After the recent exenatide results, what’s next in Parkinson’s disease research and clinical trials?

Earlier this week, The Lancet published results of a phase 3 clinical trial that explored whether the Type 2 diabetes medication exenatide could slow Parkinson’s disease progression.

Despite high hopes, that does not appear to be the case. After conducting the largest and longest trial to date on exenatide in Parkinson’s, researchers from University College London (UCL) found no evidence that the drug impeded disease progression or reduced symptoms.

So where do we go from here?

Although the trial results are disappointing, they still provide important information that can refine future studies and suggest new opportunities.

About The Trial Participants and Location: 194 people with Parkinson’s participated in the trial across six sites in the U.K. It was led by a team at University College London. Trial Length: 96 weeks Trial Design: The trial was randomized and double blinded. This means that participants were randomly assigned to either a group that received exenatide or a group that received a placebo (a treatment that visually appears like real medication but that has no active ingredients). Randomized, double blind trials are considered the gold standard for clinical trials.

The UCL research team continues to examine the results in a process called post-hoc analysis. This type of work occurs after initial data analysis and looks for associations or patterns that may shed additional light on the findings. Specifically, the team is exploring if subgroups of participants, such as those who are pre-diabetic, may have experienced a different response than the overall group.

Cure Parkinson’s and Van Andel Institute also funded two sub-studies as part of the exenatide trial. The first sub-study used a type of brain imaging called DaTscan that measures dopamine in the brain. Dopamine is a chemical messenger that is lost in Parkinson’s, leading to the disease’s movement-related symptoms. Understanding dopamine changes in the brain may help monitor disease progression and assess if a medication is working or not.

The second sub-study evaluated whether a wearable device — called a gait monitor — and an accompanying smartphone app accurately monitored participants’ movement-related symptoms. Currently, Parkinson’s symptoms are assessed using a comprehensive questionnaire. It is our hope that wearable devices will provide more and better information on a person’s symptoms.  

Researchers are analyzing data from these sub-studies and results are expected later this year.  

What about other diabetes drugs?

Exenatide is a GLP-1R agonist, a type of Type 2 diabetes medication that helps control blood sugar by promoting insulin production. Although exenatide was the focus of the recent trial, it is not the only GLP-1R medication being studied in Parkinson’s. Because of variations in how different drugs work, it is possible that another GLP-1R may have better success.

For example, analysis of spinal fluid samples from exenatide trial participants suggests that only small amounts of the medication reached the area in the brain affected by Parkinson’s, potentially limiting its effectiveness. Other similar drugs may be more effective in this regard.

In April 2024, a phase 2 clinical trial of the GLP-1R medication lixisenatide suggested that the treatment may slow progression of movement-related symptoms in Parkinson’s.² A phase 2 trial of liraglutide, another GLP-1R drug, did not slow symptom progression but did appear to improve non-movement-related symptoms and quality of life.³

Like the exenatide trial, the lixisenatide and liraglutide trials were part of the Cure Parkinson’s–Van Andel Institute International Linked Clinical Trials program, the largest drug repurposing effort for Parkinson’s in the world. Better understanding the effects of GLP-1Rs — and why some may work better than others for Parkinson’s — is an important goal for the program’s collaborative network of scientists, doctors and people with Parkinson’s. 

Could other medications slow Parkinson’s progression?

There are many different types of medications being studied for their potential use in Parkinson’s. Other drugs in iLCT’s pipeline include:

• Ambroxol, a cough medicine commonly used in Europe. A phase 3 trial is planned following results of a phase 2 trial that demonstrated ambroxol’s ability to reach the brain and increase levels of a protective protein.
• Low-dose lithium, a treatment for mood disorders. A small, phase 1 trial will explore lithium’s ability to affect two Parkinson’s related biomarkers.
• Dapansutrile, an anti-inflammatory medication. A small, phase 2 trial will assess safety and tolerability of the drug in Parkinson’s and evaluate its ability to reduce inflammation in the brain.

These medications have been prioritized for research because they target pathways and processes in the body that also have been linked to Parkinson’s disease. You can read more about iLCT and drug repurposing here.  

Although we hope that every clinical trial will produce a new therapy that improves quality of life, the unfortunate reality is that such success can be rare. By simultaneously pursuing multiple promising potential therapies, we hope to increase our chances of finding effective ways to reduce symptoms, slow progression and improve quality of life.

Where do we stand in better understanding the disease and its causes?

Parkinson’s is a complex disease. Truly understanding its causes and finding new ways to address them requires a collaborative, multi-pronged approach. We can do more — faster and better — when we work together.

Here are a few examples.

The first is from VAI: Our researchers study how different genes contribute to Parkinson’s, how the structure of the brain may protect or predispose people to Parkinson’s, the role of aging and inflammation, and the impact of epigenetics, which are changes that affect how genes work without altering the gene itself.

Importantly, we consider how all these factors work together to influence disease risk and progression. We also collaborate with colleagues both at VAI and other institutions to tackle complicated questions.

This approach is called team science, and it brings together experts from different fields to address challenging problems.

In addition to iLCT, another great example of team science is the work enabled by Aligning Science Across Parkinson’s (ASAP), which aims to accelerate discovery by providing resources, enhancing collaboration and improving data sharing.

I’m fortunate to be part of an ASAP team, along with VAI’s Dr. Michael Henderson and colleagues at University of Minnesota. We’re studying how age-related loss of function in cells, a process called senescence, affects Parkinson’s onset and progression. Targeting senescence may offer additional options for potential new therapies.

Dr. Henderson is also part of another ASAP team led by colleagues at Yale University. They’re exploring how deep connections between cells — called networks — influence the development of Parkinson’s-related dementia.

This is just a snapshot of the research and team science going on around the world to understand Parkinson’s in deep detail. The insights generated from this important work give us potential new targets to explore for treatment and, if successful, in clinical trials.

A closing note

From participating in clinical trials to sharing insights and experiences, we are immensely grateful for the contributions of the Parkinson’s community. Progress would not be possible without the dedication and support of the people most affected by the disease.

Together, we will continue to move forward in pursuit of our common goal — improving quality of life for people with Parkinson’s and finding therapies that slow disease progression.

Funding Acknowledgements

¹ The exenatide trial was funded by the National Institute for Health & Care Research (NIHR) with support for sub-studies from Cure Parkinson’s and Van Andel Institute.

² The LixiPark trial was sponsored by the Toulouse University Hospital and co-funded by Cure Parkinson’s, Van Andel Institute and the French Ministry of Health, with drug and placebo support from pharmaceutical company Sanofi.

³ The liraglutide trial was funded by Van Andel Institute and Cure Parkinson’s.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.