NeuroDerm Ltd., a clinical-stage pharmaceutical company developing drugs for central nervous system (CNS) diseases, has announced that continuous, subcutaneous delivery of the company's proprietary liquid levodopa/carbidopa (LD/CD) product candidates, ND0612H and ND0612L, led to clinically-significant plasma levodopa levels. These results suggest that the high dose version, ND0612H, intended for severe Parkinson's disease patients, may provide an effective therapy alternative to current treatments requiring surgery.
"Maintaining consistent levodopa concentrations has been the most significant hurdle in Parkinson's disease therapy," said Sheila Oren, MD, NeuroDerm's Vice President of Clinical and Regulatory Affairs. "The results from this study demonstrate that ND0612H can reach high LD plasma levels that, to date, could only be reached and maintained by products that require surgical intervention. ND0612H is designed to be delivered continuously, thus we believe it should offer a simple and effective treatment option that will minimize the need for surgical intervention in advanced Parkinson's patients."
Due to the short half-life of oral levodopa, patients are required to take multiple LD/CD doses daily. This results in sharp fluctuations in levodopa levels which are associated with erratic "off" and "on" periods experienced by many patients. Continuous LD administration can overcome this limitation, but steady LD delivery can currently only be achieved after undergoing an invasive surgical procedure whereby a tube is permanently implanted into the duodenum, the upper part of the small intestine.
The primary endpoints of the IIa study were to assess the safety, tolerability and pharmacokinetics (PK) of six dose regimens of ND0612H and ND0612L, which provide continuous, subcutaneously-delivered liquid LD/CD formulations through a belt-worn pump, in Parkinson's disease patients. Sixteen (16) advanced PD patients, with motor fluctuations, chronically treated with standard of care oral LD/CD, were enrolled in the study and were treated with ND0612L (n=9) or ND0612H (n=7) for eight hours per day, for three consecutive days, with high and low doses of CD, and with adjunct oral entacapone. The pharmacokinetics of LD/CD were assessed and compared to baseline pharmacokinetics of orally administered, immediate release LD/CD tablets. A top-line, intent-to-treat analysis showed that levodopa plasma levels were proportionate to dose and, with ND0612H, achieved maximum daytime concentrations of 1,333ng/ml and 1,436ng/ml (with different CD concentrations in the formulation), and 1,807ng/ml with adjunct dosing of oral entacapone. ND0612L achieved maximum daytime concentrations of 528ng/ml and 477ng/ml (with different CD concentrations in the formulation), and 596ng/ml with adjunct dosing of oral entacapone. Fluctuations in LD plasma levels were markedly reduced when comparing oral LD/CD dosing to ND0612H and ND0612L. Per-protocol analysis, that omitted three data sets from two patients because of concomitant use of oral LD, yielded similar LD plasma values.
Treatment with ND0612L and ND0612H did not raise safety and tolerability concerns, causing only minimal and transient local reactions at the infusion site and no particular systemic adverse events, which corroborates the results obtained in previous studies. All patients completed the study.
"These results add to the growing body of clinical data confirming our thesis that continuous, subcutaneous delivery of LD/CD leads to more consistent therapy, which we expect to have a dramatic effect on patient outcomes and quality of life, replacing in most cases the need for surgical intervention" said Oded S. Lieberman, PhD, CEO of NeuroDerm. "Based on these positive PK results, we will proceed with the clinical development of ND0612H and ND0612L in the United States and the European Union in 2015."
Oral administration of LD/CD is regarded as the "gold standard" treatment for patients suffering from Parkinson's disease. Levodopa crosses into the brain and converts into dopamine to complement the reduced brain-dopamine levels. Virtually all patients diagnosed with Parkinson's disease will require levodopa at some point over the course of their treatment for the disease, and 70% to 80% of patients receive the drug at any given point in time. However, levodopa is limited by its short half-life. Approximately three to four hours after a single dose, almost none of the drug remains in the plasma. In addition, levodopa suffers from low absorption when administered orally, with only about 30% of the levodopa entering the blood stream.
ND0612H and ND0612L are designed to significantly reduce motor complications in Parkinson's disease patients through continuous, subcutaneous delivery of LD/CD, maintaining steady, therapeutic levodopa plasma concentrations both day and night. ND0612H is intended to provide an alternative to surgical treatments associated with serious side effects that are currently offered to patients with severe Parkinson's disease.