Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

Abstract

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87% ) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized, placebo-controlled phase 2 study

“…Despite the higher levels of levodopa achieved in the ND0612 treatment group, it was not associated with an increase in peak-dose dyskinesia, as often seen with oral levodopa administration [26]; no dyskinesias were reported as TEAE and mean UPDRS Part IVa scores remained relatively unchanged in both groups. These data support the findings of another Phase 2 study which evaluated higher levodopa/carbidopa dosing with ND0612 (levodopa/carbidopa dose of 720/90 mg) and found that 24 h infusion with ND0612 reduced OFF time by an adjusted mean of 2.8 h (p = 0.004 vs. baseline) [27].…”

Subcutaneous Levodopa Infusion for Parkinson's Disease: 1‐Year Data from the Open‐Label BeyoND Study

“…Previous studies have shown that ND0612 provides stable plasma levodopa concentrations, 1 significantly reduces daily OFF time, 1,2 and increases ON time without significant dyskinesia. 2 The primary aim of this study was to assess the long-term safety and tolerability of ND0612 over 12 months of treatment, with a particular focus on infusion site reactions (ISRs) that are often associated with SC drug administration.…”

“…Conclusions: Subcutaneous levodopa/carbidopa continuous infusion with ND0612 is generally safe, with typical infusion site reactions for SC delivery as the main adverse event. 1 significantly reduces daily OFF time, 1,2 and increases ON time without significant dyskinesia. 2 The primary aim of this study was to assess the long-term safety and tolerability of ND0612 over - --------------------------------------------------------12 months of treatment, with a particular focus on infusion site reactions (ISRs) that are often associated with SC drug administration.…”

Treatment Options for Motor and Non-Motor Symptoms of Parkinson’s Disease

“…Alternatively, Duodopa is a continuously infused intrajejunal gel of carbidopa/levodopa [59]. Additionally, subcutaneous infusion of carbidopa/levodopa is under evaluation [60,61]. The major side-effects of carbidopa/levodopa are the development over time of dyskinesia and fluctuating 'off-on' periods of effectiveness [5].…”