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. 2019;9(2):301-313.
doi: 10.3233/JPD-191576.

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease

Alan L Whone  1   2 , Mihaela Boca  2 , Matthias Luz  3 , Max Woolley  4 , Lucy Mooney  2 , Sonali Dharia  2 , Jack Broadfoot  2 , David Cronin  2 , Christian Schroers  2 , Neil U Barua  2 , Lara Longpre  3 , C Lynn Barclay  3 , Chris Boiko  3 , Greg A Johnson  3 , H Christian Fibiger  3 , Rob Harrison  4 , Owen Lewis  4 , Gemma Pritchard  4 , Mike Howell  4 , Charlie Irving  4 , David Johnson  4 , Suk Kinch  4 , Christopher Marshall  5 , Andrew D Lawrence  6 , Stephan Blinder  7 , Vesna Sossi  7 , A Jon Stoessl  8 , Paul Skinner  4 , Erich Mohr  3 , Steven S Gill  2   4
Affiliations

Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson's Disease

Alan L Whone et al. J Parkinsons Dis. 2019.

Abstract

Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson's disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18F]DOPA uptake throughout the entire putamen.

Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks.

Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline to Week 80 in the OFF state Unified Parkinson's Disease Rating Scale (UPDRS) motor score.

Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: -13.9, 14.6, p = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (-9.6±6.7 vs. -3.8±4.2 points, p = 0.0108) and activities of daily living score (-6.9±5.5 vs. -1.0±3.7 points, p = 0.0003). No treatment-emergent safety concerns were identified.

Conclusions: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose.

Keywords: Glial cell line-derived neurotrophic factor; Parkinson’s disease; convection enhanced delivery; neurorestoration.

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Conflict of interest statement

Matthias Luz, Lara Longpre, Chris Boiko, Greg A. Johnson, H. Christian Fibiger and Erich Mohr are employed by and have shares and/or share options with MedGenesis Therapeutix Inc., owners of the license for GDNF. Lynn Barclay is a consultant to MedGenesis Therapeutix, Inc. Max Woolley, Rob Harrison, Owen Lewis, Gemma Pritchard, Mike Howell, Charlie Irving, David Johnson, Suk Kinch and Paul Skinner are employees of Renishaw plc, contract manufactures of the drug-delivery system. Steven Gill is the Medical Director of Renishaw plc and is the inventor of the drug delivery system from which he may have a future royalty share. He is on the scientific advisory board of MedGenesis Therapeutix Inc. for which he is reimbursed with share options. No other potential conflict of interest relevant to this article was reported.

Figures

Fig.1
Fig.1
A. OFF State UPDRS Motor Score: Change over Time. Note: Data points represent means, and error bars represent standard errors. One GDNF/GDNF patient had a conus injury due to a car accident and was included in the motor score without items 22, 27, 28, 29, and 30. B. OFF State UPDRS ADL Score: Change over Time. Note: Data points represent means, and error bars represent standard errors. One GDNF/GDNF patient had a conus injury due to a car accident and was excluded from the analysis. C. OFF State UPDRS Motor Score: Frequency Distribution of Change at Week 80/e40. Note: One GDNF/GDNF patient had a conus injury due to a car accident and was included in the motor score without items 22, 27, 28, 29, and 30.
Fig.2
Fig.2
A. Total OFF Time per Day: Change over Time. Note: Data points represent means, and error bars represent standard errors. B. Total Good-Quality ON Time per Day: Change over Time. Note: Data points represent means, and error bars represent standard errors. Total good-quality ON time per day is defined as the sum of ON time per day without dyskinesias + ON time per day with non-troublesome dyskinesias.
See this image and copyright information in PMC

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