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Exenatide for Parkinson Symptoms: Early Results Are Positive

Exenatide for Parkinson Symptoms: Early Results Are Positive

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Exenatide is a licensed drug for the treatment of type 2 diabetes mellitus. It is a glucagon-like peptide 1 (GLP-1) receptor agonist that improves glucose control by stimulating insulin release from the pancreas and inhibiting glucagon release. In laboratory models of several neurological conditions, including some for Parkinson disease (PD), exenatide has been shown to protect neurons and induce beneficial neuroplastic changes.

In an open label trial published in 2013, patients treated with exenatide for 1 year had a clinical advantage over patients not receiving injections, in terms of motor severity and cognitive function that persisted a year after cessation of the drug. As the trial was open label, it was uncertain if any placebo effects contributed to the results and it was difficult to draw firm conclusions regarding efficacy.

We recently published the results of a phase 2 double-blind placebo control trial. In this study, 60 participants with “mid-stage” PD who were already receiving dopaminergic replacement therapy were randomized to self-administer exenatide 2 mg as Bydureon® (a slow release, injectable formulation of exenatide) or matched placebo on a once weekly basis for a period of 48 weeks. The primary outcome was the severity of PD motor symptoms using the MDS-UPDRS part 3 in the “Practically defined OFF medication state” at the 60-week time-point, ie, after a 12-week washout period.

The primary outcome was achieved with similar results to the previous open label trial. At 48 weeks, patients receiving exenatide exhibited better motor function compared with those on placebo. The difference adjusted for baseline scores was 4.3 points. Most importantly, this difference persisted (3.5 points) after the 12-week washout period, at which point exenatide was no longer detectable in the serum.

Another tool used to objectively measure change was DaTscan imaging. Each participant was imaged at baseline and again at the end of the trial after exenatide washout. Although our analysis showed a gradual decline in dopamine uptake in both groups, in 3 areas (right caudate, and right and left putamen) patients treated with exenatide had reduced rate of decline compared with the placebo group (at P<.003 uncorrected for multiple comparisons).

Importantly, the drug was well tolerated in this patient group, who reported common adverse GI effects and injection site reactions in similar frequencies to previously reported diabetes trials. Weight loss was more common in the exenatide group (patients lost an average of 2.6 kg, which was reversed on drug cessation). The trial had a number of limitations, common to any small phase 2 trial. The relatively small number of participants meant that the trial only had the power to detect substantial effect sizes and only if there was little variation in the size of the effect between participants.

Simple clinical, metabolic, and genetic observations of patients with PD compared with age-matched control patients with other neurodegenerative disorders can help shed light on the relationship between insulin resistance and neurodegeneration.

While the trial achieved its primary outcome, none of the secondary outcome measures reached the threshold for statistical significance. Therefore, it is absolutely vital that these findings are reproduced in a much larger sample of patients across multiple sites to allow the scientific and health care communities, as well as regulatory agencies, to assess the consistency and reproducibility of these findings across the broader range of outcome measures, including those most relevant to patient function and quality of life.

A further issue that complicates trials with small numbers of participants is that even with randomization, differences between groups allocated to active drug or placebo can occur at baseline. It can be impossible to know if these baseline differences had an impact on any differences at trial end although our analysis was preplanned to adjust for baseline severity of PD, and was further adjusted for differences in baseline Levodopa Equivalent Dose (LED) and/or the change in LED over the course of the trial. Importantly, these adjustments did not change the statistical effect favoring exenatide detected in the primary outcome.

This study underscores the importance of having the relationship between GLP-1 receptor stimulation and neurodegeneration be studied in more detail. Simple clinical, metabolic, and genetic observations of patients with PD compared with age-matched control patients with other neurodegenerative disorders can help shed light on the relationship between insulin resistance and neurodegeneration.

For patients, the advantage of 3 points over the course of 1 year is still relatively small, and over the course of the trial translated to trivial effects on quality of life. However, if the effects of long-term exenatide treatment turn out to be cumulative year on year, that would be definitive evidence that exenatide can alter the course of Parkinson disease.

Therefore, to provide irrefutable evidence that exenatide confers a therapeutic advantage to patients with PD requires a larger multisite replication study with longer-term follow up, to show that the magnitude of its effects compared with placebo increase with each year of use.

Ultimately, however, a truly meaningful advantage of this drug will require that the severity of PD symptoms is less among people on exenatide, irrespective of optimal dopaminergic replacement therapy. This may require alternative tiral designs, all of which have their strengths and weaknesses, or the use of even longer-term follow up to evaluate the emergence of dopa refractory motor and non-motor symptoms. Also, while relatively well tolerated, exenatide causes weight loss and gastrointestinal upset and these factors need to be weighed against any positive benefits before exanatide can be considered as a PD treatment.

 

 
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