Overview

Continuous subcutaneous (under-the-skin) infusion of carbidopa/levodopa (CD/LD) using the investigational device-drug combination ND0612 led to rapid improvement in clinical status and quality of life for patients with advanced Parkinson’s disease. These patient-reported outcomes come from a Phase 2 clinical trial presented at the 23rd International Congress of Parkinson’s Disease and Movement Disorders in Nice, France.

Background: The Challenge of Motor Fluctuations in Parkinson’s Disease

As Parkinson’s disease progresses, patients typically require increasing doses of oral levodopa — the standard dopamine-replacement therapy — taken multiple times per day. This oral dosing regimen produces fluctuating brain levels of dopamine, which can trigger “off” periods: episodes during which motor symptoms such as tremor, rigidity, and slowed movement return before the next dose takes effect. These motor fluctuations significantly impair daily functioning and quality of life.

ND0612, developed by NeuroDerm (a subsidiary of Mitsubishi Tanabe Pharma Corporation, along with Mitsubishi Tanabe Pharma America), is designed to address this problem by delivering CD/LD continuously via a small subcutaneous pump. Continuous delivery aims to maintain steadier brain dopamine levels, potentially reducing the frequency and severity of motor fluctuations.

Phase 2 Study Design

The 28-day, open-label study (ClinicalTrials.gov identifier: NCT02577523), titled “Impact of ND0612 on patient reported outcomes: A blinded rater study of 2 dosing regimens,” enrolled 38 patients between the ages of 30 and 80 with advanced Parkinson’s disease.

Participants were randomly assigned to one of two ND0612 infusion schedules:

• 24-hour continuous infusion group: Received a daily CD/LD dose of 720/90 mg via subcutaneous infusion.
• 14-hour infusion group: Received a CD/LD dose of 538/68 mg via infusion, supplemented by a morning oral CD/LD dose of 150/15 mg.

After one day of standard oral CD/LD, patients received ND0612 treatment over the following 27 days. Supplemental oral CD/LD was permitted as needed.

Outcome Measures

Patient-reported outcomes were assessed using validated Parkinson’s disease scales:

• Unified Parkinson’s Disease Rating Scale (UPDRS) Part II (activities of daily living): Measured at day 28.
• Parkinson’s Disease Questionnaire (PDQ-39) (health status and quality of life): Measured at day 27.
• Patient Global Impression of Improvement (PGI-I): Self-rated impressions of overall clinical status collected at days 3 and 28.

Key Findings

Rapid Clinical Improvement

More than 70% of patients reported an improvement in overall clinical status as early as day three of ND0612 treatment, suggesting a rapid onset of benefit.

Activities of Daily Living (UPDRS Part II)

In the 24-hour continuous infusion group, UPDRS Part II scores showed a statistically significant improvement — a mean decrease of 2.9 points from baseline — at day 28. Scores in the 14-hour group also trended toward improvement, though the degree of significance was not detailed in the presented data.

Quality of Life (PDQ-39)

Patients in the 24-hour group showed a mean reduction of 7.5 points on the PDQ-39 scale — a clinically meaningful improvement in health-related quality of life. The 14-hour group also showed a trend toward improvement. Six of the eight PDQ-39 domains demonstrated improvement:

• Bodily discomfort
• Activities of daily living
• Emotional well-being
• Mobility
• Communication
• Stigma

Expert Commentary

“Many people with Parkinson’s disease take multiple doses of oral CD/LD as their disease progresses, which can cause additional motor fluctuations that may be debilitating and contribute to poor quality of life,” said Atsushi Fujimoto, president of Mitsubishi Tanabe Pharma America (MTPA). “The data presented at MDS add to the body of research on ND0612.”

Sheila Oren, MD, Chief Medical Officer at NeuroDerm, noted the “potential impact of stabilizing CD/LD levels with continuous treatment on a variety of clinical, daily living and quality of life measures.”

Phase 3 Trial: BouNDless (NCT04006210)

Building on the Phase 2 findings, a global Phase 3 randomized, double-blind, double-dummy, active-controlled trial called BouNDless (NCT04006210) was initiated and began enrolling patients. The trial is being conducted at approximately 120 sites worldwide and aims to enroll around 300 patients.

Eligible Patients

• Diagnosed with Parkinson’s disease and not adequately responding to standard oral treatments
• Experiencing a minimum of 2.5 hours of motor fluctuations per day
• Spending at least two hours per day in the “off” state (loss of motor control) during waking hours

Primary Endpoint

The primary objective of BouNDless is to determine whether ND0612 increases self-reported daily “good on time” — defined as the combined total of “on” time without dyskinesia (involuntary movements) and “on” time with non-troublesome dyskinesia — compared to oral immediate-release CD/LD.

“We look forward to gaining additional insights on this investigational treatment through the Phase 3 study,” Fujimoto said. “We are proud of the research behind ND0612 to date and committed to learning more about this investigational treatment for people with fluctuating Parkinson’s disease,” added Oren.

Summary

The Phase 2 data for ND0612 indicate that continuous subcutaneous delivery of carbidopa/levodopa can produce meaningful, rapid improvements in motor function and quality of life for patients with advanced Parkinson’s disease who experience motor fluctuations. The ongoing Phase 3 BouNDless trial will provide more definitive evidence of efficacy and safety compared to standard oral therapy. These results reflect the growing interest in device-aided therapies as an alternative to conventional oral levodopa regimens for patients with advanced disease.

Note: ND0612 is an investigational therapy. It has not been approved by the FDA or any other regulatory agency as of the original publication date of this article (September 2019). Readers should consult current clinical trial registries and regulatory databases for the latest status.