Robert Hauser, MD, MBA, talks about amantadine extended release for management of dyskinesia and OFF episodes.
Robert Hauser, MD, MBA: Amantadine extended-release capsules are indicated for both the treatment of dyskinesia and OFF episodes. The initial indication was for dyskinesia, and in phase 3 trials, patients were enrolled who had at least 2 and a half hours of troublesome dyskinesia. And we saw that amantadine extended-release capsules significantly reduced dyskinesia, and this was the basis of its approval. But we also noticed that OFF time was significantly improved. So the company went back and asked the FDA for approval for treatment of OFF and was granted that approval. This is unique in that it can help both ends of the spectrum. We’re trying to reduce troublesome dyskinesia. We’re trying to decrease OFF or trying to gain more of that good ON time in the middle, so-called ON without troublesome dyskinesia, also known as good ON. And in an analysis of the 2 phase 3 trials of amantadine extended release, what we saw was that troublesome dyskinesia was reduced by about 1.5 hours per day and OFF time was reduced by 1 hour per day. And when you look at those things in total and look at, well, how much was good ON time increased, it turns out it was increased by 2.4 hours per day, which is a very robust response. The other thing to think about with regard to OFF [is that] these trials weren’t designed for patients with regard to OFF. They were designed for patients who had troublesome dyskinesia. Although most of these patients do have OFF, they have some OFF, and in the trial, they didn’t end up having as much OFF as typical motor fluctuation trials for patients with OFF. So we did an additional analysis looking at patients who had at least 2.5 hours of OFF time in those trials. And it turns out that the amantadine extended-release capsules were able to reduce OFF time 1.2 hours more than placebo. Again, a very robust response with regard to reducing OFF time.
Once many patients are in the later parts of the 5- to 10-year range from diagnosis, they may be on immediate release 5 times per day for more and experiencing motor fluctuations with OFF and dyskinesia. When you think about these patients, they are experiencing several problems. No. 1, their own episodes have become quite short. And when we looked at a database of patients, we saw that for these patients, their ON episodes were on average only about 2.3 or 2.4 hours, so very short. In addition, we saw that these episodes were very variable with regard to when they come. So, if you’re thinking about planning, the day is very difficult. You’ve only got these short episodes of a little over 2 hours to go out on to your daily activities, but you’re not sure whether they’re going to come, or [if] they’re going to come at 10 AM or 10:30. So in our analysis, when we looked at the amantadine extended-release capsule databases and we looked at the results of these trials, what we saw was that amantadine extended-release capsules extended these short good ON episodes from 2.3 hours [and] extended them to about 5 hours compared to about 2 hours for placebo. So, one gets the much longer good ON periods, and that gives patients much longer times, these extended, continuous good ON times, to go out and do their activities. In addition, we did an analysis to look at the predictability of good ON periods. That is, we looked at 2 days of diaries and said, “Well, if we look at a half-hour at a particular time of the day, let’s say 10 AM, were they experiencing good ON, which is ON without troublesome dyskinesia, at the same time on those 2 days?” And when we looked at baseline, we saw that this predictability or consistency only occurred at about 30% of the half-hours through the day. But with treatment, with amantadine extended-release capsules, this was increased to about 60% of the half-hours of the day. So amantadine extended release not only extends robustly the length of the benefit from carbidopa/levodopa immediate release, it also makes the response much more consistent from day to day.
On-demand therapies that are currently available include inhaled levodopa as well as apomorphine subcutaneous injection and apomorphine sublingual. These on-demand therapies are used for the treatment of OFF episodes, and they can be used when patients feel they need them. Some can be used for OFF episodes first-thing in the morning, and that’s a particularly good use for them. But later in the day, one of the best uses is for unpredictable OFF [times]. I think that if a patient has multiple OFF [times] through the day, the best thing to do is to ask, “Well, what about your base therapy? Are you giving levodopa frequently enough, or are using the right levodopa formulations? Should they be switched to a extended-release levodopa formulation? Should they have an adjunct medication added?” But for patients who have an OFF episode here and there and it’s somewhat unpredictable, that’s where I think these on-demand therapies are best suited.
Transcript is AI-generated and edited for clarity and readability.