Subcutaneous Levodopa Infusion Smooths Blood Levels in PD

Daniel M. Keller, PhD

June 22, 2015

Both ND0612L and ND0612H produced steady, therapeutic LD plasma levels, with the H preparation producing about three-fold higher plasma concentrations than the L preparation. Adjunctive entacapone increased the steady-state levels with both formulations by about 25% without affecting the fluctuation index.

Dr Oren noted that safety and tolerability of ND0612 were good. Eight patients reported a total of 10 treatment-emergent adverse effects. One patient in the ND0612H group had an elevation of liver enzymes considered possibly related to the treatment. Most patients did have positive results on Draize tests, indicating mild infusion site erythema and edema, which resolved.

Dyskinesia was not a problem. "It's an 8-hour infusion," Dr Oren said. "We didn't have any dyskinesia."

In a 6-month safety follow-up, all patients had relatively small infusion site nodules that resolved in 4 to 6 months. Interestingly, although the ND0612H group had twice the number of infusion sites and a higher infusion rate as the ND0612L group, the groups did not have any major difference in the number of nodules.

Previous exploratory efficacy analyses have shown that ND0612L reduced daily "off" time by more than 2 hours from baseline and improved sleep quality, quality of life, and clinical global impression of change scores Advantage of Subcutaneous Route

Dr Oren noted that delivery of LD by subcutaneous infusion may have an advantage over more invasive surgical procedures for treating PD.

"We have a patent on the way to do a liquid formulation as opposed to Duopa [LD/CD, Abbvie], for example, that is not a liquid formulation but a semisolid gel…that cannot be administered parenterally," she said.

Duopa is infused enterally directly into the jejunum through an implanted jejunostomy tube. The NeuroDerm device holds 6 or 12 mL and is fairly small, about the size of an insulin pump, in contrast to the Duopa device, which is larger and can hold a 100-mL cassette.

She said the ND0612L formulation is now going into phase 3 trials.

Maurizio Facheris, MD, senior associate director for research programs at the Michael J. Fox Foundation for Parkinson's Research, commented on the findings for Medscape Medical News.

"What I think is striking is truly having that flat pharmacokinetic in blood, specifically in the later stage of disease where your dopaminergic neurons are so much reduced and potentially the serotonergic neuron reuptake of levodopa and transforming it into dopamine," he said. "So the synchronization between the pharmacokinetic of the blood and the brain becomes important.... So that's what I like about this specific program."He noted that with the low dose, coadministration of entacapone was necessary to reach therapeutic LD levels.

"With the higher dose…you can see from the data that [they] are able to get closer to what the normal range would be," he said.

There is some debate as to whether patients should receive infusion-type LD therapies before getting surgery for implantation of a deep-brain stimulation (DBS) device.

"I do think that [this] would be a logical step to go before getting into DBS… Unlike [Duopa] intestinal gel, this is actually less invasive," Dr Facheris said.

The trial was sponsored by NeuroDerm (Rehovot, Israel). Dr Oren is an employee of the company. Dr Facheris is an employee of the Michael J. Fox Foundation for Parkinson's Research. The foundation supported early development of ND0612L.

http://www.medscape.com/viewarticle/846798?src=wnl_edit_tpal#vp_2