Dyskinesia – eltoprazine

Although in the short term levodopa can give significant improvements in the motor symptoms of Parkinson's disease, in the longer term dyskinesia is a problem

Parkinson’s disease remains untreatable in the long term. Although in the short term levodopa can give significant improvements in the disease’s motor symptoms with few short-term side-effects, in the longer term dyskinesia is a problem, along with a loss of efficacy and motor fluctuations. The dyskinesia gets worse as the dose is increased to counteract the reduction in efficacy. As a result, therapy is often delayed until the patient has more advanced disease.

A drug being developed by San Francisco-based Amarantus BioScience may provide some relief from levodopa-induced dyskinesia. Eltoprazine, originally invented by Solvay, has been shown in animal tests to inhibit the sensitisation of striatonigral medium-sized GABA spiny neurons to levodopa, the overactivation of which is associated with the appearance of dyskinesias.1 It simultaneously activates 5-HT1A and 5-HT1B receptors, being a selective partial agonist.

This activity may be of benefit to patients in the advanced stage of the disease, where serotonergic terminals take up levodopa and then convert it to dopamine. This abnormally released dopamine may lead to the induced dyskinesias.

In a double blind, randomised, placebo controlled dose finding Phase I/IIa trial, 22 patients with Parkinson’s disease were given a single oral dose of 2.5, 5 or 7.5mg of eltoprazine, in combination with a suprathreshold dose of levodopa.2

Eltoprazine

Following the levodopa challenge, the 5mg dose gave a significant reduction of levodopa induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale and Rush Dyskinesia Rating Scale, and also a maximum Clinical Dyskinesia Rating Scale score. There was also an antidyskinetic effect with the 7.5mg dose. The most frequent adverse effects with eltoprazine were nausea and dizziness.

It has potential in non-Parkinson’s related conditions, too, notably adult ADHD and Alzheimer’s aggression, and clinical trials are underway in both of these indications.

The company has announced Phase II results via press release of a study in elderly patients with Alzheimer’s aggression. No drugs are currently indicated for this specific condition, although many different products have been assessed in clinical trials, such as neuroleptics, antidepressants, anticonvulsants, anxiolytics and sedatives. The off-label prescription of a range of psychoactive medications is common, but significant adverse effects such as excessive sedation are common.

In the Phase II trial, subjects were given 5mg or 10mg of the drug twice a day, following a five-day taper on period there was a significant improvement in aggression in the group treated with eltoprazine compared with those given placebo, as measured by the Social Dysfunction and Aggression Scale at the end of a four-week treatment period. This treatment followed on from a washout from previous psychoactive treatments, and then a three-week placebo lead-in period. Further evaluation of the results is underway.

References

1. G. Paolone et al. Mov. Disord. 2015, 30, 1728

2. P. Svenningsson et al. Brain 2015, 138, 963

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