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expert reaction to results of clinical trials of GDNF (glial cell-derived neurotrophic factor) in Parkinson’s disease patients

Research published in Brain and the Journal of Parkinson’s Disease demonstrates the use of a brain implant in the administration of Parkinson’s drugs.

Prof Marios Politis, Director of the Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, said:

“Disease-modifying treatments is a current unmet need for patients with Parkinson’s disease.  Over the last 30 years surgical treatments have been implemented aiming to change the course of the disease in Parkinson’s patients with variable results.

“Whone and colleagues have used infusions with GDNF to enhance the function of dopamine neurons that are impaired by Parkinson’s following their previous pilot results.  The workers show improvements in the imaging marker measuring capacity of dopamine neurons following GDNF therapy, however not a clinical benefit in the 40 week period studied.

“The study by Whone and colleagues adds to the literature and the pursuit for meaningful new approaches for treating Parkinson’s disease.  The study shows potential as it alters the state of an affected pathology, however the fact that they did not meet their primary outcome – i.e. clinical benefit – could be received with some disappointment.

“An important aspect that needs consideration is the assessment period of 40 weeks that could be considered short and it is possible that if the assessment period was longer it may influence the results.  This was indeed the case with some patients who received foetal cell transplantation in previous trials.  In these Parkinson’s patients the clinical benefit was delayed compared to improvements in imaging markers measuring dopamine capacity.”

Prof Roger Morris, Professor of Molecular Neurobiology and Associate Head of the Department of Chemistry, King’s College London, said:

“These two linked papers, led by collaborating Bristol groups, do not describe an effective cure for Parkinson’s Disease.  Nor do they make any claim to do so.  However, I believe they do report two landmark steps in that direction.

“First, they report two stages of a clinical trial of the efficacy of a glial-derived nerve growth factor that, it was hoped, would reverse the loss of neuronal fibres and their synaptic connections in a group of 41 volunteer patients, recruited from all over Britain, who had shown recognisable symptoms of Parkinson’s for the previous 5 years.  For the first trial, the patients were divided into growth factor vs placebo groups.  Overall, similar, statistically indistinguishable improvement in clinical outcome was found in both growth factor (17.3 ±17.6%) and placebo (11.8±15.8%) groups.  The large ± figures indicate some patients improved much more than others: 9 of the growth factor, but not the placebo, group improved by more than 35%, although some did not improve at all.

“In the second, follow up trial of another 40 weeks duration, all 41 patients received the growth factor (including those previously on placebo), and all improved in clinical scores by around 27%, again with a variance of about 20%.

“For a neurodegenerative condition of this complexity, I think the results are remarkably positive.

“There are bound to be major uncontrollable factors: the patients have shown symptoms of Parkinson’s for 5 years before beginning treatment – although they have been staged by their clinical condition to be similar, how similar really is the state of their neurons, which have to be alive if they are to regenerate their fibres?  The factor was delivered once every 4 weeks – how long does this protein survive as active growth factor (possibly only hours)?  Would the growth factor be much more efficacious if delivered early in the disease, and once a week rather than month?

“In addition to the particular importance of these experiments to the development of a therapy that potentially reverses Parkinson’s, not just eases the symptoms, the development of an intra-brain pumped cannulation system that is safe and efficacious will have much wider impact.  Most drugs do not enter the brain, restrained by the Blood-Brain Barrier.  The system developed for use here has been proven safe in practice over 80 weeks, which is a remarkable achievement.  If intra-brain perfusion can be safely achieved for long term drug delivery inside the brain, the range of medication that can be used to combat brain diseases (stroke and cancer as well as neurodegeneration) will be massively expanded.”

Prof K Ray Chaudhuri, Director of King’s International Parkinson’s Centre of Excellence, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, said:

“The recent reports from the Glial Cell Line Derived Neurotrophic Factor (GDNF) putaminal infusion study in people with Parkinson’s have raised hope for the possibility of ‘neuro-restoration’ in a small number of subjects, although there were no significant clinical benefits.  The results of the PET scan are promising and significant in a subset of the patients undergoing this treatment, but it is far too early to suggest that this may be evidence of neuroresoration or protection, which is only valid when one sees improvement translated to clinical benefit in key motor and nonmotor symptoms.

“It is disappointing that clinical benefits were not significant, and in addition the authors also did not address nonmotor symptoms which affect and influence the quality of life of people with Parkinson’s adversely.  Improvements in PET scans, although not to a same great magnitude, were also reported in early studies with dopamine agonists as well as the levodopa (ELLDOPA) study but as we know those promises have not been realised.  However, the data and the study nonetheless is of great interest and should point towards a new horizon and direction to restoration based treatments, rather than lesioning treatment in Parkinson’s, and longer well designed studies using GDNF addressing motor and nonmotor outcomes are required.”

Prof Tipu Aziz, Professor of Neurosurgery, John Radcliffe Hospital, University of Oxford, said:

“The two papers are interesting in that on imaging GDNF has a significant effect on improving the brain scans in parkinsonian patients – however, the effects in terms of patients’ symptoms are nowhere near this.

“Although encouraging the study should not yet be taken by patients and carers as a major breakthrough in the treatment of the condition.  This will become apparent with a continuation of the study and in controlled trials.  This is an incredibly complicated procedure for patients to undergo considering the marginal benefit.”

Prof John Hardy FMedSci, Professor of Neuroscience, UCL, said:

“In clinical trials, researchers have to say in advance what they would consider a clinically successful outcome.  This is called the primary outcome and this is what is used to judge whether a trial has proved clinical benefit.  The investigators also can analyse other aspects of the data to decide for themselves whether the research programme for that treatment should continue.

“This trial did not meet its primary outcome: it has not been shown to be useful to patients.  The investigators believe that the results (the secondary outcomes) were interesting enough for them to continue to work on this programme of work and they seem to believe it is.  It is important to recognise this distinction between primary and secondary outcomes which is fundemental to the way in which we discuss clinical trials.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“I know from family experience how devastating Parkinson’s disease can be, so the prospect of a potentially effective treatment is very appealing.  But there are glass-half-full and glass-half-empty ways of looking at these new research findings.

“As the researchers are careful to point out in their reports, placebo effects can be important in studies of Parkinson’s disease.  That is, favourable changes can occur in patients’ condition as a result of them receiving treatment that does not include the active ingredients.  In the main double-blind part of this trial, the average score that was the primary measure of patients’ condition improved by about 12% during the first nine months in patients who had, up to that point, received none of the GDNF that is the active substance being tested.  That’s less than the 17% improvement in those who did receive GDNF, but the difference isn’t large enough to be statistically significant, that is, it remains plausible that it’s just due to chance and not to active effects of GDNF.  In the second part of the trial, when all patients received GDNF even if they had had none of it in the first part, it’s true that there were improvements in both groups of patients (those who had GDNF in the first nine months and those who did not).  But because there was by that stage no control group of patients who had received no GDNF, it’s not really possible to say how much of this improvement may again be due to placebo effects.  Also, there was very little difference between the two groups in the improvements across all eighteen months of the trial.  The researchers describe several reasons why it’s possible that placebo effects could be quite strong in this study.

“So, though the research has provided valuable information, it hasn’t really been able to move the new treatment beyond the level of being promising.  The researchers mention several reasons for optimism about the treatment, but they cannot yet know whether they will eventually find more positive evidence.  It’s true, and encouraging, that brain scans found changes showing improved functioning in parts of the brain affected by Parkinson’s disease, only in patients who received GDNF, though not all the relevant areas had a change as big as the 100% mentioned in the press release.  But that did not lead to statistically significant improvement in the main measure of symptoms.  The researchers propose several reasons why that might have happened.  Possibly the initial treatment period of nine months was not long enough – but given the results in patients who did not receive GDNF for the first part of the trial, we can’t be sure of that.  Possibly the dose of GDNF was too small – but perhaps if the dose had been larger, there would have been more adverse side effects and perhaps the treatment would not have been considered safe.  We just can’t tell.  Possibly a new way of measuring the effects of treatment would have shown more encouraging results in this trial, even with the same length of treatment and dose – but the new way that is mentioned [by Dr Erich Mohr in the press release] has not yet been scientifically validated to be an appropriate measure.  Maybe it will be validated, but that hasn’t happened yet.

“So there’s still a long way to go before the treatment can move from promise to actual routine use, and it remains possible that that move may never occur.”

Brain paper: ‘Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease’ by Alan Whone et al. was published in Brain at 00:01 UK time on Wednesday 27 February 2019.

Journal of Parkinson’s Disease paper: ‘Extended Treatment with Glial Cell Line-Derived Neurotrophic Factor in Parkinson’s Disease’ by Alan Whone et al. was published in the Journal of Parkinson’s Disease at 00:01 UK time on Wednesday 27 February 2019.

Declared interests

Prof Marios Politis: “No interests to declare.”

Prof Roger Morris: “I confirm that I have no vested interests in this research, or its funding or outcomes.”

Prof K Ray Chaudhuri: “No conflict of interest.”

Prof Tipu Aziz: “None.”

Prof John Hardy: “No CoI.”

Prof Kevin McConway: Kevin McConway is a Trustee of the SMC.

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