Expert Briefing: Research Update: Working to Halt PD

Crista Ellis 00:00:00
Hello everyone, and welcome to our Expert Briefing. I am Crista Ellis, Community Engagement Manager at the Parkinson's Foundation. Our Expert Briefing today will be focused on research being done to support and advance treatments for Parkinson's disease. There is still a lot we don't know about Parkinson's disease, and through research, efforts are being made to close the gaps in our knowledge and understanding. During today's Expert Briefing, we will learn about current research that is taking various approaches to develop a treatment that may significantly slow Parkinson's disease progression.

Before we begin the formal briefing, I will share a little bit about the Parkinson's Foundation. The Parkinson's Foundation is a nonprofit focused on bettering the lives of those living with Parkinson's through improving care and advancing research. Importantly, everything we do is done in close concert with our community to ensure that our actions are aligned with the needs and priorities of those living with and impacted by Parkinson's. Today's program is just one example of how we are meeting our goals.

It's officially Parkinson's Awareness Month. This year, we'll be sharing the ABCs of PD to spread the word about Parkinson's disease from A to Z. Follow along this month as we highlight one aspect of PD for each letter of the alphabet. Find resources or help spread the word about Parkinson's disease by visiting Parkinson.org/Awareness.

We want to thank this webinar's sponsors, UCB and Novartis, for supporting our mission. Thank you, UCB and Novartis.

The Parkinson's Foundation provides weekly education and wellness programs virtually through our PD Health at Home series, including Mindfulness Mondays, Wellness Wednesdays, Fitness Fridays, our Expert Briefings and our Spanish-language programming, Epi Salud en Casa. Find out more and register for our PD Health at Home programs at Parkinson.org/PDHealth.

Now we'd like to get to know who's joining us today. We're going to launch a poll, and if you're on Facebook, please respond by using the comments section. Tell us what best describes your connection to Parkinson's disease. Are you a person with PD, a spouse or partner? Does your parent have Parkinson's? Are you a healthcare professional? Perhaps you're joining us with a different perspective. Let us know.

Wow. Looks like we're having an overwhelming response from our community who are living with Parkinson's. I see you. Thank you so much for being here. Seventy-five percent of our community members are people with Parkinson's disease. Sixteen percent are joining as a spouse or partner, and the remaining have a parent with Parkinson's. Other healthcare professionals are here. Thank you all so much for being here today.

Please know, for your convenience, we are recording today's Expert Briefing, and the recording will be available online. We will also be emailing a link to the recording and other resources related to today's topic. So sit back and enjoy learning through conversation with our expert.

Crista Ellis 00:03:15
Now I'd like to introduce our expert presenter, Lorraine Kalia. She's an associate professor and clinician scientist in the Division of Neurology at the University of Toronto, and a senior scientist at the Krembil Research Institute of the University Health Network. She holds appointments with the University of Toronto's Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology. She's also a staff neurologist in the Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson's Disease at Toronto Western Hospital. Her clinical work and research program focuses on Parkinson's disease and related movement disorders.

With an eye always on the clinic, she heads a research team focused on understanding the key molecular mechanisms responsible for neurodegeneration in Parkinson's disease to identify therapeutic agents that can modulate these molecular targets. Dr. Kalia holds the Wolfond-Krembil Chair in Parkinson's Disease Research, and she is the co-editor-in-chief of the Journal of Parkinson's Disease. Dr. Kalia, welcome, and thank you for sharing your time and knowledge with us today.

Dr. Lorraine Kalia 00:04:22
Thanks so much for inviting me, and I'm so excited to be here today. I'm going to start sharing my slides.

Right. I am so excited to be here today, and I thank you so much for the invitation. As you already heard, I first put up here disclosures, some of which are related to what I'm going to speak to today, which are related to treatments that are in development for Parkinson's disease.

As you already heard, it is April, and April is Parkinson's Awareness Month. Tomorrow is actually World Parkinson's Day. Such an important part of awareness is education. It's important that we educate others about Parkinson's disease. It's important that we educate each other about Parkinson's disease.

I hope today that over the next 40 minutes or so, I'm going to be able to share with you some things that maybe you didn't know about Parkinson's disease and make you think about things. Most importantly, I hope that I'll be able to share with you the optimism that I have regarding where we're moving forward with understanding the disease and making progress with respect to novel treatments.

The learning objectives for this session that the Parkinson's Foundation really wanted us to discuss today are laid out here. I'm going to discuss advancements in disease-modifying approaches for Parkinson's disease, and these are going to include pharmacological and non-pharmacological types of ways. This is not going to be exhaustive. There's so much going on and so much complexity to the research that's going on that I'm really going to give you a bird's-eye view of aspects that I'm particularly excited about and probably aspects that you've heard about from others or reading on the internet, to maybe give you a little bit more understanding of what's happening in this area.

The bulk of the conversation will be about advancements, but I think it's really important for us to actually take a moment, which I will at the end, to discuss challenges because, although there's a lot of optimism in the field and there's a lot of progress being made, obviously these things aren't going to happen overnight, and there are a number of challenges that we will face and will continue to face as we advance toward disease-modifying therapies.

The first thing that I want to lay out here, and I'm sure that this is familiar to almost everyone in the audience, primarily because the audience members are primarily those living with Parkinson's disease, is that Parkinson's disease is not a static condition. It's a progressive disease that changes over time. This is a very somewhat simplistic diagram that tries to capture a couple of aspects of this progressive nature of the disease. I'm just going to point out a couple of things because I'm going to come back to these aspects throughout the talk.

Dr. Lorraine Kalia 00:07:26
What's shown here across this x-axis of this graph is time. So time is moving from left to right, and moving from the bottom of the graph to the top of the graph is the degree of disability that can be associated with Parkinson's disease. What each of these triangles are trying to depict is how there are different aspects of the disease that develop over the course of the disease, as well as the way that they can impact each other and be additive to the experience that people have with Parkinson's disease.

This triangle here represents non-motor features of the condition, such as sleep disruption, cognitive difficulties and mood difficulties. On top of that are the classic motor features that basically define the condition. Then on top of that are complications that come with some of the medications that we have. What I have at the top of the graph here are really symptoms, things that are experienced by people who have the condition.

What I want to also point out is that what's happening underneath is the process of the disease, primarily what we call neurodegeneration, which is the loss of brain cells over time. We're all losing brain cells over time. This happens in adulthood, but in Parkinson's disease, this happens at a faster rate. This is really what underpins the symptoms that people experience.

While currently we have a lot of different therapies and medications that we can prescribe to treat symptoms, we really are at the very beginning stages of being able to have any impact on the actual process of the disease, which is the loss of these neurons, and ways to actually slow the progression or stop these cells from dying.

With that, before I launch into this term I used at the beginning, disease-modifying therapies, which is what we're going to be talking about, I want to make sure that we're all on the same page as to what that actually means. There are a variety of different strategies we can take to tackle Parkinson's disease progression. Here I just want you to imagine this arrow as the progression of Parkinson's disease over time, a simplified version of what I showed you in the previous graph.

What we have right now, as I mentioned, are symptomatic therapies. I put a Band-Aid over top of this because we have therapies that can kind of mask what's happening underneath by treating the symptoms, so making tremor less, making mobility easier, making mood better, but really underneath, the disease is still progressing.

In the best-case scenario, our ideal would be to actually prevent the disease entirely, so be able to, even before it starts, nip it in the bud. Nobody ever has to develop Parkinson's disease. This is really the gold standard. This is what we will be, and continue to, aspire toward.

Dr. Lorraine Kalia 00:10:33
I'd say the second-best scenario is having a cure, meaning that you can start developing the disease, but then we have a treatment that can reverse that and bring you right back to where you were, where you didn't have a disease. Of course, that's a huge ideal for us to try and reach as well.

But where we're at right now, and probably what's going to happen before we are able to accomplish these two really huge goals, is to be able to have therapies that we call disease-modifying. What we mean by that is that it doesn't stop the disease. It doesn't prevent the disease, but it can slow the disease. I've put a little arrow here to suggest that the progress is slower or less severe.

I would hope that these kinds of therapies would have a meaningful benefit for people because instead of the progress that one experiences normally with the condition, we'd be able to maybe at least reduce it substantially so that what symptoms were like in the first couple of years of the disease would be similar to what they are a couple of years in and further and further.

That's what we're going to talk about today because, although we are all working on these aspects of tackling Parkinson's disease, I think we're probably going to see the biggest progress in disease-modifying therapy in the upcoming years. I want to give you an update as to where that's progressing.

With respect to disease-modifying therapies, I often like to show this slide, which is a non-Parkinson's disease slide, because currently in Parkinson's disease, we don't really have any disease-modifying therapies. Sometimes people argue that this is because brain disease is very complicated, which it is. But I often like to show this slide because this is actually a slide of disease-modifying therapies that exist for a different brain disease, multiple sclerosis.

In fact, this is an outdated slide because there are even more of these therapies now available, but as you can see, there's a huge number of therapies that exist in multiple sclerosis that have been able to be used for patients and slow and change the course of their disease. I think this is something for us to aspire to and really shows us that brain diseases are amenable to disease-modifying therapies.

This here is a Parkinson's disease slide, and it doesn't show actual disease-modifying therapies that exist. But I like to show this slide as well just to give a snapshot as to how active this area of research is. Let me just orient you to this slide, and I really want to give credit to Kevin McFarthing, who's a person with Parkinson's disease who is involved in generating a summary of the different kinds of drugs that are in trial and publishes them in the Journal of Parkinson's Disease.

Dr. Lorraine Kalia 00:13:09
Together with colleagues, he's put together this graph that is very helpful for us to get an idea of where we are in terms of research and is really useful for researchers to just see the different types of therapies that are being pursued. Just to orient you to this, this large circle is all different therapies that in 2023 Kevin had found to be in clinical trials. These are phase one trials, so very, very early trials, all the way to phase three trials, which are the more advanced trials where, if successful, the medications often go to market.

The top half of this circle represents drugs that are potential disease-modifying therapies, so DMTs, whereas the bottom half are just symptomatic therapies. You can see in Parkinson's disease research there's a lot of activity going on, and there's a huge amount of activity going into disease-modifying therapy. I will not be going through all of the different drugs that are being tested in clinical trials for disease-modifying therapies, but I really thought it was important for us to be able to see this bird's-eye view snapshot as to how much is actually going on.

I also point you to this website here, which is actually Kevin McFarthing's real-time updated list of different therapies that are in clinical trial, which he calls the Hope List.

Let's dive in. As I said, we're going to discuss advancements in disease-modifying approaches, and I wanted to use those first couple of minutes to make sure that we all are on the same page as to what I'm talking about when I'm talking about disease-modifying therapies. This is going to be a bit of a whirlwind tour.

This is a short list of the different kinds of disease-modifying therapies that are actively being investigated. Like I said, I'm not going to be able to go through all of the different disease-modifying therapies that are in active research, especially things that are early on. But these areas, I think, are ones where we may start to see a lot of progress in the near term. Also, I wanted to highlight some of these because some of these terms are probably things that you've heard about from colleagues, family members or read on the internet. I wanted to maybe be able to provide a little bit more depth and understanding of each of these aspects.

We're going to start from the beginning and go through this list.

Dr. Lorraine Kalia 00:15:35
The majority of things that I want to talk about for the disease-modifying therapy discussion is around another term that I just want to clarify before we move on, which is cell protection. I have a cartoon here that is showing you, and you're going to see a couple of cartoons that I also want to orient you to. This here is a brain cell. We call it a neuron, hence the term neurodegeneration. Sometimes I'll call it a brain cell.

What happens in the context of neurodegeneration, this is a healthy, normal brain cell. At the very extreme end, the brain cell dies and is dysfunctional. But it is a bit of a process, and along the way, in the middle, there's probably some dysfunction to the cell that happens that may or may not be reversible, and that eventually leads to the loss of this cell. Cell protection is an approach where we try and prevent this from happening. A cell becomes more dysfunctional, we try and revive it. A cell is on its way to dying, we try and prevent that.

For most of what I'm going to talk about next in terms of disease-modifying therapies, except for the final topic at the end, these are really ways where we're trying to protect cells.

The first I'm going to talk about is exercise. As I mentioned at the beginning, we're going to talk about pharmacological therapies, which are drugs, but also some non-pharmacological therapies, so non-drug ways of hopefully protecting brain cells. Exercise, as I'm sure many of you are aware of and probably have conversations with your neurologist about, can be an important feature for Parkinson's disease, for people with Parkinson's disease and for people without Parkinson's disease.

When talking about exercise, I often like to start with just reminding us all, myself included, as well as others in the audience who don't have Parkinson's disease, that there are benefits to exercise that we all continually have to remember. It's well known that exercise is good for our heart and our lungs. It gives us good cardiorespiratory fitness. It's good for our muscles and our bones. It's good for our cognition.

If I were giving a talk to an Alzheimer's group, or a colleague of mine were giving a talk to an Alzheimer's group, exercise would probably be a part of that conversation as well because it's good for thinking and memory. It's good for mood. We know that it reduces risk of fractures and falls. Outside of the realm of Parkinson's disease, we know that exercise can reduce the risk of some very common conditions like hypertension and diabetes, as well as other conditions that can shorten our lifespan, such as heart disease and cancer.

Already, we have a number of reasons why we should all be exercising. But what I want to just touch on briefly, and one of the reasons why your Parkinson's disease neurologist probably spends some time talking about exercise with you, is that there is some suggestion that exercise itself may provide some cell protection.

Like I mentioned, we're just going to have a bit of a whirlwind tour, and I'm not going to be able to go into depth with all of the data and all of the details of the studies around each of the topics that I'm going to talk about. But I do want to provide some high-level summaries of each of these areas.

Dr. Lorraine Kalia 00:19:29
For exercise, I chose to show this recently published summarized slide of three of the larger and more convincing studies that have suggested to us that exercise may have some potential for cell protection. Let me just explain to you what's being shown here.

The three different studies are: one tested high-intensity activity on a treadmill, one tested high-intensity activity on a stationary bike, and one tested brisk walking together with a more complicated exercise program focused on balance, a little bit more multidisciplinary program.

In each of these studies, there was a group that didn't do the activity. This group didn't do the treadmill, whereas another group did the exercise, so this group did do the treadmill. What the bars here are showing you are changes in a score of mobility, a score that we use in clinical trials, but we also use it in the clinic. Some of you may be familiar when neurologists get you to move your hands and tap your feet and walk down the hallway, and maybe they pull you to see if you're unbalanced. We give that a score, which gives us an indication of how affected people are from a motor point of view.

A higher score means more motor abnormalities, and a lower score means fewer motor abnormalities. If you look here, in this group that didn't do treadmill exercising, at the beginning of the study, this was the number that they started with. But as time went on, because Parkinson's disease progresses, six months later, their numbers went up, which is typical for what happens in Parkinson's disease. Whereas in the group that exercised, it stayed level. Similar was found with the stationary bike.

Even in this scenario here, people who did the exercise, whereas they started at this relatively high number of their motor score, six months after they did exercise, they were actually able to reverse that and drop the degree of motor dysfunction. This gives us some potential suggestion that exercise may be able to actually slow the progression of the disease or, in this scenario, actually improve the symptoms of Parkinson's disease over time.

We still have a lot of work to understand why that may be the case, and we actually need more clinical trials to really hone down, look longer term, and understand what exercise can actually do. But at the level of the biology and how it is that exercise may be able to protect brain cells from dying, one possibility that is suggested from laboratory studies is that exercise might, for one, reduce inflammation, which in general we know can be bad, especially in the brain.

Importantly, it can also increase growth factors. Growth factors are naturally occurring factors that our brain makes that can actually support brain cells. One can imagine if you have an activity that can actually make the brain make more growth factor, and if growth factors support and help to prevent brain cells from dying, this can be a very viable and feasible way that exercise can help. But we obviously need more research to really understand if that is indeed the case, if that's indeed the case that happens in humans.

Then really, how can we make the most of that in terms of maximizing out the growth factors that lead to all of the good things that happen in the brain, such as protecting brain cells, allowing in some cases for new brain cells to be made in certain parts of the brain and also to allow more blood to flow to areas of the brain that need it. This is an exciting area that does require more research, but definitely tells us that there is much to be gained by exercise.

Dr. Lorraine Kalia 00:23:27
I'm going to move on now to another topic on the list, which is alpha-synuclein. This may be a topic that's familiar to many of you. This may be a topic that you've heard very little about. I'm going to give you a little bit of a 101 around alpha-synuclein.

First, it's a protein that exists in our body, is very highly present in all of our brains, and exists in all of our brains. It has a day job. It probably helps brain cells to communicate with each other. But for reasons that aren't entirely clear, in Parkinson's disease, that protein alpha-synuclein can go a bit rogue.

What I'm showing here in this cartoon, again, you can see this brain cell that you're going to see a lot of in this cartoon, but right here, this little cylinder represents normal alpha-synuclein in all of our brains. Sometimes, and some research suggests that it can form little structures together that also probably do something physiological, meaning it has a normal function in the brain.

But once it crosses this dotted line here, when alpha-synuclein starts to actually stick, one alpha-synuclein starts to stick to another alpha-synuclein, starts to stick to another alpha-synuclein, it forms what we call oligomers, protofibrils or even fibrils. The reason that they're called that is because they look like fibers. When they actually then clump up even more, they form something that pathologists many years ago called Lewy bodies or Lewy neurites.

We think that this clumping up of alpha-synuclein in some of these forms is detrimental to the brain cell. It stops doing its day job, but it also probably starts to disrupt things in the cell.

I don't intend for you to read through all of this or even to understand all the science behind this, but what I want to highlight is that again, I have a brain cell here, and within it is a variety of different things that are required for the brain cell to be healthy. Mitochondria make energy. This proteasomal system, the autophagy lysosomal system, they're important for getting rid of bad things in the cell because you need garbage disposal systems in the cell to get rid of the garbage.

What alpha-synuclein does when it starts to aggregate and clump in these different types of forms is we think that it affects many of these systems so that the cell can no longer produce much energy. It's no longer able to dispose of its garbage, and this is what leads to its demise. As a consequence, the idea is that if we can actually target alpha-synuclein, especially bad alpha-synuclein, then we'd be able to actually protect the cell from dying.

Dr. Lorraine Kalia 00:26:13
Again, another depiction of a brain cell, just to show you ways that are being explored as to how we could target alpha-synuclein. This is one brain cell here. This is another brain cell that lives next to it and communicates with it. Again, this is some basic biology that I'm not going to go through in its entirety, but just to say that in a brain cell, to be able to make this protein alpha-synuclein, there is a process that's involved. What I showed you in the previous cartoon is that alpha-synuclein can exist by itself, but then when it starts to clump up, it starts to be problematic.

What you didn't see in the other cartoon, but I want to point out here, is there is research to suggest that bad alpha-synuclein in one brain cell may actually move to a neighboring brain cell and basically infect that brain cell with bad alpha-synuclein. This cell that was initially affected by alpha-synuclein and perhaps on its way to neurodegeneration has the capability of actually spreading bad alpha-synuclein to its neighbor and then making this actual brain cell sick. What researchers are doing are trying to approach this in a variety of different ways.

One way is to potentially degrade bad alpha-synuclein. Another way is to actually reduce its production in the cell. So instead of making the normal amount of alpha-synuclein, we try and make brain cells make less alpha-synuclein. If you have less alpha-synuclein, then you're going to have less alpha-synuclein that's going to aggregate and clump up, and then you're going to have less alpha-synuclein that's going to infect a neighboring cell.

There are also strategies to try and actually just reduce these aggregates of alpha-synuclein or prevent them from forming. Lastly, strategies to try and actually just prevent. Maybe this cell is affected by bad alpha-synuclein, but if you can actually prevent alpha-synuclein from moving from one cell to another, then you can potentially protect the neighboring cells and prevent the spread of bad alpha-synuclein from one to another.

These are a couple of different strategies, and just what I've highlighted here, just so that you know, and some of them are very numeric names, but these are actually drugs that are being investigated in clinical trials. This is not even an exhaustive list, but these are a couple of different drugs that are being tested in clinical trials that are testing each of these approaches.

I think the expectation is that we'll get results from some of these clinical trials in the next year or so, and depending on what that shows, it may progress on to the next phases of the clinical trial. This is a very active area of investigation, and I hope that for those who haven't heard of alpha-synuclein before, you now are familiar with it because I think we'll be hearing more and more about it in the upcoming years.

Dr. Lorraine Kalia 00:29:06
Next on the list are two other different proteins called GBA, or glucocerebrosidase, and LRRK2. I mention these two because, again, this is an area that's being very actively investigated. GBA and LRRK2 are interesting proteins and discoveries in that we think that they're involved in Parkinson's disease, and why we came up with this idea is basically based on genetics.

This isn't a talk about genetics, and I'm sure some of you may have questions about genetics, but again, I'll just give you a brief overview of what we know about genetics and Parkinson's disease. We know that approximately, again, this is just approximate, maybe one out of 10 people with Parkinson's disease has an abnormality in a gene that we can identify. One of these genes is called GBA1 and makes the protein GBA, and one is called LRRK2.

With the discovery that abnormalities in these genes can cause Parkinson's disease, this allowed us to understand how these proteins actually may cause neurodegeneration. As a result, they have allowed us to start to try and find ways to affect these different proteins to find benefit for cells. This is just a table of a couple of genes that have been identified to be associated with Parkinson's disease. Like I said, only one in 10 people with Parkinson's disease may have an abnormality in their gene, and the most common ones are GBA1 and LRRK2. But let me just tell you a little bit about what we know about GBA and LRRK2.

Here's an even simpler diagram. This circle represents a brain cell. This circle within the brain cell represents what we call a lysosome, which is one of the disposal systems of the cell. The lysosome disposes of a lot of things. One thing we think it gets rid of is actually alpha-synuclein.

Interestingly, GBA, or glucocerebrosidase, lives within the lysosome. In scenarios where people have a mutation in their GBA gene, this enzyme, which breaks down things and actually disposes of things, is actually underactive. That's why I have the red arrow here.

Understandably, if you could actually enhance its activity, activate it, one could potentially reverse its dysfunction and make it work again or work better. Similar to the previous diagram I showed you, these are a couple of examples of different drugs or strategies that are in clinical trial right now that are intended, in Parkinson's disease and related diseases, to actually enhance GBA function. These again are areas that are actively being investigated, and we'll be excited to see what the results are.

Dr. Lorraine Kalia 00:32:18
On the flip side, this other protein called LRRK2 is an interesting protein that probably has a number of different functions, but it probably also works on the pathway that includes the lysosome. We call this the autophagy-lysosomal pathway, which again is a disposal system of the cell. What is known about LRRK2, when it's mutated and causes Parkinson's disease, is that this protein, actually the mutation, causes it to be overactive. So it does too much. Too much in this scenario is a bad thing, so it doesn't help the degradation, but it actually causes this to be a dysfunctional system. Based on that, logically, if one could dampen down the activity of LRRK2 and make it not so overactive, one could presumably find a way to actually reduce its negative effects on neurodegeneration.

Dr. Lorraine Kalia 00:33:19
Again, shown here are two examples of drugs that are in clinical trial that are intended to do exactly that: they are trying to either reduce alpha-synuclein activity by trying to reduce its amount, or trying to make its activity decrease by using a chemical. Similarly, like I said, these are in clinical trial, and we'll start to get answers as to whether or not this is a useful approach in Parkinson's disease.

Now we're going to move on to a really big area of discussion, but I wanted just to highlight maybe some of the most recent highlights, most recent discoveries, and I'm going to talk about this topic called repurposed drugs.

Again, just to get us all on the same page, I'm going to define for you what a repurposed drug is, or similarly what the process of drug repurposing is. The intention with drug repurposing is for us to actually, at the end of it, have a repurposed drug. What this approach is, is looking at drugs that are already approved for human use for treatment of other diseases and seeing if we can actually find, in the context of Parkinson's disease, drugs that are out there that we're using for other indications that may, unbeknownst to us, have some cell protection or disease-modifying capabilities in Parkinson's disease.

I'm going to talk about that in one moment, but just before that, to solidify this notion of drug repurposing, I'm going to use this one example that may be a drug that's familiar to many of you, which is amantadine.

Amantadine, in and of itself, is not a disease-modifying therapy for Parkinson's disease. It's not something that is protective for cells, but it's a symptomatic therapy that is commonly used. I think it's a nice example of how drugs can be repurposed even within Parkinson's disease. Many of you may or may not know that amantadine itself, currently the most common use that we have for amantadine in Parkinson's disease, is actually to treat dyskinesia. People who have developed dyskinesia due to having Parkinson's disease and being on levodopa, in many scenarios, amantadine can reduce those dyskinesias. The majority of the time when I'm prescribing amantadine, that's what it's for.

But in fact, it was not developed for that at all. It was actually developed as a treatment for flu. For influenza back in the 1960s, it was used if people had an influenza infection or to actually prevent influenza infections.

It's a wonderful story of how important it is to listen to each other and to learn from each other. Back in the 1960s, a woman with Parkinson's disease who was on amantadine due to the flu told her doctor, 'You know what? I think that my Parkinson's symptoms are better since I've been on this medication amantadine.' Her doctor listened, which was an important thing, and that led to studies to say, 'Is what this person actually observed true?' Studies actually showed that amantadine can be useful for Parkinson's disease symptoms. In the 1970s, before levodopa became our most potent and available medication, and even just before it really took off in terms of being available for treatment of Parkinson's disease, if you were diagnosed with Parkinson's disease, amantadine probably would have been the medication you were started on to help your tremor and your stiffness and your slowness.

Dr. Lorraine Kalia 00:37:15
Eventually, we found other medications. Levodopa is a more effective medication, and some people will still be started on amantadine for their Parkinson's disease symptoms. But in the same vein, what was also discovered was that people who were on amantadine when they had Parkinson's disease, and levodopa started to be used more frequently, it became obvious that amantadine was helping dyskinesias. This drug that was developed for influenza got repurposed as a Parkinson's disease drug for motor symptoms, and then eventually got repurposed as a medication to treat levodopa-induced dyskinesias. I like to use that example because it hits close to home and because it's a really nice example of double repurposing of a drug.

But getting back to disease-modifying therapies, it's interesting, and I like to point this out, that if we go back to this figure of Kevin McFarthing's that has all of the different disease-modifying therapies that are in clinical trial, I did a count out of all of them of how many of these drugs are already approved drugs for other indications. Over a third of them that are being tested as potential disease-modifying therapy drugs and are in clinical trial are actually repurposed drugs.

Oops, not quite sure what happened there. Give me one moment. Okay.

As I was saying, over one-third of drugs being tested as potential disease-modifying therapies are actually repurposed drugs. The advantage of repurposed drugs is that they've already been tested in humans, so these are not drugs that have only been tested in the laboratory and now we're moving them into safety studies within humans. We know that they are safe in humans because they've been used for other indications. This allows for us to potentially get quicker results because we don't have to go through all the safety stages of testing drugs, and many drugs will actually fail at the safety stages. The expectation is that we may be able to get to success in terms of having a drug for treatment faster.

One drug that you've already seen in the list that I showed you, that is actually a repurposed drug, comes off of this list of medications that might activate GBA. Ambroxol is being tested in clinical trial, and in its earlier clinical trial showed some promise. It's actually a cough suppressant. It needs to be used at higher doses for the potential to reduce disease progression, but it is a drug that has already been used for a different indication. This has allowed it to go quite quickly from a phase two and on to a potential phase three trial.

One that's been in the news just very recently, and I bring this up here because I can tell you that in this past week I've had patients in my clinic asking about it, and I imagine maybe many of you have the same kinds of questions, is this drug category of medications called GLP-1 receptor activators. I use the trade name because you'll be most familiar with this, but the most familiar drug in this category is Ozempic. Of course, Ozempic is not the only drug that exists in this category, but these are drugs that were primarily developed for diabetes.

This here is just another cartoon that's complicated because cell biology is complicated, but I just wanted to point out that what GLP-1 receptor activators do is bind to a receptor that sits on the outside of a cell. As a consequence of that, many things happen within the cell, which is just shown here in this rectangle. With all of these effects that happen in the cell, there's a lot of suggestion that they have a lot of positive outcomes. They can improve memory, they can improve cell survival, they can improve the effects of the mitochondria, they can reduce inflammation, and they can reduce alpha-synuclein.

Dr. Lorraine Kalia 00:41:40
You can see there's a number of reasons why this class of drugs may be beneficial in Parkinson's disease, and understandably, these drugs are being very actively investigated. Exenatide is probably the first one to ever be tested. There are various versions of exenatide that have been in clinical trials or are in clinical trials. There are two related medications that have been in clinical trials or are in clinical trials, with the last one, lixisenatide, actually, the results of the phase two trial just being published in the New England Journal of Medicine last week and causing a lot of excitement.

This trial showed that in Parkinson's disease, I told you at the beginning in exercise, in those graphs that I showed you around exercise, how we score abnormalities in motor function, that it was shown that treatment with lixisenatide can again stabilize the change in those numbers over the course of approximately one year. More work definitely has to be done here, and this is a phase two trial. The question becomes, and the hope is, that we're going to move on to a phase three trial, but it's the beginnings, I think, of a bit of a signal that this class of drug may be beneficial in Parkinson's disease.

We talked about cell protection for the last minute or so in this realm. I want to talk about a topic that many people often ask about, which is cell replacement. We talked about cell protection, trying to prevent these cells from degenerating. The alternative, in terms of trying to have an effect on the neurodegenerative process, is actually to replace the cells. Forget about the sick and dying cells. Why not bring in brand-new spanking cells to try and replace the ones that are dying? This approach is cell replacement or cell transplant. One of the areas that is really active for this is in stem cell replacements.

I'm not going to go through the long history, but for many, many years, there have been studies to investigate whether or not we could actually replace cells in the Parkinson's disease brain. Very early studies used tissue from human fetal tissue to dissect out cells that made dopamine and do a surgery to put them, prepare the cells, and do a surgery to actually put them into the brain of people with Parkinson's. It was shown that they, I mean, there's a lot of nuance to this and a lot of complications, but there were long-lasting clinical benefits.

However, the real feasibility of it was limited because it was too hard to actually have enough tissue to study and, in the long term, really to provide. But within the past decade or so, technology around stem cells has really blossomed, and the technological advances have been remarkable. One can actually take blood cells or skin cells from somebody, or embryonic stem cells, and make them into dopamine cells. Now this has really invigorated the field to use this new formulation and new generation of stem cells in stem cell transplants. This is again just a bird's-eye view of how enthusiastic people are around it. What's shown here in blue are countries around the world where there are clinical trials that are investigating different types of stem cells in Parkinson's disease, all being delivered into the brain.

For the last minute or so, I do want to touch on, you know, we just had a whirlwind tour through the advances. I'm excited about the advances that are being made. I'm hoping that you're finding some of excitement in this as well. But I also just want to temper things a little bit by talking about some of the challenges, some of the things that we don't have answers to, and some of the things that we're really going to need to focus on over the upcoming years to decades. Again, this is not comprehensive. These are a couple of things for us to keep in mind.

Dr. Lorraine Kalia 00:46:03
The four different things that I'll just touch on are questions: Do we have the right dose? Are we targeting the right targets? Are we treating at the right time? And most importantly, are we treating the right people?

From a right-dose point of view, I just use the example, this really, I mean, with drugs, we can test a whole bunch of different drug doses, and there's always the question of whether or not we have the right dose. But I think especially in the exercise realm, what is the right dose is really an area of active investigation, and I think we're going to start seeing many, many studies to try and get this right. This I've taken actually from the Parkinson's Foundation, a wonderful sheet to give you an outline as to what kind of exercise you should be doing, and there are some doses listed here, but we don't know what the best dose is. This is the best that we could guess.

I think that there's going to be studies to be able to really hone in on what kind of amount of exercise we should be doing, how frequently it should be, to really glean all the benefits, the most benefit that we could from exercise. I think that's one area that there's still some challenges in. There become challenges in being able to study this in a clinical trial because exercise in a clinical trial is actually a more challenging type of intervention to study than giving a drug. This is one thing that we have to keep in mind in terms of the challenge.

The other challenge is I showed you lots and lots of different cell biology today, and it's backed by a huge amount of laboratory research, but we still need to learn more. We think we have things right in terms of what we want our drugs to target. I told you about alpha-synuclein, about the underactivity of GBA, the overactivity of LRRK2, about this GLP-1 receptor that seems to have great effects if it can get activated. We think we have the right targets, but we may not. We may be missing targets. With all the evidence that we have from the laboratory, we may be missing things there. I think we have to keep an open mind, that we go with the best evidence that we have and the best knowledge that we have today, but we also have to keep an open mind that we're not always right. If the evidence starts pointing us in a different direction, we need to explore that, and that's where we need more research.

The other important challenge is really the right time. I show this graph again that I showed at the very beginning. From left to right here is the time of disease. Right here is where you'd be diagnosed with Parkinson's disease, but we think that the disease process happens earlier. The question becomes, when we have that great drug that's going to slow the progression of the disease, when is going to be the best time to give it? Do we need to give it super early before the disease even really takes hold and we can actually see the symptoms? Is it okay if we just start the treatment as soon as somebody gets diagnosed with Parkinson's disease? Will there be benefit for people who are many, many years into their Parkinson's disease with these treatments? Again, these are unanswered questions, and these are going to be challenges. In our clinical trials, we tend to just study people who are right here, at the very beginning of their disease. We're going to have to understand if that's going to be applicable to people at other stages of the disease.

Dr. Lorraine Kalia 00:49:36
Lastly, and most importantly, we have to know, with all of these treatments that we're developing, who is the right person for them. This is a wonderful diagram by colleagues Melissa Armstrong and Michael Okun, just to remind us that Parkinson's disease looks different. Not everyone with Parkinson's disease looks like the old-fashioned diagram that we often see from the 1800s, but people can look different. It's a global disease. It affects a range of ages, different genders, and as I'm sure many in the audience know, medication regimens that you're on now are probably different than the person who you meet at your support group or the other person you know, your neighbor who has Parkinson's disease.

I think the expectation is going to be the same with disease-modifying therapies, that not everybody is going to be a person who's going to need a medication to reduce alpha-synuclein. Not everybody's going to be a person who needs a medication to reduce LRRK2 activity. We're going to have to really understand who the right person is to get the right treatments and, in some cases, probably a number of these different treatments.

With that, I just want to close out, just to remind you, and hope that we've had a useful discussion around advances in disease-modifying approaches for Parkinson's disease. We talked about non-pharmacologic measures such as exercise, as well as surgical measures such as stem cell replacement, which is taking stem cells and surgically putting them into the brain. Then we talked about a lot of different pharmacological approaches. I showed you some of the drugs that are in clinical trial that are targeting alpha-synuclein, GBA1, LRRK2, and then the repurposing drug approach.

I want to lastly just remind everyone that this is not a linear road, that research is necessary. Sometimes we hit roadblocks. Sometimes we go down paths that are not fruitful. But I think the importance is that we're all in it together, and we're here to really try and make a difference. Like I said at the beginning, I'm optimistic that we're going to see more and more progress over the upcoming years.

With that, I just want to thank you so much for your attention. Again, I want to thank the Parkinson's Foundation for giving me the opportunity to talk during Parkinson's Awareness Month. Please teach others about Parkinson's disease. People who have not been touched by the disease, make sure they understand what it is, and we continue our job of teaching each other. Thanks very much.

Crista Ellis 00:52:30
Thank you, Dr. Kalia. I really appreciate your knowledge and time today. I'd like to introduce the Foundation's senior director of research, Svetlana Cvejic, who will be moderating our question-and-answer session.

Svetlana Cvejic 00:52:43
Thank you, Doctor. Thank you, Lorraine, for an excellent and incredibly organized and detailed presentation. I'd like to acknowledge that many of the questions that we received, you already answered through your presentation.

Before we go with additional questions from our listeners, I was wondering, one thing that struck me the most is that there's such a wide range of research that is being done in so many different areas. I know that in 2023, over 1,800 publications have been published on PD. Why is such a wide range of research necessary? I really want if you can please emphasize that.

Dr. Lorraine Kalia 00:53:32
Yeah, for sure. Parkinson's disease is complicated. It is a really complex condition. I started at the beginning about how brain diseases are complicated, and maybe it's my own bias, but I think Parkinson's disease is one of the most complicated neurological diseases. Early in the discovery of the disease, it was thought that it was a movement disorder, a simple movement disorder, and so if we could improve mobility and tremor, it would be done. But we know that it's a multifaceted disease. It has more than just movement abnormalities. It has all of the other non-motor aspects.

I think what I was also trying to touch on at the end, which tells us about the complexity of the disease, is each person is so very different. If we were looking at just a homogeneous, single, very simple disease, I think we wouldn't need as many different avenues of investigation. But because there are so many facets to it, that's one reason why there's a lot of research. Today, I just really highlighted the approach toward trying to understand disease modification. That really needs to be coupled with biomarker research, which is a whole other area of investigation, and that's partly also where we're seeing a huge amount of research and a huge contributor to probably those number of publications you saw.

I think we really also have to understand that these are advances that we're hoping are going to happen, but they're probably not going to happen tomorrow. They're going to be years away. There's a ton of research for us to really make Parkinson's disease the best that it can be today. A good amount of research is also trying to find ways to live well and things that we could do today and now as we wait and continue to work toward those better treatments.

Svetlana Cvejic 00:55:24
With all the complexity that you just described and individual differences, do you think it will eventually be only a single treatment or a single cure, or should we expect that we will have to have a combination of different things?

Dr. Lorraine Kalia 00:55:45
Yeah, I definitely think it's not going to be a single treatment. As many people with Parkinson's know right now, even our symptomatic therapies, right? Not everybody's on one single drug at one dose. One can see that the disease-modifying therapies are going to also be the same. I think probably the initial therapies that we find aren't going to be applicable to everybody. I think that makes sense when you have a disease that has different aspects. One wonders if there's going to be treatments that we might want to give just early in the disease, and maybe as the disease changes, stop those ones. Maybe there's going to be other ones that we're going to want to give at a different stage of the disease.

We always talk about a silver bullet, and I think that it's fair to say that we're not going to have one silver bullet, that it's going to be a number of different therapies, which is why I think it's important that we have our eggs in multiple baskets. If we had our eggs in only a single basket, I think we're going to miss out on probably being able to have therapies for different people. That's I think another reason why there's so much of a need for so much research. We want to be able to spread things out to really maximize our potential for finding therapies for everyone.

Svetlana Cvejic 00:57:09
Our viewer Kevin is asking for further clarification on disease-modifying therapies, and he's wondering, why are we finding that they are working to help multiple sclerosis and not Parkinson's?

Dr. Lorraine Kalia 00:57:22
Yeah. That's a great question, and I can tell you that I think it's such a great question that I worked with a colleague to bring together Parkinson's disease specialists and multiple sclerosis specialists in Toronto a year ago for us to just really learn from them. I think there's a variety of different things that came out of that discussion. One, and again, my talk wasn't about biomarkers, and I'm sure that you guys are going to have talks or have already had talks about biomarkers, but one is that multiple sclerosis has the advantage of being able to do a brain scan and say, 'Yeah, this really looks like this person has multiple sclerosis.'

We're only at the beginnings of maybe having what we call a biomarker to be able to identify people with Parkinson's disease. That's been an important thing. Some of my colleagues will argue that multiple sclerosis, being an inflammatory or an immune disease, is an easier disease to treat. It's not as complicated as the neurodegenerative disease. But I think in multiple sclerosis there is also neurodegeneration, and the multiple sclerosis colleagues will argue that the neurodegenerative piece is actually a challenge for them to treat as well.

They are different diseases, but I think there are things to learn from the multiple sclerosis field that can help us in Parkinson's disease.

Svetlana Cvejic 00:58:46
Well, I think we are running out of time, so we definitely have not been able to answer all of the questions our viewers had, but our Helpline and resources on our website will certainly address that. I want to thank you, Dr. Kalia. It was a pleasure having you and learning from you about the latest research updates and how scientists are working to find new ways to slow down and hopefully end Parkinson's disease. I will turn it to my colleague Crista.

Crista Ellis 00:59:26
Thank you, Svetlana. Dr. Kalia, before we close, are there any final remarks that you would like to make before we do our outro remarks and thanking our community for being here today?

Dr. Lorraine Kalia 00:59:35
I just want to say thank you to all of you. Thanks for coming out today. The whole Parkinson's community is my inspiration, so thank you.

Crista Ellis 00:59:45
Thank you to everyone for joining us in this time today through Zoom land. We did have a significant response during our Q&A session, and unfortunately, we weren't able to get to them all. Please, if your question was not answered, call our Helpline at 1-800-4PD-INFO. You can learn more about Parkinson's and research and how you can get involved at Parkinson.org/Research.

This concludes today's Expert Briefing. Next month, our Expert Briefing series will dive into the sleep challenges of Parkinson's. You can learn more about our future topics and register at the webpage listed here on the screen.

Again, thank you to our webinar sponsors, UCB and Novartis, for supporting the mission of the Parkinson's Foundation.

Please don't hesitate to reach out to us. We have a comprehensive website and many more resources that address everything related to PD at Parkinson.org, and you can call our Helpline. That number again is 1-800-4PD-INFO, or email us at Helpline@Parkinson.org. But before you go, please know that our programming is fueled by your input and your feedback. As we close the Zoom screen today's webinar, a survey will prompt up. Please, we appreciate if you take the time to let us know what you hope to learn in future sessions. Take care, and we'll see you soon on the next Expert Briefing.