BOSTON – A novel levodopa/carbidopa delivery system fitted to a
retainer worn in the mouth appears to achieve the advantages of
continuous drug delivery without the need for surgery or external pumps,
according to an early clinical experience described in the Emerging
Science session at the 2023 annual meeting of the American Academy of
Neurology.
C. Warren Olanow, MD
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.
More delivery strategies are needed
This
device is in an early phase of development, but several specialists in
Parkinson’s disease agreed that there is a need for more strategies to
provide continuous levodopa in patients with advancing symptoms. Stuart
Isaacson, MD, director, Parkinson’s Disease and Movement Disorders
Center of Boca Raton, Fla., is among them.
“Novel
delivery devices that can provide more continuous levodopa delivery
would be an important therapeutic advance,” Dr. Isaacson said. He called
levodopa “the cornerstone of treatment through the course of
Parkinson’s disease,” but more physiologic dosing in advancing disease
has been a challenge.
“While there
are many therapies currently available to manage OFF time, many people
living with Parkinson’s disease continue to spend only half of their
waking day with good ON time,” he added.
The
currently approved method of delivering continuous levodopa through a
surgically placed catheter into the gastrointestinal system is
effective, but has limitations, according to Aaron L. Ellenbogen, MD, a
neurologist at Beaumont Hospital, Farmington Hills, Mich.
“One
of the challenges with the current treatment landscape of Parkinson’s
disease is that medication can be absorbed variably through the
gastrointestinal system,” he said. “As the disease progresses, this
often becomes more troublesome.” Although this new device is likely to
share this issue, Dr. Ellenbogen said that several devices might be
useful to match patients with the one that works best for them.
Dr.
Olanow is the founder and CEO of Clintrex Research Corporation, through
which he also serves as chief medical officer of SynAgile, the company
developing DopaFuse. Dr. Isaacson has financial relationships with more
than 30 companies, including those that produce levodopa and levodopa
delivery systems. Dr. Ellenbogen has financial relationships with
Allergan, Acorda, Supernus, and Teva.
For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
View access options
