A New Treatment for Fluctuating and Dyskinetic L-dopa Complications
Parkinson's disease is characterized by a range of motor and non-motor symptoms, many of which are linked to a deficiency of dopamine in the striatum, a crucial area of the brain. This deficiency results from the degeneration of dopamine-producing neurons in the substantia nigra. These neurons are vital for regulating automatic functions like walking, talking, and emotional responses. Unfortunately, dopamine cannot be administered orally because it doesn't cross the digestive or blood-brain barriers. To address this issue, L-dopa, a dopamine precursor, has been used since the 1970s. However, L-dopa has limitations, including a short half-life and issues with distribution, leading to fluctuations in symptom control known as "off" and "dyskinesias."
After about five years, nearly 50% of individuals with Parkinson's disease experience complications associated with these fluctuations, prompting the exploration of alternative therapies. Second-line treatments, such as deep brain stimulation or external pumps delivering dopamine agonists or L-dopa, are available. However, these treatments may not be well-tolerated or effective for all patients. Due this this challenge, there is an ongoing quest for delivering dopamine directly to the brain.
Direct administration of dopamine to the brain was considered in the 1980s but faced challenges, including rapid oxidation of dopamine in the open air. To combat this issue, a novel approach involving continuous intracerebroventricular administration of an anaerobic (oxygen-free) dopamine formulation, termed "A-dopamine," was developed and demonstrated efficacy and safety in various Parkinson's disease models (mouse, rat and non-human primate).
Building on this innovative treatment concept, a study was conducted on 12 Parkinson's disease patients experiencing severe L-dopa-related complications, all under the age of 70 without significant cognitive impairment. Once the recruitment of the study was finished the patients underwent a minimally invasive surgical procedure to implant a thin catheter into the brain, connecting it to a subcutaneous pump in the abdomen for dopamine delivery. This is same surgical procedure as for brain stimulation, but less dangerous as it is a small, flexible catheter inserted only a few centimeters into the brain to reach the ventricle (water pocket in the brain close to the striatum). No cerebral surgical complications were observed. Dosing was individualized and programmed to meet each patient's specific needs, with injections required every 7 to 10 days instead of daily external pump filling. The dose is set by telemetry to program dopamine doses throughout the day and night according to individual needs (see photo).
The outcomes of the study reported no serious adverse reactions to the A-dopamine treatment, with only two patients requiring pump replacement. Mild side effects such as nausea, vomiting, and fatigue were transient and manageable. Importantly, there was no significant worsening of behavioral issues such as impulse control disorder, apathy and hallucination/confusion compared to oral treatment alone.
In terms of efficacy, the A-dopamine treatment led to an average improvement of four hours in "off" periods and dyskinesias, along with a 65% reduction in oral treatment. All patients experienced less than 1.5 hours of dyskinesia and off-time, and all expressed a desire to continue the treatment long-term, with the first patient successfully treated for nearly four years. Only two patients had to stop: one patient died of a lung infection unrelated to treatment or Parkinson's disease. Another patient had to stop temporarily because of breast cancer treatment.
These promising results in terms of safety and feasibility are paving the way for a large international therapeutic trial involving 25 centers across Europe and the United States in 2025. This trial aims to establish the risk-benefit balance of this innovative treatment and its role within the broader strategy of second-line Parkinson's disease therapies.
NB: The treatment is not currently available and must continue to be evaluated before its approval can be considered for all patients suffering from complications related to oral L-dopa therapy.
Trial involvement: If you would like to hear more about this trial when it launches in 2025, or would learn how to participate, please check www.inbrainpharma.com.
(A) Degeneration of dopaminergic neurons in the substantia pars compacta leads to dopamine depletion in the striatum (to a lesser extent dopamine depletion in the mesocortical (intellectual disorder) and mesolimbic (behavior disorder) pathways). The dopamine deficit can be compensated for by direct continuous administration of dopamine through an abdominal pump and its catheter (middle). (B) The preparation, storage and delivery of dopamine occurs under anaerobia conditions (A-dopamine) to avoid rapid dopamine oxidation. (C) Delivery takes place via a commercially available pump (Prometra™ Flowonix). Fine tuning of the dose is determined by telemetry. (D) Neurosurgical targeting (red circle): right frontal horn of the lateral ventricle at the entrance of the interhemispheric foramen connecting the third ventricle allowing the perfusion of A-dopamine right next to the striatum (C: caudate nucleus; P: putamen); (E) Ergonomics: transcutaneous filling of the abdominal pump every 7‒15 days under local anesthesia and then adjustment by telemetry of hourly and circadian doses
Prof. David Devos, MD, PhD works at Lille Neuroscience & cognition center. He presented this work at the WPC 2023 in Barcelona as a poster presenter. This research outlined above was executed with a large cohort colleagues at six different French research centers.
Prof. Devos completed this research in collaboration with the following individuals:
Caroline Moreau, MD, PhD, Pascal Odou, PharmD, PhD, Alexandre Demailly, PharmD., Gustavo Touzet, MD, Nicolas Reyns, MD, PhD, Christine Barthelemy, PharmD, Damien Lannoy, PharmD., PhD, Natacha Carta., Benjamin Palas, PharmD, Felix Marchand., Bastien Gouges, PhD, Céline Leclercq., Thavarak Ouk, PharmaD, PhD, Camille Potey, PharmaD., PhD, Kathy Dujardin, PhD., Louise Carton, MD, PhD, Pauline Guyon, Anne Sophie Rolland, PhD, Luc Defebvre, MD, PhD, Jean Christophe Devedjian, PhD, Dominique Deplanque, MD, PhD Matthieu Fisichella, PhD
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®