This transcript has been edited for clarity.
Andrew N. Wilner, MD: Welcome to Medscape. I'm your host, Dr Andrew Wilner. Today I am interviewing Dr Jason Aldred about his presentation at this year's American Academy of Neurology (AAN) meeting. Dr Aldred is a movement disorders specialist at Selkirk Neurology in Spokane, Washington, who has been searching for ways to improve treatment for Parkinson's disease (PD) and other movement disorders. Welcome, Dr Aldred.
Jason L. Aldred, MD: Thank you for having me.
Wilner: You presented a pretty interesting paper at AAN. Tell us about it.
Aldred: This project was accepted for presentation at the recent AAN meeting. Basically, it is a 52-week, phase 3, open-label, single-arm, multicenter study that I was fortunate to be involved in, with a group of fellow collaborators and investigators from institutions around the country. This was an open-label, subcutaneous infusion of foscarbidopa/foslevodopa (ABBV-951), which is the preparation for subcutaneous infusion of levodopa, which was delivered as the therapeutic drug.
We all know that patients with PD do well with levodopa, many for a long time, some for shorter periods of time. But a real problem, of course, is the wearing off of medication. There are problems with gastric emptying of oral levodopa. And there is definitely a significant need for more advanced therapies. We have advanced therapies right now, such as deep brain stimulation (DBS); newer, better oral medications than standard carbidopa/levodopa; and adjunctive medications and Duopa, which is an intestinal infusion of carbidopa/levodopa. So the whole idea here is that this treatment ABBV-951 is a subcutaneous continuous infusion via a pump. That's what we were dealing with in terms of why this specific preparation was studied.
The study used an initial screening period of about 1 month (10-40 days). During that period, there were a couple of days where the participants were monitored closely and then converted over from oral carbidopa/levodopa plus the COMT inhibitor, if any of that was on board. Those were all calculated together to determine a levodopa equivalence dose. We converted those subjects to the study drug foscarbidopa/foslevodopa and then they were optimized for a period. The other drugs had the stay level, but the infusion foscarbidopa/foslevodopa was adjusted for a period of up to 4 weeks and then then the dose was maintained for 48 weeks.
The analysis I'm going to summarize briefly today is just looking at the 26-week mark. This study was designed primarily for safety; that was our primary endpoint. A total of 223 patients were enrolled across about 56 sites. There were a few discontinuations; about 39% had a premature discontinuation. But keep in mind that this is the first time there's been a subcutaneous levodopa experimental therapeutic like this, where we're trying to deliver it in a very different way. So there was a bit of a steep learning curve. Once the patients got the hang of it, we saw fewer discontinuations overall as patients got more experience.
These were PD patients with disease duration of around 10 years. Some had mild disease, some had more significant disease with the Hoehn-Yahr staging. So it's a wider range. These were all nondemented patients and all of them had taken a variety of PD medicines in the past, which you would expect if they've had PD for 10 years or so.
Looking at the adverse effects and safety, overall there were significant findings with erythema, nodules, cellulitis, and edema. Those were at the top of our list. And we weren't really surprised by that because this was a subcutaneous infusion treatment. But when we went back and looked at some of the literature for other subcutaneous infusions, whether it was insulin or subcutaneous apomorphine, you see a lot of skin reactions, particularly when people are starting out. So that kind of fit, more or less. Now, just because the subjects had adverse skin effects, did it mean that they all discontinued? In fact, most of the patients who had side effects actually ended up continuing in the study. We were focused primarily on specific adverse effects related to this method of treatment, and this is still very much a learning process.
In terms of some of our secondary outcome measures, we found that initially a significant proportion of patients spent about 36% of their day in off time at baseline. We did this analysis at week 26 and found that among patients who made it to week 26 (about 100 patients), their off time reduced from about 36% of the day to 17% of the day, which makes sense with a type of levodopa therapy that has some potency. What was very interesting was the finding that on time without dyskinesia initially started out to be about 40% but actually increased to almost 69%. This is patient ratings of on time without dyskinesia, and there was a significant increase in that variable. What was also interesting was that on time with nontroublesome dyskinesia actually decreased because there was such an increase in on time without any dyskinesia in a good chunk of these patients.
Another finding we reported at the week 26 mark was the first motor state upon awakening. Initially, off time on awakening was seen in 77% of the time. By week 26, only 20% had off time on awakening. Thus over time, the proportion of patients who woke up "off" declined, and a much larger proportion woke up "on" while receiving this 24-hour subcutaneous infusion treatment.
We have ways of looking at other quality-of-life measures as well. Again, this is through that halfway mark. The PD Questionnaire (PDQ-39), PD Sleep Scale (PDSS-2), and the Movement Disorder Society's Unified PD Rating Scale Part II motor experiences of daily living (MDS-UPDRS part II) all improved pretty quickly by week 6 and maintained that more or less through the week 26 measurement.
It's early in terms of reviewing this data. This is just the halfway mark of a study that has a 52-week total duration. But we felt that it was very encouraging that these patients potentially have a therapeutic alternative to other advanced therapies. In general it was safe and well tolerated. The skin adverse effects were what we expected the main difficulty to be, and those were consistent, more or less, with other subcutaneous therapies. Of the discontinuations that occurred, I would say that most of them occurred in the first 12 weeks of the study. We're still learning a lot about this, and we are learning along with some of the subjects involved in the study. Once we get over that initial hump and hopefully learn how to better counsel and educate patients undergoing this treatment, we might see other improvements down the road. So far, it seems to be an efficacious 24-hour treatment, but we still have more work to do.
Wilner: Dr Aldred, thank you for that excellent summary. I just want to ask a few questions. One of the reasons the abstract caught my eye was this foslevodopa. I'm an epileptologist and I'm familiar with fosphenytoin. Is it similar in that it's less toxic? Is it a prodrug of levodopa? It is infused without irritation and then is metabolized. What's going on there?
Aldred: Levodopa, for all of its miraculous, wonderful abilities, is a remarkably simple chemical. It's a large neutral amino acid. But the problem is solubility. That has always been the problem with levodopa formulations. The idea of getting it into a soluble form that can be concentrated enough to put it into a pump-type device that one could wear in a convenient manner is a feat of chemistry from the designers. "Prodrug" is the right term, I believe. Once it is infused into the skin, it's converted by alkaline phosphatase to carbidopa/levodopa. That enzyme is ubiquitous throughout the body, allowing the metabolic profile to be fairly even based on continuous delivery over the course of a couple of days. So far, it looks very promising.
Wilner: From a practical point of view, you mentioned infusion pump size. Is this like an insulin pump? How big is the device that patients are carrying around?
Aldred: It's much smaller than the Duopa pump and slightly larger than an insulin pump. It's fairly small and convenient and user-friendly with respect to how it's positioned on the body. People are able to wear it throughout the day and night. We had quite a few subjects at our site, and key questions we always asked were, "Do you like it? Are you satisfied so far? Tell us what we need to know and learn about." It was pretty encouraging to have the majority of the subjects pretty positive about the device itself. Of course, we are still struggling with the skin reactions. But it didn't seem that the device itself was particularly problematic in the people that I encountered.
Wilner: I know this is an initial exploration of the efficacy of this approach. But in your experience as a movement disorder specialist, you've been following these patients for a year now, and we'll hear about the 52-week result at some point.
Aldred: We're working on that data right now.
Wilner: How do you think these results compare to more invasive treatment, like DBS? In other words, if I were a patient and I said I really want DBS, would you say, well, let's try this first?
Aldred: It's a good problem, I think, for neurologists, and potentially for patients, if this ultimately is shown to be useful and approved. I think we're entering a situation with advanced therapies for PD. It used to be that we didn't have any options — just use your medicines better. Then we had DBS and Duopa. Now we're looking at a potential subcutaneous infusion. So I think that it absolutely throws more options out there. You know, it's not just one or two; it's three. And not only three options, but how do we potentially use one with respect to the other? Because ultimately, we're just trying to do the best thing for our patients — get the best benefits with the fewest side effects and the most practical therapy so they can go back and live their lives. There is a lot to think about. And fortunately, that's a good problem that we will be busy with for a while.
I could see patients choosing this before DBS. I could see people who were very impressed with how DBS worked for them, and they might choose that first. And then, rather than struggling with oral meds, if we were still doing that later on, they might choose this, perhaps.
I don't think that we should write off the role that Duopa still plays for advanced PD. It's been FDA approved. Some patients may not be able to do this or have the care support for subcutaneous administration and reapplying it to the site every few days. For those patients, a semipermanent PEG/J-tube actually might be a really good option. It definitely muddies the waters, but we need more options in advanced PD. I hope that this is something that will get us there if we can follow up on the work and see what the long-term safety and efficacy data show.
Wilner: One last question. In the best of all possible worlds, when can I prescribe this? What's our timeline?
Aldred : First, the group is working on the data review and making sure that we interpret that well. And now there is an ongoing placebo-controlled trial as well. So I think we'll have to wait for the results of that and see what the evidence shows in terms of the effect and further information about safety. And hopefully we'll see in that randomized, placebo-controlled trial that we've learned more about how to administer this even better and have better safety outcomes as well. So stay tuned, and hopefully in the next year or two, maybe, it will be ready. But we want to make sure we understand it all first.
Wilner: That's pretty exciting, Dr Aldred. Anything else you'd like to add?
Aldred: Just that I'm looking forward to having to navigate a lot of options in the future for these patients.
Wilner: That's terrific. I want to thank you and your colleagues for all your hard work. And thanks very much for joining us. I'm Dr Andrew Wilner, reporting for Medscape.
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Cite this: Long-Acting, Subcutaneous Levodopa In Parkinson's Disease: Is It Safe? - Medscape - Sep 07, 2022.