Understanding the GDNF trial results

Original article: Results are published in Brain and Journal of Parkinson’s Disease and can be accessed here
https://www.cureparkinsons.org.uk/news/gdnf-trial-results-published The Cure Parkinson’s Trust: 2019. 

The takeaway

The results of the UK based GDNF trial (glial derived neurotrophic factor) delivered by a novel convection enhanced delivery (CED) mechanism have now been published. The neuroimaging results of the 40 week long GDNF trial indicated neuronal changes with GDNF compared to placebo however, the study did not meet its primary endpoint of improvement in movement-related symptoms in people with Parkinson’s, nor did the open label extension study. A subgroup of individuals did show significant clinical improvement.

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NB:  A documentary called The Parkinson’s Drug Trial: A Miracle Cure? was broadcast in the UK on BBC 2 on 28th February and on 7th March 2019. Both episodes are available to rewatch in the UK only, on iPlayer until April 17th – https://www.bbc.co.uk/programmes/m0002tjw

Why is it important?

This is the first randomised trial in Parkinson’s to employ CED to administer a neurotrophic factor to the putamen every 4-weeks via a skull-mounted port. As evidenced by the PET brain scans, the trial showed that this method of administration affords a spatial delivery of GDNF sufficient to achieve a biological effect across the entire putamen.

Recruiting patients from across the UK and delivering study treatment on an outpatient basis, this trial shows that, independent from conclusions on GDNF, attending for monthly putamenal infusions of a putative neuro-restorative therapy is feasible and tolerable. This study, therefore, marks a potential shift in direct-target delivery of future novel therapies as they become available, for a host of neurological conditions.

Impact Opinion

While this clinical trial of GDNF did not meet its primary end point, there are some very interesting findings in the data, and it would be wrong for the Parkinson’s community to view this study as a failure. The brain imaging data alone suggests that GDNF was having an interesting effect in the brain and is therefore worthy of further investigation. It will be particularly interesting to see if the ongoing CDNF or AAV-GDNF clinical trials demonstrate similar effects.


Glial derived neurotrophic factor, GDNF, belongs to a family of substances called trophic factors, which help neurons survive, grow and function. There has been a great deal of preclinical research published that suggests GDNF has beneficial effects in models of Parkinson’s. And the potential of GDNF as a disease modifying treatment was recently tested in a clinical trial, involving 41 people with Parkinson’s. One of the great challenges to developing treatments that can slow, stop or reverse Parkinson’s is ensuring that the therapy in question reaches its target in the brain. So, in addition to putting GDNF to the test, this trial also implemented a new way of delivering the molecule directly into the brain called convection enhanced delivery – or CED.

The details

After extensive screening, 41 people with Parkinson’s, between the ages of 41 and 72 years old, approximately 8 years since diagnosis, were assigned to one of two groups: one group received GDNF and the other received a placebo, similar to the fluid found naturally in the brain. The primary endpoint was a clinical rating scale (the motor score on the Unified Parkinson’s Disease Rating Scale (UPDRS)) which was assessed during the OFF state, that is, after withdrawing from dopaminergic medication overnight.

A new surgical technique was trialed, in which a drug delivery device was mounted on the skull through which the therapy could be delivered, directly targeting an important movement-related region in the brain, called the putamen. To ensure that this region received the treatment evenly in its entirety, which had been problematic in a previous GDNF trial, a new Convection Enhanced Delivery (CED) system was used. With this system, GDNF is administered intermittently, once every four weeks.

In the first phase of the trial, 6 individuals underwent this surgery to optimize the method, and after a 12 week safety assessment, the second phase of the study began. 35 participants were assigned to either the placebo or the GDNF group. In order to avoid any bias, neither the participants nor the clinicians in the trial knew which group each participant had been assigned to. All participants came in every 4 weeks for the GDNF infusion, had assessments after stopping their medication overnight, were given a number of questionnaires assessing their activities of daily living and non-motor symptoms, and were asked to complete a symptom diary.

These procedures were safe and well tolerated. After 40 weeks, there was no overall difference between the GDNF and placebo group in terms of their UPDRS motor score. A subgroup of 9 individuals (43% of the GDNF group), however, did in fact show a clinically significant improvement. Moreover, neuroimaging used to assess underlying neuronal effects reported significantly greater changes in the GDNF-treated group compared to the placebo group.

All 41 participants in this trial were given the opportunity to take part in a further open label extension study, in which all individuals received GDNF for an additional 40 weeks. At the end of another 40 weeks, there was again no clear difference between patients who had received GDNF versus placebo. One important question regarding the study was whether a longer administration period might have been more optimal. Since both the GDNF and placebo treated participants enrolled in the extension study, the researchers compared the absolute UPDRS change at the end of the additional 40 weeks, compared to its start, between the two groups. The group who had received GDNF in the original trial showed a greater absolute improvement after the additional 40 weeks of GDNF treatment in the extension study, compared to those who had initially been in the placebo group. Activities of daily living also showed a similar improvement.

Next steps

Could there be a rationale for a larger dose of GDNF, or longer treatment duration? Might people with milder symptoms benefit more from GDNF? These and many more critical open questions will need to be answered in order to fully understand the potential of GDNF as a disease modifying treatment for Parkinson’s. There are ongoing clinical trials for Parkinson’s involving GDNF (a gene therapy study in California) and other neurotrophic factors (the Herantis-supported CDNF clinical trial in Finland and Sweden) which may help to address these questions.

Related work and trials

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For those in the UK:  A documentary called The Parkinson’s Drug Trial: A Miracle Cure? was broadcast at 9.00 pm on BBC 2 on 28th February and on 7th March 2019 and is now available to re-watch on iPlayer.

Original article: Bagnoli, E. & FitzGerald, U. 2018. Mitral cells and the glucagon-like peptide 1 receptor: The sweet smell of success?


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