Parkinson Therapy ND0612 Receives Complete Response Letter

According to a recent announcement, the FDA has issued a complete response letter (CRL) to NeuroDerm for its submission of ND0612, a 24-hour/day subcutaneous infusion of liquid levodopa/carbidopa (LD/CD), as a potential treatment for ON time in Parkinson disease (PD). Mitsubishi Tanabe Pharma and its wholly owned subsidiary, NeuroDerm, noted that they are reviewing the CRL and will work closely with the FDA to address its comments to consider the future direction.¹

ND0612’s application was supported by data from the phase 3 BouNDless trial (NCT04006210), a double-blind, double-dummy, active-controlled trial that featured 259 patients with PD who experienced at least 2.5 h/day of OFF time. In the study, treatment with the investigational agent resulted in an additional 1.72 h (95% CI, 1.08-2.36) of ON time without troublesome dyskinesia compared with oral LD/CD (change, –0.48 h; 95% CI, –0.94 to –0.02; P <.0001).²

The study, published earlier this year in The Lancet Neurology, met its primary end point and first 4 secondary end points as well. Of the 9 prespecified hierarchical outcomes, significant treatment differences favoring subcutaneous ND0612 included daily OFF time (–1.40; 95% CI, –1.99 to –0.80), Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)-II scores (–3.05; 95% CI, –4.28 to –1.81), Patients Global Impression of Change (OR, 5.31; 95% CI, 2.67-10.58), and Clinical Global Impression of Improvement (OR, 7.23; 95% CI, 3.57-14.64). Of note, hierarchical testing ended after the 4th secondary end point.

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Of those randomized, 94% (n = 243) completed the study, where they continued on into the open-label extension. Throughout the open-label optimization and double-blind phase, most patients experienced at least 1 adverse event (AE) while on ND0162. Infusion site reactions, most of which were mild, were the most commonly reported AE (open-label ND0612: 83%; ND0612 double-blind: 57%; oral LD/CD: 43%). There were 7 reported serious AEs found in 4 patients, which included infusion-site cellulitis (n = 2), infusion-site abscess and infusion-site ulcer (n = 1), and parasthesia and peripheral sensorimotor neuropathy (n = 1).

ND0612 is designed to improve the drugs’ pharmacokinetic profiles by avoiding gastric involvement and maintaining stable and continuous therapeutic levodopa plasma concentrations. The thought behind the drug is that it may provide sustained relief of motor fluctuations in patients with PD, backed by robust long-term safety data. To date, the therapy has a documented cumulative exposure exceeding 500 patient-years, with some patients already in their 7th year of treatment in the long-term safety trial.

During BouNDless, a relatively small number of patients discontinued therapy in both groups, 5.5% (n = 7) in the ND0612 and 3.1% (n = 4) in the immediate-release LD/CD group, The rates of AEs were similar, with 80.5% (n = 103) of those in the ND0612 group reporting AEs compared with 74% (n = 97) of those in the immediate-release LD/CD group.

REFERENCES
1. Mitsubishi Tanabe Pharma Corporation provides US regulatory update on ND0612. News release. June 11, 2024. Accessed June 19, 2024. https://neuroderm.com/our-company/news-and-events/fda-letter/
2. Espay AJ, Stocchi F, Pahwa R, et al. Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612 for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomized, double-blind, double-dummy, multicenter trial. The Lancet Neuro. Published online March 15, 2024. doi:10.1016/S1474-4422(24)00052-8