Investigational Parkinson Treatment ND0612 Demonstrates Efficacy, Safety in Published Phase 3 BouNDless Trial

Alberto Espay, MD, MSc

NeuroDerm has published the phase 3 results of BouNDless, a double-blind, double-dummy, active-controlled study (NCT04006210) assessing ND0612 as a potential therapy for patients with Parkinson disease (PD). All told, the data showed that ND0612, a continuous 24 h/day subcutaneous levodopa-carbidopa (LD/CD) solution led to increased ON time without troublesome dyskinesia and reduced OFF time, when used in combination with oral immediate-release (IR) LD/CD.^1,2

ND0612 currently remains under review by the FDA with a PDUFA date for the second quarter of 2024. The trial, led by Alberto Espay, MD, MSc, director of the James J. and Joan A. Gardner Family Center at the University of Cincinnati, randomized 259 patients with PD who experienced at least 2.5 h/day of OFF time to either subcutaneous ND0612 (n = 128) or oral LD/CD (n = 131). After 12 weeks of double-blind treatment, results showed that the active agent provided 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).

"Orally administered levodopa/carbidopa tablets remain the most essential pharmacological intervention in Parkinson disease; however, over time, the reliability of its benefits can decrease, leading to the onset of motor fluctuations,” Espay said in a statement.¹ "We are encouraged by these positive data, which we believe support ND0612, if approved, as a potential treatment option for people with Parkinson's disease experiencing motor fluctuations who have thus far had limited options."

Overall, the study met its primary end point and the 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.

The trial, which included patients who had a Hoehn and Yahr stage of less than 3 in the ON state, included a 12-week run-in phase during which optimal dosing regimens were established for both groups. In total, 243 (94%) participants completed the study. During the open-label optimization and double-blind phase, most participants (optimization: 89%; double-blind: 80%) on ND0612 experienced at least 1 adverse event (AE).

READ MORE: UB-312 Reduces α-Synuclein in Parkinson Disease in Phase 1 Trial

Of the AEs reported, infusion site reactions, most of which were mild, were the most common (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 paresthesia and peripheral sensorimotor neuropathy (n = 1). Notably, there was 1 participant on ND0612 who died during the double-blind phase because of a fall leading to traumatic brain injury; however, this was not deemed related to the study intervention.

In January 2023, when NeuroDerm originally announced the study met primary end point, Ryan Case, PhD, head of clinical medical affairs at the company, gave insight on the agent and its long-term outlook. “ND0612 is designed to improve the drugs’ pharmacokinetic profiles by avoiding gastric involvement and maintaining stable and continuous therapeutic levodopa plasma concentrations," he said. "It potentially offers reliable, sustained relief of motor fluctuations in people with Parkinson disease. ND0612 is currently the only continuous subcutaneous, levodopa/carbidopa product with such robust long-term safety data."

"The long-term safety and tolerability profile of ND0612 is well documented with a cumulative exposure exceeding 550 patient-years and with some patients already in their 7th year of ND0612 treatment in the long-term safety trial. The tolerability profile of ND0612 looks very promising, with only 6.3% of patients randomized to ND0612 discontinuing the DBDD period of the pivotal efficacy study due to any reason, including 5.5% who discontinued due to adverse events,” Case added.

Later that year, at the 2023 American Academy of Neurology (AAN) Annual Meeting, 3-year outcomes from the pivotal phase 3 BeyoND (NCT02726386) were presented. Of the 114 patients who entered the open-label extension, 94 (82.5%) completed at least 2 years of treatment and 76 (66.7%) completed at least 3. Overall, results showed that the incidence of infusion-site infection decreased from 19.3 in year 1 to 9.9% in year 2, and 11.7% in year 3, while the incidence of other infusion-site reactions decreased from 60.5% in year 1, 26.1% in year 2, and 27.7% in year 3.

REFERENCES
1. NeuroDerm announces publication of positive results from phase 3 BouNDless trial evaluating ND0612 in Parkinson’s disease patients with motor fluctuations. News release. March 18, 2024. Accessed March 18, 2024. https://www.prnewswire.com/news-releases/neuroderm-announces-publication-of-positive-results-from-phase-3-boundless-trial-evaluating-nd0612-in-parkinsons-disease-patients-with-motor-fluctuations-302091264.html
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
3. Ellenvigeb A, Adar L, Salin L, Case R, Yardeni T, Espay A. Safety and efficacy of subcutaneous levodopa/carbidopa infusion for Parkinson disease: three-year data from the open-label BeyoND study. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 003019