In 2017 results of a large phase ll trial showed that exenatide, a drug used to treat diabetes, may slow the progression of Parkinson’s. This trial added further evidence to exenatide’s potential as a drug that might interrupt the progress of Parkinson’s. It paved the way for the large phase III clinical trial that is now underway. Cure Parkinson’s is funding two sub-studies in this promising phase of research into exenatide for Parkinson’s.

At the tail-end of 2019 and part of 2020, the first participants of the ‘Exenatide PD3 Study’ were recruited – a clinical trial involving six UK hospitals. The trial will recruit 200 people with Parkinson’s who will be followed up for two years.

Half the cohort will take a weekly injection of exenatide (brand name Bydureon) alongside their normal symptom-controlling medication. Together with Van Andel Institute (VAI), Cure Parkinson’s is funding two sub-studies within the trial to create a more complete picture of exenatide’s effects. The first will use brain imaging to assess the level of dopamine signalling at both the start and the end of the trial.  The second will use smartphone app technology to gather day-to-day information about trial participants’ motor functions, such as tremor and walking speed.

Diabetes and Parkinson’s – what’s the link?

Evidence suggests that people with type 2 diabetes are at greater risk of developing Parkinson’s than people without diabetes. The reasons for this are not yet clear and researchers are working hard to understand the curious connection between these conditions.
Current data theories suggest that excess glucose in the brain – which is seen in uncontrolled type 2 diabetes – may be reacting haphazardly with surrounding proteins and interfering with their function. These interactions can also create toxic end products which can cause inflammation and the clustering of alpha synuclein, both of which are features of Parkinson’s.

How does exenatide work?

Exenatide is a GLP-1 agonist. These are molecules that mimic a type of naturally occurring hormone which stimulates a reaction. GLP-1 agonists are used in the treatment of diabetes because they stimulate the release of insulin from the pancreas. But GLP-1 agonists also have beneficial actions in the brain.

In models of Parkinson’s, exenatide can improve dopamine neuron function, reduce inflammation, improve energy production and switch on brain cell survival signals. Researchers are now trying to uncover if all of these effects also occur in humans, while simultaneously assessing its impact on the day-to-day symptoms and progression of Parkinson’s.

Read More About the ‘Exenatide PD3 Study’ and Sub-studies

The Exenatide-PD3 trial aims to confirm whether exenatide is slowing the progression of Parkinson’s, and to check that the results can be reproduced across more patients at multiple research centres. It will also extend the treatment to 96 weeks, to see if the treatment is safe and the improvements accumulate over time.

The study is funded by the National Institute for Health Research, and is being run in hospitals in London, Plymouth, Lothian, Oxford and Salford.

The first substudy we’re funding (thanks to support from the Frank Brake Charitable Trust), alongside the VAI, is a brain imaging study. It will allow researchers to quantify the levels of dopamine neuron branches in the brain of participants at the start and end of the trial. This gives a measure of the health of dopamine neurons in the brain, and will show if exenatide is preventing their deterioration.

The second substudy we’re funding with VAI is the use of a smartphone app to capture real life evidence of participants’ motor symptoms. The app has been developed by Professor Michele Hu at Oxford University. The substudy will help the team to counteract and highlight any variability in motor symptom scoring by assessors in different hospitals during the trial. It will also test whether apps could be a better way to assess Parkinson’s motor symptoms in future studies or in patients’ check-ups.

The Research Steps

Cure Parkinson’s has been at the forefront of exenatide’s journey since the start. We funded the first ever clinical study of exenatide in people with Parkinson’s. It was a year-long pilot study involving 45 volunteers – half of whom had twice-daily injections of exenatide on top of their normal medicines. Those who took exenatide did not experience the decline in movement that we normally see due to Parkinson’s. In fact, they even improved a little. Crucially, some of these benefits were still present when measured one year after they’d stopped taking exenatide, giving hope that the medicine had interfered with the underlying disease process, rather than simply masking the symptoms.

The results of this trial were presented to a group of the world’s top Parkinson’s experts at a meeting of our International Linked Clinical Trials (iLCT) programme. At that event, scores of existing medicines with potential application to Parkinson’s were evaluated. Exenatide was singled out as the top priority for advancing into further clinical trials.

Read More About The 2008 Pilot Study

By 2008, the laboratory and preclinical evidence for the brain-protective effects of exenatide had built up. We already knew it was a safe medicine for humans, so it was relatively easy to test if it could help people with Parkinson’s.

We funded Professor Tom Foltynie and his team to run a small proof-of-concept trial at University College London. The 45 people who took part were between 45 and 70 years of age, and were all taking L-dopa medication for their Parkinson’s.

At the start of the trial, at six months, at one year and at 14 months, the volunteers’ motor symptoms (movements such as speech, tremor and walking) were assessed after pausing their medication the night before. By the end of the study the difference in Parkinson’s severity was modest but real; those taking exenatide had slightly improved, those not taking exenatide had slightly worsened .

With our support, Professor Foltynie assessed the study participants again, one year after the conclusion of the trial. He found that the motor symptoms of those who’d taken exenatide during the trial still had not worsened, while those who didn’t take exenatide during the trial had declined as expected in Parkinson’s .

Due to the size and design of the trial, this was not enough to conclude that exenatide was interrupting the disease in the brain, but it provided strong encouragement to look further. It led the iLCT committee to prioritise exenatide and galvanise the Parkinson’s research community to take exenatide forward.

Link to the study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3668846/

Link to the study: https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd140364

In 2017 the results of the larger, longer, and more robust phase II clinical study also showed a delay of motor symptom progression.

The 2017 Phase ll Clinical Study

With Cure Parkinson’s encouragement and the backing of the iLCT committee, Professor Foltynie designed a Phase II trial that would address the limitations of the first study. It needed to be a double-blind placebo-controlled trial. That’s to say, neither patients nor doctors would know which of the participants were taking exenatide and which were taking a placebo, until the end of the study.

This was too expensive for us to fund. However, thanks to our earlier investment to build the evidence for exenatide and our close relationship, the US-based Michael J Fox Foundation for Parkinson’s Research agreed to finance the study.

Between June 2014 and March 2015, 62 patients enrolled to the study. They were given either exenatide or placebo for 48 weeks. Their motor symptoms were assessed at the start of the study and again 12 weeks after finishing exenatide or placebo.

At 60 weeks, the group who had taken exenatide had a small improvement in their motor symptoms, while the group taking placebo had declined. The study results were published in the prestigious journal The Lancet.

The results of the Phase II trial were announced on the evening of the 3rd August 2017. Overnight, our goal of finding a cure for Parkinson’s was no longer considered to be fanciful, and people’s mindsets began to shift from ‘if’ to ‘when’

Dr Simon Stott, Deputy Director of Resarch, Cure Parkinson’s

Around the world, there is great interest and lots of research into exenatide and other GLP1-agonist medicines. Cure Parkinson’s will continue to drive these efforts forward, and to ensure that – if exenatide proves to slow the progression of the disease – it becomes available to patients as rapidly as possible.