The Potential of Device-Assisted Therapies in PD: Insights From the Phase 1/2 DIVE-I Trial

David Devos, MD, PhD

Parkinson disease (PD), the second most common neurodegenerative disorder, is typically treated through a comprehensive, personalized approach combining medications, possible surgery, physical rehabilitation, and lifestyle adjustments to optimize symptom management and maintain quality of life. In recent years, the therapeutic landscape for PD has started to gain more ground, with different ways to administer levodopa, the gold standard of treatment.

At the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania, a unique study focused on the potential of a device-assisted therapy (InBrain Pharma) to treat PD. Otherwise known as DIVE-1, the phase 1/2 trial included 12 patients with PD who experienced motor complications. Overall, the study featured 3 phases: an initial feasibility and safety phase (Phase 1), a second phase evaluating efficacy and safety (Phase 2), and a long-term follow-up phase that is still ongoing.

Study investigator David Devos, MD, PhD, a neurologist and pharmacologist at CHU de Lille, Lilly University, in France, sat down to discuss the findings from the study, along with the therapeutic potential of the device-assisted therapy. In the conversation, he provided an overview of the function of the device, the background and rationale for direct dopamine delivery, and the initially promising data. In addition, he gave comments on the therapy’s role in the PD treatment landscape, how it fits among other existing options such as deep brain stimulation, as well as the next steps in its development.

NeurologyLive: What is the function of this device-assisted therapy?

David Devos, MD, PhD: In fact, what the brain of people with Parkinson's disease needs is dopamine, and this has been known for a long time, but we can't take dopamine orally, and we can’t infuse dopamine either because it doesn’t cross the digestive barrier or the blood-brain barrier. The idea was to use a pump, which is already on the market for baclofen or opioids like morphine. The pump is placed in the belly, under the skin but above the muscle, so you don't have to open the muscle. It's an easy procedure. Then you have a very small and soft catheter under the skin, and the neurosurgical part is based on the experience from deep brain stimulation. We use the same system, but it’s less invasive because the small catheter crosses just three centimeters of cortex, then goes into the ventricle, up to the lateral ventricle, third ventricle, and the tip of the catheter is in the third ventricle. And beside each part, you have the striatum, which is where the dopamine needs to be. The system allows for a drop-by-drop infusion of dopamine, and you can refill the pump transcutaneously with a needle. It’s a painless procedure, and you also have the possibility, with telemetry, to titrate the dose. It takes a few weeks to adjust, but you can increase the dopamine dose and reduce the patient's oral treatment to achieve significant benefits.

And the question is: why did no one do this before? Because it seems very simple. In fact, back in 1987, publications from American colleagues like Stanley Fahn and others in Boston and Melbourne tried this in one patient. But at that time, it was just the beginning of the levodopa era, and they observed dyskinesia and hallucinations and thought, "Wow, there's something wrong with levodopa." Maybe it was the metabolites of levodopa. They tried putting dopamine directly into the brain, but they were afraid of oxidation. Stanley Fahn in Columbia asked a colleague, Doug Benes, who was a Spanish sports doctor, to do some trials in mice, rats, and monkeys. He observed that dopamine was rapidly oxidized, and he published it, which killed the concept. They said, "OK, maybe the brain needs dopamine, but we can't give it because it's rapidly oxidized." Our discovery was to prepare, store, and deliver dopamine in an anaerobic environment. So we put dopamine in anaerobic conditions, and it’s very stable—and it’s working.

Can you provide an overview of the study and some of the top-line findings from it?

In fact, we did a monocentric trial. It was a phase 1/2 trial, because this has never been done in humans before. We took the first patient and titrated slowly. It was a lot of work to find the right dose since we had no clue what the correct dose was. We observed that it was well-tolerated. The neurosurgical procedure and the pump worked fine—we had no problems, really. It’s an easy surgical process. It takes four hours, and by the afternoon, the patient can walk freely. It’s less invasive than deep brain stimulation (DBS), in fact. You also don’t need the same precision as DBS, because you just put it in the third ventricle, so it’s easy for neurosurgeons.

The first major discovery was that dopamine does not induce dyskinesia—ever. It is totally different from levodopa. We observed that the clinical symptoms with dopamine were clearly different. With levodopa, you get dyskinesia, but with dopamine, we never observed dyskinesia, not in mice, rats, monkeys, or humans, even at very high doses. It was dangerous for the monkeys in some cases, but still, no dyskinesia. Once the patient was satisfied with phase 1, we moved to phase 2. Since we implant a system, we needed first data on efficacy. The patients wanted to keep the pump because they felt much better. We designed a crossover trial where patients started with either exclusive oral treatment or dopamine infusion. We observed massive efficacy on home diaries and using activity monitors, which were unbiased by placebo effects since it was not a double-blind trial. The main takeaways were the excellent safety profile and the absence of dyskinesia. We saw a massive reduction in off-periods and residual treatment as well.

While it is early in its development, how would this therapy fit in with the therapeutic landscape of Parkinson Disease?

Yeah, you're right, this is a key question. We believe this therapy could have an important role, but it has to be tested further. No one device-assisted therapy is right for every patient. What’s crucial is the patient’s choice. Right now, we have external pumps—though not much in the US, more in Europe. You have the apomorphine pump, and coming soon, subcutaneous foslevodopa and levodopa. The downside with external pumps is that they need to be carried daily, and some people don’t want that. They feel like it reminds them of end-of-life care. These patients might prefer DBS, where everything is inside the body, but DBS is an invasive procedure with risks, like missing the target in the brain. With DBS, you can reduce medication by about 40%, but it’s not perfect. That’s why we developed this new method. Patients want something internal, so we offer them this internal pump system. It’s simple to refill every one or two weeks, and it allows for flexible, adaptive treatment. You can adjust the dosage as needed, and we’ve seen a 60% reduction in overall medication use.

Ultimately, it’s about risk-benefit and ergonomics, allowing patients to choose. We know that half of the patients with external pumps stop using them within a year, so retention is an issue. They might switch to something else, like DBS or this new dopamine intracerebral system. Our open-label trial showed results that were even more effective than DBS, but we need to be cautious—it’s still early, and there could be a placebo effect with new surgical procedures.

What are the next steps in this therapy’s development?

Right now, we want to move quickly to large clinical trials to better define the risk-benefit balance for a large population of patients. We’ve planned phase 3 trials. We’re skipping a small phase 2, because we already know the results are promising, so we want to design a robust trial. We’re also talking to the EMA and starting to get feedback from the FDA to ensure our phase 3 trials will meet their standards. Hopefully, we can move toward registration by 2030.