Exenatide and Parkinson’s

Glucagon like peptide-1 receptor agonists (GLP-1R agonists) are a class of drugs used to treat Type 2 diabetes. These drugs work by mimicking the action of the hormone (messaging proteins) GLP-1, which stimulates the release of insulin when we eat. Insulin helps blood cells absorb sugar from our food, which allows it to be transported around the body. In tests in the laboratory, exenatide has shown to also 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.

Learn more about Parkinson’s and diabetes: https://staging.cureparkinsons.org.uk/about-parkinsons/the-science-behind-parkinsons/parkinsons-and-diabetes/.

The first sub-study Cure Parkinson’s funded (thanks to support from the Frank Brake Charitable Trust) alongside Van Andel Institute (VAI) was a brain imaging study. This allowed 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 producing neurons in the brain and shows if exenatide is preventing their deterioration.

The second sub-study used a smartphone app to gather day-to-day information about trial participants’ motor functions (their everyday movements), their tremor and their walking speed. The app was developed by Professor Michele Hu at Oxford University. The sub-study helped the team to mediate variability in movement symptom scoring by assessors in different hospitals during the trial and will also test whether apps might be a better way to assess Parkinson’s movement symptoms in future studies or in clinical check-ups.

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 had taken exenatide during the trial still had not worsened, while those who did not take exenatide during the trial had continued to decline with their 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: https://pmc.ncbi.nlm.nih.gov/articles/PMC3668846/

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.

Between June 2014 and March 2015, 62 people with Parkinson’s were enrolled in the study funded by US-based Michael J Fox Foundation for Parkinson’s Research. 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.