ND0612 Subcutaneous Levodopa Delivery System Demonstrates Efficacy in Phase 2 Setting

Ryan Case, PhD

Results from the open-label, nonrandomized, phase 2b BeyonND study (NCT02726386) demonstrated that treatment with ND0612 (Neuroderm), an investigational subcutaneous levodopa/carbidopa delivery system, increased good ON time while reducing OFF time and motor disability in patients with Parkinson disease (PD) and motor fluctuations.¹

The results, presented at the International Parkinson and Movement Disorder Society (MDS) Virtual Congress 2021, September 17-22, showed that the agent improved good ON time by an adjusted mean of 2.3 hours at month 3 in the 24-hour dosing regimen (n = 44) and 2.6 hours in the 16-hour dosing regimen (n = 83). The improvements were maintained over the 12-month study period. Presenting author Ryan Case, Phd, head, Clinical Medical Affairs, Neuroderm, and colleagues, wrote that "these results are above those achieved with oral adjunct therapies and well above the 1-hour change that is considered clinically relevant."

The investigators evaluated the long-term safety and efficacy of a duo of ND0612 dosing regimens in patients with PD who had Hoehn & Yahr scores of at least 3 during ON time and experienced at least 2 hours of daily OFF time. In addition to evaluating ON time and OFF time, investigators assessed activities of daily living (ADL) and motor through the Unified Parkinson’s Disease Rating Scale (UPDRS) score.

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At month 3, those in the 24-hour regimen group experienced decreases in OFF time by an adjusted mean of 2.3 hours while those in the 16-hour dosing regimen experienced similar OFF time decreases of 2.4 hours. Both reductions were sustained over 12 months. Both treatment regimen groups showed improvements in UPDRS-motor scores that began within the first month and were maintained through month 12 (24-hour regimen: month 1 least square [LS] mean change from baseline, –6.62 [95% CI, –8.56 to –4.67]; month 12, –6.09 [95% CI, –8.61 to –3.57]; 16-hour regimen: month 1, –6.61 [95% CI, –8.30 to –4.91]; month 12, –5.12 [95% CI, –7.37 to –2.87]).

Patients in the 24-hour regimen group had improvements of –3.06 (95% CI, –3.92 to –2.20) and –2.47 (95% CI, –3.75 to –1.19) in UPDRS ADL scores at months 1 and 12, respectively. Those in the 16-hour regimen group experienced similar results, with improvements of –3.68 (95% CI, –4.43 to –2.93) at month 1 and –2.49 (95% CI, –3.62 to –1.36) at month 12.

ND0612 is also currently being assessed in a phase 3, multicenter, double-blind, parallel-group randomized trial (NCT04006210) dubbed BouNDless. Announced in 2019, the study is evaluating 300 patients in 2 groups, randomized to either the infusion of ND0612 plus placebo carbidopa/levodopa and active carbidopa/levodopa tablets 25 mg/100 mg, or a placebo comparator.²

In previous phase 2 studies, the investigational therapy 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

As well, preliminary data from a phase 2a trial (NCT02577523) of ND0612H were presented at the 2017 MDS Congress. 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 the 9 AM time point, three-quarters of patients experienced symptom relief.⁴

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REFERENCES

1. Poewe W, Stocchi F, Adar K, Case R, Yardeni T, Espay A. Subcutaneous levodopa infusion for Parkinson disease patients with motor fluctuations: open-label efficacy outcomes from the BeyoND study. Presented at MDS Virtual Congress; September 17-22, 2021. Abstract

2. Phase 3 Clinical Trial Evaluating Continuous Subcutaneous Carbidopa/Levodopa (ND0612) Initiated In The United States For Parkinson's Disease With Motor Fluctuations. News release. Mitsubishi Tanabe Pharma America. Published August 28, 2019. Accessed September 15, 2021. 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.

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