Liquid Levodopa Formulation May Simplify Continuous Drug Delivery

VANCOUVER—A liquid formulation of levodopa and carbidopa delivered continuously and subcutaneously is generally well tolerated and may reduce motor fluctuations in patients with Parkinson’s disease, according to research described at the 68th Annual Meeting of the American Academy of Neurology.

Levodopa has a short half-life, and long-term oral levodopa treatment is associated with motor fluctuations and dyskinesia. Continuous levodopa delivery may be the best way to overcome those limitations of the drug, said Sheila Oren, MD, MBA, Vice President of Clinical and Regulatory Affairs at NeuroDerm in Rehovot, Israel. Current continuous infusion systems, however, must be surgically implanted to permit direct infusion of the drug in gel form into the jejunum.

Sheila Oren, MD, MBA

Until recently, poor levodopa solubility had prevented the development of a liquid formulation of the drug that could be delivered subcutaneously. ND0612L, a novel, proprietary formulation of levodopa and carbidopa, “is the first time that this [drug] is a real liquid,” Dr. Oren said. “Not a suspension or a gel, but a liquid that can be administered parenterally.… In this way, we hope to be able to deliver levodopa continuously in a much simpler way.”

Safety and Tolerability Trial

To study the pharmacokinetic and clinical profile of ND0612L in patients with Parkinson’s disease with motor fluctuations, Dr. Oren and colleagues conducted a phase II randomized, placebo-controlled, double-blind study in 30 patients with Parkinson’s disease.

Patients were randomized two-to-one to receive a low-dose formulation of ND0612L (ie, 60 mg of levodopa and 14 mg of carbidopa per milliliter) or placebo in addition to their standard of care oral treatment for two weeks. A belt pump system delivered ND0612L or placebo subcutaneously at a nightly rate of 0.08 mL/h for eight hours (ie, from 6 pm to 2 am) and then at a higher daily rate of 0.24 mL/h for the next 16 hours.

Investigators enrolled patients with idiopathic Parkinson’s disease who had more than two waking hours of off time per day and took optimized doses of levodopa three or more times per day. The researchers excluded people taking controlled-release levodopa formulations, people who had undergone neurosurgical intervention for Parkinson’s disease, and people with severe, disabling dyskinesia.

Participants had a mean age of approximately 64 and mean disease duration of about eight years. Participants had received levodopa therapy for about seven years and took 700 mg of levodopa daily, on average. Participants had experienced motor fluctuations and dyskinesias for several years, and their average total daily off time was almost six hours.ND0612L was generally well tolerated and safe. Cutaneous side effects included mild and transient edema and erythema at the injection site. In addition, most patients developed at least one small, painless nodule, Dr. Oren said. Nodules typically resolved within two months. Researchers did not observe systemic adverse events, dyskinesia, or psychiatric symptoms.

Compared with the placebo group, patients who received adjunctive ND0612L had a reduction in plasma levodopa concentration fluctuations. Their plasma levodopa concentrations consistently remained above a mean of 800 ng/mL, thus avoiding the low trough levels that occurred in the placebo group. The ND0612L group had a lower peak-to-trough ratio and fluctuation index, compared with the placebo group.

Preliminary Evidence of Efficacy

In an exploratory efficacy analysis, researchers observed that ND0612L treatment reduced off time in clinic by 2.42 hours, compared with a 0.41-hour reduction with placebo.

Treatment also improved sleep quality (Parkinson’s Disease Sleep Scale score improvement from baseline of 17.1 with ND0612L vs 0.5 with placebo), quality of life (Parkinson’s Disease Questionnaire-39 score improvement of 6.6 with ND0612L vs 1.78 with placebo), and global impression (90% of patients treated with ND0612L had improved Global Impression of Change scores, compared with 36% of patients treated with placebo).

Investigators are developing a way to deliver ND0612L via a patch pump. Investigators also are investigating a high-dose formulation of the drug, ND0612H, developed for advanced patients as an alternative to surgical interventions. Researchers plan to conduct further studies of the drug’s safety, pharmacokinetics, and potential clinical benefits, Dr. Oren said.

—Jake Remaly