PHILADELPHIA — Continuous intracerebroventricular administration of an anaerobic dopamine formulation (A-dopamine) appears safe in patients with Parkinson’s disease (PD) and may avoid complications associated with levodopa, results from a first in-human trial suggest. 

A-dopamine induced a dose-dependent improvement in motor symptoms in refractory patients with severe levodopa complications and had a “really great” safety profile, said study investigator David Devos, MD, PhD, a neurologist and professor of medical pharmacology at the University of Lille, France. 

“Even when I made a mistake by program measure, the patient can have nausea, drowsiness, but we never observed dyskinesia, even with a huge dose, “he said. “So, dopamine is not doing the same thing as levodopa.” 

The findings from the phase 1/2 trial were presented here at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.

Less Invasive than DBS

Levodopa is the cornerstone treatment for motor symptoms in PD but has many pharmacokinetic and pharmacodynamic drawbacks that can trigger motor fluctuations, off time, dyskinesia, and non-motor complications, said Devos. 

In the 1980s, preclinical studies and two clinical cases showed that intracerebroventricular administration of dopamine was feasible and improved motor symptoms but resulted in tachyphylaxis, likely due to dopamine oxidation.

To overcome oxidation, Devos; co-investigator Caroline Moreau, MD, PhD; and the biotech InBrain Pharma developed A-dopamine by replacing the oxygen in a dopamine solution with dioxide and nitrogen in an anaerobic chamber and opted to deliver it directly into the brain. “It’s the heart of the innovation,” he said. The novel approach has been shown to be safe and effective in mice, rat, and non-human primate models of PD.

To evaluate feasibility, safety, and dose in humans, the researchers conducted a phase 1 study of A-dopamine titration with concomitant reduction of oral dopaminergic medication in 12 patients with advanced PD. Nine patients continued into a randomized controlled, open-label crossover phase 2 study comparing 1 month of A-dopamine on top of oral background therapy and best oral medical therapy. 

A-dopamine was administered with a telemetry-controlled intra-abdominal pump connected to a subcutaneous catheter implanted through the right frontal horn into the third ventricle. 

“The concept is based on the same strategy as deep brain stimulation, but it’s much less invasive because we just put a very small and soft catheter in 3 cm of cortex and then through all the ventricle systems up to the third ventricle, close to the caudate where the dopamine is needed,” Devos explained.

The 4-hour surgery was well tolerated; patients recovered quickly and were walking freely within hours, he said. There were no severe complications or infections. Before starting the phase 2 trial, three patients were lost: one died from an unrelated pneumonia, and two others temporarily stopped treatment due to a pump malfunction and an unrelated malignancy diagnosis. 

The primary endpoint of the phase 2 trial was blinded assessment of percentage over target (time off and dyskinesia) recorded by actimetry at home using a wristwatch and supplemented with additional data from home diaries. 

The median improvement in time to “on” without dyskinesia was 3 hours, 2.7 hours for time to “on” without troublesome dyskinesia, and 6.2 hours for time “on” or with mild dyskinesia or bradykinesia.

A dose effect was observed with a greater reduction in the levodopa daily dose with higher doses, cutting the daily dose by 42% at the 180 mg/day dose. 

The pump needs to be refilled every 7-14 days, but the physician can easily adjust the dose depending on need, Devos said. The average therapeutic dose appears to be in the range of 150 mg to 280 mg/24 hours.

More Tools in the Toolbox 

Commenting for Medscape Medical News, Per Svenningsson, MD, PhD, professor of neurology at Karolinska Institute, Stockholm, Sweden, said “the concept of continuous dopamine stimulation has been established with pumps where we give levodopa in adipose tissue or directly into the gastrointestinal tract.” 

“This is another way of giving continuous stimulation — a little bit more invasive — but at the same time it was really targeting the region of the brain where dopamine needs to act so, it will be interesting to follow this,” he added. 

The findings provide compelling evidence that continuous dopaminergic stimulation via intracerebroventricular A-dopamine can offer substantial clinical improvements in motor disability, Andrew Evans, MBBS, MD, director of the movement disorders service at the Royal Melbourne Hospital, Australia, said in a press release. 

“Remarkably, the absence of dyskinesia with continuous A-dopamine infusion suggests that this approach may have the potential to reverse the aberrant plasticity in the corticobasal ganglia system — a key factor in the pathophysiology of L-dopa-induced dyskinesia and its associated neurobehavioral issues,” he added. 

Evans noted that the study is small and long-term risks of the procedure remain unknown, but the promising results warrant further investigation.

“This novel approach could ultimately offer superior outcomes compared to existing therapies, such as direct delivery of continuous gel L-dopa to the duodenum or subcutaneous apomorphine infusions,” he said. 

Notably, positive results have been reported recently for other continuous dopaminergic delivery therapies including AbbVie’s foslevodopa/foscarbidopa continuous subcutaneous infusion with an external pump and a continuous subcutaneous L-dopa/carbidopa delivery system. 

“A-dopamine intracerebral infusion will play in the league as the device-aided therapies (DAT),” Devos said. “Although more invasive, this new dopaminergic stimulation approach holds the promise to become a best-in-class DAT.” 

The novel approach will be positioned as an option for advanced patients who start to deteriorate quickly after 5 to 7 years on oral treatments and need to move into DAT treatment, he added.

The next steps are to confirm these early results with a phase 3 trial, while continuing to follow 11 patients currently receiving A-dopamine and followed for up to 3.5 years to date, Devos said.