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

• Published in: Parkinsonism & related disorders 2021-10, Vol.91, p.139-145
• Main Authors: Giladi, Nir, Gurevich, Tanya, Djaldetti, Ruth, Adar, Liat, Case, Ryan, Leibman-Barak, Shelly, Sasson, Nissim, Caraco, Yoseph
• Format: Article
• Language: English
• Subjects: Administration, Oral; Aged; Antiparkinson Agents - administration & dosage; Carbidopa - administration & dosage; Catechols - administration & dosage; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Humans; Infusion; Infusions, Subcutaneous; Levodopa; Levodopa - administration & dosage; Levodopa - blood; Male; Middle Aged; Motor Activity - drug effects; Motor fluctuations; ND0612; Nitriles - administration & dosage; Parkinson Disease - drug therapy; Parkinson Disease - physiopathology; Parkinson's disease; Pharmacokinetics; Proof of Concept Study; Treatment Outcome
• ISSN: 1353-8020; 1873-5126
• DOI: 10.1016/j.parkreldis.2021.09.024

ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations. This was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h. ND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H0 of μ0 ≤-1.6). Levodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design. •Continuous levodopa/carbidopa infusion with ND0612 was generally well-tolerated.•ND0612 provides stable levodopa plasma levels compared with oral levodopa.•Steady levodopa concentrations were associated with reduced motor fluctuations.•Adjunct COMT inhibition increased levodopa exposure versus ND0612 monotherapy.