Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, Hibbert S, Budnik N, Zampedri L, Dickson J, Li Y, Aviles-Olmos I, Warner TT, Limousin P, Lees AJ, Greig NH, Tebbs S, Foltynie T. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3; PubMed.
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National Institute on Aging, National Institutes of Health
This Dilan Athauda/Tom Foltynie Lancet article evaluating the GLP-1 agonist exenatide in Parkinson’s disease (PD) patients in a randomized, double-blind, placebo-controlled trial provides a highly promising finding, in that this approved Type 2 diabetes mellitus drug holds potential to impact the course of the disease itself, and not merely the symptoms of PD. Currently available treatment strategies can mitigate many of the symptoms of PD over several years, but—similar to Alzheimer’s disease (AD)—the disease continues to progress and worsen. Hence, for both disorders, finding and developing well-tolerated drugs that reduce disease progression is imperative.
The results from this exenatide PD clinical trial, together with those of Tom Foltynie and colleagues’ prior study (Aviles-Olmos et al., 2013) and a huge number of preclinical studies that include our own (reviewed in Kim et al., 2017) fully support continued clinical evaluation of exenatide in PD over a longer duration and in well-designed, multicenter clinical trials with the potential to recruit more participants. With our increasing knowledge of the synergistic mechanisms via which exenatide and related incretin mimetics appear to inhibit pathways that drive disease progression in cellular and animal models of PD, it would clearly be valuable to know whether such pathways are affected in PD patients administered exenatide. This can potentially be evaluated in well-designed biomarker studies, and provide insight into which PD patients might better respond to exenatide.
Finally, many of the pathways that exenatide and incretin mimetics positively impact are relevant across neurodegenerative disorders—both acute, like traumatic brain injury and stroke (Tweedie et al., 2013; Greig et al., 2014), and chronic, like AD and multiple system atrophy (Hölscher 2014; Basil et al., Brain 2017, in press), and hopefully the recent positive results from this exenatide PD trial will encourage the consideration of clinical trials in these disorders that, like PD, lack effective treatments.
References:
Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T. Exenatide and the treatment of patients with Parkinson's disease. J Clin Invest. 2013 Jun 3;123(6):2730-6. PubMed.
Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH. A New Treatment Strategy for Parkinson's Disease Through the Gut-Brain Axis: The Glucagon-like Peptide-1 Receptor Pathway. Cell Transplant. 2017 Apr 26; PubMed.
Tweedie D, Rachmany L, Rubovitch V, Lehrmann E, Zhang Y, Becker KG, Perez E, Miller J, Hoffer BJ, Greig NH, Pick CG. Exendin-4, a glucagon-like peptide-1 receptor agonist prevents mTBI-induced changes in hippocampus gene expression and memory deficits in mice. Exp Neurol. 2013 Jan;239:170-82. Epub 2012 Oct 8 PubMed.
Greig NH, Tweedie D, Rachmany L, Li Y, Rubovitch V, Schreiber S, Chiang YH, Hoffer BJ, Miller J, Lahiri DK, Sambamurti K, Becker RE, Pick CG. Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury. Alzheimers Dement. 2014 Feb;10(1 Suppl):S62-75. PubMed.
Hölscher C. The incretin hormones glucagonlike peptide 1 and glucose-dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimers Dement. 2014 Feb;10(1 Suppl):S47-54. PubMed.
View all comments by Nigel GreigUniversity of Alabama at Birmingham
This is an interesting study that has prompted a lot of discussion among both scientists and patients. It is a relatively small-scale trial, and enrolled people with moderate to advanced PD who were already on levodopa and a number of other medications. The only effect they saw was a change in the UPDRS 3 measured after being off their medications overnight. I would not call this effect “significant motor improvement,” as it was seen only under the artificial circumstance of withdrawing other medications. In terms of day-to-day “on” state motor symptoms, exenatide did not demonstrate any significant improvement over conventional treatment.
The deeper question here is whether exenatide has any long-term disease-modifying effects. Preclinical studies have suggested this is possible, but the current trial doesn’t resolve this question. While the improvement in “off” state could be a disease-modifying effect, it could also be a long-lasting symptomatic effect, or an effect on the pharmacodynamics of the other medications. There were also some significant side effects, including weight loss. These are a concern, but at least at present don’t seem to be a barrier to further study of exenatide.
On the whole, I think this study accomplished what is possible in a trial of relatively small scale—it established reasonable safety and tolerability, and provide the parameters needed for a larger-scale trial to address the question of long-term disease modifying effects.
And to answer the question I always get from my patients—outside of a clinical trial, I would not recommend treatment with exenatide to any of my patients with PD at this time. The benefits are uncertain at best, and there are clearly risks of therapy.
View all comments by David StandaertHenan University of Chinese Medicine
This is a very promising result that shows that the concept of using growth factors such as GLP-1 that can cross the BBB does improve progressive neurodegenerative conditions such as Parkinson's disease. We should keep in mind that all efforts to affect disease progression in AD or PD have failed, and here we see a clear result in improving the condition. When seen in the context of other positive outcomes of clinical trials, such as the nasal insulin treatment of Alzheimer's patients by Suzanne Craft and colleagues and the positive outcome ot the liragutide trial by Gejl et al., 2016, showing a protection of progressive neurodegeneration in18-FDG-PET imaging, it should be clear by now that this approach does genuinely improve the condition. By how much we do not know, but other clinical trials that test liraglutide or lixisenatide (both GLP-1 receptor agonists) are on the way. The main takeaway message from this trial is that we have found a target that does show clear improvements, and that is worth exploring further. We finally have a strategy that shows clinical improvements, which we were looking for in the last 60 years without success!
References:
Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, Rodell A, Brændgaard H, Gottrup H, Schacht A, Møller N, Brock B, Rungby J. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016;8:108. Epub 2016 May 24 PubMed.
View all comments by Christian HolscherMake a Comment
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