"The Cure Parkinson's Trust (CPT) has invested in developing GLP-1 agonists as potential disease-modifying treatments for the last 8 years. With Professor Tom Foltynie we supported and designed the first study of exenatide in people with Parkinson’s that provided the pivotal groundwork for this more recent trial. Importantly we are supporting and shaping the trials that need to follow to ensure that we can find the right route to develop these drugs into viable treatments for people with Parkinson’s as quickly as possible. Our mission to slow, stop and reverse the progression of Parkinson’s, and these pioneering findings, exemplify CPT’s innovative strategy” - Richard Wyse, Director Research & Development.

The Bydureon Trial - key findings. 

'Is exenatide a treatment for Parkinson's disease?' - Commentary written by Dr Athauda, Dr Wyse, Professor Brundin and Professor Foltynie, published in the Journal of Parkinson's Disease.

CPT believes that the key element needed to determine how best to slow, stop or even reverse Parkinson's is excellent science, carried out in a collaborative way and this is the key mission of the Linked Clinical Trials initiative. As Tom Isaacs, late president and co-founder of CPT said: “We all need to work as a team because this game is not about who finds the cure, it’s about how and when we find the cure.”

This ethos underpinned a recent meeting hosted by CPT during which attendees discussed the groundbreaking results of the recently published Bydureon trial and related research on GLP-1 agonists, drugs commonly used to treat diabetes which hold promise for repurposing as potential Parkinson’s therapies. 

Tom Isaacs' enduring aim was to fund and facilitate research with the potential to slow, stop and reverse the disease. When CPT funded the initial exenatide study, we recognised then the potential this molecule has as a disease modifying treatment for Parkinson's. The results of this recent study are testament to Tom's belief that the science to slow or stop the progression of the condition is within our grasp.

Professor Tom Foltynie, UCL, who led the Bydureon trial (a once weekly injectable version of exenatide) said:

This is the strongest evidence we have so far that a drug could do more than provide symptom relief for Parkinson’s disease

In 2012, the charity’s international Linked Clinical Trials Committee pioneered the prioritisation of three GLP-1 agonists to move forward into clinical trials: Liraglutide, Lixisenatide and exenatide (Bydureon). The Liraglutide study is underway, the Lixisenatide trial will start later this year and the Bydureon trial has now completed.

The GLP-1 meeting focused on a series of presentations with Q&A sessions guided by Professor Nigel Greig (National Institute on Aging, National Institutes of Health), and Dr. Jamie Eberling (Michael J. Fox Foundation for Parkinson’s Research). These sessions identified the next steps needed to make these treatments available for people with Parkinson’s in the shortest possible time frame as well as the research investigations required to advance the field.

The meeting opened with the results of the Bydureon trial. This was followed by a discussion around the next steps required before considering this drug for licensing in Parkinson’s.

The team from University College London’s Institute of Neurology, led by Professor Tom Foltynie and supported by Dr. Dilan Athauda, recently published results of a Michael J Fox Foundation funded Phase II trial evaluating the injectable diabetes drug Bydureon in people with PD. Early indications are that it could be beneficial in Parkinson’s, but additional investigations are necessary to define its effect fully.

The objective of the study was to measure whether Bydureon had an effect on the movement (motor) symptoms of people with Parkinson's when not taking their regular medication, and results showed clear benefit (as measured by the MDS-UPDRS scale). This benefit persisted 12 weeks after stopping the Bydureon injections. The trial also indicated that the drug was safe and generally well tolerated. A larger study is needed to evaluate whether exenatide actually slows disease progression. The results were in line with an earlier, smaller clinical trial in which participants also showed improvements in motor symptoms.

This trial was not designed to definitively prove whether Bydureon changes the underlying disease in cells (disease modification) or whether it only produces symptomatic change. This is why we urgently need to carry out further investigations to define its effect more fully. 

Click here to read the Michael J Fox Foundation blog about the trial results.

As background, why might a diabetes drug provide benefit in Parkinson’s?

Exenatide (the synthetic form of exendin-4) is a safe and well tolerated medication that is commonly used to treat insulin resistance in Type 2 Diabetes Mellitus. It is usually taken as a twice daily injection (Byetta, as tested in 2010) or once weekly injection (Bydureon).

Exenatide works by activating glucagon-like peptide (GLP-1) receptors in the pancreas to stimulate insulin release. GLP-1 receptors are also found throughout the brain and have other properties that may be relevant in Parkinson’s. Earlier work has shown that GLP-1 agonists, drugs that switch on GLP-1 receptors, can improve dopamine neuron function, are anti-inflammatory, can switch on cell survival signals and can help improve energy production. 

Insulin resistance, a feature of type 2 diabetes, is also thought to be associated with the onset of Parkinson’s. Some people living with Parkinson’s display impaired glucose tolerance, which can induce brain insulin resistance. This has been related to a build-up of misfolded alpha-synuclein in neurons (and this aggregation is a feature of Parkinson’s), mitochondrial dysfunction and impaired cognition, anxiety and depression, all of which can be features of Parkinson’s. It is also thought that alpha-synuclein aggregation can itself induce worsening insulin resistance in the brain, thus contributing to a vicious cycle of worsening alpha-synuclein toxicity. 

The Bydureon trial has produced an early signal of benefit in movement aspects of Parkinson’s and now our efforts must be directed toward two key areas: the potential new licensing pathway for repurposing Bydureon and for extended research.

The first debate at the recent meeting in London focused on the immediate next steps and what information is relevant and required to facilitate securing a license. It is our intention to proceed with urgency; should Bydureon prove beneficial for people with Parkinson's we must work to ensure it is available as a Parkinson's treatment as soon as possible. This involves the design, funding and implementation of a phase III trial to collect the evidence required to license the drug for use in Parkinson’s. This new study will replicate previous work using a similar methodology with additional key outcome measurements and with more participants over a longer period of time to ensure results are correct and relevant to the progression of the disease. This further study will also address previous procedural limitations and provide insight into longer-term use of the drug.

In a series of presentations, researchers discussed the details of other planned clinical trials using GLP-1 agonists, both in Parkinson’s and Alzheimer’s. The meeting debated the outcomes being used and compared similarities and differences in methodology.

There are two additional clinical trials underway with parallel compounds to Bydureon (Lixisenatide in France and Liraglutide in the USA). These trials involve patients at different stages of Parkinson's and have different primary objectives.

The Liraglutide trial primary end-point will be the effect of GLP-1 agonist treatment on cognition, as measured by the Mattis dementia rating scale. Motor (MDS-UPDRS) and non-motor (NMSS) scores will also be measured before and after treatment. Through the Liraglutide trial, Professor Michele Tagliati and his team at Cedars-Sinai in Los Angeles are interested in evaluating the role and prevalence of peripheral insulin resistance in Parkinson's; understanding its impact on the body and any link with central insulin resistance in the brain; and whether the two are related. To this effect, every trial participant will be also tested with a cerebral PET scan in order to measure the effect of Liraglutide on brain energy metabolism.

In the Lixisenatide trial, a French multicentre study being run by Professor Olivier Rascol, University of Toulouse and Professor Wassilios Meissner, University of Bordeaux, like the Bydureon trial, the primary end-point is motor scores on the MDS-UPDRS. These tests are completed whilst participants are taking their normal medication. There is also a comparison after the end of the treatment period with tests taken without medication. Cognition is being assessed as a secondary outcome based on ‘MoCA’ scores (the Montreal cognitive assessment is a brief cognitive screening tool for mild cognitive impairment), while patients are not expected to show relevant cognitive impairment because they are being recruited to the trial at an early stage of Parkinson’s.

Professor Paul Edison, Imperial College, presented his trial of Liraglutide as a potential disease-modifying agent in Alzheimer’s disease. This well-resourced trial is already significantly underway with over half of the participants recruited. The trial will include both long-term clinical and imaging measures to determine whether this agent has the potential to slow down the progression of Alzheimer’s. The results of this study will further inform work in the field of GLP-1 agonists.

Professor Patrik Brundin, director of the Center for Neurodegenerative Science at Van Andel Research Institute and chair of the Linked Clinical Trials committee, presented his plans to move the agent MSDC-0160 into a clinical trial. This drug has similarities to another licensed drugs to treat type 2 diabetes, but MSDC-0160 is better able to enter the central nervous system and has few side effects, which together make it a more compelling candidate for clinical study in Parkinson's.

The meeting discussed the tactics we can employ to understand target engagement and stratification of Parkinson’s in trials of GLP-1 agonists: exosomes, imaging and genetic information as potential biomarkers.

Extracellular vesicles or exosomes have specialised functions and play a key role in processes such as intercellular signalling and waste management. Clinically, exosomes can potentially be used for prognosis, for therapy, and as biomarkers for health and disease, making them a powerful marker of change. 

Exosomes are a by-product of many processes within cells. As they are produced, they take a part of the process (usually proteins or genetic material) with them, rather like a memory. Most exosomes remain in their tissue of origin but some are found in the bloodstream. Dr. Dimitrious Kappogiannis at the National Institute on Aging, National Institutes of Health (NIH), in the US has examined exosome samples from participants on the Bydureon trial to compare the profile of the exosomes of those taking the drug and those on placebo. The difference found between the two groups suggests evidence for stimulation of the GLP-1 receptors. As a result of the discussions at the meeting, Professor Tagliati also expressed interest in using this technique for the Liraglutide trial.

Many studies, including the Liraglutide trial, are now employing brain imaging as a secondary end-point. This is important as it is impartial evidence of target engagement, and can also act as a further biomarker for changes in the brain.

Genetic evidence is also important and may highlight why some people might respond better to GLP-1 agonists than others. Professor Foltynie proposed genetic screening for all the participants in the Bydureon trial to enable sub-analyses according to genotype. Professors Meissner and Rascol reported that they are collecting genetic information in the Lixisenatide trial which could help detect genetic differences between the trial participants.

The meeting then focused on defining delivery and longevity for all these treatments and the new generation of drugs that are currently being developed

Those present discussed which of the GLP-1 agonist drugs were deemed “best” for patients; this being the most effective, best tolerated, easiest to administer and of longest effect.

Dr. Dong Seok Kim, from the Korean biotechnology company Peptron, reported on the company’s “Smart Depot” technology of an optimal slow-release form of Exenatide (PT302) in collaboration with the NIA and the NIH. PT302 (a once weekly or once fortnightly formulation of Exenatide now in phase 2 clinical trials in diabetes) delivers greater amounts of Exenatide into the brain to maximise its potential for the treatment of neurological disorders like Parkinson's. Peptron is planning a 'proof of concept' clinical trial to appraise the potential disease modifying effects of Exenatide, to optimise dosing as well as to define biomarkers of biological responses in PD.

Professor Christian Hölscher, Lancaster University, presented his work with the future of GLP-1 agonists combined with GIP agonists. These two groups of drugs are collectively called dual agonists – both are incretin hormones that work on a similar pathway to reduce insulin resistance and increase insulin signalling. Early indications in models of Parkinson's are revealing that, when combined, these drugs are potentially more potent on the movement aspects of the condition. There is further evidence they reduce oxidative stress and mitochondrial damage by reducing the activation of the inflammatory response. Importantly, these drugs also permeate through the blood brain barrier and seem to promote cell survival. However these dual agonists need to be tested in multiple models of Parkinson’s, such as an alpha-synuclein model, before they can progress into trials in people living with Parkinson’s.

Conclusions and collaboration

In keeping with CPT’s strong ethos of global alliances, this meeting forged a series of exciting collaborations that will further progress this important and pioneering area of research.

Immediate next steps include the design and funding of a further, larger and longer-term clinical trial using Bydureon aimed at replicating existing findings, investigating potential disease modification and consolidating the evidence needed to present to licensing bodies. This trial will begin in the spring 2019.

New trials will incorporate not only the lessons learned from these earlier trials, but also techniques to stratify patient cohorts and evaluate target engagement and change. Perhaps the most important issue is to define the most relevant primary outcome, whether related to patient quality of life, the time to major motor milestones, or the rate of progression of motor or non-motor symptoms despite optimal conventional medication.

Further Reading: 

Utility of neuronal-derived exosomes to examine molecular mechanisms that affect motor function in patients

with Parkinson Disease - A secondary analysis of the Exenatide-PD trial - Foltynie et Al. 2019

Read the late Tom Isaacs' Speech which he presented at the GLP-1 meeting.