Erratum: Zhao et al., "Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala".

Abstract

<h3>Objective:</h3> Characterize the levodopa pharmacokinetic profile achieved with continuous subcutaneous administration of ND0612. <h3>Background:</h3> Continuous levodopa/carbidopa infusion is the optimal delivery route for patients with advanced Parkinson’s disease (PD), but current delivery systems require invasive surgical interventions. ND0612 is a proprietary liquid formulation of levodopa/carbidopa administrated subcutaneously through a mini-pump delivering a range of levodopa doses from 270mg/day to 720mg/day. <h3>Design/Methods:</h3> Two Phase II studies were performed. The first was a phase IIa study in which 16 PD patients were randomized to low-or high- dose ND0612 for 8-hours administration. The second was a double-blind, placebo-controlled study, in which 30 PD patients received low dose ND0612 or placebo, as adjunct to their current optimized oral treatment for 2-weeks, followed by a 1-week open label extension of ND0612 either with or without oral entacapone. <h3>Results:</h3> In the first study, fluctuations in levodopa plasma levels were markedly reduced (both doses) in comparison to baseline oral levodopa/carbidopa. Levodopa maximal plasma concentrations were dose proportionate; low and high ND0612 doses achieved 487ng/mL and 1454ng/ml respectively. Co-administration of entacapone BID increased levodopa plasma levels to 604ng/mL and 1844ng/mL in the low and high dose arms respectively. In the second study, adjunct treatment with low-dose ND0612 eliminated the levodopa troughs associated with oral levodopa/carbidopa. Furthermore, when oral levodopa was discontinued, peaks and troughs in levodopa plasma levels were abolished, and mean levodopa levels were maintained at 550ng/ml. Co-administered entacapone further increased levodopa levels to 800ng/ml. In addition, the trial met its futility analysis endpoint; adjunct ND0612 reduced mean OFF by 2.42h in clinic and 2.13h in pilot home diaries, (vs. 0.41h and 1.39h with optimized oral therapy and placebo). <h3>Conclusions:</h3> Subcutaneous administration of ND0612 provides steady, therapeutic levodopa plasma concentrations that were associated with clinical improvement, and may provide an effective, non-invasive alternative for continuous levodopa delivery. <b>Study Supported by:</b> NeuroDerm Ltd. <b>Disclosure:</b> Dr. Giladi has received personal compensation for activities with Teva-Lundbeck, Merz Inc., and UCB for activities with the Advisory Boards . f Teva-Lundbeck, Merz Inc. Dr. Giladi has received personal compensation for activities with Teva Israel, Intec Pharma and NeuroDerm Inc. as a consultant. Dr. Caraco has received personal compensation for activities with NeuroDerm Ltd. as a consultant. Dr. Caraco has received research support from NeuroDerm Ltd. Dr. Gurevich has nothing to disclose. Dr. Djaldetti has nothing to disclose. L. Adar has received personal compensation for activities with NeuroDerm Ltd. as an employee. Dr. Cohen has received personal compensation for activities with Neuroderm as an employee. Dr. Rahmilevich has received personal compensation for activities with NeuroDerm Ltd., a an employee. Dr. Oren has received personal compensation for activities with NeuroDerm Ltd.