Exenatide — latest trial results explained
We discuss promising results from a clinical trial of type 2 diabetes drug exenatide in people with Parkinson’s.
The findings offer hope that drugs like exenatide can slow the course of Parkinson’s — something no current treatment can do. But there are many questions that need to be answered before exenatide, or drugs like it, will become approved treatments for the condition.
In this blog, we go behind the headlines and look at the findings in a little more depth.
First a little background
Exenatide has been used since 2005 to treat type 2 diabetes. It works by targeting glucagon-like peptide-1 (GLP-1) receptors in the pancreas, which causes insulin to be released. GLP-1 receptors are also found in the brain, and lab-based experiments have suggested that activating them can boost the function of dopamine connections, have anti-inflammatory properties, improve energy production, and switch on cell survival signals.
In 2013, an exploratory trial of exenatide for Parkinson’s reported promising results.
But because there was no placebo group, both the participants and researchers knew who was receiving exenatide and who wasn’t. This meant that the placebo effect could have been responsible for these positive findings — and more research was required.
Is it mind over matter, or is something else behind this powerful phenomenon?medium.com
The current trial
The latest trial involved 60 people with Parkinson’s over 60 weeks and began in 2014. Half the participants injected themselves with exenatide once a week for 48 weeks. The other half (the placebo group) did exactly the same but were receiving a dummy version of the drug.
Crucially this trial was double blind, which means neither the participants nor the researchers knew who was getting the real drug and who got the placebo until after the study came to an end and the results had been analysed.
Throughout the study all the participants were carefully and comprehensively monitored to assess any changes in their symptoms and to identify any potential safety issues or side effects.
The results: promise and questions
The results show that those who received exenatide had a slight but statistically significant improvement when their movement was assessed while off their regular Parkinson’s medication.
After 48 weeks of treatment those who received exenatide were 4 points better off than those on placebo when they were assessed on a 132-point scale that measures aspects of mobility such as tremor, agility and speech.
Crucially, this difference between the two groups was still there when they were re-assessed 12 weeks after treatment had been stopped.
At this 60 week point, those who had received exenatide were on average 1 point better than at the start of the study, whereas those in the placebo group had worsened by an average of 2 points.
The first drug that can slow the course of Parkinson’s?
As Professor Tom Foltynie who led the study says, these findings offer hope that exenatide can actually slow the course of Parkinson’s:
“This is a very promising finding, as the drug holds potential to affect the course of the disease itself, and not merely the symptoms.
“With existing treatments, we can relieve most of the symptoms for some years, but the disease continues to worsen.
“This is the strongest evidence we have so far that a drug could do more than provide symptom relief for Parkinson’s disease.”
While encouraging, the difference between the two groups was quite modest and does not provide conclusive evidence that exenatide is neuroprotective.
Interestingly, all participants underwent brain scans (called DaTscans) at the start and end of the trial. There were subtle signs in the scans that exenatide may be slowing deterioration, but again, the differences — though encouraging — were too small to be conclusive.
What about other aspects of the condition?
Throughout the trial, every aspect of Parkinson’s was carefully recorded through a huge range of assessments, including:
- quality of life
- non-motor symptoms
- changes in mood, memory and thinking
- comprehensive assessments of mobility while participants were on their regular Parkinson’s medication
One of the most puzzling things about these results is that there was no improvement in the exenatide group on any of these other assessments compared to the placebo group.
This is particularly surprising considering the results from the 2013 trial, which showed that exenatide improved performance on both movement assessments and cognitive tests that assess memory and thinking.
Did enough exenatide reach the brain?
One reason that exenatide may not have achieved the same benefits as in the previous study is that there was a slight difference in the way exenatide was given.
In the first study, participants injected exenatide twice a day over a 12 month period. In this current study, the participants injected a different formulation of the drug once a week.
This formulation releases more gradually and aims to provide a more constant level of exenatide in the body, but it’s possible it isn’t quite so effective.
When the researchers tested the levels of exenatide in the blood and the cerebrospinal fluid (the clear fluid that surrounds the brain and spinal cord), their findings suggest that only a small percentage of the exenatide in the blood stream was successfully finding it’s way into the brain.
Finding drugs that can successfully cross the blood-brain-barrier, is one of the major challenges in treating conditions like Parkinson’s and you can learn more about this in this excellent talk from Professor Matthew Wood.
What’s next for diabetes drugs and Parkinson’s?
There’s no doubt these findings add further evidence to the case that diabetes treatments could be a route to new and better treatments for Parkinson’s, and there’s lots to watch out for on the horizon.
The research team at UCL are already developing plans for further studies of exenatide involving more participants to investigate these promising signs in more detail.
And exenatide is not the only diabetes drug being investigated for Parkinson’s.
There is already a trial underway in the United States of liraglutide — an appetite control drug that also targets GLP-1 receptors. The trial started earlier this year and is expected to report results in 2019.
While another drug, originally developed for the treatment of diabetes called MSDC-0160, has also shown potential in the lab and clinical trials in people with Parkinson’s will hopefully start soon.
As always, we’ll be keeping a close eye on developments in this area and reporting on any advances, so watch this space!