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The clinical development of ND0612 includes 2 doses; a low dose for mid-stage Parkinson patients experiencing loss of motor control on oral therapy, and a high dose for severe disease in which oral drugs are no longer effective.
Werner Poewe, MD
Mitsubishi Tanabe Pharma America (MTPA) has presented details of the design of the upcoming phase 3 BouNDless study of ND0612, its investigational non-surgical drug-device combination that provides continuous delivery of carbidopa/levodopa subcutaneous solution (CLSS) for patients with fluctuating Parkinson disease.1
The study design, presented at the 2019 International Congress of Parkinson’s Disease and Movement Disorders, in Nice, France, will feature 288 patients with Hoehn and Yahr disease severity scores ≤3 who are on ≥4 daily doses of carbidopa/levodopa therapy (≥400 mg) who are experiencing a minimum of 2 hours of daily motor fluctuations in their off state.
It will feature 6 periods: a 4-week screening period; a 6-week open-label adjustment period; a 6-week open-label conversion period; a 12-week, double-blind, double-dummy, active-controlled maintenance period; an optional 1-year open-label extension; and a 12-week safety follow-up period. The primary end point will be the change from baseline—the 6-week open-label conversion period—to the end of the 12-week maintenance period in mean on time without troublesome dyskinesia, with findings normalized to 16 waking hours and using patient-rated on/off assessments.
"While oral CD/LD is the established standard for treating motor symptoms in Parkinson's disease, many patients experience a decline in benefit as their disease advances requiring them to take multiple doses throughout the day in an effort to control symptoms, often with unpredictable results," said Atsushi Fujimoto, president, MTPA, in a statement.2 "We look forward to researching the potential efficacy and safety of continuous subcutaneous treatment with ND0612 on managing motor fluctuations and other complications of Parkinson's disease, through the BouNDless study."
During the 12-week, double-blind, double-dummy, active-controlled maintenance period, patients will be randomized to either ND0612 infusion and dummy immediate-release carbidopa/levodopa, or to dummy infusion and immediate-release carbidopa/levodopa.
The key secondary outcome will be the change in off time, and other secondary outcomes will be the changes in Unified Parkinson Disease Rating Scale (UPDRS0 parts II and III, Patient’s (PGI-C) and Clinician’s Global Impressions of Change (CGI-C), on time without dyskinesia, PDQ-39 scores, and Parkinson’s Disease Sleep Scale (PDSS) scores.
Additionally, safety and tolerability will be assessed via adverse event (AE) reporting, including local skin safety assessments, rates of discontinuation, and study treatment compliance.
“BouNDless will be the first phase 3 randomized, active-controlled trial to establish the efficacy and safety of maintenance treatment with continuous subcutaneous ND0612 in comparison to oral immediate-release carbidopa/levodopa in patients with Parkinson disease experiencing motor fluctuations,” Werner Poewe, MD, director, department of neurology, Medical University of Innsbruck, and coinvestigators wrote.
The clinical development of ND0612, being led by NeuroDerm, includes 2 doses: a low dose for mid-stage Parkinson patients experiencing loss of motor control on oral therapy, and a high dose for severe disease in which oral drugs are no longer effective.
In a phase 2 placebo-controlled study, ND0612L was shown to maintain consistent, therapeutic levodopa plasma concentrations associated with major changes in clinical parameters, including off-time reduction, when added to optimal oral standard of care. Off time was reduced by 2 hours, or 41%, in the treatment group (n = 18) compared to 9% in the placebo group (n = 11). Overall, the global clinical improvement in disease severity for the treatment group was 90% compared to 36% for placebo, and quality of life was improved by 17% compared to 5%, respectively.3
Additionally, preliminary data from a phase 2a trial (NCT02577523) of ND0612H were presented at the 21st International Congress of Parkinson’s Disease and Movement Disorders in Vancouver, British Columbia, Canada. It enrolled 38 patients who received either 24-hour or 14-hour infusions for 28 days and showed that off time was significantly reduced. All told, off time dropped from 5.5 hours per day to 2.8 hours, and on time increased from 11% to 50% after 28 days. By 9 AM, three-quarters of patients experienced symptom relief.4
"Given the limitations of current therapeutic options for Parkinson's disease, we recognized the importance of developing a potential non-surgical continuous treatment that may stabilize CD/LD plasma levels and alleviate the disabling motor fluctuations that are often exacerbated with disease progression," said Sheila Oren, MD, MBA, chief medical officer, NeuroDerm, in a statment.2 "We are excited that the Phase 3 study of ND0612 is underway, and we may be one step closer to potentially bringing a much-needed treatment option to patients."
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1. Poewe W, Kieburtz K, Oren S, et al. BouNDless: An active-controlled randomized, double-blind double-dummy study of continuous ND0612 infusion in patients with fluctuating Parkinson’s disease. Presented at: MDS 2019; September 22-26; Nice, France. Poster 179.
2. Phase 3 Clinical Trial Evaluating Continuous Subcutaneous Carbidopa/Levodopa (ND0612) Initiated In The United States For Parkinson's Disease With Motor Fluctuations [press release]. Jersey City, NJ: Mitsubishi Tanabe Pharma America; Published August 28, 2019. prnewswire.com/news-releases/phase-3-clinical-trial-evaluating-continuous-subcutaneous-carbidopalevodopa-nd0612-initiated-in-the-united-states-for-parkinsons-disease-with-motor-fluctuations-300908477.html. Accessed September 25, 2019.
3. Giladi N, Caraco Y, Gurvich T, et al. Pharmacokinetic profile of low-dose ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with moderate to severe Parkinson’s disease. Presented at: 4th World Parkinson Conference; September 20-23, 2016; Portland, Oregon. Poster 03.
4. Onalow CW, Stocchi F, Poewe W, et al. Safety, efficacy, and tolerability of continuous SC LD/CD (ND0612H) infusion in PD patients with motor fluctuations. Presented at: 21st MDS Congress; June 4-8, 2017; Vancouver, BC. Poster LBA41.