Yesterday, biotechnology company Amarantus BioScience Holdings, Inc. (AMBS-OTC) announced that the clinical trial results of its Phase 2a study of eltoprazine to treat Parkinson’s disease levodopa-induced dyskinesias (PD-LID) would be published in an upcoming print edition of Brain: A Journal of Neurology.What is Eltoprazine?
Amarantus is developing eltoprazine to treat the primary side effects of PD-LID, a condition linked to the Parkinson’s disease medication levodopa. A small molecule drug candidate, eltoprazine is a selective partial agonist on the 5-HT1a/1b receptors of the serotonergic system in the brain. The serotonergic system is linked to a wide range of motor and behavioral disorders, including aggression, cognition, attention, and control. Over 700 patients to date have been given eltoprazine at varying doses as high as 30mg, with the active dose typically being 5mg. Primary and secondary endpoints were met in Phase 2 trials for eltoprazine to treat PD-LID as well as in Phase 2 trials of the drug as a potential therapy for Adult Attention Deficit Hyperactivity Disorder (“Adult ADHD”). Eltoprazine has been reported to be well tolerated with no serious adverse events reported.
The next step in eltoprazine’s development is Phase 2b or Phase 3 clinical studies in the areas of PD-LID and Adult ADHD. To this end, Amarantus submitted a request to the FDA in September 2014 for a review and written feedback of its proposed Phase 2b clinical trial design for eltoprazine in PD-LID.
Parkinson’s Disease Levodopa-Induced Dyskinesia (PD-LID)
Parkinson’s disease treatment was revolutionized in the 1960s by the introduction of levodopa. Following its discovery, however, patients undergoing continuous treatment reported complications, such as choreoathetoid movements and “off episodes.” Levodopa-Induced Dyskinesia (LID) is characterized by a variety of hyperkinetic movements, such as chorea (abnormal involuntary movement) and dystonia (involuntary muscle contractions). LID typically begins in the lower extremity ipsilateral (occurring on the same side of the body) to the side first affected by PD. In the beginning, patients may not notice subtle hyperkinetic movements; though, as it progresses, LID may interfere with activities, leading to functional impairment, disability, and poor quality of life. The risk for developing LID has been linked to the disease’s severity, younger age of onset, female sex, duration of levodopa treatment, and total levodopa exposure. A literature survey of more than 2,000 publications identified LID in roughly 40% of PD patients treated with levodopa for four to six years. An alternative review found a prevalence of LID in up to 85% of patients with PD (noting that different methods to recognize LID have resulted in disparities in its frequency rate [as reported in literature]).
The current standard of care for LID is amantadine, which is believed to work reasonably well but carries a number of side effect profile issues as well as pharmacokinetic issues—thus, it is not ideal. Amantadine extended release has achieved improved pharmacokinetics though it still carries significant side effects. As a result, there remains a significant unmet medical need for improved therapy, which Amarantus believes that its development candidate, eltoprazine, may satisfy.
Publication of Phase 2a Data
A Phase 2a dose-finding study was conducted with eltoprazine to determine its effect against PD-LID. The double-blind, randomized, placebo-controlled clinical study was led by Professor Per Svenningsson, M.D., Ph.D., Centre for Molecular Medicine, Karolinska Institutet; Professor Anders Bjorklund, Ph.D., Faculty of Medicine at Lund University; and Professor Hakan Widner, M.D., Ph.D., Faculty of Medicine at Lund University. The study was partially supported by a grant from The Michael J. Fox Foundation for Parkinson’s Research.
Excerpt from Amarantus’ February 10, 2015, press release describing the Phase 2a study…
“The study in 22 patients with long-standing PD-LID was a randomized, four-way crossover design in which patients received a single dose of placebo and eltoprazine, at 2.5, 5, and 7.5 mg, in combination with a challenge dose of levodopa (1.5 times usual dose), on four different days, separated by an interval of a week. Data from the study demonstrated that eltoprazine significantly reduced peak dose dyskinesia at both the 5 and 7.5 mg doses using the Combined Dyskinesia Rating Scale. The 5 mg dose also showed a significant anti-dyskinetic effect on other measures of dyskinesia, including the Rush dyskinesia rating scale. Importantly, there were no adverse effects on levodopa efficacy at any dose level as evidenced by United Parkinson’s Disease Rating Scale (UPDRS Part III) observation. Additionally, all dose levels of eltoprazine were well tolerated with no major adverse effects reported.”Amarantus further reports that results support advancing eltoprazine into Phase 2b chronic dosing clinical studies as a treatment for patients with PD-LID—which could occur as early as the first quarter 2015.
Thus far, the results have been published online in Oxford Journals' Brain under the paper title “Eltoprazine Counteracts L-DOPA-induced Dyskinesias in Parkinson’s Disease: A Dose-Finding Study.” Print publication in Brain is forthcoming.
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