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Medscape
a day ago
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- Medscape
Lessons for Parkinson's From MS, and Vice Versa
This transcript has been edited for clarity. Indu Subramanian, MD: Hi, everyone. Welcome to Medscape. I'm so excited to have my friend and colleague, Prof Lorraine Kalia, join us today to talk about a very cool topic: what we can learn from multiple sclerosis (MS) studies and therapies, and how we can maybe translate that to some of the problems that we've been having in the Parkinson's world. Prof Lorraine Kalia is a clinical scientist at the Krembil Institute. She's also an amazing neurologist at the University of Toronto, which is my alma mater. Welcome, Lorraine. Lorraine V. Kalia, MD, PhD: Hi, Indu. Thanks for having me. Meeting of MS and PD Minds Subramanian: My name is Dr Indu Subramanian. I'm based at UCLA. Maybe we can get right into this. You had this very cool meeting in November 2022, and you had experts in the MS world as well as the Parkinson's disease world. Tell us a little bit about what inspired that meeting in the first place. Kalia: It's a bit of a personal story, actually. I might date myself a little bit, but I was a medical student during the time of the natalizumab development. At that time, I thought I was going to be an MS neurologist. Even back then, they already had a couple of disease-modifying therapies for MS and I thought, You know what, I think MS is good. I think they're in good shape. As a scientist with an understanding of the biology behind disease, it was clear to me that there still was a large amount of work needing to be done in Parkinson's disease because that's obviously how we translate things into having disease-modifying therapies. That was part of the reason — not the only reason — why I shifted into the movement disorder space. Fast-forward many years later: I often give talks around the lack of disease-modifying therapies for Parkinson's disease by introducing MS. Sometimes when you ask why we don't have a disease-modifying therapy for Parkinson's, people throw up their hands and say, "Well, you know, neurologic diseases are complicated." I'll often use the MS example to demonstrate that actually there is much that can be done in the neurologic space and there's been a lot of successes in MS. I was once giving this talk, and as a consequence of this talk, had a conversation with Parkinson Canada who thought, wow, that's an interesting idea around MS being so successful and PD lagging behind. We came up with the idea of having a meeting in Toronto. We obviously have very strong Parkinson's researchers in Toronto, but also a very strong MS team at the Saint Michael's Hospital. I collaborated with a colleague — actually, we were residents together — to bring world experts to Toronto to sit around a table, which is what we did, and talk about where we are in MS and where we are in Parkinson's disease. We were looking for common ground but also looking to see what is different and how we might think about things differently that might have led to the different paths that we've experienced in our fields. Lessons From MS Subramanian: What do you think some take-home messages for the clinician would be from that discussion? I think it was a very cool paper. Kalia: Maybe the take-home messages is it's complicated, which is not as simple as I had hoped. I hoped that we'd come back with clear messages of what we really need to do with Parkinson's. I think we found common ground for one thing. I think it's fair to say that MS has done remarkably well at treating inflammation. All of their drugs are based on that, and they will recognize that they have challenges in terms of treating the neurodegenerative part of their condition. Now that we increasingly recognize that inflammation is a part of Parkinson's disease and there's increased work around the immune basis to the disease, I think we are going to be able to take advantage of what MS has done and learn to hopefully make advances that way. For anybody who's learned about MS , its successes have hanged heavily on its neuroimaging biomarkers of MRI. Of course, biomarkers are needed for the development of Parkinson's disease , and perhaps more work into the neuroimaging piece as well as the biospecimen biomarkers is key to starting to be able to have different kinds of outcome measures. Not the clinical outcome measures that we're using right now in basically all of our clinical trials, but to have early biomarker outcome measures that will help to inform us for our later clinical trials. The other commonality between the two is this concept of earlier disease. We have our prodromal Parkinson's disease and MS has their radiologically isolated syndrome. Up until now, logically, it has made sense to us that we should treat earlier in Parkinson's disease, and that will likely give us better successes. In the MS space, there's actually proof of that. They have clinical trials showing the benefit of treating people in the radiologically isolated syndrome state. While in Parkinson's disease, it has been theoretical and seems to make sense to all of us, we don't have any hard proof to say that treating earlier is better, whereas in MS they have already demonstrated that. I think this then provides us with actual proof in the pudding that that approach really does have implications for disease progression. PD Ahead of MS for Lifestyle Subramanian: Absolutely. I think both diseases in many ways have revolutionized since back in the day when we were in training. The MS models have really come a long way, with many patients doing very well for a long time. I think we have to really take a look at where our feelings are and how we can do better. I'm excited just about the concept of identifying people early and then getting people who may be even at risk for developing Parkinson's into lifestyle measures and wellness choices. I think MS has done a great job of that as well. Can you speak a little bit about that from your own perspective? Kalia: I don't think it came out in the paper, but it came out in our discussions that as a field and as a patient population, there's probably been more embrace of lifestyle measures and physical activity in Parkinson's, which I think is kudos to us in Parkinson's disease. Maybe it's in part because in MS they have these drugs that came through one after another after another, and there's this heavy pharma management of MS that they haven't had to explore the lifestyle assets. There's a large amount that MS has to learn from Parkinson's disease, in terms of putting in place so many of the things that we discuss in Parkinson's, whether it be diet, sleep, stress or mindfulness — all of these things. I think that in Parkinson's, we're further ahead. Subramanian: Absolutely. I agree with you. I'm excited to learn from these other disease states that we train under in residency. We see these patients and we can open our minds to looking at different lenses, for sure. Thank you so much for spending the time and chatting about this. Kudos to you for having that meeting. It sounds like a great opportunity to bring great minds together. Kalia: Yes. Hopefully, we can do more of this in the future. Subramanian: Go Canada. Thank you for joining us, everyone.
Medscape
28-07-2025
- Health
- Medscape
What to Know About Infusion Therapies in Parkinson's Disease
This transcript has been edited for clarity. Indu Subramanian, MD: Hi, everyone. This is Dr Indu Subramanian, from UCLA. I'm excited to have you join us at Medscape today. I'm delighted to have my friend and close collaborator, Professor Ray Chaudhuri, join us from Europe. He's a professor of neurology at King's College London and King's College Dubai. He's a groundbreaking clinician who's really changed the field of movement disorders and Parkinson's. He's introduced us to many novel therapies over the years and set the stage for nonmotor Parkinson's disease. It's been a pleasure to learn from him over the years. I'm excited to have him teach us about the many options in the infusion therapy world. Welcome, Ray. K. Ray Chaudhuri, MD, DSc: Hi, Indu. Thank you for having me. Infusion Therapies Subramanian: One of the things that we wanted to talk about today was infusion therapies, including subcutaneous foslevodopa/foscarbidopa. There's also been, as you know, a longstanding history that you've had exposure to of apomorphine pumps, Duopa pumps, and the patch. Chaudhuri: Infusion therapies have been a mainstay, shall we say, underpinned advanced therapies for Parkinson's for a long time. In fact, originally it was developed in the 1970s, but commercially, I think the first sighting of infusion therapy in Parkinson's, certainly in Europe and in the UK, came in the 90s with apomorphine: apomorphine infusion and injection. I understand apomorphine injection is available, and apomorphine infusion has recently been made available in the US. The subcutaneous field developed into infusion of levodopa, and there are two forms. The first one, commercially available now in many countries in the world, is the foslevodopa/foscarbidopa preparation, which is an approved drug of levodopa and carbidopa. When infused with this very small Vyafuser pump, it immediately gets converted to levodopa and carbidopa in the skin and is then absorbed and provides continuous nerve stimulations over 24 hours. Another form, is the NeuroDerm product, which is levodopa infusion with carbidopa, not foslevodopa/foscarbidopa. That's infused with a different pump system with two syringes, but that's not yet commercially available. The one that's commercially available is foslevodopa/foscarbidopa, and there is an accumulated experience of over 67,000 patients in the world now with the use of this product. It is novel in the sense that it's the first time ever levodopa has been made available to be given in a subcutaneous infusion format. It was previously available as intrajejunal levodopa with levodopa/carbidopa, Duodopa or Duopa. Now, it's available subcutaneously, and the great advantage is that it's much less invasive. It doesn't require a surgery, which you needed with the Duodopa. Third, it is probably the only treatment option at the moment that really effectively gives you a 24-h treatment option, so it gives you treatment option during the day and through the night. The other additional advantage of this very sophisticated pump is that it allows you to do the setting high and low. For instance, you can set the dosing at a high level during the day, depending on the patient's requirements, and then cut the dose down at night about 30%, which is your normal dopaminergic neurotransmission as it occurs during the sleep-wake cycle. It has great advantages also over the early morning OFF periods, which many other therapies do not really affect, because they're usually effective for only 14 hours. You don't get that cover all through the early morning periods when the patients are often OFF. They wake up with severe, dystonic pain, difficulty turning in bed or passing urine, urgency, and even depression or other nonmotor fluctuations that might occur. All of that seems to be helped by the use of foslevodopa/foscarbidopa. Infusion vs DBS Subramanian: Sleep is so important in our patients. I think we've really under-recognized that. You've been doing a large amount of work and even put a whole collection of articles together on sleep. It's just pretty amazing how little we have to offer patients in the sleep realm, and it can affect, presumably, cognition, daytime symptoms of motor and nonmotor issues, and quality of life both for the patient and their caregivers who are also not getting sleep. In the landscape currently of infusion therapy and deep brain stimulation (DBS), you have DBS available in the UK as well as other parts of Europe, along with these infusion therapies. You've had these infusion therapies for much longer than we've had in the United States, for example. Can you tell me a little bit about the decision algorithm if you have a patient in front of you, what type of patients do you send to DBS? Chaudhuri: Great question. Before I go into the DBS option, I think you mentioned a really important part, which is sleep. I think sleep is often under-recognized. It's part of this dashboard of Parkinson's, which we introduced, and we should be recommending at least 6-8 h of sleep per day because of the activation of the glymphatic system and potential effect on amyloid clearance. Any treatment option like foslevodopa/foscarbidopa, which is helping this early morning OFF period — and we've shown that in two long-term studies— actually helps with sleep, because it cuts down the fragmentation of sleep in early morning and, therefore, helps you have a good quality of sleep, which will then indirectly affect the issues around cognition and so on. That sort of study will need to be done in the future, but it's an enormously new development and a great advantage of this 24-h therapy. In relation to an algorithm, in addition to DBS and apomorphine, now we have foslevodopa/foscarbidopa, levodopa infusion into the jejunum with Duopa, but also LECIG gel, which is levodopa/carbidopa/entacapone infusion. That's also available in some countries in Europe. In terms of when, ideally, you would choose DBS, my algorithm would suggest the age parameter. Most centers would operate up to 70 years of age. After 70, it becomes a little bit tricky. It depends on the local surgeon's preference and the patient's condition. If you look at people below age 70, if they have clear dyskinesia as the dominant problem or pharmacoresistant tremors, in that situation, I would go with DBS first. That seems to be very effective and a quick fix. Now, the data would also suggest patients must be given an option of subcutaneous therapy. Some patients might want to try the subcutaneous option first, which also works for dyskinesia, and specifically works very well for early morning OFF and sleep. They may say: What if I try that first, and if that doesn't work, I can still have DBS? Over the age of 70, at this moment in time, foslevodopa/foscarbidopa infusion would probably be the first choice, given that apomorphine has dopamine agonist side effect issues, such as somnolence, postural hypertension, and the potential for impulse control disorder. I would think most people would go with the levodopa-based option, but there are, of course, situations where you might want to use apomorphine. If somebody's very profoundly depressed or is very anhedonic or apathetic, you might want to try apomorphine first because of it's antagonist effect, which helps with apathy and depression. Below the age of 70, if a patient has dominant problems with bad dyskinesia, troublesome dyskinesia, diphasic dyskinesia, ballistic dyskinesia, along with pharmacoresistant tremor, probably DBS is the first option. Such a patient should also be given the option of subcutaneous therapy, and they might actually choose subcutaneous levodopa or foslevodopa/foscarbidopa first because it also has antidyskinetic action after an initial period when the dyskinesias might be there. After a few weeks, there's a delayed effect, the dyskinesias tend to go down. If that doesn't work or if the patient develops skin issues or neuropsychiatric problems, DBS can still be an option. Over the age of 70, however, we would probably go for a subcutaneous option first. The majority of patients will probably choose levodopa, but apomorphine remains a potential option if the patient's severely depressed or apathetic. You want to give apomorphine and agonist properties a little try first. Skin Side Effects Subramanian: You mentioned skin issues. Could you describe those a little bit? Chaudhuri: With any subcutaneous anti-parkinsonian treatment, skin problems become an issue with chronic therapy. It was an issue with apomorphine. Apomorphine causes nodules and you have to be aware of that and take action so that you don't get these nodules or reduce the frequency. With foslevodopa/foscarbidopa, the situation is a little bit different because of the pH issue and possibly because there's some skin intolerance with levodopa. We had recently suggested that there are asymptomatic skin problems and symptomatic skin problems. Among the symptomatic skin problems, you can get redness or a little bit of inflammation around the area. Very rarely, that might develop into cellulitis. That's what we must prevent. You can take preventive actions. For instance, you can use a low pH soap water wash. You can change the needles daily. You can keep the skin area very clean. At the first sign of any inflammation or infection, use a combination of antibiotics and perhaps some steroids as well. These are potential steps you can take, but that's something to remember. I think with good management, it should not be a major issue. The other side effect problem that you might get is neuropsychiatric problems. We have noticed this, and it might be related to the overnight infusion. What one might have to do is cut down the dose of the overnight infusion — and in very selected, rare cases — even stop the nighttime infusions for a few days and then restart it. That tends to sort the problem out. In some cases, you might need to use a drug such as quetiapine. When you're selecting a patient, therefore, it's important to screen for this or keep in mind the use of nighttime infusion and the prospect of any psychosis issues. Subramanian: That makes sense. Preventing hallucinations by not infusing as much medicine or no medicine overnight could be an option. This type of therapy gives you some flexibility there, which sounds great. I think this has been really edifying to me. I love learning from you. Thank you so much for joining us in your busy day there. We appreciate viewers out there on Medscape joining us as well.
Medscape
14-07-2025
- Health
- Medscape
Stem Cell Therapy for Parkinson's Disease Reality Check
This transcript has been edited for clarity. Indu Subramanian, MD: Hello, everyone. Welcome to Medscape. I'm so excited to have Prof Roger Barker here, who is a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge in England. I am Indu Subramanian. I work at UCLA, and I'm excited to speak about the very hot topic of stem cells, and specifically today, about stem cells and Parkinson's. We may end up talking about stem cells in general as a focus, so keep watching and you'll learn a lot. Prof Barker, I know that you are an amazing fount of knowledge in this space. Perhaps we can start with you describing a minute or two of your background and the history of stem cells. Fetal Dopamine Cells Roger A. Barker, MBBS, PhD: I started on cell-based therapies to repair disease of the brain many years ago — probably best to leave it at that rather than be too specific, otherwise it gives away my age. I'm essentially a neurologist here in Cambridge. I see patients half the week and the other half of the time I do research. My original work was with Steve Dunnett here in Cambridge, and we were looking at how we could better repair the brain in Parkinson's. Particularly, the premise is, as you know in Parkinson's, you critically lose this population of dopamine cells. You have half a million on each side of your midbrain. When you lose half of those, you get the first features. In theory, if you could transplant back a quarter of a million healthy dopamine cells of the type that are lost in Parkinson's, you should be able to put that bit of the brain back to normal. It's not a cure, but you should be able to repair that. This has been a topic people have looked at since the 1980s, and I came into it and did my PhD in the early 1990s to look at this. Those early studies showed that you could put dopamine cells into the brain. They weren't stem cells; they were fetal dopamine cells. In some cases they survived, and in some cases they had very marked clinical benefits to the patients. Best-case scenario, patients could go 20 years off medication with normal dopamine levels in their brain and looked normal, for all intents and purposes. It was a minority, and it was ethically a big problem because fetal tissue was being used. In different parts of the world, that receives different types of concerns. There was also a problem with logistics. We recently published a trial called TransEuro, which used human fetal dopamine cells to treat Parkinson's. We found that there were major problems with getting sufficient tissue. With the 21 transplants we did, we had another 86 that were canceled because we didn't have sufficient tissue. Regardless of the benefits from using fetal dopamine cells, logistically it's not possible. It's ethically very contentious. That work laid the foundation for the recent stem cell work because it showed that it could be done. When it worked well, it worked very well. It was just rather inconsistent. Pluripotent Stem Cells Subramanian: That brings us to the nonfetal type of stem cells. What are those exactly and why are we using them? Barker: The main problems with the fetal tissue were, as I say, with logistics and ethics. It was very difficult to get sufficient amounts of them because you needed tissue from at least three or four fetuses to transplant one side of the brain, so the numbers needed were quite high. Each person had their own individual product, so what we needed was a source of cells where we could manufacture large numbers of the dopamine cells that we needed, we could do it consistently, and ideally we could then freeze it and you could say we've got a standard package of therapy we could give any patient. This was the ambition, but there wasn't much scope for it really until 1998 when human embryonic stem cells were first made by Jamie Thomson. Obviously, in 2006-2007, Shinya Yamanaka and the team in Kyoto made induced pluripotent stem cells and human pluripotent stem cells. Now you have the capacity to make human lines of embryonic and induced pluripotent stem cells. The next trick was, could you turn those into the dopamine cells you needed for Parkinson's? That was really solved by the labs of Lorenz Studer in New York and Malin Parmar in Lund, who both came up with protocols in 2011-2012 to show that you could convert human stem cells into dopamine cells of a midbrain type. That started a whole process of work about taking these therapies to the clinic from that starting point. It was also shown at around the same time by the group in Japan, led by Jun Takahashi, that they could do it as well. They could make human induced pluripotent stem cells into dopamine cells. Just under 15 years ago, we now had all the substrates to make the dopamine cells, which we could then use in clinical trials. Obviously, a large amount of work needed to take place before we could get to the clinical trials, which have recently just published. Subramanian: Can you explain the pluripotent stem cells? How do you make them make dopamine? How does that work? Barker: It's an interesting question because obviously an embryonic stem cell is a stem cell you get from an embryo. We were all at some point an embryonic stem cell. Those cells can turn into any cell in your body. When you do an induced pluripotent stem cell, you get an adult cell, skin cell, or a blood cell, you reprogram it back to a stem cell state, and then you try and flip it into a dopamine cell. The trick is, can you work out what you need to give a stem cell to convince it to become a brain cell and then convince it to become a dopamine cell? Now, I'm not clever enough to do that, but there are various people who are. That, in part, relates to knowing what happens in normal development. One of the challenges that put the field back for a number of years was thinking that human development in terms of dopamine cells was the same as you'd see in a mouse. People could convert mouse stem cells into mouse dopamine cells quite easily, and that was established over 25 years ago. People thought it'd be the same with human, but it proved not to be the case. It was a different developmental program you had to follow. Once that was cracked, then people could add this cocktail of factors, convince your stem cells to become a neural stem cell, and then to become a dopamine stem cell. Then, the idea is when you put in a dopamine stem cell precursor, which is what we do, that will then mature into the dopamine cell that you want once it's put in the brain. Recent Nature Studies Subramanian: Tell us about the most recent trials, because they're very exciting to many people but I think there's still some caution to be had. Tell us what your thoughts are. Barker: It's been very interesting. Obviously, from those original discoveries back in 2011-2012, the next 10 years was spent trying to show that you could make human stem cells into dopamine precursors of the type needed to replace those lost, and it could be done at clinical grade. That involved an enormous amount of work to show you could manufacture these things to a standard necessary to put into a human. You had to show that they were safe so when you transplanted them, they didn't form tumors or they didn't go and make the wrong type of cells. That was done by the team in Japan, it was done by the team in New York, and we've also done it in Europe. More recently, the two teams led by Viviane Tabar and Lorenz Studer in New York, who set up a company called BlueRock, published their data, and the group of Jun Takahashi and his team in Kyoto published theirs. Both of them published papers in Nature . The Japanese study took seven patients and they used two doses of cells, and the group in New York used 12 patients. They grafted some in New York, some in Toronto; five at one dose, seven at a higher dose. Those studies both showed, if you look at them in totality, that it was safe. Of the 19 patients that were grafted, there were no major problems within them. It wasn't that they weren't without side effects, but there was nothing serious that would give one concern. The patients could tolerate the procedure, they could tolerate the immunosuppression, which they had to make as a result of having this therapy. There were no abnormal signals on the scan that would worry you that they were forming tumors or that things were happening in the brain. It was feasible and it was safe. The question is, was it effective? That, I think, is a little more questionable in the sense that these are very early studies. One of the big challenges is knowing what dose of cells to give, because you can only guess how many you need to put in to make the number you want. Those are often made from assumptions you've made in the lab, so in rats or mice, which is difficult to then translate into the adult human brain. They had to guess how many cells to transplant, which is why there were two doses. If you look at the efficacy and you look at the survival of the cells, which is done using special imaging, using PET imaging, particularly with F-DOPA, which is picked up by dopamine cells, you find that the clinical response in the Japanese study was a bit variable. The response in the New York group, the BlueRock study, was that the higher dose seemed to have more of a clinical response than the lower dose. In the PET imaging, looking at dopamine survival, in the Japanese study, there were little hotspots. There was some evidence that the cells survived, but it was a bit hit-and-miss. In the New York BlueRock study, the signal changes were relatively small. Although there was a clinical response, the imaging was less impressive. The other way, then, to look at it is to ask how much medication did people take. Obviously, if the transplant's working very well, then it's replacing the dopamine and you need less medication. Actually, in both studies, there wasn't a huge reduction in the amount of medication that people took. My conclusion from those trials would be that it was safe, it was feasible, and it was encouraging, but we haven't quite solved the problem. We haven't quite solved the problem of how many cells to give. We certainly haven't restored patients back to normal. There are other things we need to do before we could say that this therapy is ready for a big trial or for primetime in the clinic. Do We Know Where in the Brain to Put Stem Cells? Subramanian: I appreciate that analysis because that's very helpful. I think people are always wanting to jump to conclusions that we're ready for real time, and I think it's still some time away. Just one or two other last thoughts. Where are we putting those cells in the current studies? Barker: It's a very good question. Obviously, at the bottom part of the brain is the substantia nigra at the top of the stem of the brain. They project up to a thing called the striatum, and the striatum has two parts called the caudate and putamen. In Parkinson's, the putamen takes the biggest hit. That's where you lose most of the dopamine and the cells die off in the nigra. The transplant itself is not put in the nigra because we're not convinced the fibers will grow back. We put the cells where the dopamine is lost and where the dopamine is lost the most, so we transplant them directly into the putamen, into the place where we think dopamine will have its maximum effect if these cells survive and innervate. Linked to that is, of course, we're not quite sure how to do that either because there is no device for injecting cells into the brain because no one's done it before. As I say, we don't quite know the dose. We don't quite know how many deposits to put in. The two groups who've published have used slightly different doses, slightly different cannulae to put the cells in the brain, and a slightly different number of tracks. Those may be critical factors. In our own trial, which is yet to finish, we've used slightly different doses, slightly different devices, and slightly different numbers of tracks. I think the other important message to get across is that these trials are not all the same. There are subtle differences between them. They're fundamentally tackling the same problem, but they're not exactly the same. Putting them all together and saying that, together, they show this, is a useful headline, but the detail is actually quite important. Subramanian: Absolutely. The devil is always in the details, isn't it? Thank you so much, Prof Barker. I so enjoyed this conversation. Thank you for joining us today. Barker: Thank you very much.
Medscape
30-06-2025
- Health
- Medscape
GLP-1s in Neurodegenerative Disease: Hope or Halt?
This transcript has been edited for clarity. Indu Subramanian, MD: Hi. Welcome, everyone, to Medscape. It's with great excitement that I present today a friend and colleague, Lorraine Kalia. Professor Kalia is a senior scientist at the Krembil Research Institute in Toronto, and she's also a neurologist at the University of Toronto. She's been prolific. We use her graphics many times in our slide decks. She's a great clinician and scientist, bringing you today some knowledge about clinical trials. We're excited to talk about a very hot topic, the GLP drugs. I am Dr Indu Subramanian. I'm based at UCLA. Welcome, Lorraine. Lorraine V. Kalia, MD, PhD: Hi, Indu. Thanks for having me. Why Try GLP-1 RAs in Neurodegenerative Disease? Subramanian: I was excited to read your commentary in The Lancet about the GLP-1 trials. Perhaps we could start with your thoughts and maybe a brief introduction about GLP-1 drugs and where they fit into neurodegenerative disease and Parkinson's, specifically. Kalia: I'm sure that the audience is aware of GLP-1 receptor agonists, as they've been such a hot topic with respect to treating diabetes and probably more so around treatment for obesity. They've been heavily investigated for increasing number of indications around those areas, including sleep apnea, osteoarthritis of the knees, cardiovascular disease, and in the field of neurogenerative disease, which is obviously near and dear to our hearts. They've been heavily investigated with the idea that there might be a component of insulin resistance that leads people to be at risk for neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, and that maybe repurposing these drugs for neurogenerative diseases would have some benefit. From the laboratory side, there have been tests of some of these GLP-1 receptor agonists in Parkinson's disease models that show that if you give them peripherally to animals, you can reduce the neurodegeneration of dopaminergic neurons. Importantly, there are also some epidemiologic studies that suggest if people have been treated with a GLP-1 receptor agonist, they're less likely to develop Parkinson's all of these different lines of evidence, there have been now a good number of clinical trials testing the hypothesis that treatment with a GLP-1 receptor agonist will slow the progression of Parkinson's disease. Subramanian: I think it's an exciting group to look at because we don't have to do many of the safety studies in general because we are basically repurposing a drug that's already out there. Maybe you could briefly summarize the studies and what they've shown to date. Exenatide Study Kalia: There have been a number of studies running up to this phase 3 trial of exenatide that was relatively recently published in The Lancet . Similar to the preclinical and the epidemiology work, there was a large amount of signal there that suggested some benefits. A phase 2 trial using exenatide in individuals with moderate Parkinson's disease on dopaminergic therapies showed that there was a slower progression or an increase in the number of points on their motor scores. A study using lixisenatide, which is another GLP-1 receptor agonist,also showed something similar. I, along with many others in the field, was really anticipating what the results of this phase 3 trial were going to show. It was a big study — approximately 200 participants and multicenter — which was different from the phase 2 trials, which tended to be single center. I think it was five or six UK sites. It was long for a Parkinson's disease trial at almost 2 years, solike a 96-week trial, which I think is important when we think about a slowly progressive disease. We can ask questions as to whether or not some of our earlier trials, which didn't capture any differences, was because we didn't wait long enough. This was, I'd say, a pretty good trial in terms of length. The primary outcome for this was the same primary outcome that they saw benefit with in the phase 2 trial,so learning from the phase 2 trial and hoping that that would translate to the phase 3 trial, which was basically motor scores in the off state because all of thepatients who were enrolled were on a dopaminergic therapy. Unlike the phase 2 trial, there was no difference between the placebo control group and the group that received could ask, was that the right measure? We always have discussions around whether or not our outcome measures are sensitive enough or was that the right one. All of the secondary outcome measures — so all of the other measures, including the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score, Montreal Cognitive Assessment (MoCA) score, quality of life scores, and how muchdopaminergic therapies had to be changed over the course of the trial — were absolutely identical between the two groups. There was no signal in any of the secondary or exploratory outcomes, so really negative across the board. Subramanian: I think the patients have been really hungry to see the results of this trial. I don't know about you, but I think everyone and their mother is on a GLP drug, it seems like. People have been trying to use some of these even off-label and acquire them and get themmade in compounding pharmacies. Patient Guidance Kalia: I think that's a great point that you bring up that I thought was useful for discussion also. If patients come to you and ask to be put on a GLP-1 receptor agonist, even though there's no indication for it, then my answer — especially now with a negative trial — would be that there's really no indication to do that, especially in the context of no benefit and potential for side effects. Subramanian: Let's talk about the side effects, because I think one of the things that I've been really interested in is weight loss in Parkinson's. We've been doing some work on women, especially Asian women like you and me, who may have lower body mass and end up getting dyskinetic and sometimes getting into the cycle of losing weight and getting very bone fractures, fall risk, and other issues can come up. Maybe we could talk a little bit about your sense of that. Kalia: Everyone's concern around the GLP-1 receptor agonists in a Parkinson's disease population where you don't want people losing weight, per se, was if that's going to be the side effect of these drugs, it's going to increase frailty. At least in this trial with exenatide, the extended-release version in the phase 3 trial, there wasn't as much weight loss as had been seen in prior studies. One could wonder if maybe that was then an indicator of insufficient dosing. That's just speculation. I guess, as expected, for anyone who's familiar with the side effects around GLP-1 receptor agonists, there were gastrointestinal (GI) side effects, so GI upset and diarrhea, and then nonspecific things. Overall, if we were to look at the silver lining, the trial demonstrated, as did the phase 2 trial, that exenatide can be well tolerated in a Parkinson's disease population. Whether that's the case for all GLP-1 receptor agonists is not known. Perhaps for some that are much more efficacious at weight loss, we will still probably need to be cautious as to that kind of side effect or that effect that people want in a non-Parkinson's disease population, and how that might have negative ramifications in a Parkinson's disease population. The 'Lessebo' Effect Subramanian: We do have to weigh the risks and the benefits, and I don't personally see an indication at the moment either. You brought up also, a point about lessebo. Maybe we could talk about lessebo. What is that? Kalia: I brought that up, again, entirely as speculation. It was related to the amount of weight loss seen in this trial that was not as much as anticipated. Obviously, participants in these clinical trials are very likely going to knowsomething, if not a lot, about GLP-1 receptor agonists. Knowing that they're in a placebo-controlled trial and knowing that they might be on placebo vs exenatide, if they weren't actually experiencing weight loss, they may have assumed,and so then the effects that come with a placebo effect are absent. That's entirely speculation on my part to try to explain why maybe the differences seen in this trial were not as obvious as they had been in the previous phase 2 trial. Subramanian: There's so much to consider and so much complexity. Thank you so much, Lorraine, for joining us today. It's been a pleasure to talk about this rather complex area and get your insights. Kalia: Thanks for having me. It was a great chat.
