NeuroDerm Announces Positive Topline Results of Phase II, Placebo-Controlled Study of Continuous, Subcutaneously Delivered Levodopa/Carbidopa (ND0612L) in Patients with Moderate to Severe Parkinson’s Disease
Company also reports encouraging partial results from Phase IIa study of continuous, subcutaneously delivered high-dose liquid levodopa/carbidopa (ND0612H) therapy for advanced patients
Data presented at the Michael J. Fox Foundation 2014 Parkinson’s Disease Therapeutics Conference
REHOVOT, October 29, 2014 /– NeuroDerm Ltd., a clinical-stage pharmaceutical company developing drugs for central nervous system (CNS) diseases, today announced that patients with moderate to severe Parkinson’s disease who received continuous, subcutaneous doses of liquid levodopa/carbidopa (LD/CD) (ND0612L) exhibited clinically significant reduction in fluctuations of plasma levodopa concentrations compared to patients receiving a placebo as part of a randomized, placebo-controlled, double-blinded Phase II study. Patients receiving ND0612L also experienced a corresponding in-clinic two-hour reduction over placebo in “off” time, improved sleep, better quality of life and global clinical improvement without an increase in troublesome dyskinesia.
The topline results were presented at The Michael J. Fox Foundation’s 2014 Parkinson’s Disease Therapeutics Conference today in New York.
Also at the conference, the company presented preliminary, partial results from a Phase IIa safety and pharmacokinetic study with its high-dose, continuous, subcutaneously-delivered liquid LD/CD product, ND0612H. Results demonstrated consistent levels of levodopa in plasma, proportionate to dose, achieving daytime concentrations of approximately 1,500ng/ml and 1,900ng/ml, alone and with oral entacapone, respectively. Based on those results, the company believes that ND0612H could provide an effective day and night treatment option for the majority of advanced Parkinson’s disease patients who are considering continuous LD/CD intra-duodenal gel infusion therapy (LCIG, DuoDopa®) or deep brain stimulation (DBS). The company anticipates final results of this study by the end of the year.
“The results of these two mid-stage studies show that continuous, subcutaneous dosing with the world’s first-ever liquid formulation of levodopa, the gold standard treatment for Parkinson’s disease, helps overcome the poor pharmacokinetics associated with oral therapy that often have debilitating ramifications for patients,” said Sheila Oren, M.D., NeuroDerm Vice President of Clinical and Regulatory Affairs, who presented the data of both studies at the meeting. “These encouraging results reinforce our belief that steady levodopa concentrations translate to clinical benefits. The clinically-significant impact on reduction in ‘off’ time and the positive outcomes from the other exploratory efficacy endpoints, suggest that ND0612L should have a profound impact on patients’ quality of life by greatly improving disease symptoms, while ND0612H may be a very attractive alternative to surgical intervention in advanced patients.”
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.
About Parkinson’s Disease
Parkinson’s disease is a progressive neurodegenerative illness characterized by reduced dopamine in the brain, resulting in a debilitating decrease in the patient’s motor and non-motor functions. Its symptoms, such as trembling in the extremities and face, slowness of movement and impaired balance and coordination, worsen over time and gravely impact the patient’s quality of life. As the disease progresses, these symptoms become more severe, resulting in debilitating periods of decreased motor and non-motor functions, also referred to as “off” time. In addition, mainly as a result of excessive/intermittent oral doses of levodopa aimed at treating the “off” time, some patients experience involuntary movements, or dyskinesia. The “off” time and dyskinesia affect the majority of Parkinson’s disease patients and interfere with day-to-day functions, causing patients to become severely disabled. Continuous administration of levodopa has been shown to effectively treat motor fluctuations in Parkinson’s disease patients, however, a convenient route of continuous administration has not been introduced to date.
Phase II Study Design
Study design included two treatment periods. In the first period, all patients (30) received optimized, current standard of care (SOC) with ND0612L or placebo on top of their oral medication for 14 days. After 14 days, 16 patients, per protocol, were asked to voluntarily enroll to the second period, an additional week, in which they were randomized to receive ND0612L as monotherapy or ND0612L with oral entacapone. All parameters were compared to the patients’ baseline (SOC) and between groups.
Phase II Results
The results demonstrated that patients treated with ND0612L adjunct to their current medication, maintained a relatively stable levodopa level of an average minimum of 815ng/ml, avoiding the low trough concentrations observed in the placebo group (176ng/ml). In addition, peak-to-trough ratio, an important measurement of levodopa plasma concentration swings, decreased from 54 at baseline to 5 in the ND0612L treated group after 2 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 corroborates 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 in all objective, in-clinic, pre-specified, exploratory efficacy end points, in spite of being a low powered study that was not designed to achieve statistical significance of an efficacy endpoint.
ND0612L successfully met the primary end point of the exploratory efficacy futility analysis, pre-specified in the statistical plan, a reduction in “off” time greater than a threshold of at least 1.6 hours compared to baseline, by demonstrating an average reduction of 2.1 hours in “off” time based on subjective home diaries. The reduction in “off” time was not accompanied by an increase in troublesome dyskinesia, as often experienced with high doses of oral levodopa. 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.
Similar trends were observed in the second period of the study where, per protocol, 16 of the 30 patients were offered an additional week of treatment with ND0612L. All patients markedly reduced their oral levodopa intake by a median of 80%, with 19% of the patients discontinuing oral levodopa treatment completely.
“The efficacy trends demonstrated in this study, fit the company’s working hypothesis that steady state levodopa concentrations lead to reduction in OFF time and improvement in other disease parameters, all pointing in the same direction of a better disease control,” said Dr. Warren Olanow, Professor in the Department of Neurology and the Department of Neuroscience at the Mount Sinai School of Medicine, president of Clintrex LLC and a member of NeuroDerm’s Scientific Advisory Board.
Based on these two studies, the company is planning to carry out pivotal studies of longer duration and larger patient numbers to confirm these results and generate statistical significance on all efficacy endpoints.
The ND0612L Phase IIa study was funded in part by The Michael J. Fox Foundation for Parkinson’s Research which granted Neuroderm $1 million for the second time.
NeuroDerm is a clinical-stage pharmaceutical company developing central nervous system (CNS) product candidates that are designed to overcome major deficiencies of current treatments and achieve enhanced clinical efficacy through continuous, controlled administration. In Parkinson’s disease, the company has four product candidates in different stages of development which offer a solution for almost every Parkinson’s disease patient from the moderate to the very severe stage of the disease. The company has developed a line of LD/CD product candidates administered through small belt pumps that deliver a continuous, controlled dose of LD/CD. The LD/CD line of product candidates includes: ND0612L and ND0612H, delivered subcutaneously, for moderate and for advanced Parkinson’s disease patients, respectively, and ND0680 for a subset of severe Parkinson’s disease patients whose symptoms have advanced to a highly advanced stage, requiring even higher doses of LD/CD. In addition NeuroDerm is developing ND0701, a novel subcutaneously delivered apomorphine formulation for patients who suffer from severe Parkinson’s disease and who do not respond well to LD/CD. NeuroDerm is headquartered in the Weizmann Science Park, Rehovot, Israel.
Oded S. Lieberman, PhD, MBA, CEO
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