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Alleviating late motor complications of Parkinson's disease by a continuous dopaminergic treatment with transdermal delivery of L-DOPA Pro-drug

NeuroDerm Ltd. is developing a novel delivery system of levodopa for the treatment of Parkinson's disease. Levodopa, a well-established medication for the treatment of Parkinson's disease (PD), is considered the most effective treatment of PD. However, when given orally, it is eliminated from the body very quickly. This results in cycles of sharp fluctuations of its concentration in the blood. It has been suggested that these frequent changes in levodopa blood concentrations, inherent with the oral administration of the drug, is a major factor responsible for the development of late motor complications, such as dyskinesia and on/off fluctuations. Conversely, it has been demonstrated that constant levodopa blood levels, achieved by intravenous infusion of the drug, are beneficial to PD patients who suffer from late motor complications. Yet, long-term intravenous infusion is not a practical solution for patients. NeuroDerm's new transdermal delivery system, which is designed to achieve a constant level of levodopa in the blood in a non-invasive manner, is practical for a long-term use, thus providing an effective treatment for PD patients who suffer from late motor complications. Previous efforts to deliver levodopa transdermally have failed because levodopa is insoluble, unstable in solution and does not penetrate through the skin. The main innovation of NeuroDerm's system is the use of a pro-drug, levodopa ethyl ester, (instead of levodopa itself) as the active component, in combination with stabilizers and skin penetration enhancers that allow a continuous delivery of the drug through the skin. Indeed, pre-clinical trials with this system in pigs demonstrated steady levodopa blood levels within the therapeutic range without intolerable adverse effects. Should testing of this new, non-invasive system in humans prove successful, it will provide a solution to the problem of late motor complications in PD, helping millions of patients world-wide for whom no satisfactory treatment is yet available.

Final Outcome

A phase 1 clinical study successfully demonstrated steady blood levels during the period the levodopa patch was applied to the subjects’ skin. However, irritation at the site of patch application was unacceptable for a product intended for chronic use. Ensuing efforts to eliminate this said local irritation to an acceptable level failed, preventing the project from moving forward and leading to its termination. The company has since embarked on a new project for a patch that is based on a different formulation. This new patch acts through a different mode of action. It is able to maintain constant therapeutic plasma levodopa levels without causing any detectable local or systemic toxicity. Having successfully completed a 14-d repeated toxicity study and an acute local irritation study in multiple preclinical models, NeuroDerm is planning to initiate a Phase I clinical trial with this new product. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}


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