Daniel M. Keller, PhD

June 22, 2015

SAN DIEGO — For almost 50 years, oral levodopa (LD) has reigned supreme as the major treatment for Parkinson's disease (PD). Although it is still overall the most effective oral therapy, better routes of delivery may improve its activity and convenience.

ND0612 is a proprietary formulation of LD/carbidopa (CD) with good solubility for subcutaneous delivery via pump that maintains more constant blood LD levels and reduces the fluctuations in pharmacokinetics that are seen with oral LD, a study shows. Two formulations with low or high concentrations of carbidopa were used in the study: ND0612L and ND0612H, respectively.

"We have been able to show much less fluctuation than oral levodopa…. We are able to maintain a steady levodopa level all day long," Sheila Oren, MD, vice president for clinical and regulatory affairs at NeuroDerm, the developer of ND0612, told Medscape Medical News here at the 19th International Congress of Parkinson's Disease and Movement Disorders (MDS).

The phase 2a multicenter, open-label trial used preparations of LD/CD containing a constant 60 mg/mL LD concentration. Sixteen adult patients with idiopathic PD with well-defined morning "off" periods and a good response to LD were randomly assigned to one of two groups.

The ND0612L group received 240 μL/h over 8 hours (115.2 mg total dose), and the ND0612H group received 640 μL/h over 8 hours via two injection sites (307.2 mg total dose). Patients' usual PD medications were stopped the previous evening before the infusion day.

The two groups were fairly well matched at baseline, with some moderate differences between them because of the small sample sizes.

Patients remained in the clinic throughout the study period. On day 1, they received their standard oral LD. On day 2, they received ND0612L or ND0612H with low-concentration CD (7.5 mg/mL). On day 3, they received low- or high-dose LD but with high-dose CD (14 mg/mL). An optional day 4 regimen consisted of LD infusion, high-concentration CD, and oral entacapone.

The primary pharmacokinetic endpoint was the fluctuation index of plasma LD concentration, calculated as the ([mean peak concentration] – [mean trough concentration])/average concentration.

Therapeutic Plasma Levodopa, Low Fluctuations

The researchers reported that fluctuations in LD plasma levels were all significantly reduced with the ND0612 preparations compared with oral LD (all P < .001).

Table. Levodopa Pharmacokinetic Parameters

Regimen Fluctuation Index Cmax (ng/mL) Area Under the Curve, 0 - 8 h (ng-h/mL)
Oral levodopa (n = 16) 534.6 2013.8 6911.8
ND0612H      
   Low CD (n = 7) 97.3 1354.8 6465.8
   High CD (n = 7) 129.9 1454.4 7548.9
   High CD + entacapone (n = 7) 111.1 1843.6 8853.2
ND0612L      
   Low CD (n = 9) 103.4 618.2 2487.1
   High CD (n = 9) 65.4 486.8 2434.3
   High CD + entacapone (n = 8) 72.9 603.6 2923.0

 

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."

 
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. Dr Maurizio Facheris
 

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.

19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Abstract LBA8. Presented June 17, 2015.

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