The results of a large phase 2 clinical trial in 2017 showed that exenatide, a drug used to treat diabetes, may slow the progression of Parkinson’s. The results of this trial added further evidence to exenatide’s potential as a drug that might slow the progression of Parkinson’s and paved the way for the larger phase 3 clinical trial that is currently underway; Cure Parkinson’s is co-funding two sub-studies within this phase 3 trial called the ‘Exenatide PD3 Study’.

All 200 people with Parkinson’s involved in the ‘Exenatide PD3 Study’ have been recruited across six UK hospitals; each will be assessed for the two year study and the top-line results are expected in the summer of 2024.

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 and potential. The first will use brain imaging to assess the level of dopamine activity at both the start and the end of the trial.  The second sub-study will use smartphone app technology to gather day-to-day information about trial participants’ motor functions (their everyday movements), their tremor and their walking speed.

Read more about the ‘Exenatide PD3 Study’ and sub-studies

The Exenatide-PD3 trial aims to confirm whether exenatide can slow the progression of Parkinson’s, and to check that the results can be reproduced across more people with Parkinson’s at multiple research centres. The trial will be run for an extended treatment time of 96 weeks to see if it is safe, and to see if the anticipated 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 sub-study Cure Parkinson’s is funding (thanks to support from the Frank Brake Charitable Trust) alongside Van Andel Institute (VAI) is a brain imaging study. This will allow researchers to quantify the levels of dopamine neuron branches in the brain of participants at the start and then at the end of the trial. This gives a measure of the health of dopamine producing 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’ movements which are affected by Parkinson’s progression. The app has been developed by Professor Michele Hu at Oxford University. The substudy will help the team to mediate variability in movement symptom scoring by assessors in different hospitals during the trial and will also test whether apps could be a better way to assess Parkinson’s movement symptoms in future studies or in patient check-ups.

Professor Tom Foltynie presents on the Exenatide PD3 trial at our Research Update Meeting

How does exenatide work?

Exenatide belongs to a group of drugs called glucagon-like peptide 1 receptor agonists (or GLP-1R agonists). GLP-1R agonists function by mimicking the action of GLP-1, a natural gut hormone produced in the stomach when food is consumed. GLP-1 stimulates insulin release from the pancreas into the bloodstream, which helps cells absorb glucose. Exenatide was the first GLP-1R agonist to be approved for the treatment of diabetes. Importantly, GLP-1R agonists have beneficial actions in the brain.

In tests in the laboratory, exenatide has shown to support dopamine brain cell (or neuron) function; reducing inflammation, improving neuron energy function and ‘switching on’ neuron survival signals. Researchers are now investigating if all of these effects can also occur in people with Parkinson’s in a clinical trial, while simultaneously assessing the impact of GLP-1R agonists on the day-to-day symptoms and progression of the condition.

Why is exenatide of interest for Parkinson’s?

Cure Parkinson’s has been at the forefront of exenatide’s journey as a potential treatment for Parkinson’s from the outset. We funded the first ever clinical study of exenatide in people with Parkinson’s. This was a year-long pilot study in 2008 involving 45 people with Parkinson’s – half of whom had twice-daily injections of exenatide on top of their normal medicines, half were part of the placebo or ‘dummy pill’ group. Those who took exenatide did not experience the decline in their movement that we normally see due to Parkinson’s. In fact, these participants improved a little. Crucially, some of these benefits were still present when measured one year after the participants had stopped taking exenatide, giving hope that this medicine had interfered with the underlying disease process, rather than simply masking symptoms.

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

Read more about the 2008 pilot study here

By 2008, the laboratory evidence for the brain-protective effects of exenatide had built up. Cure Parkinson’s 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 progression of the disease in the brain, but it provided strong encouragement to look further. It led the iLCT committee to prioritise exenatide and influence the Parkinson’s research community to take exenatide forward.

Read more here.

 

In 2017 the results of the larger, longer, and more robust phase 2 clinical trial of exenatide also showed a delay of motor symptom progression.

Read more about the 2017 phase 2 clinical trial of exenatide

With Cure Parkinson’s encouragement and the backing of the iLCT committee, Professor Foltynie designed a phase 2 trial that would address the limitations of the first small pilot study of exenatide in people with Parkinson’s. This phase 2 trial was a double-blind placebo-controlled trial. That’s to say, neither those people taking part nor the researchers would know which of the participants were taking exenatide and which were taking a placebo (or dummy drug), until the end of the study.

As a small charity this study proved too expensive for us to fund on our own. However, thanks to our earlier investment in building the evidence for exenatide and our close relationship with the US-based Michael J Fox Foundation for Parkinson’s Research, they agreed to fund the study.

Between June 2014 and March 2015, 62 people with Parkinson’s were enrolled in 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 movement symptoms, while the group taking placebo had declined. The study results were published in the prestigious journal The Lancet.

The results of the phase 2 trial were announced on 3 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 Research, Cure Parkinson’s

Around the world, there is great interest and research into exenatide and other GLP-1R agonist medicines including liraglutide and lixisenatide.

Cure Parkinson’s continues to drive these research efforts forward, and to ensure that if GLP-1R agonists prove to slow the progression of Parkinson’s, these drugs become available to people with Parkinson’s as quickly as possible.

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