: Hi, and thank you for joining me for this NeurologyLive® Peers & Perspectives® presentation, titled “Optimal Management of Off-Episodes in Parkinson Disease.”

Today we are going to discuss the diagnosis, management, and treatment of off-episodes in Parkinson disease.

I am Dr Dan Kremens from the Sidney Kimmel Medical College at Jefferson University in Philadelphia, Pennsylvania. Joining me today is my colleague Dr Rajeev Kumar, from the Rocky Mountain Movement Disorders Center in Englewood, Colorado. Thanks so much for joining us. Let’s begin.

: Rajeev, could you give me an overview of off-episodes in Parkinson disease? How do you think about them?

: When we think about off-episodes, we’re defining a time in which motor symptoms and, to some extent, nonmotor symptoms are not adequately managed. If a patient has an optimal on response, they’re functioning normally or very close to normal. They may or may not have dyskinesia if they have advanced Parkinson disease, and they typically have good relief of nonmotor symptoms. Nonmotor symptoms include such things as anxiety, sweating, and apathy. Cardinal motor symptoms, of course, are symptoms such as tremor, rigidity, bradykinesia, and gait disorder.

In somebody who has an off-episode, it could be predictable, such as end of dose wearing off. For example, if somebody is taking Sinemet [carbidopa-levodopa] 3 times a day, they may notice that the first dose of medication takes half an hour to kick in. The efficacy in terms of motor and nonmotor symptoms is 3 hours, and it wears off a half hour before their next dose if they’re taking doses every 4 hours. Surrounding each dose, they may have wearing off a half hour before, and it takes a half hour to kick in. Therefore, they’re off for an hour toward the end of a dose through the beginning of the next dose. That would be a predictable off-episode.

Off-episodes can also be characterized as a dose failure. Suppose somebody takes a dose and it doesn’t kick in at all. This may especially occur when somebody is relatively protein sensitive and may have gastroparesis. They take a dose at noon and have a lunch consisting of a heavy meal (eg, hamburger and fries). But the dose doesn’t kick in, and they’re off from noon to 4 PM, which is their next scheduled dose.

Another form of off-episode could be a delayed on response. They have their meal with their medicine, for example, and they have delay in gastric emptying because food stays in the stomach longer. Therefore, instead of their medication kicking in within a half hour, it takes an hour or an hour and a half. That would be a delayed on response.

Another form of off-episode could be unpredictable. The patient has taken their medication and seems to be doing well, but the medication doesn’t last the full 3 hours or so. For example, they took their medication at 8 AM and it kicks in, but at 10 AM it wears off and they have 2 hours till their next dose. That would be an unpredictable off-episode.

The pathogenesis of off-episodes is interesting. We think there are both pharmacokinetic and pharmacodynamic factors in play. Most of our therapies for the off-episodes revolve around treatment of the pharmacokinetic factors. We acutely apply a dopaminergic stimulus to take this person with a low amount of dopaminergic stimulus to a normal amount of dopaminergic stimulus, either by applying levodopa therapy or by applying a quick-acting dopamine agonist therapy (e.g. apomorphine).

: One of the other off-episodes that a lot of my patients complain about is morning off-episodes. They wake up in the practically defined off-episode state. They haven’t had any of their medicine since the day before, and they wake up and they’re off. They take their medicine and sometimes get dose failure. In that case, protein really isn’t an issue because they hadn’t eaten. It’s probably both a combination of the central mechanisms as well as the peripheral mechanism that you were referencing earlier (eg, gastroparesis). Another really important point that you highlighted for our colleagues who might not be movement disorder specialists is this notion that an off-episode isn’t just the classic wearing off described, and it’s not just motor symptoms. You emphasized off-episodes can definitely be nonmotor symptoms (eg, anxiety, dread, fogginess) and more than just classic wearing off. Delayed on responses, dose failures, morning off-episodes, and unpredictable off-episodes are forms of off-episodes that sometimes people don’t think as much. But the patients are certainly aware of them.

: I agree with your point, especially about the morning off-episodes. That is usually the worst off-episode of the day because they haven’t taken their levodopa for an extended period of time (maybe 8 or 12 hours). The plasma level of levodopa has really dropped, and the pharmacokinetic aspect is pretty much at its nadir, right?

: They may require a much higher amount of dopaminergic stimulation to get them on again in that scenario. When given levodopa therapy, even orally, they may need a higher dose to kick them in than their regular dose because their plasma level is so low. When we think about plasma levels of levodopa, for those people who like to look at pharmacokinetic charts, we’re talking about trying to get the plasma level of levodopa typically above 1000 ng/mL. That’s quite a lot of levodopa. The amount of levodopa to take orally varies a lot. You can have a little thin lady needing very little. On the other hand, instead of needing 50 or 100 mg of levodopa, that same person may need 300 mg. It’s quite interesting how there’s a lot of interpatient variability. It really needs to be a customized dosing schedule. How we deal with morning off-episodes is really an interesting and important special case that I’m sure we’ll discuss du

Overview of OFF Episodes in Parkinson’s Disease

: We’ve had a lot of recent approvals and some data. Let’s look at some treatment options, starting with some dopamine agonist options. Let’s discuss how you think about the following dopamine agonists that have been approved or are in development to treat off-episodes. Let’s talk about 3 different apomorphine products, their method of action, and delivery system advantages.

First, a lot of people don’t realize when they hear the term apomorphine that it has nothing to do with morphine. Apomorphine means “away from morphine.” Even the word doesn’t mean morphine, although that term is in it. I know people see that and say, “Why would you give morphine to a Parkinson patient?” It has nothing to do with that. I always like to clear that up right up front.

The other thing is apomorphine is 1 of the oldest treatments for Parkinson disease [PD], historically. It was approved for treatment in the 1990s in a subcutaneous form in Europe, but it’s been around as a treatment for a long time prior to that. Let’s talk a little about apomorphine hydrochloride subcutaneous injection, commercially known as Apokyn. Why don’t you tell me a little about your experience with Apokyn [apomorphine hydrochloride] dosing, efficacy, safety, and administration.

: I started using Apokyn [apomorphine hydrochloride] when I was a fellow in the early 1990s. We used it extensively just prior to the beginning of device-aided therapy with deep-brain stimulation. We had lots of patients who had severe unpredictable off-episodes. They had PD for 10, 15, 20, or more years. We could not administer levodopa frequently enough or productively enough, and using Apokyn [apomorphine hydrochloride] was a tremendous advantage. We used it because it kicks in very quickly, as we’ll talk about in just a moment, and very predictably. 

We actually used it when we started doing stereotactic neurosurgical procedures. We’d administer it intraoperatively while recording individual cells in the pallidum and subsequently in the subthalamic nucleus to look at how we could alter firing rates and patterns. There are several publications that came out of that experiment. We’d see them preoperatively, we’d find out the right dose that kicked them in when they were off medication overnight—as you typically have them intraoperatively—we’d get very nice recordings, and then we’d inject them, taking them from a fully off to a fully on state right there in the OR [operating room] with electrodes in their brain. The effect is outstanding. You can hear the patient’s tremor cells firing away and then inject them. Ten minutes later the patient’s tremor is gone and the tremor cells are no longer firing.

: Even though levodopa is thought of as the gold standard for Parkinson disease, apomorphine is the only drug that has that levodopa-like response. In fact, as we’ll discuss, it’s potent, fast, and reliable.

: Absolutely. Like levodopa, it’s a nonselective D1 and D2 agonist. Most dopamine agonists that we administer orally are predominantly D2 preferring—D2, D3, D4, especially D3—when we think about pramipexole, ropinirole, and rotigotine. This [apomorphine hydrochloride] truly can create a full on response. Administering these other orally administered dopamine agonists typically can get somebody partly on, but in advanced disease, these by themselves cannot achieve the full levodopa-like effect. Take somebody, for example, having withheld medication overnight, to treat that early morning off-episode they can inject themselves and can jump-start, as they might call that. The patient is off, very immobile, and in bed, and they cannot get up and walk. They can inject themselves with Apokyn [apomorphine hydrochloride]. Typically the onset is very quick, 10 or 15 minutes, but the offset is also very quick. The typical duration of action of Apokyn [apomorphine hydrochloride] is about an hour. It gets you on but it doesn’t keep you on unless you have something else that will do so.

The patient who has early morning akinesia and does not have an opportunity, for example, to take oral levodopa during the night because they’re sleeping well—let’s say they’re sleeping 7 or 8 hours—is now having an off-episode. They’re sitting in bed and they’ve got to get going. They’ve got to get to work. They can inject themselves with Apokyn [apomorphine hydrochloride] and simultaneously or shortly thereafter take oral levodopa. Apokyn [apomorphine hydrochloride] kicks in within 15 minutes or so. They’re up and in the shower in 30 minutes. While they’re in the shower, the levodopa kicks in. By the time the Apokyn [apomorphine hydrochloride] starts to wane in effect, levodopa is fully on. They’re doing well right through breakfast and can get on with their day and get to work or wherever they need to be. That’s a great therapy for patients who have early morning akinesia.

Another strategy is if a patient gets up during the night, for example—many patients get up to urinate 2 or 3 times a night—they can take levodopa during the night. Taking a delayed-release formulation or controlled release—eg, Sinemet CR [carbidopa-levodopa CR]—can be a helpful strategy because you’re not trying to get the patient fully on at that time. What you’re trying to do is get the patient on, at least partially on, or have a good plasma level of levodopa so that when they wake up they’re not so immobile. They’re at least half on, if not fully on, and can take their next dose of levodopa and predictably get on quickly rather than having a delayed on response or perhaps a dose failure. 

That’s another strategy that can be used because Apokyn [apomorphine hydrochloride], although a good medication, it is not ideal for all patients. Especially if you have a very immobile patient in the morning who maybe can’t self-inject and doesn’t have a caregiver available. But a majority of patients can give Apokyn [apomorphine hydrochloride] themselves, especially using the penject system. It’s very simple, and it’s very well tolerated.

Apomorphine Subcutaneous Injection: Historical Perspective for Off-Episodes in Parkinson’s Disease

: It should be noted that when you first begin Apokyn [apomorphine hydrochloride], most patients will need to premedicate with trimethobenzamide, or Tigan. After a few weeks to a few months, most patients can titrate off the antiemetic.

: Rajeev, for the folks who aren’t as familiar with Apokyn or apomorphine, in general, it’s a pretty potent emetic for some people.

: ln fact, that’s how it was first approved in the United States. To induce emesis, right?

: When people would take something that they shouldn’t have taken—for example, in the 1950s—apomorphine could be administered and they would vomit. If you have ever been exposed to it, it can make you puke pretty nicely.

: Right. As you pointed out, for most people, when we’re using apomorphine, we have them premedicate for 3 days before starting with Tigan [trimethobenzamide]. Then the majority of the patients after they’ve been exposed to Apokyn [apomorphine hydrochloride], even for a brief period—eg, a couple of weeks—are able to titrate off the Tigan [trimethobenzamide]. The studies went out to about 2 months, but in the real world, I often have patients on it for 2 weeks. Then, if they’re using their Apokyn [apomorphine hydrochloride] regularly by that point, they no longer need their Tigan [trimethobenzamide].

: Yeah, that’s very true. As we’ll discuss with apomorphine infusion, usually before beginning apomorphine subcutaneous infusion in Europe, and also investigational use in the United States, we began with the orally administered antiemetic. In the United States, we use Tigan, or trimethobenzamide. In Europe and in Canada, we use domperidone. After a few weeks, even with continuous infusion and a higher total dose being administered throughout the day, the vast majority of patients come off the antiemetic within a few weeks.

: We’re going to get to that in a minute. For the audience, there is under development in the United States an infusion of apomorphine, which we’ll talk about in a second. It’s already approved in Europe, and that’s the drug Rajeev is referring to. There are also data for morning off-episodes, as you pointed out, with Apokyn [apomorphine hydrochloride]. They have the AM IMPAKT study. In that study, there were over 80 patients, and 96% of them had improvement in their morning off-periods using Apokyn [apomorphine hydrochloride] injections. It was a pretty robust response, and the time was reduced. Before these people were taking Apokyn [apomorphine hydrochloride], sometimes it would take them over an hour to turn on in the morning.

Could you imagine trying to get up if you were working, functioning in situations where you can’t get dressed and can’t bathe because you’re waiting for your oral medication to kick in? With Apokyn [apomorphine hydrochloride] injection in these people, the average time was reduced to 23 minutes until they were on. It’s a robust response. Also, in clinical data, 95% of off-periods were aborted in some pivotal studies submitted to the FDA for drug approval in the United States, with a levodopa-like response in the Unified Parkinson’s Disease Rating Scale [UPDRS], a 23- or 24-point improvement. The only other drug that gives that kind of improvement is levodopa. 

: Absolutely. The effect is very hard to replicate with any other drug. We’re talking about a motor improvement of about 23 or 24 points. We’re not talking about the other parts of the UPDRS. It’s quite tremendous. The patients who were in most of these studies had fairly advanced disease and often had a motor UPDRS score. This is using the older UPDRS and not the MDS-UPDRS [Movement Disorder Society–Sponsored Revision of the UPDRS]. The total score is less. The maximum motor score is 108, as opposed to the MDS-UPDRS, which has quite a few more points. A 25-point improvement is a big improvement. These people typically had a UPDRS score off-episode of around 40 points, so they were very severely affected in the off-episode state. These are patients who typically, without Apokyn [apomorphine hydrochloride], would need surgery.

Apomorphine Subcutaneous Injection: Efficacy and Administration for Off-Episodes in Parkinson Disease

: In the 1990s, we were using Apokyn [apomorphine hydrochloride] a lot, and it was often an indicator. If a patient had to use Apokyn [apomorphine hydrochloride] a lot and was having a lot of off-episodes that were troublesome, that was an indicator that you should consider a device-aided therapy like deep-brain stimulation. Even now that is a reasonable indicator.

We still have patients who’ve had deep-brain stimulation, of course, and that was done effectively when off Apokyn [apomorphine hydrochloride]. Now that they’re out 10 years from deep-brain stimulation or 15 years out from deep-brain stimulation and having reemergence of more off-episodes, they’re using Apokyn [apomorphine hydrochloride] from time to time helpfully and effectively, even in combination with deep-brain stimulation. It is a nice drug, especially for patients who have morning akinesia or unpredictable off-episodes. Those are good areas to suggest that Apokyn [apomorphine hydrochloride] should be considered.

: When you think about different patients in your practices who’ve used Apokyn [apomorphine hydrochloride], I’ve had success with patients who are the very busy working person all the way to somebody you wouldn’t necessarily think was an Apokyn [apomorphine hydrochloride] patient. I had a gentleman with advanced Parkinson disease who also had a stroke. When he was in an off-state, he couldn’t feed himself. His caregivers were able to give him Apokyn [apomorphine hydrochloride] before meals, and it restored his dignity. He was able to feed himself. He didn’t need people to help him during that period. You wouldn’t think of this guy because he’s so advanced, but it made a real difference in his quality of life. It doesn’t just have to be the young, working patient who need Apokyn [apomorphine hydrochloride]. It really can work for a variety of Parkinson disease patients.

: It’s important to ask questions about impact on quality of life. I tremendously agree with you, and on the predictability, as you said. They need to give it before meals to make sure the patient is fully on so he can eat. Maybe chewing and even swallowing may have an improvement. It is extremely important, both for quality of life and for safety in that circumstance. It can even be, if you like, a little bit of an insurance policy. You have a family that goes with the patient out for dinner, and they don’t know if the patient is going to turn off in the middle of the meal. If dad turns off before we leave, we’re going to be stuck there for an hour or 2 at the end of the meal waiting for the next dose of levodopa to kick in. 

Just having the Apokyn [apomorphine hydrochloride] pen in their pocket, even if they don’t use it, is a tremendous relief and can improve ability to get out and be social, interact with others, and restore quality of life. Get to the ballgame. OK, it’s the seventh-inning stretch, but I can’t stand up. I’m going to inject myself with Apokyn [apomorphine hydrochloride] so I can leave here when the game is ending at the ninth inning. That’s a typical example of how that insurance policy helps. You can get going when you need to. If you don’t need it, great. Keep in pocket. I can get out of here without it. It’s great.

Apomorphine Subcutaneous Injection: Patient Selection for Off-Episodes in Parkinson Disease

: We’ve talked about some of the advantages and great results we’ve had with this drug [apomorphine hydrochloride], but it’s not for everybody. There are disadvantages. I know many of my patients are reluctant to use needles. There is also a societal stigma that surrounds needle use as well, and I find that to be a challenge for a lot of patients. It’s not necessarily the physical use of the needle. Although a patient who is very, very off might have some physical challenges, more often patients are just afraid of needles or there’s a stigma.

: I agree with that. It’s interesting. I call that needlephobia. It’s very interesting. When I’ve talked to many neurologists and patients, if the concept of using a needle is approached in the correct way, then it’s amazing how accepting the vast majority of patients are of using a needle to get back on again—when it improves quality of life. It’s a very easy thing to administer, and it’s not so scary once you’ve tried it. It’s more anxiety of impression. It’s more the thinking about it than the actual doing of it that is scary. We’ve done a small survey in a large group of patients, not yet published, and found 80% to 90% of patients who have troublesome off-episodes are ready to inject themselves if you discuss it with them. My experience with asking general neurologists is there’s a fear, greater than that, of their patients not being accepting of it. It’s important, as you put it, to ask the question and have the discussion in a tempered way. If you do so, I would submit to you, the vast majority of patients who have troublesome off-episodes will say, “Yes, if you can tell me when I inject myself, it’s not a big deal. You can teach me or my caregiver how to do it in 15 or 20 minutes, and I can get back on reliably. Then I’d be willing to have that insurance policy and inject myself to get going when I need it rather than being stuck.” The vast majority of patients would be willing to do so.

: One other nice thing is there’s a program. I’m not sure how much you use it, but I use it a lot. The company that makes Apokyn [apomorphine hydrochloride] provides a program called Circle of Care in which nurses go out and help patients deal with needle problems if [there are] any. They teach them how to inject and can help with initiation of the drug. Initiation of the drug needs to be done under medical supervision, and this is for any apomorphine product. I’ve used the Circle of Care program a lot to help with any concerns patients have regarding the needle.

: I agree with you totally. Let’s review that program a little, the adverse effects one should think about, and the process of titration. In addition to beginning Tigan [trimethobenzamide] before administering the titration, the patient should be seen in the practically defined off-state, typically after levodopa withdrawal overnight. Different doses of Apokyn [apomorphine hydrochloride] should be administered roughly 90 to 120 minutes apart. The patient should be examined serially. Examine for drops in blood pressure, because orthostatic hypotension can occur as well as nausea. Also, sleepiness and yawning are not uncommon when Apokyn [apomorphine hydrochloride] is first administered and can sometimes be an ongoing problem. Those are perhaps the most troublesome adverse effects when titrating.

Most patients need between 2 and 8 mg of Apokyn [apomorphine hydrochloride] injection per dose. Then the dose can be customized based on the response during the titration. Typically, we begin at 2 mg and go to 4, then 6, and then 8 mg, depending on the size of the patient. You can adjust this based on the body mass of the patient during the titration. Once the appropriate dose is discovered, the patient can begin to use that [apomorphine hydrochloride] on an ongoing basis. Apokyn [apomorphine hydrochloride] can be used, if necessary, many times a day. Although if a patient is using Apokyn [apomorphine hydrochloride] many times a day, that’s usually a good indicator to the neurologist who’s treating them that some adjustment in their baseline medication or treatment should be implemented. That way they can prevent off-episodes in addition to using Apokyn [apomorphine hydrochloride] to get them back on when needed.

I agree, the Circle of Care nurse program is very helpful. I unfortunately and fortunately have a lot of experience with that program. One of my nurses who worked with me for more than a decade, and who I trained, is the company’s head trainer for the western United States. This nurse teaches all the other nurses how to titrate Apokyn [apomorphine hydrochloride] and how to manage patients on Apokyn [apomorphine hydrochloride]. I do use it. It’s very helpful, and it’s nice that I can call my old nurse when I have a patient and say, “Please take care of this patient. This is what I want you to do. Just call me on my cell if there’s a problem.” It gives me a lot of reassurance.

Apomorphine Subcutaneous Injection: Circle of Care Program for Off-Episodes in Parkinson Disease

: I’m somebody who believes that a rising tide raises all ships. We spent a lot of time talking about Apokyn [apomorphine hydrochloride subcutaneous injection], but I’d like to shift the conversation to a new apomorphine hydrochloride product that’s been approved by the FDA in the United States. It’s a sublingual form of apomorphine hydrochloride commercially known as Kynmobi. I know you’ve had some involvement with that. Could you tell us about Kynmobi [apomorphine hydrochloride sublingual]? Talk about its dosing and efficacy and your experience with it.

: I was involved with the phase 2 trials using the initial strips, which are interesting. They’re fairly small, about an inch by an inch. They’re rectangular and look a bit like Listerine strips. It’s placed under the tongue. The patient is instructed to keep their mouth closed and to not swallow because the medication is absorbed sublingually.

Just as with subcutaneous apomorphine, the patient should be premedicated with Tigan [trimethobenzamide] for about 3 days and will need titration. Typically, one begins at 5 mg of sublingual apomorphine or 10 mg, and then titrate up in 5-mg increments—with the highest dose being 35 mg. This can be used just as you might use subcutaneous apomorphine. It can be used for early morning akinesia and unpredictable off-episodes. It can be used for any off-episode legitimately.

It’s different in that you are now giving it sublingually rather than injecting it. The absorption kinetics are expected to be different, and as a result, the time to on and duration of action are expected to be different. If one looks at the recent Lancet Neurology publication, one can see that the time to an on-state is slower than subcutaneous apomorphine; however, the patient doesn’t need to inject themselves. For patients who have significant squeamishness or concerns about injecting themselves, this may be a reasonable option.

The duration of action is different from subcutaneous apomorphine. It’s longer. One can expect a duration of action of at least 90 minutes and up to 2 hours. Therefore, we need not be in as much of a rush to dose the patient with oral levodopa, but we do need to recognize that the duration is typically shorter than oral levodopa. This product will get you on while allowing time to get and stay on with oral levodopa.

If one looks at the trial data in terms of magnitude of on-state response, one would expect to obtain a full on-state response. This is apomorphine, and that’s what we saw in the phase 2A trials. However, if you look at the phase 3 trials, most patients can get fully on, but the magnitude of the on-state response, based on the graphs from the Lancet Neurology paper, was a little less than what was seen with subcutaneous apomorphine. We see an on-state motor response of about 15 points, which is less than the 20 to 25 points we discussed earlier with the old-fashioned Unified Parkinson’s Disease Rating Scale with Apokyn [apomorphine hydrochloride subcutaneous injection]. Perhaps a little less potent—we’re going to need more experience to know. The patient numbers in the phase 3 trial were relatively small, less than 100 patients per group. We need a lot more experience with this drug.

: In terms of reliability, it works quite well. Roughly 83% of patients got to a full on state vs 95% with the injection. Again, it’s a strip, not an injection, and for a lot of people it may be a more acceptable option. I’d love to offer patients options.

What were some of the adverse effects that you saw? Were there any that were different because of the sublingual delivery system that wasn’t seen with subcutaneous?

: That’s the key issue. The advantage of Kynmobi [apomorphine hydrochloride sublingual] is you don’t need to inject it. The disadvantage is you get all the usual adverse effects of subcutaneous apomorphine—eg, sleepiness and nausea—in addition to oral problems. Up to 30% of patients may get oral ulceration or other oral mucosal problems. It’s important to warn patients of that. It’s also important to periodically inspect the mouth for problems when you see patients. We don’t want patients to get an infection or more serious adverse effects as a result of unrecognized or untreated oral problems.

Patients’ oral problems are relatively mild. It didn’t result in serious adverse events—eg, patient getting hospitalized or osteomyelitis of the jaw. However, it is a concern, and patients should be aware of that. There was a small yet definite number of patients who discontinued therapy because of oral problems. It’s something one should be aware of. I agree, it’s nice to have additional options when thinking about apomorphine injection. If the patient is unwilling or scared of injecting, it’s reasonable to consider this option for the patient. The patient should be aware of the adverse-effect profile and should be aware of the need to titrate and customize the therapy.

: It’s different from a needle. This comes in a package, sort of like rabbit ears that a patient is able to tear apart. Most of the patients were able to do this, even in an off-state, and apply the sublingual strip. A potential challenge could be for Parkinson disease patients with bad drooling. Also, many Parkinson disease patients keep their mouths open. We have to instruct that it’s important to keep your mouth closed and don’t swallow. There were some challenges in the early studies with patients who would occasionally swallow them.

: That’s very true. It is not easy for patients to keep something in their mouth and not talk or swallow. Several of the patients at my site, in the phase 2A trials that have been published, tended to swallow the drug. That affected the efficacy of therapy. If the patient swallows the medicine, it’s not going to work well. That’s very clear. You’ve got to keep this gummy mixture of saliva plus the strip in the mouth for about 5 minutes and not talk.

: Right. Again, with appropriate instruction. It’s great to have options to offer patients having off-episodes because they’re so troublesome. I’m looking forward to when this is going to be commercially available in the United States. It’s approved, and I’m sure I have patients who will be very interested in trying this.

Recent Approval of Sublingual Apomorphine for Off-Episodes in Parkinson Disease

: There’s a form of apomorphine that’s available in Europe, not used as an on-demand therapy, but as a continual treatment for Parkinson’s disease. It’s a subcutaneous infusion. Could you speak a minute on that, please?

: Sure. [Apomorphine] subcutaneous infusion has been available in Europe for more than 20 years. I briefly used it experimentally as a Fellow in movement disorders. In the last 4 years approximately, we’ve done long-term open-label studies in the United States. I’ve had several patients in clinical trials receiving [apomorphine] subcutaneous continuous infusion with a pump similar to an insulin infusion pump and much tinier than the pump used for Duopa [carbidopa/levodopa] therapy. 

The medication is administered via a very thin small needle that is applied underneath the skin of either the abdomen, upper thigh, or upper back. Most patients can manage this independently. Some patients would like to have a caregiver apply this. Usually they have a continuous infusion during the waking hours of the day. Most patients start it first thing in the morning and discontinue it at bedtime. In Europe, many patients have used it around-the-clock to also improve nocturnal akinesia. Due to being a continuously administered product, it is not designed for acute treatment of OFF episodes. Although, there is the option to administer a bolus dose on top of the continuous infusion to improve OFF episodes at that time without repoking yourself. That is a nice option when you already have the needle in place.

It can result in a clinically significant reduction in OFF time. If we were to look at the TOLEDO study, a European publication of a multicenter study in which there was double-blinded application of the pump, there was an OFF time reduction of more than 2 hours compared to placebo. That’s a very large and clinically important benefit. In many countries in Europe, this form of device-aided therapy is used in a widespread manner. It is pretty much mandatory in some countries, for example the United Kingdom, prior to considering either Duopa therapy or deep brain stimulation. It’s quite manageable for patients and caregivers, and it’s certainly easily reversible and less invasive.

It’s not that difficult to initiate. In Europe, they tend to initiate it very rapidly, typically in a hospital or an accelerated outpatient setting. In the clinical trials—and as it will probably be administered in the United States once hopefully approved next year—it will be administered through gradual titration, usually in visits every few days to a week, in which the pump rate is increased and oral drug dose is reduced. The goal is to continue a stable ON response. To do so, often the dose of the intermittent levodopa needs to be reduced to prevent overshooting. It does reduce dyskinesia, prevents undershooting, and reduces OFF time. Some patients, in my experience and in the European experience, could get rid of almost all or all the oral levodopa. If you’re able to do so, that produces a very smooth continuous ON response. You can achieve the sweet spot ON state without dyskinesia all day long. That’s the ideal patient. Not all patients can achieve that.

: In general, it does still have the typical [adverse] effects that we see with dopamine agonists. Additionally, there have been some reports of nodules at the site of the subcutaneous needle. However, there are also some data that suggest with proper skin hygiene you can help reduce that nodule problem. 

: The cutaneous problems are quite manageable, not only with hygiene but also by massaging the nodules. Usually the nodules are quite painless, which is good. It should be kept more in mind that with any dopaminergic medication, including intermittent Apokyn [apomorphine hydrochloride subcutaneous injection] and more importantly subcutaneous continuous infusion of apomorphine, impulse control disorder is a risk. Patients should be warned about this and monitored for the development of impulse control disorder with apomorphine subcutaneous but especially with continuous infusion.

: Well, that was a great discussion about apomorphine. It’s wonderful to have such an old drug resurging again. We’ve had Apokyn for a while. We’re now going to have Kynmobi [sublingual apomorphine hydrochloride]. Hopefully in the future, we’re going to have in the US the subcutaneous continuous infusion formulation, commercially known in Europe as APO-go.

Continuous Subcutaneous Apomorphine Infusion in Development for OFF Episodes in Parkinson’s Disease

: There are other on-demand therapies aside from apomorphine. Recently in the United States, we had levodopa inhaled powder [Inbrija] approved for the treatment of OFF episodes. What do you perceive are the advantages and potential disadvantages of this drug?

: Inbrija is an interesting medication in that it’s levodopa without carbidopa. It’s a relatively small dose, about 84 mg of levodopa, and results in 50 mg of absorbable levodopa. It’s about the equivalent of taking half of an immediate release Sinemet [carbidopa/levodopa] 25/100 mg tablet in terms of the amount of levodopa administered.

Although that sounds like a relatively small amount, you’re absorbing it from the large pulmonary tree relatively quickly, it would seem. If one looks at the PK [pharmacokinetic] data, the time to increase levodopa concentration by 300 to 400 ng/mL is quite fast—less than 10 minutes or so. You can take a patient who has some levodopa in their system from feeling OFF or partially OFF to back ON and over 1000 [ng/mL] again. The majority of patients, upon taking the inhalation, which consists of 2 standard-dosed capsules, can get back ON in about 20 to 30 minutes in most situations.

It’s a small amount of levodopa, and it’s a standard dose. It does not require titration, and that’s an advantage compared to Apokyn [intermittent subcutaneous injection apomorphine hydrochloride]. However, the small amount is a disadvantage. It can’t take someone from fully OFF to fully ON. The absence of carbidopa is also a disadvantage. If the patient has not taken their last dose of oral levodopa/carbidopa for many hours, such as overnight, it’s unlikely to make much of an impact in getting the patient back ON because the levodopa that is absorbed is going to get metabolized fairly quickly by DOPA [dihydroxyphenylalanine] decarboxylase. One should be aware of that.

It might be helpful to simultaneously inhale it while taking the oral levodopa/carbidopa in the morning. It might slightly reduce the time to ON. There are some data that suggest that, but it’s a small study that wasn’t powered adequately to truly assess the efficacy of that strategy. Regardless, I think it would be a small benefit.

On the other hand, if somebody took controlled-release Sinemet CR 4 hours earlier, let’s say at 4 AM and then again at 8 AM, and were OFF at that time, it would be very reasonable for them to inhale Inbrija, as well as take their oral drug to decrease their time to ON. That might have a very substantial effect because they would still have a fair bit of carbidopa in their system at that time. That’s a nice advantage of the drug.

: One of the keys to using Inbrija successfully, this is what I instruct my patients to do, is as soon as patients start to feel that they’re turning OFF, that’s when to use Inbrija. At that moment is when it will work best to help bridge to your next dose, as opposed to waiting till you get to that deep OFF state. In a situation like that [deep OFF state], you may need something more like apomorphine, either subcutaneously or sublingually, to get you back to that full ON state. When you look at the UPDRS [Unified Parkinson’s Disease Rating Scale] motor scores between the apomorphine products versus inhaled levodopa, the apomorphine products tend to be more robust. I do think in the appropriate patient, if the patient can inhale at the start of recognized turning OFF, it can be a nice option.

The other thing is for a lot of people the inhalation formulation is more socially acceptable and relatively easy to use. In the study, 99.8% of patients who were in an OFF episode were able to do their inhalation successfully. Some people have a little bit of a challenge when they first do inhalation. You must teach them how to inhale appropriately; some people had cough in the study. In the real world, I’m finding for some people cough is a challenge. However, they can learn not to suck it in all at once. Take a gentle inhalation and breathe in slowly. Sometimes taking a little water with it can help with coughing issues.

: Yes, that’s very well put, Dan. That’s the most common adverse effect that’s specific to the therapy. The particles, which are an interesting new formulation designed by Arcus Technology, [Inc], can be irritating, especially to the upper airway, and can induce cough. Being in the right position and slow inhalation are helpful. Because it can be irritating, the most important contraindication for the use of Inbrija is patients who have asthma or COPD [chronic obstructive pulmonary disease]. Patients with reactive airway disease, or any kind of chronic pulmonary disease, should be considered for other therapies rather than Inbrija.

It is a helpful drug. I have 1 or 2 patients who have used both Apokyn and Inbrija, and they recognize, “In the morning, I take my Apokyn, and if I’m starting to wear off between doses, I take my Inbrija. If a have a really bad OFF, I take out my Apokyn.” Therefore, it’s nice to have options.

: Again, I like having options for patients. I also have patients who have tried both and like one or the other for particular situations.

Levodopa Inhalation Powder for OFF Episodes in Parkinson’s Disease

Kremens and Kumar review istradefylline and opicapone oral capsules—both recently approved for treatment of OFF episodes in Parkinson’s disease.

: We’ve focused a lot of our time today on OFF episodes—treating them acutely. However, there have been a couple of medications approved recently in the United States. Although, indicated for OFF episodes, they’re more for treating OFF periods in general in my mind. One of them has a novel mechanism. It’s an A2a antagonist called istradefylline [Nourianz], and it became available in the United States earlier this year. It’s been available in Japan since 2013. Do you want to say anything about A2a antagonism?

: Yeah. This is an interesting mechanism of action. This is the first of 3 different A2a antagonists that I’ve been involved with in terms of clinical trials. I was involved in all the phase 2 and subsequent phase 3 trials. It is a useful medication. A2a receptor antagonism is not the first thing that comes to mind when we think about Parkinson’s disease treatment because it’s acting downstream of the dopaminergic system. 

When dopamine is released in the striatum, it binds to D1 and D2 receptors on medium spiny GABAergic neurons. When it binds to D2 receptors mediating the indirect pathway, we reduce the overactive indirect pathway. On those same neurons that are D2 bearing, we have A2a receptors. If we antagonize the A2a receptor overactivity, we can reduce the activity of the indirect pathway. If we take our foot off the brake—which is what the indirect pathway does, to keep it very simple, then we can improve the severity of the OFF period.

It’s quite interesting that in the earlier animal model data there was suggestion that istradefylline would be effective in monotherapy. Unfortunately, that did not pan out in the early human clinical trials in monotherapy. However, it has been shown to be effective as an adjuvant to levodopa to improve OFF time. 

It is a little disappointing that in the phase 3 clinical trials there was not as much reduction in OFF time as I had hoped. In the phase 2 clinical trials, we had almost 2 hours of OFF time reduction compared with the placebo-treated arm. In the subsequent phase 3 trials—there have been several, and this is why it took so long to get approved in the United States, there was reduction in OFF time by about 45 minutes to an hour compared with the placebo-treated arm. Good improvement, but perhaps not at the same level of magnitude as some of the other therapies.

What’s nice about this therapy is it’s extremely easy to use. It’s used once a day. The majority of patients do well with 20 mg, but you can also use 40 mg a day. It’s a very long half-life drug—about 80 hours—and it has relatively few drug interactions. CYP3A4 is the main one. Interestingly, smokers require a higher dose and go straight to the 40-mg dose. Typically, one doses it for about a month at the lower dose—20 mg. If the patient tolerates it well and does not have adequate efficacy, it’s reasonable to give them a trial at the higher dose of 40 mg per day.

It’s not a really dopaminergic medication, and doesn’t suffer from a lot of the adverse effects that we get with typical dopaminergic therapy. Hallucinations are very uncommon. Orthostasis and nausea are uncommon. Since it’s acting downstream to improve motor function, the main adverse effect one should be aware of is increased dyskinesia—seen in maybe 10% to 15% of individuals. There are various ways of handling it. Of course, you can stop the medication, but that’s not really what you want to do. What you want to do is keep that patient ON. In my experience, if patients have dyskinesia, then—in the majority of patients—that also means that their OFF time has been significantly improved. My usual strategy is first try to reduce the amount of levodopa to see if I can keep them ON—keep that benefit—but reduce the dyskinesia to a level that is not troublesome or hardly noticeable.

This is an interesting new drug to our armamentarium. I use it not up front as an add-on to first-line drug, because we have less experience with it and perhaps the potency may be a little less. However, it can be used in patients who have commonly tried or are currently taking multiple medications or 1 other medication as an add-on and are still struggling.

I especially find it helpful in patients who have had trouble with dopaminergic adverse effects. For somebody who has had nausea or hallucinations with other drugs, this might be a good drug to try. For somebody who has had orthostasis with the other drugs, this is a good medication. For somebody whose options are now limited because they’ve had troublesome impulse-control disorder, this may be a good drug. It’s rarely been reported with this medication.

It’s a unique medication and a nice addition to our armamentarium.

: Yeah, I agree. The only thing I would add is although the effect we saw in the phase 3 trials wasn’t necessarily as robust as in the phase 2 trials, I still think it’s important that people understand that these were patients getting an additional 45 minutes or hour on top of already being on lots of other medications. They could be on lots of other medications in the study and weren’t just on levodopa. They were on levodopa, dopamine agonists, or MAOB inhibitors and achieved an additional 45 minutes to an hour. That’s important.

Another medication that was recently approved in the United States, and has been available in Europe since 2016, is opicapone [Ongentys]—a COMT inhibitor, right? We haven’t heard about COMT inhibition in Parkinson’s disease in a while. What thoughts do you have on opicapone?

: From the trial data, it looks very nice, interesting, and easy to use. All the studies with opicapone to date have been done in Europe. So, I don’t have personal experience. However, when I look at the data—including some additional PK [pharmacokinetic] data, it seems to last a really long time. It’s a once-a-day COMT inhibitor. It acts peripherally, so it’s like entacapone, but seems to be more potent. It achieves almost complete COMT inhibition within 1 to 2 doses. When you stop it, the effect continues for 2 or 3 days. That is quite nice, especially if the patient is a little off schedule with their dose. You know, “I forgot to take it this morning. Can I take it this afternoon?” Yeah, you can take it in the afternoon.

: Ongentys is dosed at bedtime, and that’s critical. Dose at bedtime without food because food can affect the absorption of Ongentys. That’s going to be 1 of the critical teaching points when we start patients on it. However, it is once a day. As for the safety profile, there’s none of the chromaturia that we get with entacapone. There were no signals of any liver issues whatsoever like we got with tolcapone—a good medicine, but it had a lot of safety issues. We have new options for our patients, including a once-a-day COMT inhibitor that’s been used in Europe for 3 years. I’m excited to give that a try as well.

: Yeah. What also is interesting is they’ve done some head-to-heads against entacapone and data suggest opicapone is more effective. When given the choice—if we’re given the choice from an insurance perspective, of course—I would rather go right to opicapone.

I expect because of financial issues, for many patients we may have to try entacapone and show that they’re not doing adequately, then get an approval for opicapone. However, this is mysterious right now until we actually see it marketed in the United States.

Recently Approved Oral Therapies for OFF Episodes in Parkinson’s Disease

Device-assisted and surgical therapies for more advanced issues with motor fluctuations in OFF episodes are described.

: We’ve spent a lot of time focusing on the medical treatment of OFF episodes, but at a certain point the fluctuations and OFF episodes may not respond as well to medications. What surgical options are available for these patients?

: Typically, we’ve used the term device-aided therapies to refer to both deep-brain stimulation [DBS] and to pump therapies. If we think about surgical options, we could potentially talk about lesioning therapies also.

In general, we consider device-aided therapies appropriate for patients who have troublesome motor fluctuations—often troublesome dyskinesia despite very aggressive or maximal drug therapy—without contraindications to the specific therapy.

Let’s first talk about deep-brain stimulation. That’s perhaps the most widely applied device-aided therapy in the United States. Typically, we’re placing electrodes into the subthalamic nucleus or globus pallidus, either on 1 side of the brain (unilaterally) or both sides of the brain (bilaterally). We hook these things up to pulse generators. The generators need programming. The main risk is of having a hemorrhage in the brain, which is roughly 1% to 2% for each side of the brain operated on. For bilaterally operated patients, the risk is roughly 2% or 3% for symptomatic intracerebral hemorrhage.

Other adverse effects can occur, such as cognitive impairment. Therefore, patients should undergo a detailed cognitive assessment prior to surgery. Those patients who test well prior to surgery are unlikely to experience clinically important cognitive worsening with surgery. Hardware complications and infections can occur in 5% to 10% of patients’ lifetimes. Typically, these occur in the first few months after surgery and are easily remediable without additional brain surgery.

There’s dramatic improvement. OFF time reduction and improvement in troublesome dyskinesia is typically huge in appropriately selected patients. This is probably the most potent therapy that we have for bad motor fluctuations and dyskinesia—an 80% to 90% reduction in troublesome dyskinesia, and compared with the preoperative state, 5 or 6 hours of OFF time reduction. If we compare it with patients undergoing sham stimulation, then it’s 2 or 3 hours of OFF time reduction. Truly well-validated excellent therapies, but they require a fair bit of careful patient selection and careful ongoing management of the patient. This can be applied, as I mentioned, either in the subthalamic nucleus or globus pallidus.

There are small differences. In STN [subthalamic nucleus], we typically use smaller currents. The patients can have substantially greater drug reduction than in the GPI [globus pallidus interna]. Whereas with GPI, we use larger currents, have less complex stimulation programming and much less drug reduction—typically on the order of 0% to 25% as opposed to 50% or 60% for an STN-stimulated patient.

Duopa [carbidopa-levodopa] therapy refers to a patient receiving continuous levodopa-carbidopa intestinal gel via PEG-J tube. They have to tote around a fairly large cassette hooked up to a fairly clunky pump that weighs approximately 1 to 2 pounds. They carry it in either a fanny pack in a bandolier fashion or in a holster. This really is a very good therapy. It can be applied either during the waking day or—in more severe patients who have troublesome OFF episodes during the night—for 24 hours. It’s a gel formulation and can reduce OFF time by more than 2 hours compared with placebo-treated patients. It does reduce dyskinesia, but not as reliably or as quickly as deep-brain stimulation, and you’re applying a lot of levodopa.

You can often get rid of most orally administered drugs, and that is nice in terms of pill burden. However, it does require stoma care, and it requires carrying around this pump. For many patients, that is not socially acceptable. For others, it is. It’s also a matter of risk. Sometimes we have the frank discussion, “Would you rather have a hole in your stomach or a hole in your head?” That’s a colloquial way of putting it, but it really comes down to a quality-of-life discussion. For most patients who are candidates for deep-brain stimulation, Duopa [carbidopa-levodopa] therapy can be considered.

When you have troublesome dissimultaneous dyskinesia with severe tremor, that’s a situation where DBS has greater efficacy than levodopa therapy. That’s a patient you would preferentially want to treat with deep-brain stimulation. Somebody who’s having trouble because of tolerance to high doses of drug is somebody you’d probably want to go with deep-brain stimulation, especially subthalamic stimulation.

On the other hand, if you have a patient with cognitive impairment—maybe psychosis or dementia—you may have real concerns about DBS potentially worsening cognitive function, especially dementia. If you have a patient who had, for example, gastric bypass or stomach anatomical issues, then you’re probably going to preferentially go toward deep-brain stimulation. There are reasons to choose 1 therapy or another.

: Although I’ve had patients who simply are not interested in brain surgery.

: Then they’ll opt for Duopa [carbidopa-levodopa] therapy. You are right: The size can be challenging. However, I’ve had a lot of clever patients come up with all sorts of ways to hide their pump in clothing. They design stuff.

Device-Assisted and Surgical Options for Advanced Motor Fluctuations in Parkinson’s Disease

Experts wrap up their discussion of treating OFF episodes in Parkinson’s disease during COVID-19, including overcoming initial challenges with use of telemedicine, and offer advice for community neurologists treating OFF episodes.

: Very briefly, how has it been for you to initiate these new therapies during the pandemic? Patients are starting to get used to the world right now. We’re doing a lot of telemedicine where I am in Philadelphia. Patients were very reluctant to try new medications, afraid of switches, and they wanted to avoid the emergency department. In my area, as the virus has become more under control and as patients have become used to interacting via telemedicine, they’re much more comfortable. I’m having a lot more success initiating new therapies via telemedicine, even in the COVID-19 [coronavirus disease 2019] world. What’s your experience been?

: Yeah, it’s identical. I’m a little more fortunate being in Colorado. The number of cases we’ve had has been substantially less. At the peak, we had about 500 to 600 new cases per day in all of Colorado. Considerably lower incidence and prevalence compared with the Philadelphia, New Jersey, and New York areas.

: There you go. I don’t think we had more than 20 or 30 patients at a time and no more than 5 to 10 people vented at a time in the hospital where I’m located.

We’ve been comparatively spared from such severe outbreak. However, it has been scary—there’s no doubt—and tremendous fear from patients. We have implemented telemedicine where it’s been appropriate. I must say, for patients who are good historians and have good technical connection, telemedicine can be effective. However, for patients who have trouble connecting or have a lousy connection, who are not such good historians, or have more complex features on the examination and a better examination is necessary, telemedicine is, unfortunately, not a good substitute. We are seeing most patients in person, luckily, because we are in a little safer situation than you are. 

If patients are farther away and have to travel, or if it’s known the patient is capable of doing a good job via telemedicine, then we’re often seeing telemedicine as an option. Currently, probably 20% of patients with Parkinson’s disease in my office are being seen by telemedicine. The majority are being seen in person. At the height, we were seeing probably 50% to 75% of patients who had Parkinson’s disease via telemedicine.

I would agree with you: There has been increasing acceptance of, “This is the new reality, let’s get on with things.” If you say, “We need to begin a new medication,” they’ll say, “Let’s begin it. Let’s go through it. Please email me, send me via the portal all the instructions on how to begin it, and I’ll be in touch with your nurses via the portal or phone you if I have any problems.” That’s been feasible.

: Yeah, I would say it was a real challenge at the beginning. Our health systems have adapted. They built more robust platforms. We’re learning ways around if there are difficulties using Zoom and things like that. Congress has been helpful. I’m really hoping this option remains for patients in the post–COVID-19 world. We’ve realized it’s not the same as an inpatient. It’s certainly a better way to see patients who have health or travel challenges. It’s a really exciting way. As technology gets better and patients become more educated, we’ll be able to continue this way of providing therapy.

To sum things up, what takeaway messages do you have for neurologists treating patients with Parkinson’s disease with respect to OFF episodes?

: Well, there’s good news. There are an increasing number of tools in terms of questionnaires and other means to identify OFF episodes, and we have a variety of ways of addressing them. Acutely, we can get the patient back ON with inhaled, subcutaneous, or sublingual therapy. We also have more options to keep patients ON—whether that’s via new oral medications like opicapone and istradefylline, new invasive therapies such as the upcoming apomorphine infusion pump, or well-established device-aided therapies such as Duopa [carbidopa-levodopa] and DBS [deep-brain stimulation].

We should not be accepting of disability, as I put it. When patients tell us, “We have OFF time,” I tell the patients, “It’s 1 of 3 things. Either I’m not doing a good job, you’re not helping me, or you have refractory disease. If you have refractory disease, we should be treating you aggressively to get you as good as we can, and we should have a discussion about expectations.” My expectation is we should be doing the best in assessing impact and improving quality of life. We can make a really big impact in helping our patients.

: I couldn’t agree with you more. That’s an excellent summary of the challenges we face with OFF episodes, including the fact that we shouldn’t be accepting of it. We have so many options now, and [we will have] more in the future. I’m hoping with using these options—rational polypharmacy and device-assisted therapies utilization—we can reduce the burden of OFF episodes for both our patients and their caregivers. OFF is something that affects everybody. 

This has been extremely informative. Thank you, Dr Kumar, for this insightful discussion. Thank you to our audience for watching this NeurologyLive® presentation on the “Optimal Management of OFF Episodes in Parkinson’s Disease.” We hope you found this Peers & Perspectives® discussion to be useful and informative. Thank you very much.

Optimal Management of OFF Episodes in Parkinson's Disease