AAN 2026 | Recent pharmacological advances and emerging trials in movement disorders

Of course, nearly 70% of patients that we see in our clinic have some sort of Parkinsonism. And in the pharmacological updates as well, the majority of it has been focused on the management of motor fluctuations in Parkinson’s disease. To that end, last year, we had three agents that were approved by the FDA. The first one was IPX203, goes by the brand name of CREXONT. The second one is apomorphine, goes by the brand name of Onapgo. Of course, this has been approved already in the UK and has been used in Europe, but it was approved by the US FDA last year. And the third one is foslevodopa, foscarbidopa called Vyalev. This year, the majority of the papers that we saw coming out actually followed up the clinical trial data that we have with real-world, real-life outcomes being reported. This is especially important because clinical trials, for good reason, are very selective in the patients that they choose to be a part of that trial, and such real-world data actually leads to insight into treatment of patients in clinic.

So just a quick recap, as you know, CREXONT is an oral, is a PO agent. The benefit is it leads to a good on-time per dose increased by 1 hour 55 minutes. The most common relevant side effects are nausea, dyskinesia, the same as is seen by other dopaminergic agents. Onapgo is a subcutaneous infusion. There may be some nausea, a reminder that in the U.S., domperidone is banned. So in the original trial, the TOLEDO trial, patients were given domperidone before starting the subcutaneous infusion. Regardless, this is expected to reduce off time compared with placebo by 1.89 hours a day. And the last one is a continuous subcutaneous infusion called Vyalev, which increases on time without trouble term dyskinesia by 1.75 hours. The relevant side effects include mostly the site-related infections are the most prominent ones, which are erythema, pain, cellulitis, and edema.

A number of new systematic reviews and meta-analysis came out for all of these, and subcutaneous levodopa was shown to provide a meaningful alternative for Parkinson’s disease patients experiencing severe motor fluctuations with existing levodopa formulations. There was a case series that was published out of Ireland that essentially showed that the adverse effects may be a little worse than what was shown in studies and another one that showed that foslevodopa, foscarbidopa may actually be even better if it is prescribed in younger patients earlier with an advanced Parkinson’s disease. And this specific conclusion was reached by a post hoc analysis of a randomized clinical trial.

Another trial that was really interesting and recently published called the PREMANDYSK trial looked at adding immediate release amantadine to carbidopa levodopa with the outcome of incident dyskinesia. So this was a multi-center, 22-month randomized placebo-controlled trial, which enrolled early Parkinson’s disease patients on a stable low dose of levodopa without any motor complications. And they found that in the arm with levodopa and amantadine compared to the arm on levodopa without amantadine, the arm with amantadine actually had an 11% incidence of dyskinesia, which was half that of the other arm. And they concluded that adjunctive amantadine immediate release in early Parkinson’s disease halved the incidence of dyskinesia, something for us to know about.

Other studies, other relevant papers, there was an update on treatments for Parkinson’s disease motor fluctuations. This was a Movement Disorder Society evidence-based medical review. I think it’s well worth a read for all clinicians where they outline based on available evidence what is efficacious and what is likely efficacious in the treatment of motor fluctuations in Parkinson’s disease.

Another big news that came out recently was on tavapodon as an adjunctive treatment for Parkinson’s disease, also called the TEMPO-3 randomized clinical trial. This was published in Jama Neurology. It was a positive trial with the primary outcome of change from baseline to week 26 in total daily on time without any troublesome dyskinesia or a good on time. And they found that there was a statistically significant increase in total daily on time, a good on time from baseline at week 26 in those with tavapadon. A complementary trial was on a fixed dose tavapadon for early Parkinson’s disease. So tavapadon as a first-line treatment. And what they found was that tavapadon, both 5 milligrams and 15 milligrams, demonstrated statistically significant improvement in the MDS-OPDRS combined score from baseline to week 26 compared to placebo. Both of these trials were positive and could offer a really interesting alternative or adjunctive treatment to those with Parkinson’s disease.

Another study that was published talked about mucuna pruriens. We have a number of patients who want quote-unquote natural treatments and mucuna pruriens can provide dopaminergic improvement. My personal practice has been to try and share the wealth of evidence that we have on the safety of carbidopa, levodopa and other dopaminergic treatments for treatment of Parkinson’s disease. But all of us have patients that would only take mucuna pruriens and nothing else. And in that scenario, such data can be useful. What they found was that there is the mucuna pruriens powder improved quality of life, motor and non-motor symptoms over 12 months. To be clear, this was an open label Phase II trial. And to me, in my practice, this does not demonstrate enough benefit for me to wholeheartedly recommend mucuna pruriens. I still think that established treatments are the best way to go.

Another big news this year were the two stem cell trials. There was one trial with the use of autologous cells, which reduced rejection risks and do not require immunosuppression. This was based on seven patients. Another one, which utilized human embryonic stem cells, was based on 12 patients. Both of these were positive. The Japanese equivalent of the FDA has approved them, but it’s important to note that these are not US FDA approved. And I would really caution my patients to wait till we have more evidence. Again, this was Phase I, Phase II trial data. So it talked about safety in a very small sample.

We also have a study that was published out of Oregon, the VA in Portland, which showed that obstructive sleep apnea, those with treated obstructive sleep apnea, actually have a reduced incidence of Parkinson’s disease. While this was based on veterans’ database and therefore cannot be proven to be causative, it again reiterates the importance of screening for and treating obstructive sleep apnea in patients with Parkinson’s disease.

A Phase II study of zervimesine or CT1812 in patients with mild to moderate dementia with Lewy bodies was positive. So the drug was noted to be safe and well tolerated with a favorable efficacy profile, decent enough to justify testing the drug in larger samples. So that’s an interesting positive.

Another major change was the discontinuation of the REMS program for clozapine. So those of us who know the substantial efficacy of clozapine without any worsening of secondary Parkinsonism, are often worried about the REMS program, which provided a lot of regulatory burden. And so that program was discontinued. And therefore, hopefully, it will encourage greater use of clozapine.

Another breakthrough was a FDA breakthrough therapy designation that was given to ulixacaltamide by Praxis Precision Medicine. This is based on the news of the Essential3 Phase III clinical trial. This drug is a highly selective small molecule in a bit of T-cell, T-type calcium channels, and propranolol remains the only other FDA-approved essential tremor treatment. We are still waiting on the paper being published.

Ecopipam demonstrated efficacy and reduced relapse risk in a Phase III clinical trial in Tourette’s syndrome. Again, waiting on the actual article. Finally, daxibotulinumtoxinA, which was FDA approved for cervical dystonia, showed good evidence for prolonged benefit in real world data as well.

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