Amarantus announces Phase 2a results for eltoprazine in Parkinson’s disease levodopa-induced dyskinesias

Eltoprazine reportedly demonstrated significant beneficial antidyskinesia effect at 5-mg and 7.5-mg doses, with no reduction of levodopa efficacy

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SAN FRANCISCO and GENEVA—Amarantus BioSciences Holdings Inc., a biotechnology company focused on neurology diagnostics and therapeutic products with the potential for orphan drug designation in the areas of neurology, psychiatry, ophthalmology and regenerative medicine, announced that the publication of the results of a Phase 2a study of eltoprazine in Parkinson’s disease levodopa-induced dyskinesias (PD-LID).
In an Oxford Journals paper posted online and published in Brain—A Journal of Neurology, titled “Eltoprazine Counteracts L-DOPA-induced Dyskinesias in Parkinson’s Disease: A Dose-Finding Study,” study researchers reported that the pharmacokinetic (PK) characteristics of eltoprazine in Parkinson’s disease (PD) patients are the same as those found in healthy subjects. Given the positive PK profile in PD patients and the acute antidyskinesia effect seen with the 5-mg nd 7.5-mg doses, further advancement of eltoprazine into Phase 2b chronic dosing clinical studies to treat patients with PD-LID is warranted, the authors of the paper say.
Eltoprazine is a small-molecule 5-HT1A/1B serotonin receptor agonist, investigational drug candidate, with a well-established safety profile. A Phase 2a dose-finding study was conducted with eltoprazine to determine its effect against levodopa-induced dyskinesia, in patients with PD. The double-blind, randomized, placebo-controlled clinical study was led by Dr. Per Svenningsson of the Centre for Molecular Medicine at the Karolinska Institutet, Dr. Anders Björklund at Lund University and Dr. Håkan Widner at Lund University. The study was partially supported by a grant from The Michael J. Fox Foundation for Parkinson’s Research.
As Amarantus notes, some researchers believe that, in the advanced stages of PD, as dopamine nerve terminals are lost, serotonergic terminals take up levodopa and convert it to dopamine instead. Unlike in dopamine nerve endings, the serotonin nerve terminals do not have a negative feedback loop, possibly causing an excessive release of dopamine and resulting in the development of abnormal involuntary hyperkinetic movements, known as levodopa-induced dyskinesias (LID). Presynaptic activation of serotonin receptors using a 5HT1A/1B agonist may dampen this excessive dopamine release.
In animal model studies of LID previously conducted in Björklund’s laboratory, simultaneous activation of 5-HT1A and 5-HT1B receptors was shown to effectively block LID. The Phase 2a dosing trial with eltoprazine was conducted as an initial clinical pharmacology study to determine if activation of 5-HT1A/1B receptors in PD subjects may replicate the effects of serotonin receptor activation seen in preclinical dyskinesia studies.
 “Eltoprazine’s anti-dyskinetic effect is promising, especially given the reduction in dyskinesia following a levodopa challenge at one-and-a-half times greater than the regular levodopa dose,” said Dr. Charlotte Keywood, chief medical officer at Amarantus. “Levodopa treatment is the current standard of care for patients to manage PD motor symptoms, despite the occurrence of dyskinesia with long-term use. Thus, we were very pleased to see that normal motor responses to levodopa, measured by UPDRS III, remained unchanged in all patients treated with eltoprazine.”
Amarantus expects to file its Investigational New Drug application with the U.S. Food and Drug Administration and commence its Phase 2b study of eltoprazine in PD-LID subjects in the first quarter of 2015.
“We are pleased to have the eltoprazine study results published in this prestigious peer-reviewed journal,” said Keywood. “The results of this proof-of-concept, first trial in PD-LID patients, support the findings of the nonclinical pharmacology studies conducted using animal models of PD-LID and show the predictive value of these models in aiding human drug development. The data from this study show an acute antidyskinetic effect of eltoprazine with no detriment to levodopa efficacy. With these data at hand, we are confident moving forward into longer-term dosing studies to further evaluate the utility of eltoprazine as a treatment for levodopa-induced dyskinesia.”
SOURCE: Amarantus BioScience Holdings Inc.

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