Flibanserin in Levodopa-induced Dyskinesia: MPTP-lesioned Pre-clinical Model
Therapeutics Development Initiative, 2010
Different mechanisms of action are considered relevant for provoking the involuntary abnormal jerking and hyperextensive or writhing-like twisting and turning movements called dyskinesias which appear after years of levodopa treatment and as Parkinson’s disease progresses. To find out whether a mechanism of action is of practical relevance, it is essential to test it in a pre-clinical model mimicking Parkinson’s disease as closely as possible.
Pre-clinical models having been rendered Parkinsonian by the toxin MPTP and which develop dyskinesias under levodopa treatment will be treated by either levodopa alone or in conjunction with different doses of Flibanserin to see whether Flibanserin at any dose reduces dyskinesias without hindering the antiparkinsonian effects of levodopa. To that end, the models will be assessed in a variety of tests assessing general activity, Parkinsonian disability and dyskinesias. These tests are highly standardized and the investigators who carry them out will not know whether a model has received Flibanserin or just levodopa alone. They will score the models for the different tests and the scores for the different treatment groups will be compared and analyzed statistically.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Dyskinesias are major problem in advanced Parkinson’s disease: involuntary movements make day-to-day life for the patients difficult and prevent social life; they also prevent patients from receiving the optimum treatment for their Parkinsonian symptoms, as dyskinesias often force to reduce levodopa or to substitute it by other drugs, with the price of an increase in Parkinsonian symptoms. If Flibanserin were able to reduce dyskinesias without hindering levodopa, it would allow for a much better treatment of Parkinsonian symptoms.
Flibanserin is a compound acting on a brain transmitter called serotonin, which is unlikely to have a negative impact on the antiparkinsonian effects of levodopa. So, the anticipated outcome is that Flibanserin will alleviate dyskinesias without hindering levodopa’s beneficial effects. As Flibanserin has been tested in more than 3000 patients with Hyposexual Desire Disorder, it can be considered a safe drug. If the study confirms its antidyskinetic potential, it would offer a fast inroad into the treatment of dyskinesias.
The clinical development of Flibanserin in so-called hypoactive sexual desire disorder has recently been discontinued by the pharma company Boehringer Ingelheim. The drug has been investigated in more than 5000 patients and failed due to inconsistent efficacy data. However, the tolerability was good. The pharmacological profile of Flibanserin makes it a promising drug for the treatment of dyskinesia in advanced stage Parkinson’s patients where currently no treatment is available. The unique opportunity of Flibanserin is that the clinical development in Parkinson’s patients could start almost immediately and the treatment would be rapidly available for patients. In two pre-clinical models of dyskinesia, beneficial effects of Flibanserin could already be demonstrated. In the MJFF-supported pre-clinical study, trends for an anti-dyskinetic effect could be confirmed. However, the efficacy was less compared to the prior pre-clinical studies. Due to methodological insufficiencies the study results are not unequivocally clear and should be repeated. Nevertheless, irrespective of this outcome the prerequisites for starting a clinical study in Parkinson’s patients can be met as soon as the originator of the drug embarks into collaboration.
Senior Project Manager at Monitoring Force GmbH
Location: Munster, Germany