BOSTON – , according to an early clinical experience described in the Emerging Science session at the 2023 annual meeting of the American Academy of Neurology.
Icahn School of Medicine
Dr. C. Warren Olanow
On this device, the attenuation of levodopa fluctuations “translated into dramatic improvements in clinical behavior, including highly significant reductions in OFF time and an increase in ON time with no dyskinesias,” reported C. Warren Olanow, MD, who is a chairman emeritus of the department of neurology at the Icahn School of Medicine at Mount Sinai, New York, and now an employee of the company developing this new device.
A novel strategy
Numerous studies have demonstrated that reductions in the troughs of plasma levodopa associated with oral dosing result in longer ON time with fewer dyskinesias, according to Dr. Olanow, who explained this has led to strategies for numerous strategies to achieve continuous delivery. A device that delivers levodopa into the stomach through a surgically implanted catheter has already received regulatory approval. Other devices delivering levodopa subcutaneously are in development, but Dr. Olanow said each of these has had limitations.
“The problem with these approaches is they are associated with potentially serious side effects and they require the patient to wear a cumbersome device,” he explained. Relative to the subcutaneous delivery systems, which have been associated with injection site reactions that include painful nodules, and the surgically implanted devices, which also require an external pump, the latest strategy avoids both disadvantages.
Called DopaFuse, the experimental device is designed to deliver the levodopa and carbidopa into the mouth through a micropump within a wearable retainer. Dr. Olanow said that previous experimental studies demonstrated that small doses of levodopa delivered by mouth to the gastrointestinal system reduce levodopa plasma variability. This early clinical study supports that premise. Levodopa delivered into the mouth by way of a propellant in the retainer-mounted pump improved clinical endpoints.
Encouraging trial results
In the study, 16 patients between the ages of 30 and 75 with Parkinson’s disease were enrolled. On day 1, they received an oral dose of levodopa/carbidopa consistent with their current treatment. On day 2, levodopa/carbidopa was delivered through the retainer-mounted device at equivalent doses. On day 3, they received a single morning oral dose and the received the remainder of their levodopa/carbidopa regimen through the device. On days 4 to 14, they received treatment in the same schedule as day 3.
When pharmacokinetics of levodopa on day 3 were compared with those on day 1, the fluctuation index and coefficient of levodopa concentration variability was reduced to a degree that was highly statistically significant (P < .0001). This, in turn, correlated with “striking” reductions in OFF time with equally statistically significant improvement in ON time and ON time without dyskinesias, according to Dr. Olanow.
Relative to an OFF time of 3.2 hours on day 1, the OFF time of 1.6 hours on day 3 represented a 50% reduction (P < .0001). ON time improved from 12.8 hours to 14.5 hours (P < .001). ON time without dyskinesias improved numerically from 8.8 hours to 9.6 hours.
“There were also improvements in activities of daily living when patients were on DopaFuse, which is a hard endpoint to reach in a study with such a small sample size,” Dr. Olanow reported.
There were no serious adverse events. Three patients reported vomiting and two patients each reported headache, but these events were mild and all resolved within a day. Three patients reported buccal lesions, but these also resolved within a day.
“Some patients reported trouble with speaking in the beginning but at the end of the study, patients were reporting that it was easier to speak because of the motor improvements,” Dr. Olanow said.
Overall, the device was well tolerated by the subjects, providing the evidence for the next stages of clinical studies, reported Dr. Olanow.
“If this turns out to be what we hope it is, it will allow us to deliver levodopa without motor complications, without need for a surgical procedure, and without the risk of subcutaneous lesions,” Dr. Olanow said.