COPENHAGEN — A novel, continuous levodopa/carbidopa (LD/CD) infusion appears to increase treatment on times among patients with Parkinson’s disease and improve clinician- and patient-rated outcomes, suggest results from BouNDless.
As reported earlier this year by Medscape Medical News, topline data from the trial were discussed at the 2023 annual meeting of the American Academy of Neurology. Updated results were presented here at the International Congress of Parkinson‘s Disease and Movement Disorders (MDS) 2023.
The results show that improvements seen with the ND0612 regimen, which offers continuous subcutaneous delivery of LD/CD, were not only significant but also “clinically relevant,” said study presenter Olivier Rascol, MD, PhD, professor of clinical Pharmacology at University of Toulouse Hospital, Toulouse, France.
Moreover, the “safety and tolerability profiles were considered acceptable,” he said, with infusion site reactions being mostly mild and rarely a cause for discontinuation.
Rascol began his presentation by underlining that levodopa remains the most effective drug for controlling motor symptoms in Parkinson’s disease and is therefore the “gold standard.”
He noted, however, that, with chronic treatment and disease progression, it is associated with “a number of problems related to bioavailability and the generation of motor complications,” which can become burdensome and difficult to manage with oral strategies.
There has therefore been increasing interest in developing novel interventions such as ND0612 (Mitsubishi Tanabe Pharma America, Inc.), an investigational continuous CD/LD infusion designed for 24-hour, subcutaneous delivery.
Increase in Good “ON” Time
To examine the efficacy, safety, and tolerability of the subcutaneous infusion, the researchers conducted a phase 3 trial including individuals with Parkinson’s disease experiencing at least 2.5 hours of OFF time daily while receiving four or more oral CD/LD doses per day.
After screening, patients were enrolled into an open-label, run-in phase comprising oral immediate-release LD/CD for 4-6 weeks, followed by ND0612 infusion plus oral IR LD/CD as needed for dose optimization.
The participants then entered the double-blind, double-dummy (DBDD) phase of the trial, in which they were randomly assigned to continue on the ND0612 infusion regimen or switch back to oral IR LD/CD, with an infusion placebo.
Overall, 259 patients were randomly assigned, with 120 patients completing infusion treatment, and 123 completing treatment with oral IR LD/CD plus placebo (8 patients terminated early in each treatment arm).
The study met its primary endpoint of change in good ON time, with the ND0612 regimen providing an additional 1.7 hours of good ON time without troublesome dyskinesia (OTwoTD) vs oral IR LD/CD plus placebo (P < .0001).
This was driven by the ND0612 regimen being associated with maintenance of OTwoTD at 11.2 hours per normalized 16 hours after 12 weeks vs 11.8 hours at entry into the DBDD phase.
This compared with a reduction in OTwoTD among patients given oral IR LD/CD plus placebo, from 12.1 hours per normalized 16 hours at entry into the DBDD phase to 9.8 hours at the 12-week follow-up.
Improvement in Motor Experiences
In terms of secondary endpoints, there was a corresponding significant decrease in “OFF” time with the ND0612 regimen vs oral IR LD/CD alone, at an average treatment effect of -1.40 (P < .0001).
There was also a significant improvement in motor experiences of daily living sub-scale scores on the MDS-Unified Parkinson’s Disease Rating Scale Part II, at a treatment effect of -3.05 (P < .0001), with the ND0612 regimen.
In addition, Rascol reported the novel regimen was associated with a significant improvement in Patient Global Impression of Change scores, at an odds ratio of 5.31 (P < .0001), vs the standard regimen, as well as a significant improvement in Clinician Global Impression of Improvement scores, at an odds ratio of 7.23 (P < .0001).
There were, however, no significant differences in motor experiences in OFF scores on the MDS-Unified Parkinson’s Disease Rating Scale Part III between the two treatment arms (P = .089).
Nevertheless, Rascol commented that it is “interesting to see that most of the secondary or exploratory outcomes also showed a trend in favor of the infusion regimen.”
There was a moderate increase in treatment-emergent adverse events with the infusion vs the oral LD/CD regimen, with 67.2% vs 52.7% of patients affected, and more patients assigned to the ND0612 regimen experienced serious treatment-related events, at 3.1% vs none with IR LD/CD.
Mild infusion site reactions were more common with the ND0612 regimen vs IR LD/CD alone (43.8% vs 36.6%), and the same held for moderate infusion site reactions (12.5% vs 5.3%); there was no difference in severe reactions between the two groups (0.8% for both).
Inflated Patient Expectations, Tolerability in Real World
Michael S. Okun, MD, director of the Fixel Institute for Neurological Diseases at the University of Florida Health in Gainesville, welcomed the results.
“For several decades, it has been a challenge to develop a levodopa therapy which crosses the skin to treat Parkinson’s disease,” he told Medscape Medical News.
“The results of this randomized study are promising and the almost 2 hours of improvement in OFF time will likely be meaningful for many persons with Parkinson’s.”
Okun noted, however, that “as the subcutaneous skin pump technology moves closer to the clinic, it will be important to keep in mind that those with Parkinson’s disease may have inflated expectations for this approach.
“We do believe this pump therapy will reduce motor fluctuations and it will reduce OFF dopaminergic time; however, it will be important to stress that this type of therapy will not likely impact walking, talking, and thinking,” he said.
Session chair Tanya Simuni, MD, research professor of Parkinson’s Disease and Movement Disorders at Northwestern University in Chicago, noted that there are two programs in development for continuous subcutaneous levodopa/carbidopa infusion.
She said the results are “awaited impatiently by the field — by patients first and foremost.”
However, Simuni underlined that it “remains to be determined whether tolerability will be an issue as it goes into the real world.”
The study was sponsored by NeuroDerm Ltd. Rascol declares relationships with AbbVie, Adamas, Acorda, Addex, Alzprotect, Apopharma, Bial, Biogen, Britannia Pharma, Clevexel, INC Research, Lundbeck, Lupin, Merck, Mundipharma, Neuratris, Neuroderm, Novartis, Ono Pharma, Osmotica, Oxfordbiomedica, Parexel, Pfizer, Prexton Therapeutics, Quintiles, Sanofi, Servier, Sunovion, Theranexus, Takeda, Teva, UCB, Watermark Research, Xenoport, Xo, and Zambon. Simuni declares a relationship with Neuroderm. No other relevant relationships declared.
International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2023: Abstract 1150. Presented August 29, 2023.
For more Medscape Neurology news, join us on Facebook and X (formerly Twitter)
Source: Read Full Article