Trial Doctors Respond
Trial doctors and researchers: dramatic improvement
seen in patients
According to published reports, in the fall of 2004, trial doctors have
stated that::
-
Many trial doctors believe the study design was flawed, and thus the
analysis was off, as well as the interpretation. (1)
- Amgen should have discussed their concerns with study investigators before going to the FDA.
- Phase II trials used a less efficient catheter to deliver GDNF in doses at the low end of those used in the English trial, a dose later shown to be ineffective.
- Earlier trial results were too consistent and long lasting to be attributed to a placebo effect. Several English patients, who have been off the drug for nearly three months, have not deteriorated to the degree expected with a placebo effect.
- No damage was seen on any patient’s brain scan, including those who had been on GDNF for more than two years.
- Monkeys who developed brain lesions received GDNF in doses 15 times greater than those given to patients, even though their brains are much smaller.
- With monkey brain lesions identified on scans taken after the drug was stopped, there was a real possibility that abruptly stopping the GDNF could pose risks to trial patients.
- Antibodies found in bloodstream of a few participants may or may not be harmful, and could easily be monitored while still providing patients with the drug.
“I don't think there's ever been a trial like this where so many
investigators were so indignant about the way things were handled,” said Dr.
Michael Hutchinson, associate professor of neurology at New York University
School of Medicine and one of the study investigators. (2)
“It's frustrating for me to have something in hand that could ultimately change the natural history of this disease and see its use abruptly stopped,” said University of Kentucky neurologist John Slevin.
“I see a benefit in my patients. They see improvements. We have an
incredibly devastating, progressive disease.” (1)
GDNF is one of a class of natural human proteins called nerve growth
factors that can protect brain cells from death and induce them to grow.
"This is the first drug that we might have that might influence the course
of the disease and that's why it's important that it not be killed," said
Richard Penn, a neurosurgeon at the University of Chicago. (2)
“It's hard to credit a placebo response in all of our 10 patients,” said
Don Gash who ran one section of the study at the University of Kentucky,
where all patients received the drug for more than a year. “A placebo effect
doesn't last a year.” (1)
“I follow the Hippocratic oath,” Dr. Hutchinson said. "We have to ask:
Are we doing the right thing?" (2)
(1) Talan, Jamie.
“Drug trial – and error?” Newsday,
November 22, 2004.
(2) Pollack, Andrew. “Many See Hope in Parkinson's Drug Pulled From Testing.” New York Times, November 26, 2004.
Renewed hope for Parkinson’s patients
From: Report from the University of Bristol
Post-mortem analysis of the brain of a phase I GDNF trial participant at the University of Bristol in the UK, revealed re-growth of nerve fibres in the putamen area of the brain. The findings are reported in the July issue of Nature Medicine.
The patient died of a heart attack. Professor Love, who examined his brain “found that dopamine-containing nerve fibres had sprouted back in the putamen. He said: “This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibres, in association with a reduction in the severity of Parkinson’s Disease."
Click here to read full text.
February 11, 2005
University of Kentucky Press Release (February 11, 2005):
Reaction to Withdrawal of Treatment
Contact: Allison Elliott
"The
need for new, and more effective, treatments is
inarguable. Current treatments in the marketplace become
increasingly less effective as the disease progresses,
and do little to slow the increasing loss of dopamine
cells in the brain, one of the root causes of the
disease’s progression.”
http://www.uky.edu/PR/News/050211_parkinsons_treatment.htm
John Slevin, director,
Movement
Disorders Clinic,
University of Kentucky
LEXINGTON, Ky. (Feb. 11, 2005) -- University of Kentucky
researchers learned today that pharmaceutical
manufacturer Amgen Inc. has rejected a petition to
continue compassionate use of a drug that may
dramatically improve life for people living with
Parkinson’s disease.
Ten
Parkinson’s disease patients enrolled in a phase
clinical trial at UK experienced significant
improvements in their quality-of-life while undergoing
direct brain delivery of a natural brain protein known
as glial cell line-derived neurotrophic factor (GDNF).
The
results of the trial were dramatic. Patients who had
difficulty completing simple tasks before receiving GDNF experienced substantial function improvements during
therapy. UK was one of several international sites
testing the drug, and the results of the UK study appear
in the February issue of the Journal of Neurosurgery.
Despite the promising results of this clinical trial,
Amgen halted distribution and testing of GDNF, citing
safety and efficacy concerns. “The need for new, and
more effective, treatments is inarguable,” said
principal investigator Dr. John Slevin, professor in the
UK Department of Neurology and Department of
Pharmacology and director of the Movement Disorders
Clinic at UK. “Current treatments in the marketplace
become increasingly less effective as the disease
progresses, and do little to slow the increasing loss of
dopamine cells in the brain, one of the root causes of
the disease’s progression.”
“We are
very disappointed by Amgen’s decision,” said Don Gash,
the Alumni Chair in Anatomy and Neurobiology, professor
in the Department of Anatomy and Neurobiology, and
director of the M. Margrite Davis-Ralph E. Mills Magnetic Resonance Imaging and
Spectroscopy Center. “The optimal scenario at this point
would be for a third party organization to be allowed to
take this project to the next stage by providing GDNF to
patients as part of further clinical trials.”
UK
researchers involved in the study give three reasons to
continue the trials:
First,
one of the safety concerns cited by Amgen in
discontinuing the trials is the presence of focal cerebellar lesions after treatment with heavy doses of GDNF. However, the lesions were observed not in humans,
but in animal models, said Gash. The animals involved in
testing received much higher doses of the drug than is
used in the treatment of humans.
Second,
Amgen contends that benefits demonstrated during the
trial may be the result of a placebo effect. Gash says
that assumption is based upon a phase II study of GDNF in California, in which some of the patients receiving a
placebo also experienced improvements. While some
patients in the phase II trial showed a placebo
response, there was not a significant overall placebo
effect for the control group. Moreover, the phase I
study conducted by UK did not have a placebo control
group and was not blinded.
Amgen has reported the presence of antibodies to GDNF in some patients. However it is very common for antibodies to be
generated in patients in response to protein drugs like GDNF. Gash says it is difficult to predict what the
antibodies will do, but often they are harmless.
Researchers at UK have not seen adverse responses in
patients to the antibodies.
We are
increasing our testing of potential adverse effects of GDNF when large doses are used in animal models,” said
Greg Gerhardt, professor in the Department of Anatomy
and Neurobiology and Department of Neurology, director
of the UK Morris K. Udall Parkinson’s Disease Research
Center of Excellence, and director of the Center for
Sensor Technology. “These toxicity results should be
taken very seriously.
However, the varying results in the phase I and phase II
trials are the best argument for why further testing is
warranted, using methods similar to those employed in
the successful phase I human trial conducted at UK,”
Gash said. “The patients and families who have staked
their hopes, and indeed their lives, on the testing of
new treatments for debilitating diseases such as
Parkinson’s deserve nothing less."
February 3, 2005
RATIONALE FOR GDNF THERAPY
From Phase 1 and 2 clinical trial doctors
Don M. Gash,
Ph.D.1; John Slevin M.D.1; Steven Gill, Neurosurgeon2;
Michael Hutchinson, M.D., Ph.D. 3; Byron Young, M.D.1;
Greg Gerhardt, Ph.D. 1; Richard Penn, M.D. 4
1. University of Kentucky Medical Center;, 2. Frenchay Hospital, Institute of Neuroscience, Bristol England; 3. New York University
School of Medicine; 4. University of Chicago
http://www.gdnf4parkinsons.org/thedocsspeak.html
On September 1, 2004, Amgen decided to discontinue three
small ongoing clinical trials testing the continuous infusion of a human protein
(glial cell line-derived neurotrophic factor, GDNF) into the brain for the
treatment of advanced Parkinson’s disease in about 50 patients. The decision
was made because of concerns that had arisen about the safety and efficacy of
the drug. Many of the patients receiving GDNF felt that the drug was a
“godsend,” providing relief from the pain and suffering while promoting
significant improvements in their parkinsonian condition. Many of them have
adamantly expressed their desire to begin receiving the drug again. Many of the
investigators conducting the trials also feel that the drug has great promise.
The scientists and physicians listed above have provided this consensus
statement addressing concerns Amgen has about GDNF. We strongly support making
the drug available to the patients.
CONCERN: Alternative therapy to GDNF is available
for advanced Parkinson’s disease patients.
RESPONSE: GDNF has the potential to
revolutionize the treatment of Parkinson’s disease. In contrast to
other available therapies including Deep Brain Stimulation (DBS), GDNF promises
to significantly slow disease progression and promote restoration of function in
moderate to advanced Parkinson’s disease patients.
CONCERN: Gene therapy and stem cells are better
methods to deliver GDNF.
RESPONSE: Direct infusion of GDNF into the brain
is a technology that can be used today to treat hundreds of thousands of
advanced Parkinson’s disease patients. It is the bird in the hand. This is of
utmost importance for today’s advanced Parkinson’s patients and their families
as other methods for delivering the drug are five to ten years or more away.
By the time these methods are available, it will be too late for many. They
will be either dead or totally debilitated!
CONCERN: GDNF does not work. This has been shown
in a Phase 2, double-blind clinical trial.
RESPONSE: Efficacy of GDNF is directly related
to dose and tissue distribution. Infusion procedures using Convection
Enhanced Delivery to increase GDNF penetration into surrounding brain tissue
is crucial for the direct infusion approach to work properly. The methods used
in the two Phase 1 studies achieved this goal, with 15 out of 15 advanced
Parkinson’s disease patients showing significant functional improvements. The
Phase 2 study did not replicate the Phase 1 studies in these two key parameters.
CONCERN: GDNF is unsafe to give to patients.
RESPONSE: GDNF can be safely delivered within
the clinically effective dose range. Despite the fact that GDNF was safe
and well tolerated in the Phase 1 and 2 trials, two safety issues have arisen. Cerebellar toxicity was seen with very high doses of GDNF in rhesus monkeys and GDNF antibodies have been expressed in some patients. While they remain a
concern, it is important to place them in perspective. First and foremost, to
date none of the patients have shown evidence of cerebellar toxicity or
autoimmune symptomatology. Cerebellar toxicity in rhesus monkeys occurred
outside of the clinically relevant dose range. Antibody expression frequently
occurs with other proteins used to treat diseases of the brain, such as b-interferon therapy for multiple
sclerosis, without producing recognizable clinical autoimmune disease and
without precluding clinical treatment. While both safety issues dictate that
the patients receiving GDNF be closely monitored, further testing is needed to
determine their relevance, if any, in clinical treatment.
CONCERN: It is not economically feasible to develop
GDNF as a drug.
RESPONSE: Development of the direct infusion
approach for GDNF delivery is economically feasible because GDNF qualifies as an
“orphan drug” for treating a subset of persons with Parkinson’s disease.
This subset consists of non-demented patients with progressive, advanced,
life-threatening Parkinson’s disease. These patients may have pronounced ON-OFF
responses and debilitating side effects, such as hallucinations and dyskinesis,
to conventional anti-parkinsonian medications. The drug would have intended
effects for fewer than 200,000 people a year in the United States. It is
understood that companies must make business decisions about product
development. If Amgen decides not to continue to develop the intraputamenal infusion approach for GDNF therapy, they should license this approach to another
company that can take this promising therapy forward.
February 17, 2005:
University of Kentucky press release:
Press Release: http://www.uky.edu/PR/News/050217_parkinsons_treatment.htm
Researchers : Treatment Study Should Go On
Contact: Allison Elliott
In the wake of Amgen’s latest denial, researchers and patients are seeking a
third-party sponsor to provide the drug to the patients who already have
undergone surgery for GDNF delivery to the brain and want to continue treatment.
The Kentucky research team asks Amgen not to block progress on treating
Parkinson’s disease.
LEXINGTON, Ky. (Feb. 17, 2005) -- In a recently published study, University of
Kentucky researchers say a promising experimental drug actually appears to slow
the progress of Parkinson’s disease, unlike current treatments that only treat
the debilitating disease’s symptoms.
The progress shown in an early clinical trial of glial cell line-derived
neurotrophic factor (GDNF) is why the decision by the drug’s maker – Amgen – to
halt testing is so disappointing, UK researchers and patients who have been
taking the drug contended in a news conference today.
“We are very disappointed by Amgen’s decision,” said Don Gash, the UK Alumni
Chair in Anatomy and Neurobiology, professor in the Department of Anatomy and
Neurobiology, and director of the M. Margrite Davis-Ralph E. Mills Magnetic
Resonance Imaging and Spectroscopy Center at UK. “Parkinson’s is a debilitating
disease, and the patients and families who have staked their hopes and lives on
the testing of this treatment deserve better.”
However, Amgen’s decision to deny compassionate use, announced Feb. 11, 2005,
leaves patients cut off from the drug they say they need. In its decision, the
pharmaceutical company cited safety and efficacy concerns, but their data are
based upon tests utilizing animal models and dosing procedures that differ from
the successful UK study, contend Gash and fellow researcher Greg Gerhardt.
Gerhardt is a professor in the Department of Anatomy and Neurobiology and
Department of Neurology, director of the UK Morris K. Udall Parkinson’s Disease
Research Center of Excellence, and director of the Center for Sensor Technology.
In the Journal of Neurosurgery, UK researchers report that their open label
study of direct brain delivery of GDNF, a natural brain protein, demonstrates
the safety and potential efficacy of the procedure.
According to Gash, the best hope for the Kentucky patients to resume receiving
GDNF lies in the possibility of sponsorship of Phase 2 clinical trials by a
third party. UK was one of several international sites testing GDNF.
Researchers who oversaw the various successful human trials of the drug first
joined together in a request for compassionate use of the drug by those patients
whose lives had already been improved by GDNF. Though the FDA supported their
case, Amgen did not.
In the wake of Amgen’s latest denial, researchers and patients are seeking a
third-party sponsor to provide the drug to the patients who already have
undergone surgery for GDNF delivery to the brain and want to continue treatment.
The Kentucky research team asks Amgen not to block progress on treating
Parkinson’s disease.
“For science to advance, it is very important to continue studying the patients
who chose to resume GDNF treatment,” said Gash.
The University of Kentucky study expands upon an initial report on GDNF authored
by neurosurgeon Dr. Steven Gill and colleagues at the Frenchay Hospital in
Bristol, United Kingdom. The six-month Kentucky study was an FDA-approved, Phase
1 trial of 10 patients with advanced Parkinson’s disease. The Kentucky patients
were the first in the United States to receive direct brain delivery of GDNF.
The drug was delivered directly to patients’ brains via implanted pumps.
Patients received a fixed daily dose, increased at successive eight-week
intervals, followed by a five-week “washout” period during which GDNF was not
administered.
The results were positive. Patients who were unable to complete simple tasks
before receiving GDNF experienced substantial improvements in motor skills and
physical function during treatment. Twenty-four weeks after beginning GDNF
administration, patients’ scores on the Unified Parkinson’s Disease Rating Scale
(UPDRS) – the standard clinical measure of Parkinson’s – improved 34 percent in
the “off” and 29 percent in the “on” state, compared to a baseline measured
before GDNF treatment.
Although patients received GDNF to only one side of their brains, measures using
standard neurological tests showed improvements of 40 to 50 percent in fine
motor control and speed on both sides of their bodies, along with improvements
in posture stability and gait. All improvements of motor function continued
through washout. The only side effect, reported by two of the patients, was a
mild tingling sensation known as transient Lhermitte’s sign.
“GDNF appears to slow the loss of dopamine cells in the brain – a key factor in
stemming the progression of Parkinson’s disease,” said Dr. John Slevin,
professor in the UK Department of Neurology and Department of Pharmacology and
director of the Movement Disorders Clinic at UK. Slevin said, “Amgen contends
current treatments are therapeutically equivalent to GDNF, but the drugs now
available lose efficacy as the disease progresses, and do little to slow the
loss of dopamine cells.”
One reason cited by Amgen for the withdrawal of GDNF was the observation of
cerebellar lesions when large doses of GDNF were used in an animal model.
“None of the patients have shown evidence of cerebellar injury; it has only been
seen in animals. To understand what has happened, we are increasing our testing
of potential adverse effects of GDNF,” Gerhardt said. “These toxicity results
should be taken very seriously. However, we need to push forward and examine
whether the negative results are specific to animals. Further testing is
warranted.”
On Aug. 31, 2004, at the conclusion of the successful Phase 1 trial at UK,
patients decided to continue receiving GDNF as part of a Phase 2 clinical trial
sponsored by Amgen. The next day the drug manufacturer announced they would
discontinue all testing. The patients, who met each other for the first time
when they agreed to join the Phase 2 trial, have joined with patients from other
test sites in asking for continued use of the drug they say improved their
lives.
Journal Articles
on the Research:
Click here to
read Research History
Title: “Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease”
Location of Study: Frenchay Hospital, Institute of Neurosciences, Bristol, United Kingdom
Researchers : S.S. Gill, N.K. Patel, G.R. Hotton, K. O'Sullivan, R. McCarter, M. Bunnage, D.J.Brooks, C.N. Svendsen, P. Heywood
Published in: Nature Medicine, May 2003
Methods: Phase 1, open-label safety trial of GDNF pumped into an implanted catheter and delivered into the putamen of five Parkinson patients. Outcomes measured by UPDRS scores and PET scans that track dopamine production and use.
Results: “After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score.Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. PET scans showed a significant 28% increase of dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.”
Title: Improvement
of bilateral motor functions in patients with Parkinson disease through the
unilateral intraputaminal infusion of glial cell line-derived neurotrophic
factor.
Authors: Slevin JT; Gerhardt GA; Smith CD; Gash DM; Kryscio R; Young
B
Location of study : Morris K. Udall Parkinson's Disease Research Center of
Excellence, University of Kentucky.
Published in: Journal of Neurosurgery. 2005 Feb; Vol. 102 (2), pp.
216-22.
Methods: This Phase I, open label, safety trial studied 10 subjects
with moderate – advanced PD. A pump implanted in stomach continuously
infused GDNF directly to putamen area of the brain, through a tiny tube
connecting the pump with a small catheter implanted in the brain. Trial
began March 2002. Outcome measured by UPDRS scores.
Results: “ At 24 weeks, total Unified PD Rating Scale scores in on
and off states were improved 34 and 33% compared with baseline… Notably,
there appeared to be bilateral improvements, including improved balance and
gait and increased speed of hand movements, which continued through the
washout period.” Patients showed evidence of improved affect and fine motor
control.
Title:
Intraputamenal infusion of glial cell line-derived neurotrophic factor in
PD: a two-year outcome study.
Location: Frenchay Hospital, Institute of Neurosciences, Bristol,
United Kingdom .
Authors: Patel NK; Bunnage M; Plaha P; Svendsen CN; Heywood P; Gill
SS. Published in: Annals of Neurology. 2005 Feb; Vol. 57 (2), pp.298-302.
Method: The authors reported on a 2 year outcome study of
intraputamenal infusion of GDNF in five Parkinson’s patients, conducted at
Frenchay Hospital in Bristol, United Kingdom. The authors had previously
reported good results after 6 months of GDNF treatment.
Results: After 2 years of continual GDNF infusion there were “were no
serious clinical side effects and no significant detrimental effects on
cognition. Patients showed a 57% and 63% improvement in their off-medication
motor and activities of daily living subscores of the Unified Parkinson's
Disease Rating Scale, respectively, and health-related quality-of-life
measures (Parkinson's Disease Questionnaire-39 and Short Form-36) showed
general improvement over time.”
Related Issues
Dr. Hutchinson's Certification (Exhibit A) at the Suthers' trial (part
1)
Dr. Hutchinson's Certification (Exhibit A) at the Suthers' Trial (part
2)
Trial Participants' Responses
Grassroots' responses
PD orgs' responses.
Amgen's responses
