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GDNF Research History

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 into the brains of both rat and monkey models of parkinsonism showed therapeutic promise. 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.”

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.

Title: “Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease.”

Researchers: T. Shingo, I. Date, H. Yoshida, T. Ohmoto

Published in: Journal of Neuroscience Research, 2002

Results: “Implantation of encapsulated cells producing GDNF can mitigate the effects of 6-OHDA in a rat model of Parkinson's disease, according to this study.“

Title: “Neurotrophic Factor in the Treatment of Parkinson Disease”

Researchers: Young Mi Yoo, Ph.D.; Yong Jung Kim, Ph.D.; Uhn Lee, M.D., Ph.D., (et.al.)
Published in: Focus 15(1), 2003.

Results: The researchers concluded that glial cell line derived neurotrophic factor (GDNF) delivered via a virus vector could promote functional recovery in a rat model of PD.

Title: "Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys."

Researchers: R. Grondin, Z. Zhang, A. Yi, W.A. Cass, N. Maswood, A.H. Andersen, D.E. Elsberry, M.C. Klein, G.A. Gerhardt, D.M. Gash.

Published in: Brain, 2002

Results: “GDNF delivered via pump to the striatum or ventricles improves motor function and markers of dopaminergic cell function in monkeys, according to this study.”

Clinical Studies

Title: “Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.”

Location of study: Oregon Health and Science University

Researchers: J.G. Nutt, K.J. Burchiel, C.L. Comella, J. Jankovic, A.E. Lang, E.R. Laws Jr, A.M. Lozano, R.D. Penn, R.K. Simpson Jr, M. Stacy, G.F. Wooten; ICV GDNF Study Group.

Published in: Neurology, January 14, 2003

Methods: This was a multi-center, randomized, double-blind, placebo-controlled study of 50 subjects with PD, lasting 8 months beginning in July 1996. It compared the effects of monthly injections into the brain ventricles (network of openings that channel spinal fluid through the brain) of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF.  An open-label study extended the testing up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Outcomes were measured by the Unified Parkinson's Disease Rating Scale (UPDRS).

Results: GDNF administered by ICV injection was biologically active, but GDNF did not improve Parkinson’s symptoms. The researchers hypothesized that the GDNF molecules may have been too large to move from the ventricles to the targeted brain tissues in the putamen and substantia nigra. The trial was terminated by Amgen in April 1999, and GDNF dropped from its development program.

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: AMGEN Phase II Study

Location of Study: Multi-center trials at New York University, University of Virginia, University of Toronto, University of Chicago, Univ. of Oregon.

Methods: Phase II placebo controlled study with 30 PD patients advanced to the point that medications are not working well. GDNF delivered to the putamen through a catheter. Length of trial: 6 months. Outcome measured by UPDRS, and brain scans to track dopamine production and use, which could indicate whether GDNF only prevents new cells from injury or actually helps revive weak, poorly-working cells.

Results: “Six months of treatment with GDNF (glial-derived neurotrophic factor) delivered to the putamen failed to improve UPDRS scores compared to placebo. There were “modest, but significant improvements in a PET scan index of dopamine nerve cell function at the site of the GDNF infusion into the brain.”

Source: Biotech Week, October 27, 2004, “Clinical trial failure detailed"

Amgen announced that all subjects were to be entered in an open label extension study to resolve differing trial results. 
Source: CenterWatch, NMT Weekly Trial Results, July 5, 2004 [12/09; item no longer online]

Amgen withdraws GDNF from all clinical trials (September 2004)

FROM: E-MOVE reports, October 7, 2004
“Antibodies to GDNF Force Halt to All Clinical Trials”
Platform presentation WIP 1
by Dr. Anthony Lang at the 129th Annual Meeting of the American

Neurological Association, held in Toronto October 2-6, 2004.

“Results from the double-blind trial of intraputaminal GDNF indicate no clinical benefit from treatment. In addition, four patients developed anti-GDNF antibodies. In response, the manufacturer, Amgen, has withdrawn GDNF from all clinical  trials.”

“Four patients developed antibodies to GDNF during or after the double-blind phase of the trial, including one who developed them shortly after switching from placebo to open-label GDNF after the trial concluded. Three of these patients have GDNF-blocking antibodies, but the significance of this is unknown and the patients remain asymptomatic. In addition, two monkeys who have received unilateral intraputaminal GDNF have developed “unusual cerebellar cortical pathology,” whose relationship to GDNF treatment is unknown. Amgen has withdrawn GDNF from all clinical trials due to safety concerns as a result of these developments.  http://www.imakenews.com/wemove/e_article000312494.cfm?x=b3H31sv,b1Qs8yH9

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.”

Title : Glial cell line−derived neurotrophic factor induces neuronal sprouting in human brain

Location of Study: Bristol, U.K.

Authors : Seth Love, Puneet Plaha, Nikunj K Patel, Gary R Hotton, David J Brooks & Steven S Gill

Published in: Nature Medicine (2005) 11, 703 – 704.

Methods: A brain autopsy was performed on one of the Bristol, United Kingdom phase I GDNF trial participants, who had died of an unrelated heart attack.

Results: The autopsy analysis revealed re-growth of nerve fibers in the putamen area of the brain. Professor Love, who examined the brain stated that “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."

University of Bristol press release: Click here to read the full article. [12/09; item no longer online]

Title : Trophic factor distribution predicts functional recovery in parkinsonian monkeys.

Location: University of Kentucky

Authors: . Don M. Gash, PhD , Zhiming Zhang, MD , Yi Ai, MD , Richard Grondin, PhD, Robert Coffey, MD , Greg A. Gerhardt, PhD

Published in
: Annals of Neurology. 2005. Vol. 58, Issue 2, pp.224-233.

Methods: Using pulsed infusion for convection-enhanced delivery of GDNF to Parkinsonian monkeys, the researchers compared two variables hypothesized to be important for achieving efficacy -- dose and GDNF distribution in the target tissue.

Results: This study showed 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 utilizing pulse delivery to distribute GDNF in the brain were the most effective.

Title : Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Location: Multi-center

Authors: Lang, Anthony E., et.al…

Published in: Annals of Neurology (2006) Early view retrieved online Jan. 26, 2006.

Methods: Randomized, double-blind, placebo-controlled, parallel-group Phase I / II study to evaluate the efficacy and safety of intraputamenal infusion of GDNF in patients with idiopathic PD. Thirty-four PD patients were randomized 1 to 1 to receive bilateral continuous Ipu infusion of liatermin (synthetic GDNF), 15g/putamen/day , or placebo. The primary end point was the change in the Unified Parkinson Disease Rating Scale (UPDRS), a tool used to track the longitudinal course of Parkinson's.

Results: “Liatermin did not confer the predetermined level of clinical benefit to patients with PD despite increased 18F-dopa uptake. It is uncertain whether technical differences between this trial and positive open-label studies contributed in any way to this negative outcome.”

Among the inconsistencies noted between the Phase I trials and the Amgen trial were different: GDNF dosages, catheters (diameter size, number of ports), and infusion methods (constant versus pulsed).

Click here to read the full abstract.

Title: MRI volumetric and intensity analysis of the cerebellum in Parkinson’s disease patients infused with glial-derived neurotrophic factor (GDNF)

Location: University of Kentucky;

Authors: Chebrolu, H. , Slevin J.T., Gash, D.A.., Gerhardt, GA, Young, B., Given C.A, Smith C.D.

Published in: Experimental Neurology, 2006 Apr;198(2):450-6. Epub 2006 Feb 7.

Methods: MRIs from 9 patients participating in the GDNF trial were analyzed to determine if changes could be detected in the cerebellum or elsewhere in the brain following GDNF treatment for one year.

Results: ‘In concert with the lack of evidence of cerebellar dysfunction on clinical examination, we find no imaging evidence of cerebellar injury in human subjects undergoing intracerebral GDNF infusion.”

Click here to read the full abstract.

Title: “Point Source Concentration of GDNF May Explain Failure of Phase II Clinical Trial.”

Location: The Morris K. Udall Parkinson's Disease Research Center of Excellence, University of Kentucky, Lexington, KY

Authors: Salvatore, Michael F.; Ai, Yi; Fischer, Brent; Zhang, Amanda M.; Grondin, Richard C.; Zhang, Zhiming; Gerhardt, Greg A.; Gash, Don M.

Published in: Experimental Neurology, 202(2):497-505, 2006 December

Methods: “Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint.”

Results and Conclusions: “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.“

“Placebo effects, physician judgment and technical differences in delivery protocols have been postulated as factors contributing to the difference."

“The differences in drug delivery and drug doses between the three different trials make it impossible to assess the contribution of placebo effects to the differences in results. The present study addresses only technical issues.“

“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.”

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

Location: University of Kentucky

Authors: Slevin J.T., Gash, D.A., Gerhardt, GA, Smith, C.D., et al.

Published in: Neurosurgical Focus, 2006 May 15;20(5):E1.

Methods: The authors report the safety and efficacy of continuous treatment of GDNF for 1 year or more. After the GDNF trial was halted by Amgen, the patients were monitored for an additional year to evaluate the effects of drug withdrawal.

Results: “Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted… 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.”

Title: Convective delivery of glial cell line–derived neurotrophic factor in the human putamen.

Authors: Morrison, Paul F., Lonser, Russell R. and Oldfield, Edward H.

Published in: Journal of Neurosurgy 107:74–83, July 2007.

Methods: “Computational examinations of the effects of differing catheters, infusion rates, infusate concentrations, and target placement on distribution were completed based on the protocols “ of the two phase I and the Phase II GDNF trials.

Conclusions: “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.“

Click here to read abstracts at PubMed

Statistical Analyses

Title: GDNF in Parkinson disease: An object lesson in the tyranny of type II.

Authors: Hutchinson M, Gurney S, Newson R.

Published in: Journal of Neuroscience Methods. 163 (2007) : 190-2.

Methods: The authors rexamined the study design and statistical analysis of the Phase II GDNF 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] ).

Conclusions: “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.”

Click here to read abstracts at PubMed

Title : GDNF in Parkinson’s Disease: The perils of post-hoc power.

Authors: James Matcham, Michael P. McDermott, Anthony E. Lang

Published in: Journal of Neuroscience Methods. 163 (2007) : 193-6.

Methods: Examined the re-interpretation of the GDNF phase II trial by Hutchinson, [et al.].

Conclusions: Believe their “conclusions to be flawed, in part because they are based on post-hoc power calculations… reaffirmed that the confidence interval for the treatment effect in the placebo-controlled study of GDNF shows that the trial is capable of excluding effects of GDNF of the magnitudes that were observed in the open-label studies and that the conclusions drawn in the original paper remain scientifically sound.”

Click here to read abstracts at PubMed

Amgen’s Toxicity Studies

Title: On the Toxicity of GDNF (letter)

Author: Dr. Michael Hutchinson

Published In: Toxicologic Pathology , 36:522, April 2008.

Summary :In a letter responding to the Amgen sponsored study of toxicity in monkeys infused with GDNF (Hovland et al, Toxicologic Pathology 35: 676-92 (2007), and based on data from that study, Hutchinson states that the four of thirty-six animals that developed lesions all “belonged exclusively to the subgroup of fifteen animals exposed to high doses, and within this group of fifteen, they also belonged exclusively to the subgroup of six animals withdrawn from GDNF …. Thus, lesions were seen only in animals that had first been exposed to high doses and then withdrawn from these high doses. Lesions were not seen in any other group of animals.“ Withdrawal was deliberate for three of these four monkeys who were in the Recovery group and were sacrificed 3 months after the GDNF was withdrawn. GDNF was inadvertently withdrawn from the fourth monkey, “ presumably because of catheter migration.” (i.e. GDNF ceased being pumped into the brain.

Hutchinson concludes that “beyond a reasonable scientific doubt, pathology is the result of withdrawal, and not only that, but withdrawal only from the highest doses of GDNF. It is associated neither with exposure to these high doses, nor withdrawal from lower doses…. It is also worth noting that, because of the relatively small volume of CSF in monkeys, all doses used in this toxicology study would likely be associated with CSF concentrations far higher than in humans.”

Title: Six-Month Continuous Intraputamenal Infusion Toxicity Study of Recombinant Methionyl Human Glial Cell Line-Derived Neurotrophic Factor (r-metHuGDNF) in Rhesus Monkeys

Authors: David N. Hovland Jr., et.al.

Published in: Toxicologic Pathology. 35: 676-92 (2007),

Methods: ”Results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6–9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 μg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 μl/day flow rate) for 6 months; a subset of animals (2–3/sex/group) underwent a subsequent 3-month treatment-free recovery period. multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-μg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF.”

Conclusions:The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.”

Title: Development of a Maturing T-Cell-Mediated Immune Response in Patients with Idiopathic Parkinson's Disease Receiving r-metHuGDNF Via Continuous Intraputaminal Infusion.

Authors: Tatarewicz SM, Wei, X, Gupya S, Masterman D, Swanson, SJ, Moxness MS.

Published in: Clinical Immunology 2007 Nov;27(6):620-7. Epub 2007 Jul 14.

Source:  PubMed abstract

News Articles on Autopsy Results

Amgen's GDNF Shows Signs of Effectiveness, Los Angeles Times, Business Desk; Part C; Pg. 3.
July 10, 2005 .

Parkinson's treatment works, but you can't have it, New Scientist, July 9, 2005, Pg. 18.

Parkinson's drug gains evidence; Autopsy in Britain reveals nerve regrowth from an experimental treatment withdrawn by its maker in the U.S. Jamie Talan. Newsday, July 7, 2005, Pg. A34.

Withdrawn experimental drug found to reverse Parkinson’s brain damage. Medical Research News, July 5, 2005. http://www.news-medical.net/?id=1149

Study Adds to Dispute Over Drug by Amgen. Denise Gellene. Los Angeles Times , July 2, 2005 Business Desk; Part C; Pg. 1.

Report stirs doubt on drug decision. Randolph E. Schmid. Ventura County Star (California), July 2, 2005, Pg. 1.

Drug reverses Parkinson's brain damage. Ian Sample. The Guardian (London), July 2, 2005, Guardian Home Pages, Pg. 10.

Drug find offers a glimmer of hope to Parkinson's sufferers Sam Lister. The Times (London), July 2, 2005, p.36.

Researchers: Parkinson’s drug was effective. Associated Press, July 2, 2005.

Renewed hope for Parkinson's patients. Innovations Report - University of Bristol. (UK) July 1, 2005.

Parkinson’s Drug Prompts Brain Cell Growth. Rowan Hooper. New Scientist . July 1, 2005.

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