Diabetes Medication Exenatide Shows Promise In Treating … – MedicalResearch.com (blog)

MedicalResearch.com Interview with:Dr Dilan Athauda MRCPSobell Department of Motor Neuroscience and Movement DisordersUCL Institute of Neurology & The National Hospital for Neurology and NeurosurgeryLondon

MedicalResearch.com: What is the background for this study?Response: Exenatide is a synthetic version of a naturally occurring protein exendin-4 that was originally discovered by Dr John Eng in the early 1990s in the saliva of the Gila Monster, a venomous lizard native to the Southwestern United states. He and his team were looking for bio-active peptides in insect and lizard venom that could be useful for people with Type 2 diabetes. They discovered that exendin-4 was extremely similar to a human hormone called Glucagon-like peptide-1 (GLP-1). In humans, GLP-1 is secreted after you eat a meal to stimulate insulin secretion (and inhibit glucagon production) of which the end result is a lowering of blood sugar. Unfortunately human GLP-1 is rapidly broken down by a circulating enzyme called dipeptidyl peptidase IV (DPP-IV) and its effects only last minutes.

Importantly, it was discovered that exendin-4 is naturally resistant to the actions of this enzyme, meaning its effects on blood sugar control lasts much longer in the body. These properties made it very attractive to people trying to treat people with Type 2 diabetes and following many successful randomised controlled trials of patients with Type 2 diabetes in 2005, exenatide was approved for use as a treatment. During this time, work led by Nigel Greigs group at the NIA showed that first evidence that exendin-4 had neuroprotective properties, and could protect neurons from a variety of stresses and could also improve growth and rescue degenerating cells. Over the next few years, various groups used exendin-4 in a variety of animal toxin models of Parkinsons disease and showed that exendin-4 could halt the progression of Parkinsonism and prevent cell death in these models through beneficial effects on inflammation, mitochondrial function and cell survival.

Based on this encouraging pre-clinical data, Professor Foltynie supervised the first small, open-label, human trial of exenatide in patients with Parkinsons disease. The team found that patients treated with exenatide for 1 year (in addition to their usual medication) had less decline in their motor symptoms when assessed without their medication compared to the control group (just on their usual medication) and this advantage over the control group was still present 1 year after stopping the exenatide injections. However, this trial was open-label patients knew they were getting a (potentially beneficial) experimental therapy and so we couldnt exclude the fact that placebo effects were explaining some of the results we saw.

As a result of the potentially beneficial results seen in this small open label trial we carried out a double-blind, placebo controlled trial.

MedicalResearch.com: What are the main findings?Response: We found that after 48 weeks, patients treated with exenatide had a small but statistically significant advantage in their motor severity when assessed after temporarily halting their usual medication and that this advantage persisted 12 weeks after stopping exenatide. Datscan imaging also suggested a reduced rate of decline in the exenatide group. Parkinsons disease progresses slowly, and its important to note that these results, though exciting, were small, and patients did not notice any difference in their quality of life or on their day to day activities over the course of the trial period over their usual medication. We therefore need to conduct a much longer follow up trial with a larger group of patients across multiple centres to try to replicate (or refute) our findings and determine whether this advantage that we have seen accumulates with longer term treatment in order to definitively prove that exenatide alters disease progression.

MedicalResearch.com: What should clinicians and patients take away from your report?

Response: The results are encouraging this is the strongest indication we have so far that a drug may be affecting the underlying disease itself rather than masking the symptoms of the disease, however we must be cautious and its too early for us to recommend that everyone with Parkinsons disease should be taking this drug. These results, though exciting, were relatively small, and patients did not notice any difference in their quality of life or on their day to day activities over the course of the trial period over their usual medication. We therefore urgently need to conduct a much longer follow up trial with a larger group of patients across multiple centres to try to replicate (or refute) our findings and determine whether this advantage that we have seen accumulates with longer term treatment in order to definitively prove that exenatide alters disease progression.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We urgently need to conduct a much longer follow up trial with a larger group of patients across multiple centres to try to replicate (or refute) our findings and determine whether this advantage that we have seen accumulates with longer term treatment in order to definitively prove that exenatide alters disease progression.These results support accumulating evidence that this drug (and class of drugs) should be the subject of further investigation to assess their potential as a future therapy for Parkinsons disease.

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Citation:

Exenatide once weekly versus placebo in Parkinsons disease: a randomised, double-blind, placebo-controlled trial

Athauda, Dilan et al. The Lancet , Volume 0 , Issue 0 ,

DOI:http://dx.doi.org/10.1016/S0140-6736(17)31585-4

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