What are GLP-1 Agonists and why are these drugs important to CPT’s research?

Liraglutide, Lixisenatide and Exenatide (the synthetic form of Exendin-4) belong to a group of safe and well tolerated drugs called Glucagon-like peptide (GLP-1) agonists designed to mimic the action of human gut hormones or incretins (see Christian Holscher's pre-clinical work). The glucagon-like peptide-1 (GLP-1) receptor agonists increase the incretin effect in patients with type 2 diabetes, stimulating the release of insulin. GLP-1’s are currently used to treat insulin resistance (see Konrad Talbot's preclinical work) in type 2 diabetes mellitus and in recent years there has been research based evidence to suggest that they show great promise as a new treatment for Parkinson’s. The GLP-1 drugs are more stable than the actual human gut hormones and as such are longer-lasting. They, like the gut hormones, stimulate the pancreas to release insulin into the bloodstream thus helping to keep glucose levels within physiologically appropriate levels. 

Why do researchers think these drugs have the potential to slow, stop or reverse Parkinson’s?

GLP-1 receptors are also found in the brain. Systemic insulin resistance is one feature of type 2 diabetes that is thought to be associated with the onset of Parkinson's (PD) and people with PD commonly display impaired glucose tolerance which can induce brain insulin resistance. This impaired insulin signalling has not only been related to α-synuclein build-up and mitochondrial dysfunction but also behavioural abnormalities seen in Parkinson’s such as impaired cognition, anxiety and depression.

Because of the association between diabetes and Parkinson’s, there has been a growing interest in GLP-1 receptors and Exenatide treatment for neurodegeneration. This interest has resulted in numerous preclinical studies which have demonstrated strong, reproducible evidence that Exenatide has beneficial "disease modifying" effects when tested in a range of experimental models of PD.

What will the trial/study investigate?

Based on research evidence, the trials of these drugs will investigate their effectiveness in protecting motor activity in people with Parkinson’s, enhancing neurogenesis (neurone repair), protecting neuronal function, reducing cell death and reducing and protecting against oxidative stress of neurons in the brain. The use of GLP-1’s does not affect blood sugar levels in non-diabetic people and GLP-1 therapies have good safety profiles as shown by the large use of diabetic drugs currently on the market. Liraglutide Lixisenatide and Exenatide are given by injection (- the active ingredient is a peptide protein and if taken by mouth it would be digested making it ineffective.) However the latest trial with Exenatide is using a different formulation (Bydureon) which has reduced the requirement to once weekly. There are also some new preparations in development that might allow administration as a depot injection once every 6-12 months.

What happens after the trials?

Existing therapies, such as levodopa, help mitigate symptoms but do not slow or stop disease progression. Moreover, levodopa typically becomes less effective over time and comes with side effects such as uncontrolled movements. If scientists can find a drug that impedes the progression of the disease, it could give people more years with fewer symptoms and prolong the number of years that levodopa is effective. The goal is to prevent two of the most debilitating complications of advanced disease—falls and cognitive decline.

Initial studies provided strong reinforcement for the further study of the GLP-1 drug family as a potential disease modifying agent in PD.

People with Parkinson’s who received exenatide showed a slight improvement in their motor function, although it is not clear whether this is due to the drug affecting the disease’s underlying mechanisms or if it is temporarily alleviating symptoms. A larger study is needed to evaluate whether exenatide actually slows disease progression.
Exenatide also appeared to be safe based on results from the trial. Some people experienced slight weight loss as well as injection site irritation, nausea and loss of appetite. However, more research is needed to definitively prove that it is safe and effective as a disease-modifying therapy in Parkinson’s. The results were in line with an earlier, smaller clinical trial in which participants also showed slight improvements in motor symptoms.

The success of these trials should also elicit support to conduct large scale trials which could ultimately enable regulators to judge whether the safety, tolerability and natural effects of the use of these drugs support their widespread use in PD. In the meantime there are a number of routes available to help fast track innovative breakthroughs in treatment not least that in the face of what they consider to be sufficient evidence of efficacy, health care professionals and experts in the field may choose, in consultation with patients, to prescribe them off label i.e without the formal regulatory licence for the indication. 

Source references:

www.ncbi.nlm.nih.gov/pubmed

www.ncbi.nlm.nih.gov/pmc