Objective/Rationale:
Improving consistency of plasma levodopa has been a longstanding pharmacological challenge. ND0612 is a proprietary formulation of levodopa and carbidopa continuously administered subcutaneously, providing more continuous dopaminergic stimulation that would consequently reduce or prevent motor complications in Parkinson’s disease (PD) patients. ND0612 was safe, tolerable and exhibited dose-dependent constant LD plasma levels when administered for 24 hours in Phase I-II trials in healthy volunteers and PD patients. The present study will evaluate the clinical effects and the pharmacokinetics of a 14-day repeated ND0612 administration in advanced PD patients.
Project Description:
ND-0612 will be administered subcutaneously, continuously for 24h/day, via a delivery pump system during two weeks, using different day and night rates, to evaluate the safety, tolerability and pharmacokinetics of ND0612 in advanced PD patients. The ease of use and logistics associated with the patients’ use of the pump in a conventional home setting will be evaluated. The patients will be evaluated for their symptoms improvement by recording their motor symptoms and activity of daily living, quality of life, quality of sleep and “on-off” periods during visit days. Oral levodopa dose supplementation or adjustment will be made, if needed. Blood samples will be collected at predetermined time points for the determination of plasma levodopa and carbidopa concentrations.
Relevance to Diagnosis/Treatment of Parkinson’s disease:
Continuous dopaminergic stimulation has shown to greatly improve disability and quality of life in advanced PD patients. Researchers anticipate that continuous administration of subcutnaeous levodopa and carbidopa (ND0612) will provide a highly effective, practical new therapy for the treatment of advanced PD and potentially for slowing disease progression in early stage PD patients.
Anticipated Outcome:
The investigators anticipate that ND0612 will be safe, tolerable and maintain therapeutic LD plasma concentrations in PD patients. Using exploratory clinical endpoints, it is anticipated that ND0612 will exhibit improved PD symptoms. Furthermore, it is anticipated that the ease of use and logistics accompanying the use of the delivery pump, as well as the requested oral levodopa adjustment will be determined.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Final Outcome
The results of this study demonstrated that patients treated with ND0612L in addition to their current standard medication maintained a relatively stable levodopa level above a potentially therapeutic threshold. We observed dips in levodopa plasma concentrations in patients treated with placebo on top of their current medications. In addition, peak-to-trough ratio, an important measurement of levodopa plasma concentration swings, decreased 10-fold in the ND0612L-treated group after two weeks of treatment, whereas the peak-to-trough ratio for the placebo group remained unchanged.
Treatment with ND0612L showed good safety and was well tolerated, causing only minimal and transient local reactions at the infusion site and no particular systemic adverse events, which matches the results obtained in previous Phase I and Phase IIa studies. All patients complied with treatment protocol.
Treatment with ND0612L demonstrated major clinical benefits over the placebo. ND0612L treatment reduced “off” time by a mean of 2.4h and 2.1h from baseline according to in-clinic and subjective home diaries, respectively (vs. 0.4h and 1.4h with placebo).
ND0612L improved quality of sleep by 30% compared to 1% in the placebo group, expressed by reduction in the Parkinson’s Disease Sleep Scale (PDSS). This supports the intended treatment mode with ND0612L, during both day and night, unlike the available levodopa therapies to date.
Quality-of-life scores increased by 17% in the ND0612L group compared to 5% in the placebo group as determined by the Parkinson’s Disease Questionnaire (PDQ-39).
Clinical Global Impression (CGI-C), based on physician’s assessment of a seven-point scale, showed clinical improvement in 90% of patients treated with ND0612L, compared with only 36% of patients in the placebo group.
Presentations & Publications
Abstracts have been sent to the American Academy of Neurology Conference 2015 and to the 19th International Congress of Parkinson's Disease and Movement Disorders 2015.
January 2015
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