiswell, a
monoclonal expert and former chairman of the BioIndustry Forum.

Patients who would be the target of such drugs have weakened immune
systems. Healthy people do not. Hence the puzzle over the decision to use
fit young people for the trial. Instead of prodding weakened bodily
defences into action, TGN1412 let loose a fully armed missile, unleashing
a chain reaction in which T-cells released cytokines - messengers that
control the immune system - that in turn triggered other T-cells into
releasing more cytokines. Doctors have a name for this deadly cascade. It
is called a cytokine storm.

In the lungs, fluids and immune cells accumulate and can block off air
passageways. Blood vessels become inflamed and organs are eaten up. The
effect is often grotesque. Myfanwy Marshall said her partner, one of the
trial's volunteers, had been left looking like 'the Elephant Man,
completely puffed up,' his face and head had swollen horribly, and were
now a 'weird purple and yellow colour'.

So why employ healthy volunteers who would have been susceptible to
cytokine storms? For most experts, the decision seems questionable. For
example, both Cancer Research UK and the MRC remained very doubtful about
the decision. 'We would have been much more cautious,' said Derbyshire, a
sentiment echoed by Law. 'I doubt if we would have given approval for the
trial as it was carried out.'

Only the MHRA probe will reveal the truth, though The Observer can reveal
that when TGN1412 was in pre-clinical studies in animals in 2004,
TeGenero was at that stage considering using cancer patients for initial
safety tests. Yet when they began trials last Monday, they picked eight
fit young men. Why?

One answer, put forward by a researcher involved in early work on
TGN1412, suggests the company thought toxicity data from animal studies
of TGN1412, which included experiments on rabbits and monkeys, was so
encouraging it decided to test the drug on healthy people straightaway,
in order to look at the spectrum of potential side-effects.

Or the company may simply have encountered a problem in recruiting cancer
patients, a process that takes up more more time than any other part of a
clinical trial. Almost half of all trial delays result from difficulties
in finding volunteers, and that can equate with a company losing millions
of pounds in sales for a new drug. In 2004, 11 per cent of all newly
diagnosed cancer patients agreed to participate in some kind of drug
trial. However, as more new medical technologies come on stream, a bigger
army of recruits will be needed to join in research programmes.

Whatever the answer, the issue of financial pressures that bear down on
drug researchers from their boardrooms cannot be ignored in this grim
tale. 'The people behind this company are reputable scientists,' said one
UK immunologist last week. 'I can only think they may have got carried
away and didn't see the apparent dangers in the design of this trial. But
the first question I would have asked is this: how are you going to avoid
a cytokine storm? You know this drug is going to trigger the T-cells into
a burst of maximal activity. Is anyone surprised by what happened?

Yesterday Dr Thomas Hanke, TeGenero's chief scientific officer, defended
the decision to use healthy volunteers. 'We had early evidence [from
animal studies] that the effect of the drug depends on the status of the
patient, so it dampens the immune response for patients with auto-immune
disease and it boosts the response for the other group [with cancer]. We
are so terribly sorry it went so wrong. We are devastated by the tragic
events that have happened.'

Certainly, the story of TGN1412 spells out many warnings for the
pharmaceutical industry and for the medical establishment. 'If nothing
else, the reaction of these patients tells us one thing - that there are
things going on at the CD28 site, the target for TGN1412, that we do not
understand,' said monoclonal expert, David Glover, a former chief medical
officer for Cambridge Antibody Technology.

'Any company who is researching on CD28 drugs today should stop what they
are doing at once until we find out more about what is going on there.'

It is equally clear, added Glover, that in an era in which more and more
new medicines are created by biological means, that new procedures be
urgently introduced to prevent any more disasters.

TGN1412 is a humanised monoclonal antibody. In other words, it is made up
mostly of human protein. Testing it in animals is therefore a tricky
issue. 'What you need to do is understand what the issues are that you
face and think carefully about them and find creative solutions.'
Genetically engineered mice with a humanised immune system may be part of
the answer, he added.

Another idea proposed by Glover is a new super-safe technique called
'microdosing' which was just starting to attract the attention of the
pharmaceutical industry. This involves producing a blister on a patient's
arm and exposing it to tiny amounts of the drug, rather than treating the
whole person.

The blister fills with inflammatory fluid, containing cells whose
reaction to the drug can be monitored. 'This allows you to get a handle
on the effect before you expose the whole patient to it,' added Glover.

Certainly, action will be needed to stop any repetition of the tragedy
that unfolded at Northwick Park. The sight of loved ones, horribly
disfigured, will be indelibly fixed in the minds of friends and relatives
who gathered by victims' bedsides.

Nor was their suffering helped by the behaviour of the hospital. At one
point, those watching TVs in the patients' rooms listened to a hospital
press statement which said they might die within hours. One relative,
whose son is an affected volunteer, said friends and families were left
panicking. 'One minute he [his son] was being told that in two days he
would be better. But on the outside they are saying that there was little
hope.'

Yesterday, two of the stricken volunteers had been taken off organ
support after responding to treatment and the conditions of two others
were reported to be improving. Four are now conscious and able to talk.
But two - 21-year-old Ryan Wilson, of Highbury, north London and a 28-
year-old assistant bar manager - remain in a critical condition.

Meanwhile, Parexel's recruitment website for its drug trials continues to
urge volunteers to come forward. Yesterday it was still displaying
photographs of happy young people playing pool and chess - while another
showed a cheque for an undisclosed sum being handed over to a lucky recipient.

*****

One man's experience of a clinical trial

Clint Witchalls

As someone who had been putting off having a vasectomy for years, I was
intrigued to read about a clinical trial for a male 'pill'.
Unfortunately, the trial was about to fold as not enough volunteers were
stepping forward. I called the hospital and told them I'd like to volunteer.

The 'pill' was actually a progesterone implant supplemented with a
testosterone injection. What I hadn't factored into the equation was that
all clinical trials are randomised, double-blind and placebo controlled.
That is, I might be given a placebo. The doctor explained that I would
have to continue using whatever contraception I currently used.

This wasn't enough to deter me. For the previous couple of years, I'd
suffered from severe hypochondria. On this trial a doctor would monitor
my health very closely on a weekly basis. Everything from my bone density
to the levels of C-reactive protein in my blood would be scrutinised. I
signed the contract for an 18-month trial for which I would get paid £1,200.

Things went swimmingly for the first few months, but then my moods began
to dip and rise. One moment I would be vulnerable and sensitive, the next
aggressive and distracted. (I assumed the progesterone caused the former
and the testosterone the latter.) Of course, there was a chance I'd been
assigned to the control group and the symptoms were purely psychosomatic.

As the months progressed, my moods got worse. I made an appointment with
the hospital to have the progesterone implant removed.The doctor said it
didn't sound like the effect of the hormones. What I was describing was
clinical depression. He put me on Prozac. Suspicious, I went to my GP for
a second opinion.

'I agree with the diagnosis,' he said. 'You have a text-book case of
clinical depression.' He went on to say that it's possible that the
hormones triggered the depression.

The Prozac worked. I continued taking the pills until the progesterone
implant was removed a couple of months later. Although the depression
hasn't returned, 75 per cent of sufferers have a relapse within 10 years.
I live in constant fear of my black dog returning.

I'm not angry with the doctors who ran the trial - I believe they acted
in good faith - however, I'm surprised that no one thought to ask the
volunteers about their mental health before allowing them to sign the
consent form. What I know now is that hypochondriacs are 10 times more
likely to suffer from depression than your average person. If I'd known
that then, I wouldn't have signed.

In spite of what happened to me, I haven't lost faith in the process of
clinical trials. If you want new drugs, you have to accept that they need
to be tested on humans. Whenever you take a drug, you can't be 100 per
cent sure it won't kill you. We can't live in a risk-free society, but we
need to continually strive for a better understanding of what the risks
are. Being human, we sometimes fall short.

· Clint Witchalls is writing a book about his experiences on the trial.
It will be published by Rowohlt next year




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