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Trial of New PD Treatment Halted: Some Patients and Advocates Protest

By Robin Elliott

On Friday, February 12, Amgen Inc. announced that, after much internal hand wringing, it was denying a request by participants in trials of a molecule known as GDNF, an experimental Parkinson's treatment, to continue receiving the treatment following termination of the trials.

California-based Amgen, the world's largest biotechnology company, had abruptly concluded its own double-blind trial almost six months earlier, saying that the treatment had not been shown to be effective and citing safety concerns in two areas. In one of these, several subjects were found to have developed antibodies that could potentially attack the body's own GDNF, a naturally occurring product that is essential for the production of dopamine, the chemical messenger that is deficient in Parkinson's.

The other safety concern came out of a separate trial involving monkeys. It turned out that a few of the animals were found to have evidence of lesions in the area of the brain known as the cerebellum.

Several leading 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. (Indeed, 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 the human trials.

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

What 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 - - which has be-come a rallying-point for the Parkinson's community.

Not surprisingly, Amgen's February announcement was especially galling to this group - many of whom had written personal letters to Amgen pleading for reinstatement of GDNF. They were backed by several of the community's advocacy groups, including the Parkinson's Disease Foundation, the Parkinson's Action Network and the Parkinson Pipeline Project.

To understand how GDNF got to this point, we need to look at the scientific history of the molecule.

GDNF - The trials and tribulations of a promising Parkinson's treatment
Glial-cell line-derived neurotrophic factor, or GDNF, 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 in 1993, Dr. 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, picked up the ball by conducting 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.

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. Nutt. 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. 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 continuously fed GDNF into specific areas of the brain via the catheters at a precise rate of infusion. All five patients showed improvements in "off" states comparable to their "on" states within two months of the onset of the trial. 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.

As reported by Dr. Lang at a meeting of the American Neurological Association in October, 2004, the study did not prove the efficacy of GDNF. The investigators judged the patients' "off" periods to be somewhat improved, but saw no improvement in "on" periods.

The uncertain future of GDNF
Dr. Clive N. Svendsen of the University of Wisconsin (co-investigator in the Bristol study), as well as other investigators involved in GDNF research, has suggested that the studies' dissimilar results may have been a consequence of the different dosages used, as well as by the different sizes of the catheters used to infuse the treatment.

Dr. Bohn says she is encouraged by the Bristol results but believes that a delivery system utilizing gene therapy rather than infusion via catheter may ultimately be safer (since it does not require the administration of live virus to the brain) and may offer a better long-term outcome for patients. Dr. Svendsen agrees, and suggests that another potential delivery technique might be the implantation of genetically-engineered stem cells that could in turn release GDNF.

Dr. Svendsen also reports that he and other study participants are meeting with Amgen to analyze the differing results of the studies to date and to seek consensus on whether and when there will be further studies of GDNF. Meanwhile, additional animal studies are being pursued.

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. Voluntary organizations such as PAN and PDF are continuing to explore options of persuading Amgen to reconsider its position. In the words of a recent open letter from leaders of the Parkinson Pipeline Project, a group of patient advocates: "[Reinstatement] is important not only to today's patients but to our prospects of being able to recruit sufficient numbers of people for future trialsÖ[without people to participate] all of us - companies as well as patients - will be the losers."

Robin Elliott is the Executive Director of the Parkinson's Disease Foundation.