Clinical Trials

Date: 2016-06-28

Type of information: Results

phase: 1

Announcement: results

Company: Neuroderm (Israel)

Product: ND0612H

Action mechanism:

Disease: Parkinson's disease

Therapeutic area: Neurodegenerative diseases

Country:

Trial details: Trial 005 is a pilot, open label, dose finding, comparative PK study. The first part of the study evaluated the CD concentrations in ND0612. The second part of the study included a crossover design, in which 15 subjects received the selected formulation of ND0612H and were randomized to receive two out of three doses of Duodopa®, a LD/CD intestinal gel administered to the duodenum. The Duodopa® doses were selected prior to the study based on PK modeling and simulations. The key objectives of this pilot dose-finding study were:

• To select the CD concentration in ND0612.
• To identify the dose of the reference drug (Duodopa®) that produces similar LD plasma concentrations to ND0612H.
• To assess the bioavailability of ND0612H relative to Duodopa® infused via a naso-jejunal tube.
• To study the safety and tolerability of ND0612.

Latest news:

• • On June 28, 2016, NeuroDerm announced that topline results from Trial 005, a pilot, dose-finding pharmacokinetic (PK) study on healthy subjects, demonstrate that ND0612H, the company’s continuous, subcutaneously delivered levodopa/carbidopa (LD/CD) liquid formulation, achieved comparable results to a reference dose of intra-duodenally delivered LD/CD gel suspension requiring surgical intervention (Duodopa®). Based on these results and on previous discussions with the European Regulatory Authority (EMA), the company plans to pursue regulatory development of ND0612H in the European Union (EU) based on PK similarity. The LD plasma concentrations of ND0612H in this study are in line with LD levels obtained in previous ND0612H PK studies in patients with advanced Parkinson’s disease. These results reinforce the company’s expectation that ND0612H may provide an effective alternative to currently available treatments that require surgery.
• Trial 005 enrolled a total of 36 healthy volunteers.  With respect to the second objective (identify the dose of the reference drug (Duodopa®) that produces similar LD plasma concentrations to ND0612H), one of the three tested doses of Duodopa® matched the selected dose of ND0612H, as was predicted by PK modeling and simulation. The company intends to test this dose in a larger, definitive, statistically powered PK similarity study that is anticipated to form the basis for its regulatory submission in the EU.
• With respect to the third objective (assess the bioavailability of ND0612H relative to Duodopa® infused via a naso-jejunal tube), the AUC and Cmax of ND0612H to Duodopa® ratios were within 80-125% in the relevant comparison period. Although not an objective of this trial, the 90% confidence interval of the geometric mean ratios of the two drugs in both parameters were found to lie within the bio-equivalence range, a finding that is statistically significant (p<0.001 for AUC, p=0.015 for Cmax) and lies within regulatory authorities’ bioequivalence acceptance criteria. With respect to the fourth objective (study the safety and tolerability of ND0612), treatment with ND0612 did not raise safety and tolerability concerns. These results corroborate the safety and tolerability data obtained in previous studies.
• 35 subjects out of 36 completed the study. One subject in the first part of the trial did not complete the study for technical reasons unrelated to the test drugs.
• The results of this study also show that:
• Selected doses of the two drugs’ LD plasma curves shapes and parameters were comparable throughout the relevant comparison period and conformed to the predictive PK discussed with EU regulatory authorities as a basis for the PK similarity development strategy.
• LD plasma concentrations obtained with ND0612H in this trial were in line with expectations and with levels obtained in previous studies of ND0612H in advanced Parkinson’s disease patients. This further reinforces the company’s expectation that the LD plasma concentrations achieved by ND0612H are high enough to effectively treat the majority of advanced Parkinson’s patients who would be considered candidates for either Duodopa® or Deep Brain Stimulation treatment.
• ND0612H LD exposure levels showed lower inter-subject variability (CV%) than Duodopa®.
• Administration of comparable LD doses resulted in higher total plasma exposure (AUC) from ND0612H than from Duodopa® suggesting a higher bioavailability for ND0612H. Importantly, ND0612H is designed to deliver continuous LD/CD via a patient-friendly, subcutaneous delivery system. Based on the results of Trial 005 and on previous discussions held with EU regulatory authorities, the company intends to pursue a PK similarity regulatory development route in the EU for ND0612H. The results of this study, as well as the protocol of the anticipated definitive follow-on PK study on healthy volunteers, will be presented to EU authorities later this year. Such anticipated definitive PK comparison study of ND0612H and DUODOPA (Trial 009), designed to enroll 20-40 healthy volunteers treated for up to 72 hours, is aimed at achieving statistical significance and be the basis for approval in the EU.    
• • On June 11, 2015, NeuroDerm announced that it has started a pharmacokinetic clinical study to determine the dosing of the  ND0612H, a subcutaneously administered liquid formulation of levodopa (LD) and carbidopa (CD), for the treatment of advanced Parkinson's Disease. This open-label, dose finding, PK study is expected to enroll a total of 24 healthy volunteers. In this study, the PK of subcutaneously administered ND0612H will be compared with that of Duodopa® intestinal gel, a product that requires surgical intervention. Results of this study are expected in the second half of 2015 and, if successful, will be used to design and conduct a follow-up, definitive PK similarity study in healthy volunteers.
• In October 2014, the European Regulatory Authority (EMA) confirmed that it had agreed with NeuroDerm's proposal that a PK study comparing ND0612H with Duodopa® in healthy volunteers may constitute the basis for approval in Europe. If the company is successful in demonstrating in such studies that ND0612H produces similar PK profiles to Duodopa®, then a reduced clinical data package would be the basis for a marketing approval of ND0612H in Europe through a Centralized Procedure.
• A Phase II clinical efficacy study of ND0612H is also planned to commence in the United States in the second half of 2015.

Is general: Yes