ND0612 Significantly Improves ON Time in Parkinson Disease in Phase 3 BouNDless Trial

Data from the phase 3 randomized, double-dummy BouNDless trial (NCT04006210) of the investigational therapy ND0162 (NeuroDerm) in patients with Parkinson disease (PD) suggest that the 24-hour/day subcutaneous infusion of liquid levodopa/carbidopa (LD/CD) provides a significant and clinically meaningful improvement in motor fluctuations. Additionally, the therapy showed benefits on functional measures, such as improved experiences of daily living compared with oral immediate release (IR)-LD/CD and was well tolerated.

The results were presented by Alberto J. Espay, MD, MSc, a clinical professor and the division director and Research Endowed Chair at the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the University of Cincinnati College of Medicine, at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts. In total, the 12-week double-blind, double-dummy phase of the study randomly assigned 128 patients to ND0162 (daily levodopa dose range, 496-2820 mg) and 131 patients to IR-LD/CD (daily levodopa dose range, 400-2900 mg). The average ON time without troublesome dyskinesia was 11.8 hours (SD, 2.8) for the ND0162 group and 12.1 hours (SD, 2.5) for the IR-LD/CD group, with each group reporting a mean of 3.7 hours (SD, 2.5) and 3.4 hours (SD, 2.3) of OFF time, respectively.

“In summary, 24-hour subcutaneous infusion LD/CD proved to be superior to the IR-LD/CD and that is in the order of 1.72 hours of good ON time, which as I mentioned was a combination of ON time without dyskinesia, plus ON time with nontroublesome dyskinesia,” Espay said in his presentation. “In fact, there is a change not shown here of the nontroublesome dyskinesia to ON without dyskinesia. In addition, there is an improvement in OFF time corresponding with that improvement in ON, UPDRS [Unified Parkinson’s Disease Rating Scale] Part II motor experiences of daily living, as well as the CGI-I [Clinical Global Impression of Improvement] and PGIC [Patient Global Impression of Change]."

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The treatment effect of 1.72 hours of good ON time compared with IR-CD/LD (95% CI, 1.08-2.36; P <.0001), the magnitude of which Espay noted is comparable to the open-label results also presented at AAN 2023.² “This 1.72 hours of ON time gained are subtracting the significant gain that oral IR-CD/LD had, and therefore it seems as if it is smaller in magnitude, but in fact, is very similar if we were not to account for the IR-CD/LD, which, remarkably, once optimized still [provides] quite a bit of improvement in this population,” he explained to the audience.

Espay also noted in his presentation that ND0162 “demonstrated a reasonable safety profile,” with the majority of patients experiencing infusion-site reactions—which were common but were mostly mild and not often cause for discontinuation. Infusion-site reactions were reported by 57.0% (n = 73) and 42.7% (n = 56) of those in the ND0162 and IR-CD/LD groups, respectively. Of those, 43.8% (n = 56) and 36.6% (n = 48) of patients in the respective groups were deemed mild. Only a single individual in each group reported a severe infusion site reaction.

“As far as the issues with skin irritations, which is perhaps the Achilles heel of all subcutaneous based therapies, there are some efforts to try to minimize this by application of certain massage systems,” Espay said. “Certainly, cleaning the skin is very important, and the exercise that is most meaningful here is the rotation of the infusion sites to minimize the effect on any given infusion site.”

A relatively small number of patients discontinued therapy in both groups, 5.5% (n = 7) in the ND0162 group and 3.1% (n = 4) in the IR-CD/LD group. The rates of adverse events (AEs) were similar, with 80.5% (n = 103) of those in the ND0162 group reporting AEs compared with 74% (n = 97) of those in the IR-LD/CD group.

When asked about where ND0162 might fit in the treatment paradigm for PD, Espay explained that “the way in which we, at the moment, perceive this therapy is adapting it in the early phase of advanced treatment of individuals who are experiencing motor fluctuations for whom dose optimization is really not quite effective. That, then, would be an option for individuals who are currently considered for [deep brain stimulation], for instance. There will be other infusion systems as well, so this would be one of the options for patients.”

In January 2023, NeuroDerm announced that the treatment had met its primary end point,³ and the regulatory submission for ND0162 is expected to be filed at some point in 2023. At the time, Ryan Case, PhD, head of Clinical Medical Affairs at Neuroderm, told NeurologyLive® that the therapy, “has the potential, subject to regulatory approval, to change the treatment paradigm and become an effective, well-tolerated treatment option to better control motor fluctuations,” mainly because “chronic oral levodopa therapy is often associated with the development of motor complications that result from fluctuating levodopa plasma concentrations (peaks and troughs), limiting its clinical utility."

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REFERENCES
1. Espay AJ, Albanese A, Ellenbogan AL, et al. Efficacy and Safety of Continuous Subcutaneous ND0612 Infusion Compared with Oral Immediate-release Levodopa-Carbidopa in Patients with Parkinson's Disease and Motor Fluctuations. Presented at: AAN Annual Meeting; April 22-27, 2023; Boston, MA and Virtual. ES002.
2. Adar L. Relative bioavailability of levodopa administered as a subcutaneous infusion with ND0612 versus oral immediate-release levodopa/carbidopa tablets. Presented at: AAN Annual Meeting; April 22-27, 2023; Boston, MA and Virtual. Poster 11-004.
3. NeuroDerm announces highly positive results from the pivotal phase 3 BouNDless trial evaluating ND0612 in Parkinson’s disease patients with motor fluctuations. News release. January 9, 2023. Accessed April 24, 2023. https://www.prnewswire.com/news-releases/neuroderm-announces-highly-positive-results-from-the-pivotal-phase-iii-boundless-trial-evaluating-nd0612-in-parkinsons-disease-patients-with-motor-fluctuations-301715848.html