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Background Information on GDNF Ė A Timeline

The Parkinsonís community has closely followed the development of glial cell line-derived neurotrophic factor (GDNF) as a potential treatment for Parkinsonís disease. Here you will find a history of the experimental testing of GDNF in both animals and clinical studies, as well as explanation of the controversy surrounding the Phase II clinical studies that were halted in 2004.

GDNF Ė Animal Studies


Glial cell line-derived neurotrophic factor, or GDNF, was first identified in 1993. It is one of the most powerful naturally-occurring human factors known to nourish and foster the growth of dopamine-generating neurons. Soon after GDNF was identified, Dr. Don Gash and colleagues at the University of Rochester and later at the University of Kentucky showed that the injection of GDNF protein into both rat and monkey models of parkinsonism showed therapeutic promise.


Dr. Gash's work was soon followed by the first gene therapy trial of GDNF, conducted in a rat model by Dr. Martha C. Bohn and her colleagues at the University of Rochester. This seminal study, which was published in the journal Science in 1997, showed that continuous delivery of GDNF at low levels using a so-called "viral vector" was able to protect dopaminergic neurons from neurotoxin-induced cell death.


Drs. Jeffrey H. Kordower and Marina E. Emborg, along with their colleagues at Rush University Medical Center in Chicago and the University of Lausanne in Switzerland, conducted the first study of GDNF gene therapy in a monkey model. Their studies showed improved motor performance in the animals which received the GDNF gene (compared with animals that received no treatment). In the treated animals, parkinsonian symptoms were reduced, and, after the animals were sacrificed, the numbers of healthy dopamine neurons were found to be significantly enhanced. A summary of the findings was published in Science in 2000.

GDNF Ė The Investigation in Humans


While the animal studies were continuing, scientists began to examine how GDNF might work in humans. Based on the preliminary results of Dr. Gash's studies in rat and monkey models, Amgen initiated a human, randomized, double-blind trial of GDNF, led by Dr. Jay Nutt of the Parkinson Center of Oregon. The results, published in a 2003 edition of the journal Neurology, were disappointing; the treatment showed little benefit and several side-effects, confirming that benefit in animals does not necessarily translate to benefit in humans.

Some two years later, a British team conducted a follow-up study that greatly raised world interest in the promise of GDNF. In this study, led by Dr. Steven Gill and his colleagues at Frenchay Hospital in Bristol, scientists implanted catheters in the brains and pumps in the abdominal walls of five people with moderate Parkinson's. The pumps fed GDNF continuously into specific areas of the brain via the catheters at a precise rate of infusion. Within two months of the onset of the trial, all five patients showed improvements in "off" states comparable to their "on" states. Their motor skills continued to show improvement and even gait difficulties were eased. Brain scans documented the patients' progress while the dosage of anti-Parkinson's medications was steadily reduced. The results showed significant improvement in the functioning of the dopaminergic system.

The Amgen "Double-Blind" Trial


Impressive as the new data appeared to be, the Bristol trial did not provide an answer as to whether GDNF works. The reason is that it was of the so-called "open-label" variety, in which every participant received the treatment and some of them - human nature being what it is - may have imagined that they felt better than they really were. To correct for this factor, known as the "placebo effect," scientists try to confirm early data by conducting what is known as a "double-blind" trial, in which some patients are randomly placed on the treatment and the others are given a sugar pill. To test the validity of the British data, Amgen initiated such a trial for GDNF in 2003 with 34 patients.

Data from Double-Blind GDNF Trial Show No Clinical Improvement

July 2004

Amgen, Inc. announced on July 1 that its widely-watched clinical trial testing the efficacy of GDNF in treating advanced Parkinson's had failed to demonstrate any clinical improvement after six months of use.

The finding has surprised many because it seems to be at odds with the earlier, smaller "open-label" study in the U.K. that had suggested strong therapeutic potential for GDNF.

Amgen Halts GDNF Study

September 2004

On September 1, Amgen Inc. halted all clinical trials of GDNF. This decision was reviewed and agreed upon by the U.S. Food and Drug Administration (FDA), Health Canada (HC) and the Medicines and Healthcare Products Regulatory Agency (MHRA) in the U.K.

The announcement followed the mid-summer report that showed that Phase II trials of GDNF failed to demonstrate any clinical improvement after six months of use.

In addition to arguing that GDNF had not been proved efficacious, Amgen cited two reasons for discontinuing trials in the interest of participant safety. The first reason was found in pre-clinical data from non-human primates that had been treated in the highest dosage group for six months, followed by a three-month washout period. Researchers discovered a significant loss of specialized neurons in the cerebellum, which is a part of the brain involved in coordinating movement. This finding had not been seen before in any of the previous studies of GDNF.

The other major factor in the decision to stop the trial was the detection of ďneutralizing antibodiesĒ in two study participants. Antibodies are made by cells to defend the body against foreign material. Neutralizing antibodies could clear the body of the GDNF drug, as well as possibly reduce the bodyís natural supply of GDNF. It is unclear if such a reduction in natural GDNF is harmful, and researchers are still testing blood samples to determine the cause and risks of this phenomenon. Blood sample collections will continue for at least one year.

Michael J. Fox Foundation Stages "Scientific Summit" on GDNF

November 2004

At a meeting in Chicago in early August 2004, where the efficacy data on GDNF were announced, Debi Brooks, President and CEO of the Michael J. Fox Foundation for Parkinson's Research, offered to host a scientific summit on the subject. The summit, which was held in November, drew some 30 scientists from North American and European centers for Parkinson's research and concluded with a broad consensus that while GDNF remained a promising potential treatment, more animal studies should be done to assess the health concerns before any new human trials should be undertaken. This discussion did not address was what should be done about the 48 people in the U.S. and the United Kingdom who have participated in one of the Amgen-sponsored trials, several of whom have indicated that they wish to continue receiving the treatment. Most observers believe that the "risk-benefit" calculus for these people is different from what it would be for a new patient because all of them have already undergone the surgery necessary to participate in the trial, and several of them have been on GDNF for as long as three years. Representatives of this group have set up a website,

PDF Board of Directors Passes Resolution

January 2005

In late January, the PDF Board of Directors passed a resolution supporting the view that GDNF is potentially useful for the treatment of Parkinsonís disease and urges further investigation to explore and resolve the issues of safety and efficacy that have been raised in clinical trials to date. Click on the link below to read the full text of the resolution.

Amgenís Decision on Compassionate Use

February 2005

On Friday, February 12, 2005, Amgen, Inc. announced that it was denying a request by participants in trials of GDNF to continue receiving the treatment following termination of the trials.

Scientists and advocacy groups take issue with Amgen's decision

Several of the scientists who had served as investigators in the Amgen trials, including Drs. Michael Hutchinson of New York University, Don Gash and Greg Gerhardt of the University of Kentucky, Richard Penn of the University of Chicago and Steven Gill at the University of Bristol, England, have challenged Amgen's interpretation of both the efficacy and the safety data. As to efficacy, some have argued that the wrong statistical test was used, and that an alternative test would have showed GDNF to be effective. (Amgen, supported by several investigators including Drs. Jay Nutt of the Parkinson Center of Oregon and Anthony Lang of the University of Toronto, has held to its original opinion that the trials failed to show efficacy.)

As to the safety issues, some of the doctors have argued that Amgen has overreacted on both counts. The antibody issue, they say, is frequently seen in such studies and does not necessarily have any adverse effects on the health of the patient. They note that when the antibody findings first surfaced in the spring of 2004, Amgen seemed unconcerned by the data and would have continued with preparations for a larger-scale Phase III trial of GDNF, had the second wave of monkey data not come along.

As for the monkey data, some of these doctors point to evidence that suggests that the cerebellar damage was caused, not by the toxicity of the intervention, but by its precipitate withdrawal (six months into the trial). They also point out that the dose used for the monkeys was many times the doses used in human trials.

The reinstatement issue continues

While discussions continue concerning the long-term future of GDNF, the short-term issue of the patients who were in the trials to date remains unresolved. Some have indicated that they would like to go back on GDNF if the opportunity were to be offered, but several have now had their pumps and catheters removed.

Click on the link below to read the PDF reaction to Amgenís denial of access to GDNF for trial participants.

Trial Participants Take Legal Action for Access to GDNF

Spring 2005

Two lawsuits were brought against Amgen, Inc., the manufacturer of GDNF, by patients who participated in GDNF trials in New York and Kentucky. In both cases, judges ruled that Amgen was not required to continue distributing GDNF to the trial participants.

June 2005

A theme throughout the GDNF controversy has been the role of patients in clinical trials. In the June 11, 2005 issue of The Lancet, an editorial on the on-going court case regarding GDNF included the excerpt below:

This case highlights several important clinical issues, but chief among these is patient choice. Amgen reacted responsibly to potential safety risks of a treatment with uncertain benefit by stopping the trial. But in looking for a consistent effect among the population of participants, the company could not exclude the potential benefit of the therapy to some individuals. The fact that the case has ended up in the courts highlights the lack of a suitable mechanism through which evidence from individuals can be taken into account in decision-making about experimental treatments. The case also shows that although patient choice has become a mantra for health services, when it comes to setting the research agenda, patients have barely any involvement at all.

Source: Lancet Editorial: Patient Choice in Clinical Trials The Lancet; 6/11/2005, Vol. 365 Issue 9476, p1984

UK Experts Find Evidence of GDNFís Effects

July 2005

Researchers at Frenchay Hospital in Bristol, UK, found scientific evidence for the first time that the infusion of GDNF directly into the brain of a patient with Parkinsonís disease may induce the re-growth of dopamine nerve fibers. This information, published in the July 1 issue of Nature Medicine, was discovered through an autopsy of a 62-year-old man who had been involved in a GDNF Phase I study, and who died of a heart attack in December of 2004.

In the clinical trial, participants received an infusion of GDNF through a catheter directly to a part of the brain called the putamen. The autopsy of the former study participant, who received GDNF to the right side of his brain, revealed sprouting of nerve fibers in the vicinity of the catheter tip. According to the autopsy, the dopamine fibers infused with GDNF occupied an area five times larger than corresponding fibers on the other side of the brain, which had not received GDNF treatment. The researchers state that the increase in dopamine fibers was linked to this patientís sustained clinical benefit and the improved dopamine imaging studies that had been performed during the clinical trial.

GDNF on 60 Minutes

September 2005

On Sunday, September 11, the CBS television newsmagazine 60 Minutes aired a program on the controversy surrounding Amgenís decision to halt recent clinical trials of GDNF for the treatment of Parkinsonís disease. The segment featured the patients who participated in the trial and their families, as well as a bioethicist who was consulted on the Amgen decision. The program directed a public spotlight on the complex process of drug development, including the rights and roles of manufacturers, regulators and the trial participants on whom the entire process of clinical trials depends.

A group of Parkinsonís community leaders, including members of the Parkinson Pipeline Project, People Living With Parkinsonís and Grassroots Connection, are using the 60 Minutes story to build support for a national drive to raise awareness of the issue and generate support both for the GDNF trial participants and for a commitment to serious future research on the potential of GDNF and other growth factors to help people with Parkinsonís. They have organized a network of leaders in dozens of communities and have prepared materials for use by local activists, speakers and people who want to write letters to the editors of their local newspapers.

Source Date: Sep 08 2005