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Overview of GDNF

What is GDNF?

Glial cell line-derived neurotrophic factor (GDNF) is a naturally occurring protein found in the brain, believed to nourish and promote the growth, regeneration and protection of dopamine producing neurons.

In 1993, Frank Collins, Leu-Fen Lin and their colleagues at Synergen Corporation used recombinant DNA techniques to produce a synthetic form of GDNF. It was thought to hold great promise for treating Parkinson’s disease. At the end of 1994, biotech company Amgen Inc. acquired Synergen, and its patent for synthetic GDNF. Because GDNF does not cross the blood-brain barrier, it cannot be given orally or by subcutaneous injection. Therefore other types of delivery systems needed to be developed and tested.

Topics on this page:

Pre-Clinical Studies

Pre-clinical research led by Drs. Don Gash, Greg Gerhardt, John Slevin and colleagues at the University of Kentucky indicated that the injection of Amgen’s synthetic GDNF showed therapeutic promise when injected into the brains of both rat and monkey models of parkinsonism. According to Dr. Slevin, “GDNF appears to slow the loss of dopamine cells in the brain – a key factor in stemming the progression of Parkinson’s disease.” (1)

Other promising pre-clinical research studies were conducted by Dr. Martha Bohn, at the University of Rochester, using viral vectors (genetically engineered viruses) to deliver GDNF into the brain. Dr. Jeffrey Kordower, and 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. At the University of Kentucky’s Udall Center, Dr. Gash’s team achieved good results using a pump delivery system with advanced parkinsonian monkeys.

Clinical trials


As a result of promising pre-clinical studies, in 1996, Amgen initiated and along with Medtronic (manufacturer of the pump delivery system) helped fund a combined Phase I / II multicenter, randomized, double-blind, placebo-controlled, dose-escalation trial of GDNF. Dr. J. Nutt at the Oregon Health and Science University was the principal investigator. GDNF was delivered by monthly injections into the brain through a surgically implanted shunt. The study concluded that GDNF did not improve Parkinson’s symptoms, and caused troublesome side effects. The researchers hypothesized that the GDNF molecules may have been too large to move from the brain ventricles to the targeted brain tissues in the putamen and substantia nigra. (2) Amgen halted its research with GDNF in April 1999.

In early 1999, Dr. Michael Hutchinson at New York University and Dr. Gash noted that the ventricle may not have been the appropriate target, and that the catheter tip should be in the tissue of the brain itself, in particular a structure known as the putamen. Dr. Gash and colleagues then performed an experiment where four parkinsonian monkeys had pumps implanted and catheters inserted into the putamen. Two monkeys received saline infusion and two received GDNF. At the end of four months, the monkeys receiving GDNF had largely recovered. After the monkeys were sacrificed their brains were examined for signs of toxicity. None were found. This study reawakened interest at Amgen.

Bristol, United Kingdom Phase I Study

A Phase I trial began in 2001, under the direction of neurosurgeon Steven S. Gill at the University of Bristol Institute of Clinical Neuroscience at Frenchay Hospital in the United Kingdom GDNF was directly infused into the putamen by a pump delivery system. Catheters were inserted into the brain, and GDNF was delivered from pumps implanted in the abdomen.

According to researchers, “Within a couple of months, patients were noticing dramatic improvements in their ability to move, and these continued over almost four years of treatment. Even after ceasing medication, the patients’ improvement has been maintained.”(3)

Dr. Michael Hutchinson of New York University related that videotapes of the patients taken before and after treatment were “quite amazing.” One patient initially "took five minutes to walk across a room.” After three months of infusion, “he jumps up and walks back and forth.” (4) After one year in this 2001 Phase 1 safety trial, patients averaged a 40 percent improvement in their symptoms with no serious side effects, reduced dyskinesia, and a 28 percent increase in the amount of dopamine stored in their brains.

In 2002, another Phase I trial was initiated using unilateral direct infusion of GDNF with 10 patients at the University of Kentucky, led by Dr. John Slevin. As in the Bristol trial, researchers and the patients reported positive results.

“… Notably, there appeared to be bilateral improvements, including improved postural stability, which continued through the washout period. All patients with PD also showed evidence of improved affect and fine motor control and speed.”(5)

Amgen Phase II study

After the favorable results in the Bristol trial in 2003, Amgen, which had donated the GDNF, stepped in and volunteered to sponsor future phases. The company initiated a multicenter, placebo-controlled trial that included 34 patients, all of whom had a pump-and-catheter delivery system implanted. Half the participants, however, received only saline solution for the first 6 months, and were then switched to GDNF.

Inexplicably, Amgen’s methodology differed from that of the successful phase I trials. The company used larger catheters and a different type of pump (a continuous rather than pulse delivery), and smaller doses of GDNF. Trial participants again reported improvements in their symptoms. After a 6-month analysis of the trial data, however, Amgen in June 2004 reported that improvements in symptoms were not statistically significant, and attributed them to the placebo effect. Even so, Amgen announced that all subjects would be entered in an open label extension study to try to resolve the differing trial results.

Amgen halts all GDNF trials and treatments

On September 1, 2004, however, Amgen abruptly halted the trials and withdrew treatment from participants in all of the study groups. Amgen cited lack of efficacy, and safety concerns, specifically indicating brain autopsies of some of the nonhuman (primate) subjects revealed damage in the cerebellum. It was later learned that the primates had received much higher doses than the human participants. Amgen also announced that GDNF neutralizing antibodies were found in five study participants, and these might lead to a reduction of naturally occurring GDNF in the brain. The Amgen study was initially reported on at the annual meeting of the American Neurological Association conference in October, 2004.

Some of the Phase II trial doctors, including the University of Kentucky team, Dr. Hutchinson of NYU, and Dr. Penn at the University of Chicago, did not agree with Amgen’s conclusions, nor with their safety concerns, and continue to question the statistical tests and methods used in the Phase II trials

According to Dr. Hutchinson, “Although the double-blind trial of GDNF failed to meet its preset endpoints…there was a strong signal suggestive of drug efficacy. This explains why Amgen continued to prepare for a proper Phase III study even after announcing phase II results. The present formulation of GDNF is safe and also very probably effective.”

“There is overwhelming evidence that the lesions [in the monkeys] were caused by abrupt withdrawal from very high concentrations of GDNF, not direct toxicity.” Furthermore, “we have it on good authority that senior officials at Amgen, who were in a position to speak authoritatively on this topic, did not consider the antibodies problematic.” (6)

Additionally, University of Kentucky researchers stated they “have not seen adverse responses in patients to the antibodies.”(8) All ten patients with advanced Parkinson’s disease experienced substantial improvements in motor skills and physical function during UK’s study. Improvements continued through washout. The University of Kentucky researchers agreed that the lesions in monkeys were likely caused by sudden withdrawal from high doses of GDNF and this is “consistent with confidential information that Amgen has not released.”

Dr. Stanley Fahn of Columbia University and Robin Elliott, Director of the Parkinson’s Disease Foundation, also disagreed with Amgen’s actions stating, Amgen's “decision is a mistake because it denies the patients and their doctors the opportunity to continue with a potentially useful, albeit yet unproven, treatment, and it denies us all the opportunity to gather more scientific data about the long-term effects of GDNF.” (9)

Trial participants appeal to Amgen for Compassionate Use of GDNF

Many of the trial participants were devastated both physically and emotionally by the withdrawal of GDNF. They pleaded with Amgen to reinstate the treatments that many found so beneficial. Amgen refused. Trial participants and their family members formed GDNF 4 Parkinsons – an organization whose goals are to (1) seek compassionate use of GDNF for the trial participants and (2) encourage continued research of GDNF for all people with Parkinson’s.

Patient advocates had been following the development of GDNF for many years.  Based on prior work with the company, the Parkinson Pipeline Project (PPP) began to ask questions about the equivocal results from the reports of the study and sought explanations of the company's decisions that did not seem to fit the data.  These original questions about study design and analysis which have not yet been answered satisfactorily to explain the company's actions have become the foundation of PPP’s  consistent advocacy for restarting GDNF research, especially as more contradictory information has filtered out from the study.  This bigger picture perspective reinforced and amplified the arguments of the study participants.

A campaign to support the trial participants and their mission was initiated in October 2004 by grassroots advocates from the Grassroots Connection, Parkinson Pipeline Project and People Living with Parkinson’s. This grassroots effort has been joined by the Parkinson’s Disease Foundation, Parkinson’s Action Network and individual patient advocates.

FDA gave green light for trial to continue – Amgen refused

At the request of several of the investigators selected by Amgen to conduct the Phase II placebo controlled trial, a meeting was held by the Food and Drug Administration (FDA) in January 2005 to review the safety and efficacy data and revisit Amgen’s September 1 decision to halt the trial. Amgen has never publicly revealed that at the end of this meeting, the FDA “did not see any reason why the current patients could not continue to receive the drug in extended treatment, as long as the study was well-organized and coordinated, and included more extensive monitoring of the patients…” (17) Amgen would have had to agree to supply the GDNF, but they did not.

The Legal challenge

Trial participants filed lawsuits in New York and Kentucky federal courts requesting Amgen reinstate their treatments. Patients were represented at both pre-trial hearings by attorney Alan Milstein, whose practice focuses on medical research law. The judges in both cases considered only the contractual issues of the informed consent documents and ruled in favor of Amgen. Appeals have been filed. An interview with Mr. Milstein with more information on the legal challenges can be found at: http://grassrootsconnection.com/milstein.htm (no longer online).

New research developments

The brain autopsy of one of the Bristol study participants, who died of an unrelated heart attack in 2005, revealed that dopamine-containing nerve fibers lost in Parkinson’s disease had sprouted back in the region where GDNF had been infused. Because the GDNF had been infused into one side of the brain only, the effects of the treatment could be assessed by comparing the two sides.

“This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibers, in association with a reduction in the severity of Parkinson’s,” stated Dr. Seth Love, who studied the tissue. (10)

This is also the first time any potential treatment has been shown to halt disease progression and possibly reverse the loss of nerve fibers in Parkinson’s.

In August 2005, the University of Kentucky researchers reported on a primate study that concluded that in parkinsonian monkeys, GDNF was effective in promoting recovery of dopamine producing neurons and improved motor functions, and that optimal distribution of GDNF into the brain increased the efficacy of the treatment . Multiport catheters using pulse delivery to distribute GDNF in the brain were the most effective. (11)

The successful human Phase I trials at the University of Kentucky had also utilized multiport catheters. The successful human Phase I trial at Frenchay Hospital in Bristol, UK utilized the smallest catheter and pulse delivery of the GDNF. However, in Amgen’s Phase II human trial, a single port, constant delivery system was used instead. (12)

Additionally, when the catheters were removed from the four Phase II trial participants who had developed antibodies it was found that at least one of their catheters had dislodged and slipped out of the brain, resulting in GDNF being pumped into areas of the body outside of the brain, possibly explaining the formation of antibodies in these patients.

Many questions remain, especially why the successful pump catheter systems utilized in the two Phase I trials were not utilized in the Phase II trial. Indeed it was reported that Dr. Clive Svendsen, one of the Bristol UK researchers, had advised Amgen to use the Bristol pump / catheter system, and had a disagreement with the company because Amgen “wanted to use thicker-and potentially more damaging-catheters.” (7)

“The varying results in the Phase I and Phase II trials are the best arguments for why further testing is warranted, using methods similar to those employed in the successful UK’s Phase I human trial,” states Dr. Gash. (8) “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 (who already have undergone surgery for GDNF delivery to the brain) as part of further (phase II) clinical trials (8)…. For science to advance, it is very important to continue studying the patients who chose to resume GDNF treatment. (1)

According to Dr. Clive Svendsen, “GDNF acted on the patients' remaining neurons like a tonic on a wilting plant: GDNF restores the neurons, makes them sprout, and suddenly they look healthy and happy.” (4)

These studies offer great hope to all Parkinson’s patients. GDNF delivery by infusion pump is a method that is currently viable. Other delivery techniques using gene therapy and stem cells are being investigated and offer promise for the future, but the use of these treatments in humans is likely years away. Given the typically long development times for any new therapy, resuming research on GDNF infusion may be the best last hope for the current generation of PWP.

Expressing his disappointment that GDNF was pulled so abruptly from clinical trials, University of Chicago neurologist Arif Dalvi “ believes there were many reasons to continue investigating GDNF. ‘Especially since there is no alternative… Nothing can come close." (13)

University of Kentucky to continue animal research

In September 2005, the University of Kentucky Morris K. Udall Parkinson's Disease Research Center of Excellence announced it was awarded “nearly $6 million from National Institutes of Health and National Institute of Neurological Disorders and Stroke to continue work on the promising drug glial cell line-derived neurotrophic factor (GDNF) and similar compounds.”

While this grant will help advance further pre-clinical research, it will not bring about the reinstatement of human clinical GDNF trials, because currently Amgen will provide GDNF for animal research only.

A Cure interrupted?

“Cure Interrupted” – the 60 Minutes report of the halt of the GDNF trials, aired on September 11, 2005. Phase II trial participants Roger Thacker and Robert Suthers and their families, Dr. John Slevin, and patients’ lawyer Alan Milstein were among those interviewed.

Amgen executives did not respond to 60 Minutes’ requests for an interview, however the following statements might shed light on the company’s decision-making. Arthur Caplan, a bioethicist consulted by Amgen, stated that Amgen’s decision to halt treatments was largely due to fear of being sued.

60 Minutes also included a taped statement from a speech made by Amgen's vice president of research, Roger Perlmutter. Found on the Internet, the speech was given while Amgen's phase II GDNF trial was still under way. Perlmutter stated: " This is not a therapy from our perspective that is going to be a huge moneymaker for Amgen."

60 Minutes also reported that, “Shortly after halting the trial and withdrawing all GDNF treatment from patients, Amgen applied for a new patent on a different form of GDNF that could potentially be delivered in a more economical capsule form. “ (14) Transcript of the report is available online at: http://www.cbsnews.com/stories/2005/09/08/60minutes/main828098.shtml

A video excerpt of the interview is available on-line at: http://www.youtube.com/watch?v=N5vm4ZoCmUA

Editorial in The Lancet Neurology (December 2005)

An editorial in the prestigious British medical journal, The Lancet Neurology supported advocates’ arguments for compassionate use for trial participants and for reanalyzing the Phase II data, for both medical and ethical reasons:

“Amgen should be praised for taking a prudent decision, in so far as it is rooted in scientific evidence and ethical reasoning. However, the company will gain further respect from the medical and patient communities by reanalysing their data… Even if, once they are published, the phase II trial data convince investigators of the drug’s lack of efficacy, there are still important methodological issues worth exploration… If Amgen sticks to its decision not to initiate a new study, this should not prevent the company from reconsidering the provision of GDNF on a case-by-case basis, allowing the compassionate treatment of those with exceptional needs who have participated in former trials. The case highlights the ethical complications introduced by the documents that legally give power to a sponsor over the direction of a study despite, as in this case, the opinion of some of the academic principal investigators.” (16)

Phase II trial results published

After being rejected by both Nature and The New England Journal of Medicine, Amgen’s Phase II study was published online in Annals of Neurology (Jan. 26, 2006), and data from the Amgen trial was finally revealed to other scientists and the public.

The article reported “…this 6-month, randomized, controlled study did not detect the anticipated 25% improvement in UPDRS off-motor scores despite improvements in putamen 18F-dopa uptake… using a dose of 15g liatermin/putamen/day in patients with moderate to severe Parkinson's disease. “ (15). (note: Liatermin is the synthetic GDNF produced by Amgen.)

It also states, “... It is not clear at this time whether higher doses, differences in catheters (diameter size, number of ports), or infusion methods (constant versus additional boluses) could result in different physiological effects than obtained over the 6 months of this double-blind trial. Indeed, one patient coming to autopsy after 43 months of unilateral infusion in the first open trial showed evidence of increased tyrosine hydroxylase immunopositive nerve fibers in the infused putamen...” (15)

The long-term implications of Amgen’s safety issues claims “… remain unknown; however, all of these patients remain asymptomatic.” The authors conclude that, “We cannot exclude the possibility that significant benefit could be obtained with improved distribution and/or higher doses of liatermin delivered for longer periods of time. Further dose-ranging and randomized, controlled studies with GDNF treatment are necessary, if the safety issues can be resolved, although additional preclinical experimental studies will probably be required to address outstanding technical questions before further human trials could proceed. “ (15)

Update February 2006

Seventeen months have gone by since all GDNF trials and treatments were halted by Amgen. The technology to deliver GDNF by infusion method could be available for Phase III clinical trials now. In comparison, other GDNF delivery methods such as gene therapy or stem cells will require many more years of development. There has been no news of Amgen conducting further studies on the claimed safety issues. There has been no news of resuming a well-designed clinical trial. The company continues to stonewall the pleas of trial participants for compassionate use of GDNF, and their conditions continue to worsen. Indeed Parkinson’s patients throughout the world continue to suffer and die, as our diseases relentlessly progress, and as we continue to hope and wait for word that Amgen will allow GDNF research to resume.

Continue the Research!

Researchers at the University of Kentucky report on the status of GDNF trial participants one year after Amgen halted all GDNF trials. Below is the PubMed abstract, followed by the researchers conclusion that “additional Phase II clinical trials are warranted to continue developing the approach featuring intraputaminal delivery of trophic factors for treating PD.

Full text of the article (including video clips of a participant before and after treatment with GDNF)

Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal.

Slevin JT, Gash DM, Smith CD, Gerhardt GA, Kryscio R, Chebrolu H, Walton A, Wagner R, Young AB. Neurosurgical Focus. 2006 May 15: 20 (5): E1

PubMed abstract:

Object: "Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months was previously shown to improve motor functions and quality of life measures significantly in 10 patients with Parkinson disease (PD) in a Phase I trial. In this study the authors report the safety and efficacy of continuous treatment for 1 year or more. After the trial was halted by the sponsor, the patients were monitored for an additional year to evaluate the effects of drug withdrawal."

Methods: "During the extended study, patients received unilateral intraputaminal infusion of 30 mg/day GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 ml/hour. The Unified PD Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38%, respectively, in the “off” and “on” states. Motor UPDRS scores were also improved: 45 and 39% in the off and on conditions, respectively."

"Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted. At that time, the patients had returned to their baseline UPDRS scores and required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of the risk of infection. In seven patients antibodies to GDNF developed, with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing. "

Conclusions: "Unilateral administration of GDNF results in significant, sustained bilateral benefits. These improvements are lost within 9 months after drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed."

PMID: 16711657

Researchers’ Conclusions:
  • "The results from 1-year intraputaminal GDNF infusion in our study are consistent with extensive animal data and the Bristol Phase I trial results, in which it has been stated that trophic factor treatment can be both protective protective and restorative.

  • The recent inconclusive Phase II results may be the result of differences in GDNF dosing and delivery protocols.

  • The two safety issues with GDNF-development of antibodies to exogenous GDNF and possible toxic injury to the cerebellum in nonhuman primates-require further study. In this patient group, however, neither clinical manifestations in response to GDNF antibodies nor clinical or imaging evidence of cerebellar lesions were evident.

  • Given the following three considerations:

    • that advanced PD is profoundly debilitating and life-threatening;

    • known safety concerns can be closely monitored and medically managed; and

    • methodology used in both Phase I trials shows strong indications of efficacy, we believe that additional Phase II clinical trials are warranted to continue developing the approach featuring intraputaminal delivery of trophic factors for treating PD."

August 10, 2006
New paper challenges statistical design and conclusions of Amgen’s Phase II GDNF study

A detailed statistical analysis finds the Amgen-sponsored study was underpowered, and therefore, "incapable of concluding anything meaningful about the effect of GDNF on Parkinson’s Disease."

Patients have the most to lose from these Type II errors in clinical trials. Effective interventions that incorrectly appear ineffective can lead to effective treatments being overlooked or shelved, as was the case for infusion delivery of GDNF.

The statistical analysis in this instance was conducted by Dr. Michael Hutchinson, NYU Medical School, Susan Gurney, Columbia University School of Public Health, Dept of Epidemiology, and Dr. Roger Newson, biostatistician at Imperial College, London.

Pub Med Abstract:

Journal of  Neuroscience Methods. 2006 Jul 27; [Epub ahead of print]
GDNF in Parkinson disease: An object lesson in the tyranny of type II.

Hutchinson M, Gurney S, Newson R. Department of Neurology, New York, NY, USA
University School of Medicine, 400 E. 34th Street, Suite RR 311, New York, NY, USA

"Type II errors may be having a significant impact on drug discovery. This is of particular importance in the clinical neurosciences, where endpoints are often subjective scores of disability rather than unequivocal events such as survival. Here we examine a recently published study [Lang AE, Gill S, Patel NK, et al. Randomized controlled study of intraputamenal glial cell-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006; 59:459-66] in an area of immense importance to neuroscience. This small study found no detectable clinical benefit from infused intraputamenal GDNF as a treatment for Parkinson disease. However the standard deviation of the accrued data turned out to be considerably higher than had been anticipated in the power analysis performed prior to the study. In order to determine what impact, if any, this had on the conclusions that could be drawn, the actual data were analyzed by means of both the t-test and the rank-based Somers'D.  The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease. It therefore does not contradict the large effects seen in previous open-label studies."

PMID: 16876872 [PubMed - as supplied by publisher]

Updated Summary of GDNF Research (AUGUST 2006)

Since the announcement of the GDNF Phase II six-month trial results and the subsequent halt by Amgen of  the  trial and of treatments to all trial participants,  three issues have been raised.

  1. The study failed to meet its clinical endpoint, which was a 25% improvement in UPDRS scores after 6 months.

  2. Some patients developed antibodies to GDNF. 

  3. Four trial monkeys developed cerebellar lesions.

All of these -- the trial design, the statistics, and the safety issues -- have since been challenged. Additionally, important data held by the sponsor has not been released to the scientific community and the public, in opposition to the principle of transparency in biomedical research.

A reappraisal is needed of the new evidence that has been accumulating since the scientific summit meeting on GDNF in October 2004.

Safety issues:

  1. Brain lesions found in monkey brains of experimental primates were cited by Amgen as the primary reason to halt GDNF trials and treatment in August 2004.  On the request of several study doctors, the FDA reviewed these findings in January, 2005.  Reports from that meeting indicate that FDA agreed to allow the existing GDNF participants to continue in the study, and recommended additional analyses before proceeding with new subjects.  It is believed that  lesions were seen only in monkeys that had been abruptly withdrawn from very high doses of GDNF. But Amgen has not released their monkey toxicology data, that could prove or disprove this explanation. The company claims to be preparing an article for publication (now 2 years later). 

  2. In the May 2006 issue of Neurosurgical Focus, however, researchers at the University of Kentucky confirmed that there has been no brain damage or long term side effects among their trial patients, and that they believe the research should continue. “There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing…. Safety concerns with GDNF therapy can be closely monitored and managed.” (16 )

  3. In related investigations, the University of Kentucky researchers  also reported in the April 2006 issue of Experimental Neurology, that they found "no imaging evidence of cerebellar injury in human subjects undergoing intracerebral GDNF infusion." (17 )

  4. Indeed, according to Richard Penn, one of the Phase II trial doctors, “no clinically significant adverse effects were ever seen in patients from either phase, some of whom took GDNF for 3 years.” (18)

  5. The other key safety issue regarding development of antibodies by several participants was known at the time the initial results were released.  Although this was a concern, no harmful effects from this condition were seen for GDNF or for other treatments where it has occurred.  It is likely the antibodies occurred only in patients whose catheters became dislodged during the course of treatment - a problem that could be easily remedied.  These patients were not getting the GDNF into the brain; instead it was being pumped into other parts of the body.  This data has not been made available to the public by Amgen

Pathological Evidence

The brain autopsy of one of the Bristol study participants, who died of an unrelated heart attack in 2005, revealed that dopamine-containing nerve fibers lost in Parkinson’s disease had sprouted back in the region where GDNF had been infused. “This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibers, in association with a reduction in the severity of Parkinson’s,” stated Dr. Seth Love, who studied the tissue. This is also the first time any potential treatment has been shown to halt disease progression and possibly reverse the loss of nerve fibers in Parkinson’s. (19 )

Statistical analysis:

The statistical analysis and conclusions of the Amgen phase II study (Lang, et.al) (15)  have now  been challenged  by Hutchinson et. al.  in the Journal of Neuroscience Methods.

“The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease… The study in no way contradicts the large clinical benefits seen in previous open-label studies … Furthermore there is no suggestion whatsoever of a significant “placebo effect.” (20)

In the same issue of the Journal of Neuroscience Methods,  Meacham, et.al. argued against the above conclusions ,” in part because they are based on post-hoc power calculations…” and  stated the “conclusions drawn in the original paper remain scientifically sound.” (22)

Study design:

In the Lang article itself inconsistencies were noted between the Phase I trials and the Amgen Phase II trial -- different GDNF dosages, catheters (diameter size, number of  ports), and infusion methods (constant versus pulsed), which it was admitted, may have accounted for differing outcomes.(15) In a review of the Amgen study, Dr. Roger Barker states “… this trial has not shown any efficacy for methodological rather than scientific reasons.” (21) 

The study outcome should have been described as “inconclusive,” rather than “negative” and further trials should have been initiated.


Amgen’s 12 month data on the Phase II study has also not been released. However, researchers at the University of Kentucky reported on the status of GDNF trial participants one year after Amgen halted all GDNF trials.  They concluded that  “unilateral administration of GDNF results in significant, sustained bilateral benefits.. . The results from 1-year intraputaminal GDNF infusion in our study are consistent with extensive animal data and the Bristol Phase I trial results, in which it has been stated that trophic factor treatment can be both protective  and restorative. …

Given the following three considerations:

  1. that advanced PD is profoundly debilitating and life-threatening;

  2. that the known safety concerns can be closely monitored and medically managed; and

  3. that the methodology used in the two Phase I trials shows strong indications of efficacy, we believe that additional Phase II clinical trials are warranted to continue developing t

  4. the approach featuring intraputaminal delivery of trophic factors for treating PD.” (16)

UPDATE: November 2007

The University of Kentucky Continues  to Analyze GDNF  Research.

In, “Point Source Concentration of GDNF May Explain Failure of Phase II Clinical Trial,” published in Experimental Neurology (Dec. 2006), the University of Kentucky researchers analyzed the distribution of GDNF in monkey brains using  Amgen’s Phase II delivery system and infusion protocol. They concluded :

“Optimizing trophic factor distribution in target tissue is a critical variable for achieving efficacy. The distribution of GDNF seen in the present study appears to be marginal for human therapy. While further studies are needed, the data to date support the working hypothesis that the delivery protocol and catheter used in the phase 2 GDNF intraputamenal infusion study was a principal component contributing to the failure of this clinical trial to replicate the results of numerous animal studies and the two phase 1 trials…. “The point source concentration of GDNF in the rhesus monkey striatum using the phase 2 catheter indicates that drug bioavailability may have been limited to 2–9% of the putamen in human subjects…”

“ …The results in this study do not implicate the passage of GDNF from the brain into the circulation as the primary route for inducing antibody responses. The induction of GDNF antibodies may come from other sources, such as refilling the subcutaneously implanted pump or leaks in the delivery system.” (23)

Additionally Morrison, Lonser, and Oldfield reported in the Journal of Neurosurgy ( July 2007) that they performed  “Computational examinations of the effects of differing catheters, infusion rates, infusate concentrations, and target placement on distribution …based on the protocols “ of the two phase I and the Phase II GDNF trials.

They concluded,  “Results of these computations indicated that for catheters placed exactly on the intended target, ideal drug distributions were similar for two of the trials (AmgenUT and Bristol) and different in terms of location and extent in the third study (Kentucky); yet the pattern of trial outcomes did not reflect these same groupings. This finding suggests that other factors are at play, widely varying statistical power and the possible effects of not excluding data from patients who experienced large drug losses across gray tissue boundaries due to variation in catheter placement.” (24)


1. Researchers: Treatment Study Should Go On. University of Kentucky news release, February 17, 2005. Retrieved online http://www.uky.edu/PR/News/Archives/2005/Feb2005/050217_parkinsons_treatment.htm

2. Nutt JG, Burchiel KJ, Comella CL, Jankovic J, Lang AE, Laws ER Jr, Lozano AM, Penn RD, Simpson RK Jr, Stacy M, Wooten GF; ICV GDNF Study Group. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology, 2003 Jan. 14; 60(1):69-73 .

3. Experimental treatment shown to reverse the loss of nerve fibres in Parkinson's Disease. Retrieved online. News-Medical.Net, July 6, 2005.

4. Wade, Nicholas. Promising Results Are Seen in Small Parkinson's Trial. New York Times, April 8, 2003.

5. Slevin JT; Gerhardt GA; Smith CD; Gash DM; Kryscio R; Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. Journal of neurosurgery. 2005 Feb; Vol. 102 (2), pp. 216-22.

6. Hutchinson, Michael. Comment on “GDNF powers neuron sprouting in human brain.” Alzheimer’s Research Forum, Submitted July 10, 2005. Retrieved online http://www.alzforum.org/new/detail.asp?id=1221

7. “Profile: Clive Svendsen.” Nature Medicine 10, 659 (2004)

8. Reaction to withdrawal of GDNF Treatment. University of Kentucky news release, February 11, 2005. Retrieved online. www.uky.edu/PR/News/Archives/2005/Feb2005/050211_parkinsons_treatment.htm

9. Fahn, Stanley and Elliott, Robin. “PDF Statement on Amgen’s Decision to Block Reinstatement of Experimental Parkinson’s Treatment For Trial Participants Released February 11, 2005.” Retrieved online. http://www.pdf.org/en/pd_comm_news/release/pr_1216924127

10. Experimental treatment shown to reverse the loss of nerve fibres in Parkinson's disease. Retrieved online. News-Medical.Net, July 6, 2005.

11. Gash DM, Zhang Z, Ai Y, Grondin R, Coffey R, Gerhardt GA. Trophic factor distribution predicts functional recovery in parkinsonian monkeys. Annals of Neurology. 2005. Vol.8, Issue 2, pp.224-233.

12. Notes on conference call with Katie Hood and Dr. Todd Sherer, Michael J. Fox

13. “News in Brief: Amgen’s GDNF headache. Nature Biotechnology
Published online: 31 August 2005. http://news.nature.com//news/2005/050829/nbt0905-1033.html [12/09; item not found online]

14. Cure Interrupted? Transcript of report by Leslie Stahl televised on 60 Minutes, September 11, 2005. Retrieved online October 12, 2005. http://www.cbsnews.com/stories/2005/09/08/60minutes/main828098.shtml?

15. Lang, Anthony E., et.al…Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Annals of Neurology (2006) Retrieved online Jan. 26, 2006.

16. The hard way to a Bill of Rights. (Editorial). The Lancet Neurology, December 2005, Vol 4, 787. Retrieved online: http://neurology.thelancet.com [12/09; full text not found; requires subscription]

17. Certification of Don M. Gash, John t. Slevin and Gregg Gerhardt. United States District Court for the Southern District of New York. Robert Suthers and Niwana Martin v. Amgen Inc. Retrieved online Jan. 30, 2006. http://www.sskrplaw.com/lawyer-attorney-1475652.html

16. Slevin J.T., Gash, D.A., Gerhardt, GA, Smith, C.D., et al. Unilateral intraputaminal glial cell line-derived neurotrophic factor in patients with Parkinson disease: response to 1 year each of treatment and withdrawal. Neurosurgical Focus, 2006 May 15;20(5):E1.

17. Chebrolu, H. , Slevin J.T., Gash, D.A.., Gerhardt, GA, Young, B., Given C.A, Smith C.D. MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF) Experimental Neurology, 2006 Apr;198(2):450-6. Epub 2006 Feb 7.

18. Penn, Richard, et.al. GDNF in treatment of Parkinson’s Disease: response to editorial. The Lancet Neurology. March 2006, Vol.5

19. Love, S, Plaha, P., Patel, N., Hotton, G.,Brooks, DJ, Gill, SS.  Glial cell line−derived neurotrophic factor induces neuronal sprouting in human brain. Nature Medicine (2005) 11, 703 – 704.

20.  Hutchinson M, Gurney S, Newson R. GDNF in Parkinson disease: An object lesson in the tyranny of type II. Journal of  Neuroscience Methods, 163 (2007) : 190-2.

21. Barker, Roger A.  Parkinson’s Disease : Pride and Prejudice and GDNF. Advances in Clinical Neuroscience and Rehabilitation  6 (1)  March/April 2006.

22. Matcham, J,  McDermott MP,  Lang, A E. GDNF in Parkinson’s Disease: The perils of post-hoc power.
Journal of Neuroscience Methods, 163 (2007) : 193-6.

23. 23. Salvatore, Michael F.; Ai, Yi; Fischer, Brent; Zhang, Amanda M.; Grondin, Richard C.; Zhang, Zhiming; Gerhardt, Greg A.; Gash, Don M. Point Source Concentration of GDNF May Explain Failure of Phase II Clinical Trial.  Experimental Neurology, 202(2):497-505, 2006 December.

24. Morrison, Paul F., Lonser, Russell R. and Oldfield, Edward H. Convective delivery of glial cell line–derived neurotrophic factor in the human putamen.  Journal of Neurosurgy 107:74–83, July 2007.

Related Issues

Access to Experimental Therapies

Calculated Risks

Informed Consent

Clinical Trial Participants' Bill of Rights

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