Objective/Rationale:
To confirm the found beneficial effects of DP-102 (reduced dyskinetic effects at motoric equieffective doses in comparison to regular levodopa) in a pre-clinical model of Parkinson disease. To prove comparability of peripheral pharmacokinetics of DP-102 and levodopa in order to exclude peripheral pharmacokinetic differences as a source for central beneficial dopaminergic effects in the pre-clinical model of Parkinson disease. To provide sufficient amount of active pharmaceutical ingredient (DP-102) by an upscalable synthetic procedure ensuring reasonable cost of goods.
Project Description:
An improved synthetic method, designed to be upscalable to cGMP level (technical scale) will be used and validated to obtain 100 g DP-102 at GLP quality which will allow completion of the pre-clinical program and assurance of later cost of goods to be in a reasonable range.
In order to achieve further evidence for a longer duration and/or higher motor efficacy of corresponding DP-102 doses in relation to levodopa doses and a larger therapeutic window between therapeutic motor effective dose and the lowest dyskinetic dose, a dose response relations (escalating doses) will be established in a non-primed pre-clinical model chronic MPTP model for either one of the active ingredients followed by a cross-over session in each individual. After the determination of the largest non-dyskinetic levodopa dose, this dose will be used for a pharmacokinetic re-exposition for both compounds in order to prove comparable plasma concentrations.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The triple-deuterated levodopa analogue (DP-102) provides a deuterated dopamine that is more stable against metabolic degradation leading to a prolonged half-life and improved availability in the brain. The deuteration additionally prevents excessive formation of norepinephrine. This allows a significant dose-reduction without loss of anti-parkinsonian effect and a lower degree of dyskinesias.
Anticipated Outcome:
The synthesis of a major amount of the active ingredient is a pre-requisite for further investigations. The further investigations in a pre-clinical Parkinsonian model (systemic MPTP) will be of special relevance in drug-naïve pre-clinical models exposed to escalating dopaminergic doses (5 days each) and is expected to allow to confirm a lower dose of DP-102 to induce an equivalent effect on activity and a higher dose and/or a later time to induce dyskinesia in comparison to regular levodopa.
Final Outcome
After solving a number of chemical synthetic issues it is now possible to manufacture sufficient amount of the active pharmaceutical ingredient at cGMP quality to supply the intended Clinical Phase I and II trials and the ongoing nonclinical research and pharmaceutical development.
Pre-clinical models were pre-treated with MPTP till they reached a clinically severe Parkinsonian state, then randomized into two groups (n=8/group), which were either treated with escalating single doses of deulevodopa or L-DOPA together with carbidopa each in two sessions. During this session deulevodopa turned out to be 1.5 fold more potent than regular levodopa both with respect to the immediate disability reduction and the immediate induction of dyskinesia. Furthermore, a significant prolongation of the reduction in disability and ON time could be proven for deulevodopa compared to levodopa. In primed pre-clinical models during the second half of action of single doses a larger benefit of disability reduction vs. dyskinesia was observed. The outcome motivates us to look whether this advantage can be translated into an oral levodopa analogue with lower risk for fluctuations in patients.
Researchers
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Rudolf-Giesbert Alken