Objective/Rationale:
Eboo Pharmaceuticals Inc. is developing an approach to treating Parkinson’s disease (PD) via a delta agonist/mu antagonist (DAMA) mechanism expected to provide efficacious and well-tolerated initial therapy without the debilitating side effects of current therapy. In addition, DAMA compounds are expected to lower the dose of levodopa needed in chronic treatment, thus delaying the onset of sensitization and dyskinesia.
Project Description:
This project has been developed based on a milestone-focused approach. The first stage will investigate the toxicity of the compounds in vitro and the potential risk that a DAMA compound may elicit dyskinesia in a pre-clinical model of PD. If findings show an acceptable profile of safety and toxicity, then two compounds will progress to primate pharmacokinetic studies. A lead compound will be selected based on results of the studies. The lead compound will be assessed in pre-clinical (MPTP-treated) models for antiparkinsonian efficacy as well as levodopa-sparing potential and anti-dyskinesia activity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Initial early use of this compound may postpone the need for dopamine therapy and then, as an adjunct therapy, blunt the need for rapid escalation of dopaminergic dose levels. The primary dose-limiting sideeffect for levodopa and other dopaminergics is the development of dyskinesia. By delaying the start and slowing the dose escalation of dopamine replacement therapy, the window of treatment time before development of dyskinesia will be extended.
Anticipated Outcome:
The DAMA-based mechanism of action presents a novel and vital addition to the therapeutic options for PD patients and may significantly enhance the quality of life and extend the period of high motor function. This project will identify the best DAMA compound for further clinical development through assessments in pre-clinical models of efficacy and levodopa side-effects (dyskinesia).
Progress Report
Eboo Pharmaceuticals Inc. has successfully manufactured sufficient compound (DPI-289 and DPI-290) to support the full program of grant-funded activities as well as developing the vital assay system to determine blood levels of these compounds. The first set of studies completed have addressed the likelihood that a DAMA compound (using DPI-289 as the exemplar) will produce dyskinesia following repeated oral treatment. Pre-clinical models with focal dopamine depletion resulting from 6-OHDA micro-delivery to the midbrain responded with clear behavioral correlates of positive therapeutic benefit following oral doses of DPI-289. This therapeutic benefit was equal in magnitude to that seen with levodopa in the same model. However, whereas levodopa produces such severe correlates of dyskinesia that therapeutic benefit could not be observed after the first day of treatment, there was no sign of dyskinesia effects with DPI-289 and beneficial effects were observed through the full 15 days of dosing.
Following on from this crucial demonstration that the DAMA target has the potential to be equally beneficial as levodopa but without the dyskinesia burden, we are continuing with preliminary assessments of possible targets of general toxicity or safety concerns and the assessment of the pharmacokinetics of our two lead compounds. Selection of the single candidate compound will then gate the initiation of the full program of non-human primate efficacy models that will demonstrate the full range of potential efficacy of these agents while also defining which pathway forwards to regulatory approval has the highest chance of success in the clinical trials.
March 2014
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.