Previous open-label trials testing glial cell line-derived neurotrophic factor (GDNF) family ligands in Parkinson disease have shown promising clinical effects. However, in placebo-controlled trials, the treatments have failed. A new randomized placebo-controlled trial of intraputamenal delivery of GDNF designed to resolve this conundrum has again failed to do just that.
Refers to Whone, A. et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain 142, 512–525 (2019) | Whone, A. L. et al. Extended treatment with glial cell line-derived neurotrophic factor in Parkinson’s disease. J. Parkinsons Dis. https://doi.org/10.3233/JPD-191576 (2019).
Parkinson disease (PD) is a common chronic neurodegenerative disorder of the CNS that is defined mainly by degeneration of the nigrostriatal dopaminergic pathway, leading to motor and cognitive deficits. Many of these motor deficits can be readily treated with oral dopamine drugs, but over time these treatments become less effective and are associated with increasing numbers and severity of adverse effects. A major challenge in the treatment of PD is the development of novel therapies with restorative and disease-modifying effects.
“A major challenge in the treatment of PD is the development of novel therapies”
Studies initiated in the 1990s identified glial cell line-derived neurotrophic factor (GDNF) as a potent inducer of survival and sprouting of midbrain dopaminergic neurons in animal models of PD1; these findings quickly led to clinical trials of GDNF in PD. An initial trial took the approach of delivering GDNF into the cerebral ventricles, but it failed to have any significant clinical benefit (see Supplementary Table 1), probably as a result of GDNF not gaining access to the diseased area of the brain2. Open-label trials by teams in Bristol, UK, and Kentucky, USA, then investigated intraparenchymal delivery of GDNF directly to the putamen and found that GDNF was associated with a dramatic decrease in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and an increase in putamenal 18F-DOPA uptake as measured by PET imaging1. On the basis of these findings, a randomized placebo-controlled study of GDNF in 34 patients was undertaken3. Despite significantly increased 18F-DOPA uptake on PET in the GDNF-treated group, no improvement in motor function was observed in the GDNF-treated group compared with the placebo group3. As a result of this negative outcome, questions arose as to whether the patients were too advanced in their disease course, whether the dose of GDNF given was too low (compared with the doses used in the open-label study), or whether GDNF was delivered in such a way that meant it did not enter the brain parenchyma to act on dopaminergic fibres within the striatum1,4. In the meantime, Ceregene reported on a similar approach in which the related growth factor neurturin was delivered via gene therapy to patients with PD. The group initially reported success in an open-label study but reported failure in two double-blind placebo-controlled trials5, which led many researchers to conclude that GDNF had no therapeutic future in PD.
On the basis of the argument that the earlier failures of GDNF in PD might have been caused by inadequate drug delivery, a new study was started by the Bristol team using a new convection-enhanced catheter system for the administration of GDNF to the putamen. The findings from this new study have now been published in two papers (and a two-part BBC documentary, ‘The Parkinson’s Drug Trial: A Miracle Cure?’). The first paper reports on the 9-month results of the double-blind placebo-controlled part of the study6 and the second paper reports on the open-label extension phase that covered the next 9 months, during which all patients received active treatment7.
The papers report that both the primary study and the open-label extension failed to reach their primary and secondary end points that assessed clinical improvements of motor and nonmotor PD measures, primarily based on UPDRS scores. Despite significant increases in 18F-DOPA uptake on PET imaging, as observed in previous GDNF trials (see Supplementary Table 1), no significant changes in motor function were seen in the GDNF-treated group compared with the placebo group after the first 9 months of the study, nor between the extended 18-month GDNF-treated group and the group who received the treatment only during the second 9 months of the study. But on the positive side, the new device developed to deliver the GDNF seemed to be well tolerated.
So why did this trial fail? A number of possible reasons exist. One possibility acknowledged by the authors is that GDNF is not able to rescue the dopaminergic nigrostriatal pathway in patients with PD despite the preclinical findings in animals. In other words, GDNF might be unable to rescue dopaminergic neurons and fibres in the presence of the α-synuclein pathology seen in PD owing to this pathology having downstream effects on the GDNF signalling pathway8. However, this idea ignores the fact that in some patients the benefits seen with GDNF are striking and long-lived (for example, up to 8 years) and also does not take into account the observed improvements in the GDNF-treated group on imaging and evidence for dopaminergic fibre sprouting following GDNF treatment in post-mortem studies1,9. More data on post-mortem fibres from patients receiving GDNF might become available from this latest Bristol trial given that at least one patient in the trial has died from unrelated causes.
Another possible explanation for the negative findings that was suggested by the authors is that the dose of GDNF was too low to induce significant clinical effects. Indeed, the accumulated dose of drug used in this trial was lower than that used in previous trials (see Supplementary Table 1). While the percentage increase in 18F-DOPA uptake on PET imaging was significant, it might have been insufficient to provide clinical improvement, as the absolute level did not return to the normal range. Furthermore, 18F-DOPA PET measures not only dopaminergic activity but also activity of other catecholaminergic systems, which could confound the 18F-DOPA results. Last, the volume of distribution of GDNF protein across the target structure might be less than that predicted with the standard MRI contrast agent, gadolinium, which was used to assess the volume of distribution with the new catheter system. Indeed, individual patient responses plotted against 18F-DOPA changes for the cohort might have been more informative to assess the correlation between individual clinical responses and changes in 18F-DOPA uptake on PET.
Another possible reason for the failed results is that the placebo response — which was bigger than expected — might have masked some benefits of GDNF treatment. The reasons for the large placebo response in this trial are unknown but could relate to long-lasting benefits of an increase in the brain penetrance of oral anti-PD drugs owing to chronic disruption of the blood–brain barrier in all patients as a result of cannulae implantation and monthly infusions.
Another possible problem with the study was that the follow-up of patients was too short for changes in motor score to be detected. As the patients who had received GDNF for 40 weeks and then received it for another 40 weeks in the extension study showed a statistically significant decrease in UPDRS score compared with the placebo group at 40 weeks, the authors argue that a longer study period might have been required to meet the primary end point of efficacy. Unfortunately, the open-label study design after only 40 weeks limited the interpretation of this aspect of the study.
“if GDNF is to be taken forward then it is critical that all aspects of trial design are optimized”
Last, the patient group included in the study might have been suboptimal. Given that patients had had PD for an average of 11 years, the degeneration of the nigrostriatal pathway might have advanced to a point where it could not be rescued10. This point, when considered with some of the work by Ceregene that showed more marked clinical improvements with neurturin in less advanced disease5, raises questions as to whether earlier-stage patients might have fared better. The authors argue, however, that they did not identify a subtype of patient with enhanced benefit when they analysed the data with respect to disease duration (although these data are not shown) and that some changes were seen on 18F-DOPA PET regardless of disease stage.
The results of this trial once again leave us with critical unanswered questions as to the clinical effects of GDNF in patients with PD, as well as the utility of 18F-DOPA PET as a predictive measure of clinical improvement in restorative PD trials. Some of these questions might be answered by an ongoing trial using adeno-associated virus type 2 GDNF (NCT01621581). However, if GDNF is to be taken forward then it is critical that all aspects of trial design are optimized, including patient selection, PET ligands, drug dose and trial duration.
Evans, J. R. & Barker, R. A. Neurotrophic factors as a therapeutic target for Parkinson’s disease. Expert Opin. Ther. Targets 12, 437–447 (2008).
Kordower, J. H. In vivo gene delivery of glial cell line-derived neurotrophic factor for Parkinson’s disease. Ann. Neurol. 53 (Suppl. 3), 120–132 (2003).
Lang, A. E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466 (2006).
Lang, A. E. et al. GDNF in treatment of Parkinson’s disease: response to editorial. Lancet Neurol. 5, 200–202 (2006).
Warren Olanow, C. et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann. Neurol. 78, 248–257 (2015).
Whone, A. et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain 142, 512–525 (2019).
Whone, A. L. et al. Extended treatment with glial cell line-derived neurotrophic factor in Parkinson’s disease. J. Parkinsons Dis. https://doi.org/10.3233/JPD-191576 (2019).
Decressac, M. et al. α-Synuclein-induced down-regulation of Nurr1 disrupts GDNF signaling in nigral dopamine neurons. Sci. Transl Med. 4, 163ra156 (2012).
Patel, N. K. et al. Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation. Neurology 81, 1176–1178 (2013).
Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 136, 2419–2431 (2013).
A.K. is the owner of the company Kirkeby Cell Therapy holding patents for the development of cell therapies for Parkinson disease (PD). A.K. and R.A.B. are consultants for Novo Nordisk A/S on the development of cell therapies for PD. R.A.B. also works as a consultant on cell-based therapies for Fujifilm Cellular Dynamics, Cellino and Living Cell Technologies.
The Parkinson’s Drug Trial: A Miracle Cure?: https://www.bbc.co.uk/programmes/m00031cb
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Kirkeby, A., Barker, R.A. Parkinson disease and growth factors — is GDNF good enough?. Nat Rev Neurol 15, 312–314 (2019). https://doi.org/10.1038/s41582-019-0180-6
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