Excitement Around New Therapeutics in Parkinson Disease

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EP: 1.Excitement Around New Therapeutics in Parkinson Disease

At the 2025 American Academy of Neurology Annual Meeting, held April 5-9, in San Diego, California, movement disorder expert Fernando L. Pagan, MD, sat down with NeurologyLive^® to discuss the growing promise of disease-modifying treatments for neurodegenerative conditions like Parkinson disease (PD), driven by advances in protein clearance and inflammation targeting. He emphasized the importance of continued education, the thoughtful use of AI in practice, and clear communication with patients as the field of neurology rapidly evolves.

In episode 2, Pagan talked about recent advances in therapeutics for neurodegenerative diseases like PD dementia and dementia with Lewy bodies. He explained that in a recent placebo-controlled trial, a therapy showed significant improvements in cognition, activities of daily living, and fall reduction, with biomarker evidence supporting its mechanism of action. The conversation also touched on the growing role of amyloid-targeting therapies, the evolving treatment landscape for neurodegenerative disorders, and he drew parallels to the transformation seen in multiple sclerosis (MS) care over the past 2 decades.

Transcript below edited for clarity.

Fernando L. Pagan, MD: Well, a couple of things come to mind so far with this meeting. First of all, just the excitement with all the new therapeutics that have recently been approved—I think there's a great buzz, especially in the movement disorder arena. When we take a look at cognition in Parkinson—so, Parkinson dementia, dementia with Lewy body disease—I would definitely want to attract some attention to some of the work we've done at Georgetown University Hospital with nilotinib.

So, nilotinib is a tyrosine kinase inhibitor that was traditionally used for patients with CML, so with leukemia, and it was repurposed. We've been studying it for over a decade at Georgetown. One of the things we've learned about it is that it can definitely reduce inflammation and improve dopamine production in patients with Parkinsn. Yes—and you can induce autophagy, or clearance of proteins, regardless of whether it's beta amyloid, tau, or alpha-synuclein.

So, we've researched it in Alzheimer disease, in PD, and now we'll be presenting an abstract tomorrow about nilotinib in dementia with Lewy body disease, where we showed that in 3 months—once-a-day daily dosing at 200 milligrams orally—we saw a significant improvement in the SCOPA-COG score. So, cognition improved at three months, and those improvements were sustained for 6 months, which was the trial period. Patients were on the treatment for 6 months.

In addition to that cognitive improvement, we saw an improvement in ADLs for patients compared with those on placebo. And then ultimately, we also saw a significant reduction in falls in patients who were treated with nilotinib compared with those on placebo.

So, when we first got started with treating patients with nilotinib, that's what we saw in our phase 1 trial. We saw patients with dementia with Lewy body disease and patients with PD dementia improve their Mini-Mental State Exam scores and have better motor exams as well but this was an open-label study,. So this is the first placebo-controlled trial, not only looking at safety but also at efficacy.

It was just a small number of patients, 46 patients. It was a study aimed at phase 2, funded by the NIH/NIA, to be able to determine whether this would be worth taking to a phase 3 study. But the results are very significant, and there's a lot of biomarker data to support the reduction of phosphorylated α-synuclein and the improvement in dopamine production.

We've learned a lot, both on the preclinical and clinical sides, about this particular drug—that it does inhibit a receptor called the DDR1 receptor that increases autophagy. So, this is something to look out for, because I do think that this data is robust enough that it could ultimately have a significant impact for our patients with Lewy body disorders.

The other things that are also important in this clinic—we're still learning about the use of lecanemab and donanemab. We're starting to hear a little bit of buzz that some patients with dementia with Lewy body disease also have that amyloid pathology. You know, what's the future going to look like? Are these going to be appropriate treatments for this patient population as well? And how are we going to make these drugs safer? How are we going to be able to treat ARIA? How do we prevent ARIA?

So, these are issues that you're definitely hearing a little bit of buzz about—how we're going to be able to do that. But again, with neurodegenerative disorders, we're really at a crossroads, where I think we're so close to having truly disease-modifying therapies.

We’ve started that road now with drugs like lecanemab and donanemab for cognition, for potential disease modification. But this is just the tip of the iceberg, and I think we're going to see more and more every year.

So definitely, I think it's going to be important to come to meetings like the AAN to continue to keep up, because things are moving very quickly. I feel like we're back in 1999 when the first immunomodulators for MS were coming out—and take a look at how many immunomodulators we have for MS.

I saw during my residency, MS turned from an inpatient disease that we were constantly treating—I would easily have 20 to 25 patients with MS exacerbations, in addition to all the stroke patients. Now this is an ambulatory disorder. We've managed it predominantly as an outpatient, and I think we're at the same crossroads.

By the time I finished fellowship, it was completely an ambulatory type of treatment, and we've just seen improvement year after year in the MS world. I think that's where we are with neurodegenerative disorders—Parkinson and Alzheimer, dementia with Lewy body disease. I think it can translate to the other neurodegenerative disorders as well, as we get better at clearing these proteins and decreasing inflammation.

That’s really going to be the goal. But lecanemab and donanemab are probably the first of many more treatments to come in the very near future.