A case of monotherapy with intracerebroventricular anaerobic dopamine allows complete control of Parkinson's disease symptoms

Since the identification of nigro-striatal dopamine depletion in Parkinson's disease (PD), ¹ it seems rational to compensate for it by continuous administration. Since the discovery of the key role of dopamine in the brain in the 1960s and Arvid Carlson's Nobel Prize in 2000, this treatment has never been developed. Since, dopamine does not cross the digestive and the blood brain barrier, oral administration of L-dopa remains the main treatment. ¹ However, L-dopa possesses many pharmacokinetic and pharmacodynamic drawbacks leading to the L-dopa-related complications (LDRC) in 50% of the patients after 5 years. ² To meet the challenge of dopamine biodistribution and oxidation, a novel concept of continuous intracerebroventricular (i.c.v.) administration of an anaerobic dopamine formulation (A-dopamine to avoid auto-oxidation) has been developed using a telemetry-controlled subcutaneous abdominal pump connected to a subcutaneous catheter implanted in the ventricle close to the striatum (Figure 1). A-dopamine has been shown to be safe and effective in preclinical models,^3,4 and in a phase I/II clinical trial (Trial Registration: Protocol ID: 2018_49; French Ethics Committee: 2020-000155-12; French Drug Agency: MEDAECPP-2020-04-00002; ClinicalTrials.gov ID: NCT04332276). ⁵ A-dopamine was on add therapy with a reduction of 60% of oral L-dopa on 12 patients. One patient among them (patient N°10) benefited from monotherapy of A-dopamine at long-term. The patient was a 65-year-old woman with a disease duration of 6 years since the onset of the first motor symptoms and of 3.7 years since diagnosis. She had been on L-dopa for 2.6 years and had been experiencing LDRC for 1.2 years. She was receiving a daily dose equivalent to 1500 mg of L-dopa (L-dopa/benzeraside and 1 mg of rasagiline). During phase I of the trial, she observed at the dose of 50 mg of A-dopamine during the daytime period (6 a.m. to 11 p.m.) a reduction of dyskinesia and dystonia despite maintaining the same oral treatment dose. The patient reported transient nausea and transient drowsiness after titration of 10 mg. Titration to 5 mg did not cause any adverse effects. No changes in blood pressure or electrocardiogram were observed. At the end of 2 months of titration, a total disappearance of LDRC was noted on home diaries under 150 mg of A-dopamine during the day and 30 mg at night, allowing for a concomitant reduction in oral L-dopa of 63.3%. At the time of entry into phase II, breast cancer was discovered. A-dopamine administration was discontinued to allow treatment of non-metastatic triple-negative breast cancer with surgery, radiotherapy, chemotherapy, and immunotherapy (pembrolizumab). One year later, the oncologist considered the patient to be in remission and the study's independent monitoring committee authorised the resumption of treatment. It was then decided, in accordance with the patient's wishes, to continue slow titration until monotherapy was reached. With a dose of 240 mg during the day and 40 mg at night, motor symptoms were controlled (Movement Disorders Society-Unified Parkinson Disease Rating Scale motor score of 4 ; Off drug motor score: 32; total score: 39). Schwab & England activities of daily living improved from 70 to 100. with disappearance of the 3 h of Off, morning painful dystonia, and the 1 h of mild to moderate dyskinesia. She was always on “perfect On”, except two periods of less than 30 min of very slight Off and fatigue on home diaries. She also reported the absence of psychic excitement usually present with L-dopa. She never presented impulse control disorders. For the patient's comfort, transcutaneous refills of the pump were performed at home every 7 days for 19 months without any adverse effects.

OPEN IN VIEWER

Figure 1.

Therapeutic concept of A-dopamine. (A) The preparation, storage and delivery of dopamine require strict anaerobia conditions (A-dopamine; O₂ < 0.1%). (B) Delivery takes place via a commercially available pump (Prometra 2™ Flowonix/Infusyn). (C) The catheter implantation procedure was performed with stereotactic placement guided by a Renishaw's Neuro Mate robot and intra-operative control with the O-Arm system (Medtronic™). This can be performed also with neuronavigation with preoperative magnetic resonance imaging mapping. Tip of the catheter is represented with a red circle : right frontal horn of the lateral ventricle close to 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); The catheter was attached to the right frontal bone of the skull and then tunnelled under the skin into the abdominal region where it was connected to a 20 ml telemetry-adjustable pump delivery system (Prometra II™ Flowonix/Infusyn). The pump was filled in with 20 ml of A-dopamine formulated as a solution of dopamine hydrochloride (100 mg/ml) dissolved in sterile water for injection in a sterile anaerobic isolator (oxygen level <1%) to avoid degradation by dopamine auto-oxidation, without any other excipient (Patent #WO2015173258 A1). (D) Ergonomics: transcutaneous filling of the abdominal pump every 7‐15 days under local anaesthesia, can be performed at home. (E) Fine tuning of the dose is determined by telemetry using the programmer.

After about 21 months including 16 months of monotherapy with total control, treatment had to be interrupted due to the discovery of a new triple negative cancer in the other breast.

The objective of this clinical case is to provide additional evidence about the very high clinical efficacy of A-dopamine without inducing any dyskinesia. As expected, over-rapid titration led to classic and transient adverse reactions as observed with all dopaminergic treatments, but no more adverse events on a long term.

The most surprising result was the absence of dyskinesia and efficacy fluctuation as seen under L-dopa therapy. This could be explained by a dual anti-dyskinetic mechanism: through the direct action of A-dopamine, as shown by the concomitant reduction in dyskinesias and “off” periods at the start of titration and even before the reduction in oral L-dopa, but also through the reduction in oral L-dopa. ⁵ This also demonstrates that the action of L-dopa and that of dopamine are clearly different. It is interesting to note that a specific receptor for L-dopa has been demonstrated. ⁶ It must therefore be considered that the action of L-dopa may not be solely through its metabolism into dopamine

Monotherapy achieved a better result than that observed in the previous clinical trial. ⁵ The dose equivalence between A-dopamine and L-dopa is 5 times higher with A-dopamine.

These results seem promising considering other drug based Device Aided Therapies (DATs) (levodopa carbidopa intestinal gel, continuous subcutaneous apomorphine infusion, foslevodopa/carbidopa) showed a benefit of 1.7 to 1.9 h of On without troublesome dyskinesia compared to the control group.^7–10 This criterion is used because L-dopa cannot induce motor control without complications at the advanced stage,^1,2,4,5 because of its numerous pharmacokinetic and pharmacodynamic limitations.^7,11–13 The ideal criterion would be perfect On time without any dyskinesia.

It is too early to determine the true benefit/risk ratio and what place this new therapeutic approach of pharmacological modulation will occupy in the advanced PD. It could be argued that A-dopamine appears as displaying a lower level of discomfort than other existing drug-based DATs with external pump. It can also be argued that the neurosurgical risk of A-dopamine could be lower with a thin, flexible, unilateral catheter implanted only a few centimetres into the cortex and then into the ventricle, than with two rigid electrodes implanted deep into the brain. In addition, the benefit is easy to achieve in all patients, as targeting has no risk of troubleshooting as compared with the posterolateral part of the subthalamic nucleus. ¹⁴ However, the exact balance between risks, benefits, and comfort remains to be compared between DAT.

In conclusion, this case report provides promising data on the feasibility, safety, and initial effects of this new A-dopamine DAT, which now needs to be confirmed in a large double-blind, parallel-group phase III study.