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FROM: Ventura County Star (California)

URL:
http://www.venturacountystar.com/vcs/county_news/article/0,1375,VCS_226_3
815646,00.html


Amgen caught in dispute over drug's safety, value

Parkinson's patients sue to resume use in trials

By Tom Kisken, [log in to unmask]
May 29, 2005

Robert Suthers is so desperate to hold his baby granddaughter, bathe
himself without help and live as he did before Parkinson's disease that
he's battling to take a drug despite claims it could further damage his
brain.

The retired textile salesman who once competed in the New York City
Marathon is suing Amgen in a landmark case that pits patients' hopes for
a cure against a healthcare company's responsibility to protect
consumers.

Suthers and other patients in a clinical trial say a protein, called
GDNF, breathed life into crippled bodies, allowing them to take walks and
even run again. But officials of Thousand Oaks-based Amgen, which owns
the drug, said research showed it caused brain damage in monkeys, created
a risk of unwanted antibodies and, in most patients, offered no more of a
defense against Parkinson's than a placebo.

So the world's largest biotechnology firm stopped the clinical trial and
withdrew the drug from patients though court documents say the Food and
Drug Administration would have allowed treatments to continue. The
decision started a battle that on Thursday spilled into a federal
courtroom in Manhattan. Judge P. Kevin Castel heard arguments on a
preliminary injunction that would force Amgen to provide GDNF to Suthers
and a second plaintiff, a retired teacher from West Virginia, but made no
immediate ruling.

The hearing continued a nine-month-old saga driven by patients and
research doctors who are neither convinced GDNF is dangerous nor
ineffective. They said Amgen didn't give a fair chance to a drug they
believe may still be a shield against a disease that inflicts about 1.5
million Americans.

"I wanted my patients to continue to be treated," said Dr. Richard Penn,
a neurosurgeon who helped lead GDNF clinical trials at the University of
Chicago Hospitals. "Amgen has absolutely stopped us cold."

However, Dr. J. William Langston, director of the Parkinson's Institute
in Sunnyvale, suggested patients and doctors have invested so much hope
in GDNF's potential that some of them may be ignoring health risks and
other questions about the drug. He defended Amgen's choice.

"We can't do harm," he said, finding irony in GDNF's rise and apparent
fall as a wonder drug. "Amgen was the leader. They were the champion for
GDNF. Now, they're being pinpointed as Dr. Evil. I find that sad."

Prisoners in their own bodies

Parkinson's kills nerve cells in the brain that help control the body's
movement by producing a neurotransmitter called dopamine. Slowly
debilitating, the disease can bring tremors so pronounced people may move
as if inebriated. Their bodies can become so rigid they need help getting
dressed. Face muscles can become frozen so a smile is impossible.

Eventually, people become prisoners in their own bodies.

Glial cell line-derived neurotrophic factor represented hope. While other
drugs help people control Parkinson's symptoms, GDNF is a protein
believed to reverse aspects of the disease.

"It wasn't going to be a cure," said Dr. John Nutt, a Parkinson's
researcher from Oregon, but it might restore some damaged cells and
protect others, slowing the disease's progress. Nutt said it had the
potential to affect a large majority of Parkinson's patients.

"It could have made a huge impact," he said.

Amgen bought the drug as part of a $250 million purchase of a company
called Synergen in 1994. Six years later, academic researchers thought
they solved the crucial problem of delivering the drug directly to deep
recesses of the brain. That spawned a clinical trial in England that an
observer compared to the movie "Awakenings," where people trapped by
disease seem freed.

A video from the study shows people who once shuffled as if their legs
were mummified moving like speed-walkers. Tremors diminished. Agility
returned.

Launched a trial in seven sites

The trial was open as was a similar study that produced encouraging
results in Kentucky. Patients knew they were getting GDNF and their
physical reactions could have been influenced by the knowledge. Two years
ago, Amgen launched a trial in seven sites, from England to Oregon, in
which neither patients nor doctors knew whether GDNF or a placebo was
being provided.

Just to qualify, people needed pumps surgically implanted in their
abdomens so GDNF could be delivered through a pipeline of catheters just
under the skin. Two nickel-sized holes were drilled on either side of the
skull so the drug could be administered to the brain's basal ganglia.

It was the kind of trial that attracted desperate people.

Robert Suthers fit. He is a 70-year-old Korean War veteran who spent a
decade in a Catholic monastery, then was married and raised three
daughters, once winning a father of the year award. He received a
diagnosis of Parkinson's about seven years ago. The disease slowly
crippled him.

"I ran the New York City Marathon in 1990, in four hours and 54 minutes,"
he said in a phone interview from his home about a half-mile from the
Long Island town of Greenlawn. "Now I can't walk a block. I have so much
pain."

The craniotomy surgery took more than six hours. The day after, Suthers
suffered a stroke that dislodged the catheters. He had to go through the
surgery again five weeks later. This time, it took more than two hours.

He was getting the placebo

The trial began in October 2003. Suthers struggled just as much to write
and walk. Later, he learned he was getting the placebo. However, when the
study was completed, all 34 people in the trial were told they would
receive monthly doses of GDNF.

That's when Suthers noticed changes.

He was able to walk farther, eventually strolling to Greenlawn and home
again. He could hold his granddaughter. The muscles in his face loosened.


"He could smile," said his daughter, Kristen Suthers.

Others offer similar stories. Niwana Martin, a retired special education
teacher from Harpers Ferry, W.V., could ride horses again and was
thinking of kayaking. In Kentucky, the disease had once so contorted
Roger Thacker's body that his toes jutted upward. GDNF allowed him to
wear shoes.

"It means the difference between living and existence," said Thacker, who
is 65. "It means walking my daughter down the aisle at her wedding. It
means playing on the floor with my granddaughter again."

No one showed much change

Optimism was fading at other sites. In North Carolina, three people were
in the blind trial and no one showed much change, according to a
neurologist. One of four people in Oregon said conditions improved, but
that person was on a placebo.

Of the 34 people at all the trial sites, seven showed significant
improvement, according to Amgen records. Four were on placebos.

GDNF didn't seem to be working, said Dr. Donna Masterman, the Amgen
neurologist who led the studies.

If it had worked, more changes would have emerged during the blind trial,
not only when people knew what they were getting.

"Whatever the effect was, it didn't look like it was the drug," she said,
noting the placebo effect had played havoc with Parkinson's studies
before, persuading scientists that implanting fetal cells that produce
dopamine into the brain had great potential before continued experiments
thwarted the speculation.

Amgen researchers hadn't given up, Masterman said. They were considering
increasing the drug's dosage.

Then came tests showing three people in the studies developed antibodies
that could block the body's natural production of the GDNF protein.

The biggest blow came from animal research. Of 44 rhesus monkeys who
received GDNF, four suffered brain damage, according to Amgen records
submitted to the court.

Researchers worried the drug or the way it was sent to the brain was
creating toxic reactions.

Amgen leaders decided there was too much risk. The trials were stopped,
and so was the flow of medicine.

'That was the right thing to do'

"This was about safety," Masterman said. "It was stopped, and we knew
that was the right thing to do."

Suthers backslid slowly but steadily, just as he had improved. His
tremors grew worse. So did his pain. He struggled to keep his balance and
fell more than once.

Niwana Martin kept trying to ride horses but fell and broke three ribs.
Roger Thacker's toes twisted upward again. He stopped wearing shoes.

To them and their families, it felt as if a promise had been broken.
They'd gone through brain surgery, found a drug that made their lives
better only to see it taken away.

What made it more galling was that Dr. Michael Hutchinson, the research
doctor who ran the New York trial, still thought the drug was safe and
was convinced GDNF had worked for Suthers and Martin.

"The failure to provide the drug is causing and will continue to cause
the plaintiffs immediate irreparable harm and damage because there is no
other drug currently being tested in the United States that could
potentially serve as a cure," Hutchinson said in a statement submitted to
the court.

Suthers and Martin hired Alan Milstein, a New York lawyer who previously
represented the family of a teenager who died during a gene-therapy
experiment.

They sued. About a dozen other patients from the clinical trial have come
forward in hopes that an injunction would force Amgen to supply them with
GDNF.

Researcher against researcher

The case pits patients against drug company and, in a stranger wrinkle,
researcher against researcher.

Penn, who led the GDNF trials in Chicago, agrees with Hutchinson. Amgen
made a mistake. He had two patients on the placebo and one on the
experimental drug. Not only did the person receiving GDNF improve, but he
also kept some of his mobility afterward, possibly indicating the drug
repaired some of the damage.

"If it were a placebo effect and he knew he wasn't getting it, he'd get
worse," said Penn, arguing that more clinical trials are needed. "This is
one idea that I don't think has been proven to fail yet."

Penn and others challenge the monkey research, suggesting the doses that
caused brain damage were much higher than people would receive. They said
clinical trial patients actually may not have received enough GDNF to
attack the disease. They questioned the way the drug was delivered to
damaged parts of the brain.

Other experts involved with clinical trials in Toronto, Oregon, Virginia
and North Carolina say Amgen's study was run correctly and produced data
that made the company's choice clear-cut.

"I believe that the drug does not work," said Dr. Mark Stacy, a
neurologist who ran the North Carolina study in the most recent trial and
was also involved in a failed GDNF experiment in the late 1990s. "I look
at decisions in medicine to be a balance between potential for benefit
and potential for risk. I do not see benefit."

Excitement over its potential

Stacy suggested controversies are being driven not by research data but
by the personality of the doctors involved. At the Parkinson's Institute
in Sunnyvale, neurologist Langston suggested some researchers may have
glossed over concerns about the drug because of their excitement over its
potential.

"I certainly think there were people who really weren't carefully looking
at the data, looking dispassionately at the final results," he said.

Penn said he's not convinced the drug works but thinks the plug was
pulled before definitive answers were known. He also noted that the FDA
agreed to let Amgen keep giving the drug to Suthers and other patients in
a step the researcher believed would lead to more knowledge about GDNF.

Masterman said the FDA indicated it wouldn't block treatment but also
made it clear the final decision was Amgen's. Company leaders were
convinced they'd already made the only decision possible.

"First, do no harm," Masterman said, quoting the credo that she says
governs not only doctors but the biotech company as well.

They'd sign a waiver

Suthers believes GDNF is safe. So do Martin and Thacker. But if there was
risk that it caused brain damage, they'd still take it, and they'd sign a
waiver protecting Amgen from liability.

"My husband is brain damaged," said Linda Thacker, referring to the harm
done by Parkinson's. "These patients are dying, and they're dying a very
painful death. They're willing to sign any kind of waiver."

The patients say Amgen has refused their offer. Masterman said a waiver
wouldn't change the company's responsibility.

"It's still not the right thing to do," she said. "You're still exposing
these people."

Suthers, who said Amgen is interested only in maximizing profit, scoffed
at the suggestion company officials worry about his health.

"I could do without their protection," added his wife, Elaine Suthers.

Amgen won't allow any human studies until more is known about possible
toxicity and ways to control it, Masterman said, adding the company
supports continued research and hasn't given up on GDNF. Scientists who
aren't convinced risks are greater than benefits say shelving the studies
could push GDNF research back as much as 10 years.

Suthers doesn't think he has that much time.

"To me," he said, "it's like a death sentence."

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