BOSTON – A new subcutaneous system for infusing levodopa-carbidopa continuously over 24 hours to control Parkinson’s disease met its primary and secondary endpoints in a double-blind, double-dummy phase 3 multicenter trial presented at the 2023 annual meeting of the American Academy of Neurology.
Dr Alberto Espay
When compared with optimized oral immediate-release medication, the delivery system, called ND0612 (NeuroDerm, Rehovot, Israel), improved ON time without troublesome dyskinesias while improving symptoms according to ratings from both patients and clinicians, according to Alberto J. Espay, MD, professor of neurology and director of the Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati.
The new delivery system addresses the challenge of reducing the variability in levodopa plasma concentrations, a major factor in motor fluctuations and diminishing benefit from orally administered drug, according to Dr. Espay. He said that continuous infusion strategies have long been sought as a method to preserve levodopa efficacy.
There were two phases to this multinational trial, called BouNDless. In the first, an open-label run-in phase, 381 patients with Parkinson’s disease were dose titrated for optimization of oral immediate-release levodopa and carbidopa. They were then optimized for the same drugs delivered with ND0612. The study was conducted over 12 weeks; 122 patients left the study after this phase due to adverse events, lack of efficacy, or withdrawal of consent.
In the second phase, the 259 remaining patients were randomized to the continuous infusion arm or to immediate release oral therapy. In this double-blind, double-dummy phase, those randomized to the ND0612 infusion also received oral placebos. Those randomized to oral therapy received a placebo infusion. Efficacy and safety were assessed at the end of 12 weeks.
At the end of phase 1, the ON time increased by about 3 hours when levodopa-carbidopa dosing was optimized on either delivery method. Dr. Espay attributed the improvement to the value of optimized dosing even in patients with relatively advanced disease.
However, for the purposes of the double-blind comparison, this improvement in ON time provided a new baseline for comparison of the two delivery methods. This is important for interpreting the primary result, which was a 1.72-hour difference in ON time at the end of the study. The difference was created when ON time was maintained with ND0612 continuous drug delivery but eroded in the group randomized to oral immediate-release treatment.
Several secondary endpoints supported the greater efficacy of continuous subcutaneous delivery. These included lower OFF time (0.50 vs. 1.90 hours), less accumulation of disability on the United Parkinson’s Disease Rating Scale part II-M-EDL (-0.30 vs. +2.75 points), and greater improvement on the Patient Global Impression of Change (+0.31 vs. +0.70 points), and the Clinical Global Impression of change (+0.31 vs. +0.77 points). The differences were highly statistically significant (all P < .0001).
The patients participating in the double-blind phase of the study were similar with a mean age of 63.5 years in both groups and time since Parkinson’s disease diagnosis (> 9 years). The median ON time without troublesome dyskinesias was about 12 hours at baseline in both groups and the median OFF time was about 3.5 hours.
The higher rate of treatment-related adverse events in the ND0612 group (67.2% vs. 52.7%) was largely explained by the greater rate of infusion site reactions (57.0% vs. 42.7%). The rates of severe reactions in the two groups were the same (0.8%), but both mild (43.8% vs. 36.6%) and moderate (12.5% vs. 5.3%) reactions occurred more commonly in the group receiving active therapy.
“Infusion reactions are the Achilles heel of all subcutaneous therapies,” acknowledged Dr. Espay, who expects other infusion systems in development to share this risk. He suggested that the clinical impact can be attenuated to some degree by rotating infusion sites.
BeyoND extension study
Data from an open-label extension (OLE) of the phase 2b BeyoND trial were also presented at the AAN meeting and generated generally similar results. Largely a safety study, there was no active control in the initial BeyoND or the BeyoND OLE. In BeyoND, the improvement in ON time from baseline was even greater than that seen in BouNDless, but, again, the optimization of dosing in the BouNDless run-in established a greater baseline of disease control.
In the OLE of BeyoND, presented by Aaron Ellenbogen, DO, a neurologist in Farmington, Mich., one of the notable findings was the retention of patients. After 2 years of follow-up, 82% completed at least 2 years of follow-up and 66.7% have now remained on treatment for at least 3 years. Dr. Ellenbogen maintains that this retention rate provides compelling evidence of a favorable benefit-to-risk ratio.
Fulfilling an unmet need
The favorable efficacy data from this trial represent “a big advance,” according to Ihtsham Ul Haq, MD, chief, movement disorders division, University of Miami, who was reached for comment. He noted that continuous infusion delivery has been anticipated for some time, and he expects these types of systems to fulfill an unmet need.
“This will be a useful option in a carefully selected group of patients,” said Dr. Haq, who considers the types of improvement in ON time to be highly clinically meaningful.
However, he cautioned that the nodules created by injection site reactions might limit the utility of this treatment option in at least some patients. Wearing the external device might also be a limiting factor for some patients.
In complex Parkinson’s disease, a stage that can be reached fairly rapidly in some patients but might take 15 years or more in others, all of the options involve a careful benefit-to-risk calculation, according to Dr. Haq. Deep brain stimulation is among the most effective options, but continuous infusion might appeal to some patients for delaying this procedure or as an alternative.
“We need multiple options for these types of patients, and it appears that continuous infusion will be one of them,” Dr. Haq said.
Dr. Espay has financial relationships with Acadia, Acorda, Amneal, AskBio, Bexion, Kyowa Kirin, Neuroderm, Neurocrine, and Sunovion. Dr. Ellenbogen has financial relationships with Allergan, Acorda, Supernus, and Teva. Dr. Haq reports no potential conflicts of interest.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.