Clinical Trials

Date: 2015-11-11

Type of information: update on patient enrollment

phase: 2a

Announcement: results

Company: Neuroderm (Israel)

Product: ND0612L (subcutaneous doses of liquid levodopa/carbidopa)

Action mechanism:

Disease: Parkinson\'s disease

Therapeutic area: Neurodegenerative diseases

Country:

Trial details: 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.

Latest news:

•  • On November 11, 2015, NeuroDerm announced that it has modified its U.S. development plan for ND0612H and ND0612L, continuous, subcutaneously delivered levodopa/carbidopa product candidates for the treatment of Parkinson's disease. The updated and abbreviated plan incorporates written feedback that the company recently received from the FDA within the framework of an ongoing Type C meeting communication that was initiated by the company. NeuroDerm asked the agency to provide strategic and operational guidance related to the U.S. clinical and regulatory development of ND0612H and ND0612L. NeuroDerm's new development plan for ND0612H and ND0612L consists of the following:
• ND0612H: Clinical development of ND0612H for the U.S. will proceed as planned with one Phase II trial and one Phase III trial of essentially the same design, treatment duration and patient numbers as originally planned. The Phase II trial will include centers in Israel and the EU in addition to U.S. centers, however essentially preserving the original design, number of centers, number of patients and treatment duration.
• ND0612L: Clinical development of ND0612L for the U.S. and the EU will be based on only one and not two pivotal efficacy trials of essentially the same design, treatment duration and patient numbers (200-240) as originally planned. The second pivotal efficacy trial of 360 patients that was originally planned for this product candidate is not required by the FDA.
• ND0612 Safety Follow-up: A safety follow up study for both ND0612H and ND0612L will include at least 100 patients treated for one year of whom at least half will receive the maximum dose. The safety follow-up studies that were originally planned included 50-150 patients treated for 6-12 months for each of the product candidates.
• Timelines: The supplier of the delivery devices used in the clinical trials of both ND0612L and ND0612H has been requested by the FDA to provide additional documentation pertaining to good manufacturing practices of the Quality System regulation. Until documentation is provided to the satisfaction of the FDA, this supplier may not import devices into the U.S. This does not preclude the sale or use of devices currently in the U.S. nor the importation of devices for investigational purposes if approved as part of an investigational study. Nevertheless, NeuroDerm has decided to request additional documentation from the device manufacturer before proceeding with enrollment at U.S. investigator sites. Patient enrollment in its upcoming clinical trials will thus begin at non-U.S. investigator sites. NeuroDerm expects that the requested documents will be provided by the supplier in the first quarter of 2016 enabling the company to start enrolling U.S. patients in the second quarter of 2016.
• In the EU, the pharmacokinetic pilot dose finding study of ND0612H is ongoing and topline results are now expected in the second quarter of 2016. NeuroDerm does not foresee any changes to previously disclosed timelines related to anticipated EU submission.
• • On May 8, 2015, NeuroDerm announced that the FDA has lifted the clinical hold on U.S. clinical studies of ND0612H and ND0612L for the treatment of Parkinson's disease. The hold was lifted after the FDA reviewed additional information related to the product candidates' delivery devices. U.S. clinical development of these product candidates is therefore cleared to proceed in the second half of 2015.
• • On December 30, 2014, NeuroDerm 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. 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.
• Based on these positive PK results, Neuroderm we will proceed with the clinical development of ND0612H and ND0612L in the United States and the European Union in 2015.
• • On October 29, 2014, NeuroDerm, 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 in New York.
• 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.
• 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.
• • In June 2014, the FDA placed a hold on the U.S. clinical development of ND0612H and ND0612L, requesting additional information on the accuracy, safety, and compatibility of the devices used to deliver the drug. The company completed the required compatibility study and submitted the requested additional information to the FDA. Following the FDA's decision to lift the clinical hold, the company's U.S. clinical development program is now cleared to proceed, with several studies anticipated to commence in the second half of 2015.

Is general: Yes