Revisiting the dopaminergic strategy in Parkinson’s disease
The DIVE-I study introduces a new therapeutic paradigm in the treatment of Parkinson's disease and may soon change clinical practice guidelines.
Anaerobic dopamine and brain-targeted infusion: a dual innovation
L-Dopa remains the cornerstone of symptomatic treatment in Parkinson’s disease (PD). However, its long-term use is limited by pharmacokinetic instability, off-target metabolism, and the development of motor complications such as fluctuations and dyskinesia. Device-assisted therapies (DATs), including deep brain stimulation (DBS), apomorphine infusion, and intestinal gel administration, represent a therapeutic step forward, but only a minority of patients access or tolerate them.
The pathophysiological rationale for continuous central dopamine supplementation is strong. Yet, direct dopamine administration has been considered impracticable for decades, largely due to the molecule’s rapid oxidation and inability to cross the blood–brain barrier.
InBrain Pharma, in collaboration with the University of Lille and Lille University Hospital, has developed a novel strategy: the continuous intracerebroventricular infusion of anaerobic dopamine (A-dopamine). This formulation is prepared, stored, and delivered in strictly oxygen-free conditions (O₂ < 0.1%), preserving dopamine from oxidative degradation. Delivery occurs via a subcutaneously implanted pump connected to a catheter targeting the third ventricle, adjacent to the striatum. The system allows programmable, circadian dosing of dopamine, creating a personalized neuromodulation approach for dopaminergic receptors.
DIVE-I study: design and patient population
The DIVE-I study (Dopamine IntraVentricular Evaluation), published in “Nature Medicine”, is a single-center, open-label, phase 1/2 trial evaluating the feasibility, safety, and efficacy of A-dopamine in patients with advanced PD and severe L-dopa-related complications (LDRCs). Twelve patients underwent stereotactic implantation of the device.
Phase 1 (n=12) focused on titration and safety. Phase 2 (n=9, crossover design) compared one month of A-dopamine with one month of optimized oral antiparkinsonian therapy. Blinded primary outcome was the percentage of time spent in bradykinesia or dyskinesia, measured through home actigraphy.
Clinical outcomes: efficacy and safety
The DIVE-I study showed encouraging results in terms of motor symptom control and safety. The primary endpoint (percentage of time spent in bradykinesia or dyskinesia) was significantly improved with A-dopamine compared to optimized oral therapy. Patients experienced a median reduction of 10.4%, with a statistically significant P value of 0.027 and a moderate effect size (Hedge’s g = −0.62), indicating a tangible clinical benefit.
This translated into a meaningful increase in functional “ON” time. Patients gained, on average, 4.4 hours per day without dyskinesia, and an even greater improvement - 6.6 hours daily - in time spent in good motor autonomy, defined as being in an “ON” state with no or only mild symptoms. These improvements were achieved in parallel with a substantial reduction in oral dopaminergic drugs. In particular, the levodopa equivalent daily dose (LEDD) was reduced by approximately 60%, underlining the central dopaminergic efficacy of the intracerebroventricular pathway.
It is important to note that the treatment demonstrated a favourable safety profile. No serious A-dopamine-related adverse events occurred in either the titration or maintenance phase. Mild and transient effects such as nausea, drowsiness or orthostatic hypotension were observed during dose escalation, which correspond to the typical tolerability profile of oral dopaminergic agents.
During the long-term follow-up, which included over 900 home refills of the device, only three minor adverse reactions were reported, each of which resolved without complications. The study did not observe any emergence or worsening of dyskinesia, even with high-dose A-dopamine during rapid titration. This absence of dyskinesia induction suggests a distinct pharmacodynamic behavior compared to pulsatile oral L-dopa and may point to a more physiological mode of receptor stimulation.
Long-term treatment and real-world applicability
All 11 eligible patients continued A-dopamine therapy beyond the trial. Median follow-up now exceeds 18 months, with some patients exceeding 3,5 years of continuous infusion. Long-term titration was adjusted according to patient needs, balancing clinical benefit with refill frequency (median interval: 11 days). No long-term A-dopamine-related adverse reactions have emerged.
Interestingly, the LEDD reduction remained durable, and no new motor complications were noted over time. This sustained benefit reinforces the role of stable dopaminergic receptor stimulation in mitigating disease burden.
What comes next?
This therapeutic innovation effectively ushers in a new generation of device-assisted therapies: “central infusion of neurotransmitters”, overcoming precursor-based strategies. By directly targeting the striatum and circumventing digestive absorption and transport in the BBB, dopamine A provides what oral L-dopa cannot: a stable, tailored, circadian dopamine.
Moreover, the absence of dyskinesia induction, despite robust motor improvement, raises fundamental questions about the differential pharmacodynamics of dopamine versus L-dopa. The DIVE-I results may thus inspire not only therapeutic changes, but a reappraisal of PD pathophysiology.
The results of this study need to be confirmed by a large, high-quality clinical trial (randomised and double-blind controlled) to obtain further evidence on the efficacy and safety of this treatment. A larger phase III program is currently under development, with the aim of obtaining early access authorisations by the end of the decade. Given the unmet needs in advanced PD and the limitations of existing DAT, A-dopamine infusion could rapidly become the preferred option for patients refractory or ineligible for other interventions.
- Moreau C, Odou P, Labreuche J, Demailly A, Touzet G, Reyns N, Gouges B, Duhamel A, Barthelemy C, Lannoy D, Carta N, Palas B, Vasseur M, Marchand F, Ollivier T, Leclercq C, Potey C, Ouk T, Baigne S, Dujardin K, Carton L, Rolland AS, Devedjian JC, Foutel V, Deplanque D, Fisichella M, Devos D. Intracerebroventricular anaerobic dopamine in Parkinson's disease with L-dopa-related complications: a phase 1/2 randomized-controlled trial. Nat Med. 2025 Mar;31(3):819-828. doi: 10.1038/s41591-024-03428-2. Epub 2025 Jan 7. PMID: 39775041; PMCID: PMC11922744.