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Expert Exchange: Perspectives on Established and Emerging Therapies for OFF Symptoms in Parkinson Disease

  • Authors: Mark Lew, MD, FAAN, FANA; Irene Malaty, MD, FAAN
  • CME / ABIM MOC Released: 11/30/2020
  • Valid for credit through: 11/30/2021, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for neurologists, primary care physicians, orthopedists, and orthopedic surgeons.

The goals of this activity are to increase knowledge about clinical trial data for new and emerging therapies for the management of OFF symptoms and to increase confidence in selection of an appropriate therapeutic approach for patients with Parkinson disease (PD).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical trial data for new and emerging therapies for the management of OFF symptoms in patients with PD
  • Have greater competence related to
    • Selection of an appropriate therapeutic approach for the management of OFF symptoms in patients with PD


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  • Mark Lew, MD, FAAN, FANA

    Professor of Clinical Neurology
    Joseph P. Van Der Meulen, MD Chair in Parkinson's Disease Research
    Vice Chair, Department of Neurology
    Division Chief, Movement Disorders
    Keck School of Medicine
    University of Southern California,
    Department of Neurology
    Los Angeles, California


    Disclosure: Mark Lew, MD, FAAN, FANA, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: AbbVie; Acadia; Acorda; Adamas; Cynapsus; Kyowa; Lundbeck; Neurocrine; Revance; Sunovion; US World Meds
    Served as a speaker or a member of a speakers bureau for: Acorda; Adamas; Cynapsus; Kyowa; Neurocrine
    Received grants for clinical research from: Aptinyx Inc.; Cala Labs; Neuraly; Pharm2B; Sun Pharma

  • Irene Malaty, MD, FAAN

    Barbara Padgett Dein Professor
    Associate Professor, Dept. of Neurology
    Director of Parkinson Foundation Center of Excellence and Tourette Association of America Center For Excellence
    Fixel Institute for Neurological Diseases University of Florida
    Gainesville, Florida


    Disclosure: Irene Malaty, MD, FAAN, has disclosed the following relevant financial relationships:
    Received grants for clinical research from: AbbVie; Boston Scientific; Eli Lilly; Neuroderm; Revance; Teva


  • Lisette Arnaud-Hevi, PhD

    Medical Education Director, Medscape, LLC


    Disclosure: Lisette Arnaud-Hevi, PhD, has disclosed no relevant financial relationships.

  • Asha P. Gupta, PharmD, RPh

    Senior Scientific Content Manager, Medscape, LLC


    Disclosure: Asha P. Gupta, PharmD, RPh, has disclosed no relevant financial relationships.

CME Reviewer

  • Hazel Dennison, DNP, RN, FNP, CHCP, CPHQ, CNE

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Disclosure: Hazel Dennison, DNP, RN, FNP, CHCP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Expert Exchange: Perspectives on Established and Emerging Therapies for OFF Symptoms in Parkinson Disease

Authors: Mark Lew, MD, FAAN, FANA; Irene Malaty, MD, FAANFaculty and Disclosures

CME / ABIM MOC Released: 11/30/2020

Valid for credit through: 11/30/2021, 11:59 PM EST




Dr. Mark Lew (00:05):

Hello everybody. My name is Dr. Mark Lew. I'm a professor of neurology at the University of Southern California in Los Angeles. And I'm joined today by Dr. Irene Malaty Who's an associate professor at the University of Florida. And we are going to have an expert exchange and dialogue regarding perspectives on established and emerging therapies for off symptom in Parkinson's disease. You're all aware that when we talk about off symptoms in our patients with Parkinson's disease, we're referring to patients with more advanced disease and they can be suffering from different types of off symptoms. So there are motor fluctuations, which are we typically think about wearing off where patients come to the time for a dose and they may notice re-emergence of their Parkinson's symptoms prior. Simple wearing off, they may have a sudden abrupt change. And this may at times be unpredictable where they slip into an off period.

Dr. Mark Lew (01:17):

They may notice that their dose of medication simply fails to work or kick in. Or they may take a dose and typically this may happen earlier in the morning. They may take a dose of their medication that takes a while to kick in. And we know that over time Parkinson's disease is a progressive neurodegenerative disorder and the disease progresses. And we see that patients initially may take their medication and there's talk of this "honeymoon period." Patients may have several years when they start taking levodopa that their medication lasts for a longer duration of time. And they may say, "I took my lunch dose two or three hours late, and I didn't even feel a difference." But over time, the therapeutic window narrows and they start to feel a difference and they notice their medication working and they may over time, everybody develops as I described earlier, this simple wearing off. And they may find that when their medication is working, the duration of efficacy is shorter. They may develop some mild to moderate extra movements, dyskinesias. And then they may turn off before their next dose of medication is due.

Dr. Mark Lew (02:44):

And we know that these types of motor complications are due to several factors. This is due to a combination of GI dysfunction in these patients. It's due to the actual pharmacokinetics of the medication they may be taking. And it's also due to progression of disease and the change of dopaminergic capacity centrally along with other neurotransmitter systems.

Dr. Mark Lew (03:24):

So with that brief introduction, we're going to start our program talking about the various formulations of medications that are available for the treatment of wearing off. And I think the most common medication that everybody's aware of is Carbidopa-Levodopa, it's been available for a number of decades. It's the most effective treatment that we have for patients with Parkinson's disease. And so I'd like to ask you Irene, how would you start a patient when you're evaluating a patient who's having some wearing off? Is there a particular formulation of Carbidopa-Levodopa that you might use? Is there something that you reach for in the armamentarium initially?

Dr. Irene Malaty (04:45):

So I think it depends what the patient's taking already. If they're already taking Carbidopa-Levodopa and they're experiencing wearing off, the most important thing is to figure out the schedule of their day and when they're experiencing those. So you can figure out the factors. If they're always wearing off towards the end of a dose interval, you might simply need to reduce the duration of the dose interval. So if they're dosing every six hours, you may need to go to every five or every four hours. If they're experiencing early morning wearing off, you may need to look at using a longer acting preparation at bedtime, or in some cases, even dosing overnight. If they're waking up anyway and the long acting formulation at bedtime didn't take them all the way to the next morning. So the first thing I look at are the intervals. And then we look at whether if they're on a short acting form, we might consider using some of the longer acting forms of Levodopa. Sometimes we consider adjunctive medications and in some cases we even consider surgical therapies. So I think it can be useful to go step by step.

Dr. Mark Lew (05:55):

Yeah, so absolutely. And I think one of the main points we bring to people today is that we have such a huge option for treatment today. And we'll talk about many of the medical therapies for the treatment of wearing off. But you bring up a very germane point. If you were to offer a patient a change in their daily regimen from maybe three to four times daily to bring their schedule closer together, to fractionate their medication and treat their wearing off and they're already having trouble getting their medication in three times a day, that's not an ideal situation for that patient. So it is of the utmost importance that we take the patient's lifestyle into consideration. So the good news is while we don't have that magic bullet, the once daily oral formulation of Carbidopa-Levodopa, which would be very nice, we do have an encapsulated formulation.

Dr. Mark Lew (07:03):

So let me backtrack. The immediate release formulation, which has been available to us for literally decades, has a half-life of maybe 90 minutes. And then there's an extended release formulation that's been available for probably almost two decades or so, that improves to about maybe three hours or so. And most recently there's an oral formulation of extended release Carbidopa-Levodopa, an encapsulated formulation with a half-life of about five to six hours. But due to the different pharmacokinetics of this medication and the fact that the maximal concentration is much lower and it's a slower release, the actual dosing is very different than we see with immediate release Carbidopa-Levodopa.

Dr. Mark Lew (08:38):

There is additionally another formulation under experimental design. Now that is in clinical trials, which is an even longer formulation of this encapsulated Carbidopa-Levodopa that may possibly be closer to a three time a day preparation. But we're still hoping for our patients that we could get a different formulation that might last even longer. And then the delivery systems are really what's changing so rapidly for us. I think as the technologies change, there's an inhalable form of Levodopa, which can be used for off episodes to treat as a rescue therapy. So Irene in addition to the oral formulations I've discussed and this more novel inhalable formulation of Levodopa that can be used very effectively to treat off episodes as a rescue therapy, can you elaborate on your experience with some of the other formulations that we have of Carbidopa-Levodopa that are more continuous for patients?

Dr. Irene Malaty (10:10):

Sure. I'd also like to share a couple of pearls that you touched on for people who might be newer to using the extended release form of Levodopa. I think it's really valuable that you share that often, if you're trying to approximate the target dose and you double their current daily dose of immediate release and then divide it into three or four doses, it's a good starting point. But I think you have to really be careful to counsel patients that it will need to go up or down from there. Because a lot of times when you convert over, there are dosing conversion charts, but they don't predict perfectly. And it's very common they'll need more or less. And if they're not anticipating that they may give up too quickly and also it's a little bit less predictable patient to patient. Sometimes it's an advantage that it's less acute of an onset so that if they're having peak dose side effects, you may find an advantage to avoiding that.

Dr. Irene Malaty (11:03):

But sometimes patients accustom to that immediate boost of immediate release have to recognize it's going to be a little bit different with the longer acting forms and I find that helpful to pass along. But with regard to the forms that don't go through the mouth, we've always been trying to approximate a more continuous delivery. We know that the pulsatile delivery is not the natural state and that is what probably provokes the motor fluctuations. And so, one version of doing that is continuous delivery into the intestine of Levodopa. So this is Levodopa-Carbidopa enteral solution. So patients will have a PEG J tube placed. And then each day they'll attach a pump. It's about the size of a brick. And they where usually in a waistband or a Fanny pack or a vest or a purse, and this pump will deliver Levodopa continuously for 16 hours of the day. So they'll attach that in the morning and remove it in the evening and they will have a steady delivery.

Dr. Irene Malaty (12:07):

And with the pump, we're able to administer a morning bolus to start the day and then a continuous infusion throughout the day, as well as the capacity to give an extra dose if they have an off period. And so earlier work showed that delivering it passing the stomach is an advantage and that delivering it continuously is an advantage. So this therapy accomplishes those two things. The disadvantages that patients do have to have a surgical procedure, and they do have to interact with this pump on a daily basis. It does take some dexterity to operate. So usually their care partner gets involved and there are the risks that are inherent to having an intestinal tube. So there's a risk of dislocation, especially with falls. There can be risks of infections and patients have to be aware of that and have to be deemed a good candidate to manage that.

Dr. Irene Malaty (13:00):

But in the studies that brought this therapy to the market, they were able to achieve a two hour reduction in off time, relative to oral therapy. And they're often able to tolerate a slightly higher dose of Levodopa. The reduction in off time was resulting in on-time without troublesome dyskinesia, which is also important. So you can always make someone more on at the risk of provoking dyskinesia and other side effects. So that's one therapy that we can use to try to have a more continuous delivery.

Dr. Irene Malaty (13:32):

Because of the concerns of needing to have a surgical procedure, needing to have an intestinal tube, there's always been a wish, like you said, couldn't we just have a pill that would last the whole day. And although we're not there yet, there are two companies that have an ongoing trial of subcutaneous delivery of Levodopa. So this is avoiding the intestinal tube and just infusing subcutaneously. One of those companies is NeuroDerm and their product will deliver about 700 milligrams of Levodopa. So they'll be able to deliver a portion continuously for 16 hours of the day and they'll also supplement the rest of what their needs are with pills. The other company AbbVie is creating a pump that will deliver the over 24 hours, the entire amount of their Levodopa. So these are currently in trials.

Dr. Mark Lew (14:25):

So there are a large number of options with regard to the use of different formulations of Carbidopa-Levodopa. And I'm constantly having this discussion with my patients who want to know where we are, when are we going to have a cure? And my response is it's much more likely we're going to have a radically or effective therapy before we have a treatment that will completely eradicate this disorder. And it really seems that it's most likely going to be firmly based in technology and advancement in technology. As we move along with other possible options for therapy with regard to treating their wearing off, there are a host of other medications. And again, it's probably been well over two decades that we've been able to use monoamine oxidase type B inhibitors to treat our patients. The first approved therapy was selegiline. And we now have three, if you think about maybe different formulations, maybe four possibilities in that group.

Dr. Mark Lew (16:34):

And before I ask you to tell us some of the details, I would just like to say that my personal experience has been is that patients really tolerate these medications very well. There is some data for some of these medications in this class, suggesting that maybe possibly might modify the outcome of the disease down the line. And I clinically find they're A, well tolerated. They have a clear level of efficacy and double-blind placebo controlled trials have shown this compared to again the gold standard compared to placebo and patients do well. So I have a tendency to leave patients these medications because they do so well with them and they seem to help them clinically. What's your experience been with this class and can you tell us a little bit more about some of the more specific MAO inhibitors?

Dr. Irene Malaty (18:08):

Sure. I've had a similar experience to you in that the MAO type B inhibitors are very well tolerated. They're not the most potent class of medication therapeutically, but they can be helpful with mild symptoms or adjunctive and symptoms that are more significant. So selegiline has been around the longest and is dosed twice a day and comes in an oral form and an orally disintegrating form. Rasagiline came next. This is given once a day and was able to show about one hour of off time difference from placebo in the Presto trial. The on-time did have an increase in troublesome dyskinesia. And so the most recent MAO inhibitor, safinamide, was able to show about the same reduction in off time, but perhaps without troublesome dyskinesia. Generally, I feel like the three of these are relatively interchangeable in my experience in terms of their effectiveness. So we basically have all three options to use for our patients.

Dr. Mark Lew (19:13):

Right. So additionally, there are different formulations and there's even another formulation that we don't use, but psychiatrists may use and I've had ... Our patients are very well-informed and I find them asking about that because there's a patch formulation of selegiline, again which is approved for the treatment of depression and not for use with Parkinson's disease. And the other problem I think we face as clinicians using these medications, although they're easy to use, mostly available, generic, mild, well tolerated, efficacious. When we talk about monoamine oxidase inhibitors, we run into trouble frequently with the pharmacist and patients worrying about their diets needing to be adjusted and other medications or foods they're not allowed to eat or alcohol they can’t have. And this is all impertinent because our medications, the MAO-B inhibitors are concentrated uniquely in the brain. And this is the main enzyme that metabolizes dopamine centrally. So all of the issues with the non-specific MAO inhibitors are typically not a problem if our medications, the medications you elaborated, are taken at the prescribed dosing.

Dr. Irene Malaty (20:45):

And they have high selectivity for the Type B monoamine receptor, as opposed to the type A that metabolizes tyramine, which is where all those food restrictions come up. And so I don't restrict my patients from eating anything because they're so highly selective, there's no practical issue with tyramine in the diet.

Dr. Mark Lew (21:04):

So one of the other issues with the COMT inhibitors is the relatively unique side effect profile compared to other medications or the majority of other medications that we use the. This class of medication can cause, potentially cause, diarrhea. And I was specifically talking about the first release medication, entacapone, in about 10% of people. And then there's no choice but to really stop the medication to treat the diarrhea. And then almost half of patients, maybe 40 to 50% of patients, have a side effect where their urine turns an orange color called chromaturia, which is related to the dye in the medication. So it's always very important to discuss this with the patient that they don't think they're having kidney problems or an infection or something like that.

Dr. Mark Lew (22:18):

And I did mention that entacapone was first released and that the next medication that came out tolcapone, is a much more potent COMT inhibitor and only needs to be dosed three times a day. But it is rarely used because of the potential risk of liver toxicity. It was not taken off the market. Liver monitoring was recommended in patients that continue on this medication. But because of these restrictions, it's rarely used. And we talked about the effectiveness in treatment of these medications for wearing off. Tocapone was very effective and it took the magical one hour that we usually see with all of these adjunctive medications as far as improving on time, decreasing off time and improving on time, a good on time without disabling dyskinesia, and it almost doubled it similar to a class of medication that you'll be talking about shortly the dopamine agonists.

Dr. Mark Lew (23:42):

But I think most exciting is the fact that there's a new medication in this class, called opicapone and the pivotal trials were done outside of the United States. But what's unique about opicapone is that it also does work peripherally, whereas I was starting to mention that tolcapone actually works both peripherally and more centrally, which is probably why it's a little bit more potent. But this new medication opicapone binds so specifically to the COMT, that it's a once daily dosing at 50 milligrams and it's very effective in, again decreasing off time. It does come across the magic number, once placebo is subtracted out of perhaps a little more than an hour of improvement in on-time.

Dr. Mark Lew (24:44):

But what it does is it really helps normalize the levels of dopamine. When we look at Levodopa levels, it can actually increase the levels close to three quarters or 75% by increasing the trough and the peak. And so it can be a very effective treatment and as I mentioned, it is a once a day formulation with a single dose of 50 milligrams daily. So while we haven't hit the magic bullet for Carbidopa-Levodopa once daily, the trend really is to have many of the other classes of medications available in a once daily formulation. So I think with that it would be important for you to enlighten us about the different formulations and medications that are available and another very old class of medications called dopamine agonist for the treatment of wearing off in Parkinson's disease.

Dr. Irene Malaty (26:02):

I think so far we've talked about ways to increase dopaminergic transmission with Levodopa, which can be converted to dopamine and with inhibiting the two main enzymes that metabolize dopamine, the MAO-B inhibitors and the COMT inhibitors. And so we have another class dopamine agonists, which stimulate dopamine receptors. So we're coming at all the different ways that we can improve dopamine function. And we have three of the older agents available pramipexole and ropinirole are available both in short acting and in longer acting forms. We have rotigotine, which is a patch. So that is a 24 hour delivery system. So they change the patch once a day, rotate where they place it. And that's sometimes helpful when people are fed up with pills or when they have a hard time remembering medication. The dopamine agonists as a class have important side effects that we have to take into consideration.

Dr. Irene Malaty (27:03):

So they can cause somnolence, even sleep attacks, falling asleep suddenly dizziness, swelling, and the most famous side effects the impulse control disorders, which can result in doing things compulsively. Having a hard time disengaging from activities, which could be hobbies, could be gambling, could be spending, could be preoccupying sexual thoughts. Those are side effects that we have to watch for because without changing the medication, they don't tend to just go away if they emerge. You also have to be aware of the dopamine agonist withdrawal syndrome, which is when you do try to remove those medications, you have to ween them to avoid a restlessness and an increase in anxiety that can happen if you stop them abruptly.

Dr. Irene Malaty (27:50):

On top of those three categories, we have apomorphine in different formulations, which can be used to replace dopamine therapy. So we've had for some time, apomorphine injections. This is a parenteral therapy that's considered a rescue. So it's a quick acting and short duration therapy. So a patient would inject themselves when they have sudden off periods. The advantage is the quick duration of onset, but it is an injected therapy. And the first dose has to be done in the office so that you can monitor for hypotension. And you have to pre-medicate to avoid nausea, which is a side effect of that therapy.

Dr. Mark Lew (28:33):

Irene, how do your patients adjust to that? I have the patients that use injectable apomorphine find it to be life transforming. They can go about their day and even if they don't use it, they know they have it in their pocket and they can inject themselves and 95% of the time they'll turn on and it's usually within 10 or 15 minutes. But I have literally had patients say to me, "I would rather have brain surgery than inject myself." And it can be a large hurdle to leap over. So how can you address that? But I guess now we're in a unique time where there are even really good options for those people.

Dr. Irene Malaty (29:25):

You're absolutely right. I think that it's a limited subset of patients that is comfortable with that. And it takes some dexterity also to do that if a patient doesn't have a caregiver with them all of the time. But there is that small subset of people who could walk into the grocery or walk into a large store and get in the back and have a sudden off, and that can be disabling and having that security of a rescue. We talked about other rescue therapies as well today. But it's a small, small subset of patients who typically use that. But just because of what you said, there is an aversion to injectable therapies. We now have new formulations of apomorphine that can be given in a different way. So there's a sublingual form. And if you remember the breath strips that were popular sometime back. It's a thin film that you put on the tongue. And this is another mechanism of apomorphine delivery that has a placebo controlled trial demonstrating the benefit. The main side effects of that are local oropharyngeal side effects that can lead to discontinuation. And now we have, what's been available overseas and is in trials now, apomorphine infusion, which is wearing a pump that continuously infuses apomorphine subcutaneously. So these are additional mechanisms that have emerged to avoid the injectable rescue therapy.

Dr. Mark Lew (30:51):

So, there remained to be many choices. And the good news is as well, even within a particular medication, as well as class medication, there are different formulations that may be better depending upon a person's lifestyle.

Dr. Irene Malaty (31:37):

On that same note with evolution of how we can administer these therapies, there's also a novel class of dopamine agonists that's in trials right now. And this is tavapadon which is a partial dopamine agonist that primarily stimulates D1 and D5 dopamine receptors, as opposed to D2 and D3. And the hope is that this difference in receptor profile may lead to maintaining efficacy, but perhaps with less dyskinesia, which is what was suggested in animal studies. And so this is currently in trials to see if it will be another option for dopamine agonist therapy.

Dr. Mark Lew (32:16):

So that's very exciting as well. So you mentioned there are a host of side effects and the pendulum swings back and forth over decades. And dopamine agonists are very effective therapy for patients, especially younger patients, who don't seem to have as many of the side effects. So it might be very nice to have yet a new formulation or a new dopamine agonist that may have less of a concern for the psychiatric side effects that we're so worried about with our patients. So things are moving right along.

Dr. Mark Lew (32:57):

So on that note, I would like to just reference one further class of medication, which is another new medication called istradefylline which was approved by the FDA last summer. It was August of 2019. But it is a medication that's been used in Japan for a good part of a decade, since 2013, for the treatment of wearing off. And interestingly in Japan, it's also approved for the treatment of freezing of gait. However, there's not a lot of controlled data supporting this, but it's very interesting nonetheless, with regard to the foreign labeling. So this is another very unique class of medication. It's an adenosine A2A receptor antagonist and typically adenosine influences the indirect pathway and activation of these receptors typically reduce motor activity. So using a medication like istradefylline, which is specifically an adenosine A2A receptor antagonist, has been shown in placebo controlled trials to increase on time. And again, on time without disabling dyskinesia, about an hour in patients who were relatively advanced, that were on every other class of medication at the time. And this brought them yet an additional hour of on time without troublesome dyskinesia.

Dr. Mark Lew (34:49):

This is a medication that is also dosed once daily with the goal dose being 40 milligrams, starting at 20 milligrams and working your way up. And the most common side effect that was seen in the clinical trials was increasing dyskinesia. But otherwise it was relatively well tolerated. And that has been my clinical experience. Additionally, the nice thing about it is this is a class of medications that are not directly influencing dopamine receptors. And there's probably more modulation of glutamatergic pathways. So it's really just another tool. It's another way that we can buy our patient, bring our patients more quality on time in utilizing different pathways and mechanisms.

Dr. Irene Malaty (36:07):

I think it's interesting that after more than 50 years Levodopa remains the gold standard of treatment. But over time, the duration of efficacy can change and we can see motor and non-motor offs and armamentarium has grown for different classes and different therapies and different approaches to try to alleviate those symptoms. And I think the bottom line is we have to individualize the treatments for each patient based on what they're experiencing, what side effects they may be susceptible to, and we have to take it on an individual level. But having said that, Dr. Lew thank you for conducting this program together with me. It's been a pleasure to be involved and thank you to the viewer who is expanding or reviewing their knowledge about Parkinson's therapies. Please make sure to proceed to the post activity assessment questions so that you receive your CME credit, and please make sure to complete the evaluation so that we can continually improve your educational opportunities. Thank you.


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