Expert Briefing: Medication: What’s New?

Dr. James Beck 00:00:00
Hello everyone. I'm James Beck from the Parkinson's Foundation, and I want to welcome you to the fifth in this series of our 10th Expert Briefings. Today's topic is going to be PD and medications: what's new.

As I said, I'm Jim Beck. I'm the Chief Scientific Officer at the Parkinson's Foundation. It's my pleasure to have you listening in today because we have a really wonderful talk. I just want to remind you, as I always do, that these webinars we create with input from the community. We rely on our colleagues at the Alliance of Independent Regional Parkinson's Organizations, and we rely on you, people in the Parkinson's community, to give us feedback. You'll notice at the end of our presentation there will be a survey to take. We encourage you to fill out the survey and give us the feedback that's necessary.

If you want to download the slides for Dr. Pahwa's presentation, on the viewing screen, right below his picture, there's a big blue box that says Download Slides. Click on that, and you can download a copy of the slides to look at later or take notes on. If you're a health professional, you can earn one free CEU through the American Society on Aging. You have to register as a health professional and indicate you'd like the CEUs, and you'll have an email at the end of the day that will tell you the additional steps you need in order to collect that CEU. But remember, you only have 30 days, which is until May 9, to collect your free CEU.

It's my pleasure to welcome our speaker today, Dr. Rajesh Pahwa. Dr. Pahwa is the Laverne and Joyce Rider Professor of Neurology at the University of Kansas Medical Center. He's also chief of the Parkinson's and Movement Disorder Division and director of our Parkinson's Foundation Center of Excellence at the University of Kansas Medical Center.

Dr. Pahwa received his medical degree at Seth G.S. Medical College at the University of Bombay in India. He completed an internship in medicine at Baylor College of Medicine, another one of our Centers of Excellence, followed by a residency in neurology, also at Baylor. He then completed a fellowship in movement disorders at the University of Kansas Medical Center, which is where he is now. Dr. Pahwa is a diplomate of the American Board of Psychiatry and Neurology. His research interests are centered around the various aspects of Parkinson's disease and essential tremor. He's been conducting clinical trials for over 20 years and is currently involved in studies related to medical and surgical forms of therapies for Parkinson's disease. The Center of Excellence that Dr. Pahwa leads at the University of Kansas is one of the largest clinical trial sites in the United States.

Dr. Pahwa has published, as you could imagine, extensively about Parkinson's disease and related movement disorders. He's co-editor of the Handbook of Parkinson's Disease for the third and fourth editions, Therapy of Parkinson's Disease, and Handbook of Essential Tremor and Other Tremor Disorders. As you can hear, Dr. Pahwa's topic, what's new with medications, is right up his alley. In fact, he's probably had some experience with some of the medications that are currently in clinical trials today. Without further ado, Dr. Pahwa?

Dr. Rajesh Pahwa 00:03:03
Thank you, Jim, and good morning, good afternoon, good evening for every one of you who joined my talk today. It is a very exciting time for Parkinson's disease treatment. I remember a time 15 years ago, if I were to do a talk like this, I might have maybe one new medication and maybe three or four new medications coming up in the near future. I would like to start off by pointing out that what I'm going to do today is talk about some of the new medicines we have had over the past couple of years and the new medicines that are going to be available in the United States over the next couple of years.

There are multiple medications being tested right now. In fact, at this time, we have medications that we are testing for multiple indications in Parkinson's, all the way from slowing the disease progression to helping non-motor symptoms, whether it's orthostatic hypotension or psychosis. There are a lot of studies going on. I just wanted to focus on the next two years because I could talk for the next five hours about each of the medicines that are being tested right now in clinical trials.

The other point I would like to point out is, since it's the next two years, I'm not going to be talking about stem cells or gene therapies, which a lot of people have interest in finding out about. Those are a little further away than two years before we would actually be doing phase three clinical trials that they are going to be available in the near future.

Before I start, I want to let you know that because I have a number of clinical trials, I do have a lot of disclosures to make as far as the companies and other things are concerned, and this is my slide that you have downloaded if needed.

There are still a number of unmet needs when it comes to the treatment of Parkinson's disease. By unmet needs, I mean that even though we may have treatment, we still struggle in managing patients with these conditions. For example, off time, including on-demand therapies, and I'll talk about each or at least the ones that we have treatments for down the road here; dyskinesias, which are the involuntary movements that occur; psychosis, that's the hallucinations and delusions that go with Parkinson's; orthostatic hypotension, which is low blood pressure on standing and syncope episodes; as well as constipation and urinary problems. Then we have cognitive issues, including dementia. Like I mentioned, a couple of our big ones are slowing of disease progression, where we have a number of studies ongoing, but I don't believe any of them are that close that we'll have them available in the next couple of years. Finally, falls, which is a huge burden both to the patient and the caregiver, but again, that is something way down in the future if we have treatments for the same.

Dr. Rajesh Pahwa 00:06:18
What I plan to cover are the new treatments, like I mentioned, in the last couple of years and the future treatments that are going to come in the next couple of years. Usually, when I do presentations of new medicine, I like to only use generic names. But when I talk to patient groups, it often comes down that they are more familiar with the branded rather than the generic names, and that's why I've included both of them.

If you look at PD psychosis, we have pimavanserin, or Nuplazid, that was approved. For orthostatic hypotension, we had droxidopa, commercially known as Northera. For off time, we had carbidopa-levodopa enteral suspension, also known as Duopa in the United States; safinamide, Xadago; and then we had one on-demand therapy approved, levodopa inhalation, that's Inbrija. We had our first medicine approved for dyskinesias in Parkinson's, amantadine ER, or Gocovri, and our first medication that is actually an injection for drooling, which is a botulinum toxin injection, Xeomin.

In the near future, what we are going to have is another on-demand therapy, apomorphine sublingual; another one for drooling, botulinum toxin injection, Myobloc; for off time, an adenosine A2A antagonist, istradefylline; subcutaneous apomorphine infusion; as well as subcutaneous carbidopa-levodopa infusion; and finally, other extended forms of carbidopa-levodopa preparations.

Let's talk a little bit about hallucinations and psychosis. What is psychosis? It is when Parkinson's patients start either seeing, hearing, smelling or imagining things that are not there. One of the most common things that people do is see little people, little children out there when, in fact, these children are not there. Of course, this could occur once a month initially, once a week, or it could get to the point that it is being seen more and more frequently. People could have illusions, where you see a certain object and it looks like something different. For example, a rope may look like a snake. Then you have a false sense of presence, when people feel someone else is in the room or someone is looking over their shoulder when there is no one there. Delusions are false beliefs: someone is stealing from you, someone is trying to hurt you. The presence of any of these hallucinations, illusions, false sense of presence or delusions would suggest that person may be having some degree of PD psychosis.

Like I mentioned earlier, it could happen once a month, or it could happen every day. In the studies that are out there, about 50% of the patients will develop these symptoms sometime over the disease course. The longer a person has the disease, they are much more likely to have this. This can happen with or without people who have memory problems, people who are taking Parkinson's medicines, since all Parkinson's medicines can cause psychosis to some point, or patients who are not on any medications for their psychosis.

It can occur with or without insight. By that I mean there are people early in the disease who will know these are not true because they may feel, okay, there is an elephant sitting in my office, but there cannot be an elephant in my office, and people have told me that because of my Parkinson's medicine, I can imagine that. They may blink a few times and the elephant may go away, or they may even walk over and touch the elephant and realize it's not there. Or they may lose insight, that when they see this, they truly believe there is an elephant in the office, which could be very upsetting.

Dr. Rajesh Pahwa 00:10:17
So far, this has been a big challenge for us because from the patient standpoint, they can get very upset. They can be very disabling once the hallucinations or psychosis begins, because all Parkinson's medications can cause it. We often hesitate in giving medicines for motor symptoms. We often, in fact, start reducing medications for the motor symptoms, which results in patients having more of a tremor, more physical difficulties, because they are not getting enough of the Parkinson's medicine.

We also know in one study this was the second most common reason after motor symptoms that the patients with Parkinson's ended up in the ER: because of the hallucinations. If these hallucinations and delusions become very bothersome, it becomes extremely difficult for the caregiver to manage the person at home, and they often have to end up taking them to the nursing home.

From the caregiver's standpoint, they start having issues because of the denial by the patient and the caregiver trying to convince them that there are no hallucinations. That's why we often recommend that the caregiver not argue with the patient if they see a rat running around that it is really not a rat, because that's just going to cause more problems between the patient and the caregiver. The caregiver often has to be more concerned about the patient, so it increases their burden. They often have more anxiety, depression and their own physical issues taking care of a patient with Parkinson's psychosis.

Over the years, we used medications that were used for schizophrenia to help patients when they were having these psychosis symptoms. The challenge with the medications that are currently available, which were available for schizophrenia that we were using for Parkinson's psychosis, is all of those medications can affect the chemical dopamine, which is already reduced in Parkinson's disease. What was happening is, in some patients, there was much worsening of the motor symptoms.

Even though they may be helped as far as the psychosis was concerned, the end result was that their motor symptoms were worse, just like we were experiencing when cutting back the medicine. When pimavanserin was approved about a little over two years ago, it was the first and only approved medication for Parkinson's psychosis.

Unlike the other antipsychotics, which are approved for schizophrenia, at this time pimavanserin is only approved for patients with Parkinson's having psychosis. Because it does not act on dopamine, but acts on another chemical, serotonin, it doesn't worsen Parkinson's symptoms. The motor symptoms do not get worse with Nuplazid. The other thing is, in clinical trials as well as in my personal experience, the majority of the patients do get benefit in their psychosis with Nuplazid.

Now, you can have patients, about 10% to 15%, where there is complete resolution of the psychosis, and then you have a group of patients where the psychosis is better. It's more something that they can understand and not something occurring frequently all the time. So that can also happen.

It's used once a day. In addition to helping the hallucinations and delusions, it also helps nighttime sleep, and it helps with daytime sleepiness. The other thing is it also helps with caregiver burden, so maybe the patient is sleeping better, the caregiver is sleeping better, and they feel better too. The most common side effects we see are nausea, confusion and, in some people, actually worsening of the hallucinations.

Dr. Rajesh Pahwa 00:14:14
Let's move to the next one, which is also for a non-motor symptom of Parkinson's disease, which is orthostatic hypotension.

Orthostatic hypotension is when there is a fall in blood pressure when the person stands up, and this causes lightheadedness, dizziness, feeling of passing out or, in extreme cases, even passing out. But what happens is there are certain other symptoms that are often not seen as commonly but can occur, and often a person does not realize it is due to low blood pressure. It's just generalized weakness. When a person stands up, the legs give way, generalized fatigue, slowing of thinking because the blood is not making it to the brain, vision problems, headache, neck pain and chest pain.

What happens with orthostatic hypotension is when the person stands up, the blood pressure drops, and if the blood pressure is too low, it does not have enough pressure for the blood to go to the brain. It's like the brain is living on the second floor, and the pump is not working, so the water is not quite making it to the second floor. Because the brain is not getting the blood, different organs or different parts of the brain are affected, and the most common one we see is passing out, which is the extreme one. But as you see, there are other symptoms that can also occur.

This is typically worse in the morning because a person has been sleeping flat all night in the bed. When they stand up, it does not react as well. They have not taken any fluids all night. In fact, they have gone to the bathroom a few times at night, and that's why it's worse in the mornings. The other thing is it can be worse after meals. A person takes meals, and they have more blood flow into the gut and not enough to make it to the brain.

Orthostatic hypotension can occur with multiple conditions, but one of the most common causes is Parkinson's disease. Parkinson's disease can cause orthostatic hypotension, and about 20% of the Parkinson's patients have it symptomatic. In other words, not only is the blood pressure dropping when they stand up, but it is also causing the symptoms. We have been using other medications, but in spite of that, we have been struggling in helping patients with orthostatic hypotension.

Droxidopa, also known as Northera, was approved recently for symptoms of lightheadedness or feeling of passing out. It is believed to increase the chemical norepinephrine. It should be taken three times a day, roughly at 8, 12 and 4, and you start at a very low dose, 100 milligrams three times a day, and it has to be increased to 600 milligrams three times a day.

When people are lying flat in bed, the blood pressure is fine because it's like it doesn't have to go to the first floor or second floor where the brain is, because right now the brain is at the lower level, so blood is flowing into the brain fine. It's when they stand up or sit up that you start having problems. We recommend not taking it about five hours before bedtime because when a person is lying flat in bed, they are going to have some degree of high blood pressure. The other challenge that occurs treating orthostatic hypotension is a person is never going to have that perfect blood pressure. It's always going to be a little bit low when people have symptoms or a little bit on the higher side.

With Northera, there is a significant improvement in these lightheadedness symptoms. But the most common side effects that can occur, of course, are high blood pressure, especially on lying down; headaches; you could still have dizziness; nausea; and fatigue. Again, it's not going to help every patient out there, but it's an additional medication we have to treat orthostatic hypotension.

Dr. Rajesh Pahwa 00:18:15
I'm going to shift gears here and talk a little bit about motor symptoms. I'm going to talk about one of the unmet needs, and that is off time. What is off time? Levodopa, as people are aware of, is the most efficacious medication we have for the treatment of Parkinson's disease. The way levodopa works, it goes into the brain and is converted to dopamine. As you know, dopamine is one of the chemicals that is reduced in Parkinson's disease.

When we first initiate levodopa, patients have control of their motor symptoms throughout the day and night. In other words, once they are on the medicine, whatever their symptoms might be, whether it's tremor, slowness or walking difficulty, it gets better. Then if they forget to take a dose, forget to take a medication for two days, go on a vacation and forget it even for a week, their symptoms are still under control. This provides control throughout the day and night.

However, over time, patients start having off time, and we believe roughly 40% of the patients will develop it over five years and 90% in 10 years. What is off time? It is the time during the day when the person's Parkinson's symptoms either return or worsen. Let's say someone wakes up in the mornings, and as mornings often are the best time of the day, they may not have any motor symptoms. They take their medications, but before their next dose is due, their tremor comes back, their slowness comes back or their cramping comes back, and that's when they go into an off state. They take their next medication, and their symptoms get better again and they are doing fine. That off state was aborted.

They are kind of beginning to have this little roller coaster. They take their medicine, and their symptoms are under control, which we call on. Then they get worse, which we call off, and that's the roller coaster some patients can have during the day. A person can have both motor symptoms during off as well as non-motor symptoms. Motor symptoms could be tremor, slowness, stiffness or balance difficulties. On the other hand, non-motor symptoms could be cloudy thinking, aching, anxiety or tiredness. So it could be both motor or non-motor. These symptoms are often unique for a person.

A person A, when they are off, may have just tremors. On the other hand, a person B may get anxious when their medicine is wearing off plus have tremors. This roller coaster, as the disease progresses, not only becomes more unpredictable, but at times it is difficult to manage even with medications.

When we look at these different off periods, we have patients who wake up in the morning and they are off, and that is called early morning off. When they wake up, they don't really get the best benefit of sleep, so they have maybe tremors, slowness, and they have to take their medications to start feeling better. Then one of the most common is the wearing off. They take a medication, and before their next dose is due, their symptoms return. That's often known as end-of-dose wearing off.

Then we have a delayed onset, where a person takes the medication and it takes a while for the medication to start working. That's known as delayed onset. Finally, you have dose failures, where a person takes a dose and it doesn't work at all, and they have to wait until their next dose before the symptoms improve. These are some of the common off periods, and a single individual patient could have an early morning off, could have wearing off, could have a delayed onset or could have even dose failure. They could have all these off periods in a single day.

Dr. Rajesh Pahwa 00:22:14
When we add up all the off periods that a person is getting during the day, this results in the total off time they have during the day. That's kind of the difference between off periods and off time. All the off periods together result in what is the off time during the day.

One of the medications, levodopa, was approved to be provided in a gel and could be used with a pump to provide it continuously throughout the day. It wasn't that a person had to remember to take five doses, six doses a day. They put the pump on in the morning, they leave it on all day. Some people even use it 24 hours. Providing the medication more continuously was shown to reduce off time as well as off periods during the day.

What it involves is putting a small tube through the stomach into the part of the small intestine called the jejunum, because that's where levodopa is absorbed. This tube is then connected to a pump, and the pump has a cassette where the levodopa gel is present. Every morning a new cassette is put in to provide the gel. The dose that a person needs, whether it's first thing in the morning, whether it's during the day, whether they need extra doses for some reason during the day, can be provided by the pump, and the patient has some independence on using this pump.

Who are candidates for the pump? We don't offer this pump for every patient who has Parkinson's disease, not only because it is a hassle carrying a pump around, but if the medications orally through the mouth are working, one doesn't need a pump to provide the same therapy. First of all, a person has to have a diagnosis of Parkinson's disease, not a diagnosis of atypical Parkinson's. Secondly, the symptoms have to improve with levodopa. Other oral medications have been used with levodopa. A patient continues to have at least off time of about three hours throughout the day. They can manage the pump, or they have someone, a caregiver, who can help them manage the pump. Since this tube is placed in the stomach, there is no reason that they cannot undergo abdominal surgery.

Duopa helps not only the off time during the day, but also the dyskinesias because it provides levodopa more continuously. The next medication that was recently approved is safinamide, and the commercial name is Xadago. This is an MAO-B inhibitor, and there are other MAO-B inhibitors already available in the United States, such as rasagiline and selegiline.

It is believed that safinamide may have additional benefits over MAO-B inhibition, and that's the hope behind safinamide. It is used along with levodopa to reduce off time and off periods during the day. It is available in two doses, 50 and 100 milligrams.

Dr. Rajesh Pahwa 00:25:01
There are certain medications that cannot be used with safinamide, such as opioid drugs like tramadol, meperidine, muscle relaxants like cyclobenzaprine, amphetamine-like compounds, St. John's wort, the cough medication dextromethorphan, certain antidepressants, etcetera. Those are important points to remember. In a person, when they came in the study, had roughly an off time of six hours, and this was reduced by about an hour a day. In spite of Xadago, patients did have off time, but in addition to levodopa, it can definitely reduce off time and is an option in some patients.

The other thing that was actually approved earlier this year is orally inhaled levodopa, also known as Inbrija. I talked to you about off periods and delayed onset. At times, when a person takes levodopa medication, it may take minutes to even hours before the medication actually starts working because the medication has to go from the mouth to the stomach, from the stomach into the small intestine where levodopa is absorbed, and from there into the brain.

At times, levodopa can stay in the stomach because gastric emptying may be slowed down. It may take forever for levodopa to make it through the jejunum and small intestine. Using inhalation levodopa, the levodopa is delivered into the lungs and from the lungs into the blood and then the brain. It is kind of a faster way to provide levodopa.

It can be used up to five times a day. If a person needs it up to five times for whatever reason, they had delayed on, they had a dose failure, they can take it up to five times a day. It is used with a special inhaler, and even though you have to use two capsules at a time, you can only put one capsule in the inhaler at a time, for a total of two capsules per dose. The off time begins to improve as soon as 10 minutes, and the benefit can last up to an hour with this. The main side effect seen with orally inhaled levodopa, that's Inbrija, is cough.

Let's move on to another part of levodopa therapy: levodopa-induced dyskinesias. Not only do we end up seeing off periods and off time with levodopa, but in some patients they can develop levodopa-induced dyskinesias, which are involuntary dance-like movements that occur in patients on levodopa. It's important to differentiate this with tremors because tremors usually occur when there is not enough medicine, and dyskinesias usually occur when there is too much medicine.

We can, of course, reduce the levodopa to cut down the dyskinesias, but then the end result is that the patient has more motor symptoms, more tremor, more slowness, and this often leads to undertreatment. This can bother the patient plus the caregiver, and it can be very disabling and can limit activities of daily living, cause pain, cause embarrassment and also cause falls due to balance difficulties.

Dr. Rajesh Pahwa 00:28:52
Amantadine ER capsules, or Gocovri, was the first medication in the United States that was approved for the treatment of dyskinesias. It not only helps the dyskinesias, but also reduces off time. In a way, it is our first approved medication not only for the dyskinesias, but for reducing both dyskinesias and off time. It acts on multiple chemicals in the brain, but we believe the action for off time and dyskinesias might be more related to glutamate.

It is very important to remember to take this medication before bedtime, not in the mornings, because what happens is it takes about four hours at night after the drug is taken where the drug doesn't get into the system, and then it gradually gets into the system through the night. When the patient wakes up in the morning, they have enough amantadine in their blood for it to work right away. It provides control of dyskinesias throughout the day, and its main side effects are hallucinations and lightheadedness.

It is important to differentiate this with immediate-release amantadine that has been available over 40 years. Immediate-release amantadine is used two to three times during the day. There is another form of amantadine ER capsules called Osmolex, which are given in the morning, and they are not approved for dyskinesias or off time. Do we have data showing that they reduce off time or dyskinesias? But we want to make sure that when a drug is prescribed, they know which form of amantadine they are getting, and it's only Gocovri amantadine ER that is approved and we know helps off time and dyskinesias.

One of the other major issues that Parkinson's patients have is excessive drooling. This drooling can cause wetness around the mouth, skin breakdown around the mouth, foul odor or embarrassment. The saliva itself sitting in the throat can cause choking for certain patients. Even though there are some medicines that have been used for drooling, often they don't help the patient as well and cause side effects. Using botulinum toxin injections, which requires about two injections on the face on each side, and these injections are required every three to four months, was the first approved medication for excessive drooling.

Dr. Rajesh Pahwa 00:31:02
With this, I'm going to shift gears and talk about some of the future therapies that are going to be available, hopefully in the next couple of years. The first one is sublingual apomorphine. Apomorphine injections have been approved and available not only in the United States, but in multiple other countries in Europe and other parts of the world to help with off episodes.

Apomorphine as a drug cannot be given orally through the mouth and swallowed because it cannot make it through the blood and be available for benefit. We have to provide apomorphine through other ways. Currently, what we do is give it as an injection under the skin, but a lot of patients don't like to take injections. They don't feel comfortable with injections. Whatever the reason may be, this therapy has not gotten to its full potential because apomorphine can be as beneficial as levodopa.

Right now, studies have just been completed for sublingual apomorphine strip. It's a little thin strip that a person places under the tongue, and taking that, the symptoms improve in about 15 minutes and the benefit lasts for about 90 minutes. This is used exclusively for off periods during the day, and we believe the person may be able to use it up to five times during the day. The main side effects are nausea, sleepiness and dizziness.

Another thing that will be next in line for approval, we believe, is another form of botulinum toxin injections called Myobloc. Currently, Myobloc is widely used for drooling, which is considered off-label. It is available for treatment of dystonia injections. The thing with Myobloc is it has more flexible dosing, and of course, like with any injection of botulinum toxin in the mouth, it's given actually outside under the earlobe as well as right under the chin. It helps with the drooling, but too much of the medication can also cause dry mouth and swallowing difficulty.

The next drug that this week itself FDA accepted for review is istradefylline. Istradefylline is a drug again for off time. This is approved and available in Japan, and it kind of acts similar to caffeine by blocking a new receptor, because that's not a receptor that has been targeted so far in Parkinson's disease, known as the adenosine A2A receptor. We believe that it's going to help with off time, but may also possibly reduce dyskinesias over the long term. We are hoping istradefylline will be approved in the next six months.

I talked a little bit about apomorphine sublingual. I talked about apomorphine injections that I use. But in Europe, the apomorphine pump has been widely available and used. What happens is, here, you stick a needle and it provides apomorphine under the skin with a pump. Because it is given throughout the day, and in some patients day and night, it reduces the off time during the day. In some patients, it also reduces the dyskinesias because we are able to reduce the dose of levodopa.

Dr. Rajesh Pahwa 00:34:50
Of course, patients with dementia are not candidates for this therapy because it may cause more confusion, and we also have concerns about hallucinations. But in Europe, they assess patients on how bad the hallucinations are, how bad the dementia is, and in some patients, even with those conditions, they do get this therapy. Right now, in clinical trials, we did not include these patients, but once it's available in practice, it may be offered for other patients too. Of course, this pump doesn't require any surgical therapy. All it requires is a needle where we can provide this therapy.

Carbidopa-levodopa pump delivery is right now by having a surgical therapy where a tube is placed in the stomach. This surgery takes between 15 to 30 minutes, but it still requires a surgeon or an interventional radiologist to put this tube in. Again, patients don't like a tube going into the stomach, so other forms are being looked at, providing carbidopa-levodopa subcutaneously, under the skin, via pump, rather than having to do surgery and providing levodopa that way.

There are two different companies working on providing carbidopa-levodopa continuously under the skin through a pump. Again, the idea behind it is that it reduces the off time. It could be used up to 24 hours a day. Again, we believe this therapy would or should be available, hopefully, within the next couple of years.

Dr. Rajesh Pahwa 00:36:27
There have been immediate-release carbidopa-levodopa. There are at least two extended-release carbidopa-levodopa preparations in the market. But in spite of that, our patients still have off time, and that's why we have been struggling to use other medications to reduce off time. Two companies are now working on a better extended-release carbidopa-levodopa. One is what we call the accordion pill carbidopa-levodopa. What it is is a thin film, so to speak, which is folded as an accordion and put in the capsule. This is believed to provide carbidopa-levodopa, maybe taken only three times a day, providing continuous benefit. This study just completed their phase three study. We don't have the results about it, but if the results are positive, maybe in the next year, year and a half, this would be in the market.

The other one, which is just starting phase three studies, is IPX203, and the early studies have shown that it increases on time. Again, we are looking at maybe a little over two years before this drug hits the market.

Another one that is a little closer for approval, that is already available in Europe, is opicapone. Opicapone is what we call a COMT inhibitor, like entacapone, that is currently available in the United States. Opicapone will be used in patients with Parkinson's disease who are having off time. Compared to the current COMT inhibitors that are available, opicapone will only be used, or is being used, once a day. That would be the benefit. It doesn't matter for patients taking immediate-release carbidopa-levodopa, extended-release or whatever form of carbidopa-levodopa they're using, because opicapone is used only once a day. We believe that therapy would be beneficial and benefit patients who are still having off time.

This was overall to give you a view. I went through a number of medications. I went through a number of different medications that work on different parts of Parkinson's disease. I have to let you know that I provided you with too much information in the short time we have, but it also makes it exciting, not only because of all these new medicines we have had over the past two years, but also that we are going to have more new medicines not only over the next two years, but much more over the next five to 10 years. With that, I would like to thank you for listening in, and I will open it up to any questions or comments people may have. Thank you.

Dr. James Beck 00:39:09
Dr. Pahwa, that was fantastic. I really appreciate you taking the time to go over the lots of interesting medications that have come to market and look like they're on the horizon to help people with PD. Thank you for doing that.

Before we take questions, I just want to give a shout-out to a couple of our viewing parties we have. In Lenexa, Kansas, there are 60 people watching and listening to you. In Wichita, we have a first-time viewing party there with 30 folks. In Columbus, we have another viewing party with 30 attendees. That's out of the 2,500 individuals who've registered for your talk. Most of them clearly are people with Parkinson's disease, about half, but we have a lot of people who are care partners, about 600, and health professionals and nurses as well who take advantage of the material that you're presenting. Thank you very much for doing that. We've clearly got questions coming from all over the world, so it's not only the U.S., but 42 other countries who are listening in today. Hello to everyone.

Dr. Pahwa, I thought what you presented was really interesting because it seems like a lot of medications are being developed to really help with some of these basic symptoms here. A lot of them seem to be derivatives or maybe new ways of formulating levodopa. How do you respond to people who say, "Oh no, this is the medication we've had since the '70s"? What do you say to that, and what do you think is different about the levodopa formulations we have today compared to when it first came out?

Dr. Rajesh Pahwa 00:40:52
As I mentioned earlier, dopamine is one of the most important chemicals that is reduced in Parkinson's disease. Replacing dopamine, which we cannot replace directly, we have to use the prodrug levodopa that goes in the brain and becomes dopamine, would be the best way to treat it because we are replacing the chemical that is reduced in Parkinson's disease. We have known this for over 40 years, that levodopa works great. It is most efficacious. It helps the patients a lot. The best we can do today with what we have is only 10% makes it to the brain, where it is really required to be converted. So we are still losing 90% of it.

Levodopa by itself is a great drug. The challenges with the drug have been that, one, people develop what we call off time and dyskinesias with it. We believe that this off time and dyskinesias could be related to, one, the way we are delivering levodopa, that is, giving a whole bunch of medicine multiple times during the day rather than providing it what happens in the brain is more physiologically or more continuously.

The second challenge we face with levodopa is when a person takes it through the mouth, like I said, it sits in the stomach maybe for an hour or two hours before it makes it to the small intestine, where it is absorbed and gets into the blood. The absorption through the gut may interfere with the other amino acids that are there. Then it goes to the blood-brain barrier, where again there are other amino acids that can interact before it actually makes it to the brain. That's another long journey that occurs with levodopa.

If we could have, let's say, a once-a-day levodopa or a patch of levodopa that provides continuous benefit throughout the day, we may not need other drugs because we believe providing the drug continuously, we would be able to eliminate the off time as well as not have the dyskinesias. Even though this is a drug for over 40 years that we have been going over it, we still do not have the best way to provide this drug, and that's the challenge we have had and that's what we are trying to fix.

Having said that, levodopa is still what we are providing for the motor symptoms. The disease does get worse, and there are other non-motor symptoms also that come up that levodopa doesn't provide benefit for. So we do need additional therapies for. In addition, levodopa doesn't cure the disease. It doesn't slow the disease. Those are other challenges we have. But if we look at symptomatic therapy for motor symptoms, levodopa is still our best drug, but it is not the best way we are able to give the drug. That's why we keep working on providing this drug to the brain in a better and efficient manner.

Dr. James Beck 00:43:52
I totally agree with what you just said, Dr. Pahwa. I mean, I get the question asked, and I tell people that this is a car of the '70s. We're still driving cars, but the improvements and the bells and whistles they've done for delivery mechanisms have, I think, helped people a lot.

Speaking of delivery mechanisms, the inhaler Inbrija is an interesting one. Do you have any idea if that's widely available now? A question is coming from someone in Florida.

Dr. Rajesh Pahwa 00:44:22
Yes. Inbrija, the levodopa inhaler, is available now. The thing with Inbrija is that it is through what we call a specialty pharmacy. It's not one of the drugs that you can take a prescription and go to your friendly neighborhood pharmacy and get this drug from there. The thing is, because it requires a special prescription that is sent to a special pharmacy, they have to get pre-approval for the drug, look at the benefits for different insurances that are out there, and then provide the drug.

While you are waiting for the benefits to go through, they will provide you with sampling for two weeks or whatever time is available from that. That's why it is widely available. It's just through a specialty pharmacy, and that's the important difference with it.

Dr. James Beck 00:45:12
Okay, that's good to know. With something like that, we mentioned that it had a specific use, but do you anticipate, within your cohort of people with Parkinson's you see, is this really a niche, or is it just another tool for you to use to help manage off symptoms and these freezing episodes? Is this something you think would be used on a more regular basis?

Dr. Rajesh Pahwa 00:45:38
The important point, like I went over earlier, was there are off time and there are off periods. The medications when we use for off time, like I said, usually the studies show a patient has six hours of off time a day, and we reduce it by an hour. But that hour, we don't know: is it going to happen in the afternoon? Is it going to happen in the morning? Is it going to happen in the evening? That reduction of an hour is, so to speak, throughout the day, and it might even be 10 minutes in the morning, 20 minutes in the afternoon, 30 minutes in the evening. Even though it helps the off time throughout the day, we still can't say when it is happening.

Now, medications that we call on demand are when the person needs that medicine. If that person has it that, you know, I just had lunch and my medicine is not working as well, they inhale the levodopa, it bypasses the gut, it goes to the brain, and it will provide benefit within 10 minutes, lasting for about an hour, hoping by then the oral medication would work. That gives them the benefit when they need it. There are people who may need it, like I said, up to five times a day, and there are people who may need it only once a week or once a day. So I wouldn't call it a niche medication. I would call it an on-demand medication because when we talk about Parkinson's patients, once they have off time, and as I said, about 40% will get it in five years, it really comes down to them if they want to have it more predictable. When they want it, they can get the drug. That's what it provides.

The other way I look at on-demand therapy such as Inbrija is a patient, let's say, with migraine headaches. Patients with migraine headaches, when they start having their headaches, they take a medication for that headache at that time. But in addition, they are also taking medications during the day so that the headaches don't occur as frequently. That is what Inbrija does, is give them that additional benefit that they can use it when they want to have an improvement in an off period.

Dr. James Beck 00:47:48
Perfect. Just thinking, a lot of questions are coming in about levodopa and Sinemet. One of them, again, talks about basic advantages and disadvantages of starting levodopa. This is from a care partner in North Carolina. Do you still face a battle sometimes trying to convince your patients that it's time to start levodopa? Is that something that still occurs, or is that something that you just hear about every now and then?

Dr. Rajesh Pahwa 00:48:22
Unfortunately, there are a lot of negative things about levodopa, mainly because of concerns of dyskinesias. The thing with off time and dyskinesias is there's a lot of wrong belief out there that if we delay the therapy, then we can also delay the off time and dyskinesias. In other words, if a patient has Parkinson's in the year 2015 and they delayed levodopa to 2020, then they wouldn't have the off time until 2025. That's actually a very wrong perception out there.

One of the risks of off time and dyskinesias is disease severity. By that I mean that if someone was to start the levodopa in 2015, they may get off time or dyskinesias in 2020. But if you wait until 2020, there has been a five-year progression of the disease, so the risk factors for having off time and dyskinesias are much shorter. In other words, you'll get it within a year or even six months. So delaying the therapy doesn't benefit them.

The second thing we do know is, the longer we delay levodopa therapy, the person is actually suffering from the motor symptoms and having increasing disability. If you were to look at a five-year time period in people who start levodopa earlier as compared to people who start levodopa later, at a five-year endpoint, people who started levodopa earlier have much less disability than people who started levodopa later on.

Again, the question comes down to why do we hesitate in starting levodopa? I think the concerns are more related to the off time and dyskinesias rather than anything else. We do have better treatment options for off time and dyskinesias, and these options are getting better and better. We still use, so to speak, an old thinking that we should hold it; otherwise, patients will have off time or dyskinesias. But we are increasingly getting better at managing these off time and dyskinesias.

The other thing is, even with off time and dyskinesias, patients can function much better than a person who's not having these medicines. For me, there should not really be a reason to delay therapy unless someone takes it and just cannot tolerate it, which would be a completely different reason for not using the therapy. But I disagree with people who want to hold it until they reach a point that they are very disabled.

Dr. James Beck 00:51:06
Yeah, it's like reaching a point of no return while we're doing this stuff in advance. Another question related to this is, when we talk about levodopa or just the medications in general that you presented, what do you think about it for a person at different stages? I've been getting several questions coming in from all over, asking for the medications you presented today, are they going to be useful for someone who's young onset, for instance, versus someone who's much later in their disease? What can you say about these treatments available? Are they specific to whether you're young onset or you're developing Parkinson's in your 60s, or do you have this in mind when you're also thinking about cases where you are more advanced disease?

Dr. Rajesh Pahwa 00:52:01
Sure. The thing is, first of all, these medications are approved for the indication, in other words, the symptom that is present. So yes, young patients have more off time earlier and dyskinesia earlier, so some of their therapy, they may need it earlier rather than later. But at the same time, whether it's a young person or an older person, they still have off time, they still have dyskinesias, they still have off periods. So that doesn't limit them.

The other thing, let's say for psychosis, you know, psychosis usually occurs as the disease advances. But again, it's not young versus older. Even though the older patients are a little higher risk to have psychosis, even younger patients can get psychosis. The levodopa pump, for example, now that is a little bit more advanced. It's more for people who have tried the oral medications and are still having off time or dyskinesias. That's when you would use the pump for them. But again, we are not talking that advanced that they are wheelchair bound, although you could use it in a person who is wheelchair bound. That would be the only therapy you would look at for a more advanced standpoint. Again, drooling could occur very early or could occur very late, so that's something that can happen.

These medicines are more for the specific indication rather than in a young patient versus old patient or a young-onset disease versus an older-onset disease.

Dr. James Beck 00:53:33
So you're really just out there evaluating the person in front of you and doing your best to treat the symptoms as they're presented. It sounds like, versus thinking about whether they're young onset or not. Is that a fair...

Dr. Rajesh Pahwa 00:53:47
That's right.

Dr. James Beck 00:53:48
Yeah, okay, great, perfect. Dr. Pahwa, you presented some medication for blood pressure that's come in. What about people who are already on medication for low blood pressure? Is there a concern that some of the medications people may be taking already are contributing to blood pressure? Would you mind just talking a little bit more about that?

Dr. Rajesh Pahwa 00:54:13
Right. Orthostatic hypotension, like I said, is when the blood pressure drops when a person stands up. One of the challenges in general that occurs with blood pressure is most of the time when a patient goes to a physician, whether it's their primary care or their cardiologist, the blood pressure is only taken in the seated position. Usually when they're seated, the blood pressure is good. Often, they may be on high blood pressure medicines, for example, and because their blood pressure is good seated, they are sent home with the medicine. But as soon as they stand up and walk out of the office, they already start feeling lightheaded and dizziness.

Whenever a person has a drop in blood pressure on standing, the first thing we recommend is backing up on their blood pressure medicines if they're taking it. This is a very important point because even if a person had been on high blood pressure medicines since they were in their 50s and now they're in their 60s, they may not need as much blood pressure medicine because Parkinson's itself can lower their blood pressure. Plus, all the Parkinson's medicines on top of it can lower the blood pressure.

Again, when a person starts feeling dizzy or lightheaded due to orthostatic hypotension, the first thing we do is reduce if there are blood pressure medicines on board. The second thing we often do is start by drinking plenty of fluids. Often, Parkinson's patients don't drink enough fluids. So we start with excessive fluids, making sure they're taking adequate salt in their diet, maybe using TED hose stockings to raise the blood pressure. We don't directly go to the medication. In spite of that, if patients still have blood pressure issues, then we start adding medicines that are available: midodrine or fludrocortisone.

Dr. Rajesh Pahwa 00:56:05
But the challenge is, in spite of those medicines, in spite of what we would say non-medication treatments, patients can still have orthostatic hypotension, and that's when we add additional medicines such as droxidopa or Northera. But even then, patients are not completely helped with some of these medicines, and we still find it an unmet need because there are patients out there with Parkinson's who, in spite of either trying the medicines that they had side effects for or in spite of taking other medicines to raise their blood pressure, continue to have low blood pressure. So some people may be taking multiple medications for low blood pressure.

Dr. James Beck 00:56:45
It sounds like it can be a difficult thing to manage, a lot to go through in order to help people, but it sounds like there's also maybe a medication at the end of that road, if nothing works, that may be helpful as well with Northera.

Dr. Rajesh Pahwa 00:56:59
And if someone is already on medications for it, not Northera maybe midodrine, and their blood pressure is under control and they don't have dizziness or lightheadedness, it does not mean that they need to switch their medication. It would be more that if they cannot tolerate it or continue to have these symptoms.

Dr. James Beck 00:57:17
It's a good point to make. For those who are listening, I just want to refer you to your screen. We've got a survey up right now to review and provide feedback to Dr. Pahwa on his presentation.

Previously, there was another slide asking you to help choose our topics for upcoming Expert Briefings. This is an opportunity for you, the listener, to help us decide what we should be presenting in our 11th Expert Briefing series. A link to that survey also came in the email for today's presentation.

Dr. Pahwa, I see that there are a couple different types of botulinum toxin targeting drooling, and it can be helpful, I understand, for some dystonia and stuff. Is botulinum toxin not just the same? I mean, are these actually different drugs, or is there something unique about these different forms that make them special for different uses?

Dr. Rajesh Pahwa 00:58:19
There are two main botulinum toxins available, or classes, I should say. There is A and B. We have not done any studies comparing head-to-head A versus B for drooling to say one is better than the other. The reason why some people may use B is B, when it was used in practice, was seen to have some side effects, such as dry mouth. From that area, it was brought down as maybe that might work with drooling. But broadly, both, there is an A and B that has been tested for drooling in Parkinson's. Both have been shown to be beneficial. So it really comes down to an individual. If they have tried A and A didn't work, it might be worth trying B, or vice versa for it.

Again, I wouldn't have someone do A plus B or something like that. But I wouldn't say at this stage, if someone asks me, is there a clear-cut benefit of A versus B, I don't have any head-to-head data to suggest that. All I can say is both have been used and both have been shown to be beneficial.

Dr. James Beck 00:59:30
Understood. Absolutely. A couple more questions, if I may, before we have to wrap up. You presented a background about pimavanserin for hallucinations. As you can imagine, we have a broad audience, and there's someone who's listening who has a parent with Parkinson's disease-like symptoms in Washington State, and they're asking whether pimavanserin can be used for Lewy body dementia.

Dr. Rajesh Pahwa 00:59:56
Right now, pimavanserin is not approved for Lewy body dementia. Again, even with Lewy body dementia, it has to be Lewy body dementia psychosis, not just for the dementia part. It has to be for the psychosis. The drug has not been approved for Lewy body dementia psychosis because it has not been studied for it. Right now, studies are ongoing for that indication. If you are close to a center that's doing such a study, you may be able to enroll him or her in that study, but right now it's not approved for that indication.

Dr. James Beck 01:00:31
And where would someone go to find that information about studies that might be open?

Dr. Rajesh Pahwa 01:00:36
One of the easiest ways I recommend is going to clinicaltrials.gov. If you go to clinicaltrials.gov, you can put in the disease, let's say Parkinson's disease, and then you can put in where you are. You can put in your ZIP code or you can put in the city or the state, and it'll show you all the trials related to Parkinson's disease in your neighborhood.

Dr. James Beck 01:01:00
Fantastic. One final question maybe to give you a chance to give us a longer answer. A lot of the symptoms you've addressed with some new medications help some non-motor symptoms and help some of the other motor aspects of Parkinson's disease. But there are some other troubling non-motor symptoms that people are experiencing, some regarding pain, fatigue, apathy. Do you see anything on the horizon that's farther along than maybe within the timeframe you specified that might be coming to help people with some of these issues?

Dr. Rajesh Pahwa 01:01:42
Sure. For non-motor symptoms as far as Parkinson's is concerned, we have just started paying more attention to them because we have realized that, so to speak, we have underappreciated a lot of these non-motor symptoms. Having said that, yes, in the future, there are going to be specific medications for some of these specific indications. For example, like you said, constipation in Parkinson's. Apparently there are some ongoing studies that look very positive, and if not in the next two years, maybe in the next three to four years, that might be something that might be approved.

The other thing is there are no specific studies we still have that are looking for, let's say, fatigue or apathy. But we do believe that's a major unmet need that we have. Some of the drugs that we believe might help with, say, fatigue or apathy, we are studying for some other reasons. But we are also paying attention to look at it, if the fatigue and apathy improve, and then paying more attention to those. It's not due to ignoring it anymore. It is more just finding the right medication that we believe would help with specifically those symptoms.

The other thing for fatigue especially is that it's pretty broad-ended. People can have fatigue from Parkinson's, from the medicine they're taking, from other issues like heart issues. Again, just trying in general to look at medicine for fatigue might be more challenging than, let's say, for apathy, where again, apathy might be easier to find a medicine to help.

Dr. James Beck 01:03:26
All right. With that, I think we will have to conclude our Expert Briefing. Dr. Rajesh Pahwa, director of the Parkinson's Foundation Center of Excellence at University of Kansas, thank you very much for your time today.

Dr. Rajesh Pahwa 01:03:40
Thank you very much.