Studies With Amantadine-DR/ER for Treatment of Dyskinesia


The expert neurology panel discusses clinical trial data of amantadine-DR/ER in treatment of dyskinesia and OFF episodes in Parkinson disease.

Daniel E. Kremens, MD, JD: Raj, you were the PI [principal investigator] on one of these lead studies looking at amantadine-DR/ER [delayed release/extended release]. Do you want to tell us a bit about your study and some of the other studies have demonstrated that amantadine-DR/ER is efficacious both for dyskinesia and OFF episodes?

Rajesh Pahwa, MD: Yes. Amantadine-DR/ER started with a phase 2 study, and even in the small phase 2 study we were able to show that it helped with the dyskinesia. Based on that, 2 phase 3 studies were done, one mainly in the United States and the other in Europe. The interesting part is that even in 2 different continents, 2 different groups of patients, the results were very similar, and the patients who were picked were also very similar. We found out that when the patients came into the study, they had an OFF time of about 3 hours, whereas generally when we look at OFF studies, they come into the study with an OFF time of nearly 6 hours. So even with an OFF time of 3 hours at entry, they were able to show that we reduced the OFF time by an hour, which was very significant and a finding we were not expecting.

The other thing is when we looked at dyskinesia, we were able to show that the severity of dyskinesia got better with amantadine-DR/ER. It was about a 40% improvement in the severity. The other thing is we were able to show the duration of good ON; and by good ON, I mean when you don’t include the OFF or the time that they were dyskinetic during the day. This was 2.6 hours when we subtracted the placebo response, which was amazing, because even when you look at infusion studies and deep brain stimulation, deep brain stimulation is the only one that has about 4.4 hours. We were able to show a reduction in the severity of dyskinesia and the total time during the day that they had troublesome dyskinesia, and in addition we were able to show that good ON time was significantly improved. So far this is the only drug we have that has shown to both reduce OFF time and dyskinesia.

Daniel E. Kremens, MD, JD: There has also been a 2-year open-label study subsequently that was published in 2020 that demonstrated long-term tolerability, safety, and efficacy with amantadine-DR/ER that was consistent with the 2 double-blind studies that had been done previously. Bob, you published a paper in 2022 that was a pooled analysis of the above 3 trials. Do you want to comment on what you found?

Robert A. Hauser, MD, MBA: Yes. We were looking at OFF in those pivotal trials, and as Raj mentioned, we saw that OFF was reduced by an hour compared to placebo with the amantadine-DR/ER with a baseline of just about 3 hours, so that’s a pretty striking reduction in OFF, and that was statistically significant. We also did an analysis looking at the patients with the most OFF at baseline, and lesser amount of OFF at baseline. It turned out those with more OFF had more than 2 and a half hours of OFF time at baseline, and those who had less OFF time had less than 2 and a half hours at baseline. We saw that for those who had more than 2 and a half hours at baseline, they had a reduction compared to placebo of 1.2 hours. Those who had less than 2 and a half hours at baseline, had a reduction of 0.77 hours of OFF time. So, whether patients had more or less OFF time at baseline, we saw this significant reduction in OFF, and as Raj mentioned, this was unexpected and a good result.

Daniel E. Kremens, MD, JD: We’ve now had multiple studies that have demonstrated that amantadine-DR/ER not only reduces dyskinesia, but also reduces OFF. And as Raj pointed out before, we haven’t seen that with any other preparations of amantadine, including IR [immediate release]. Fernando, you wanted to add something?

Fernando Pagan, MD: Yes, I think there’s one other important point that should be mentioned in the open-label study. There were patients who were on amantadine-IR who were converted to amantadine-DR/ER, and then they had improvement in dyskinesia, the reduction in OFF time, and improvement in ON time without troublesome dyskinesia as well. That open-label study is eye-opening to show that type of data. It is open label, but there are data to suggest that switching patients from amantadine-IR to amantadine-DR/ER can be beneficial.

Transcript Edited for Clarity

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