SNT-4728 ahead of the top-line data readout expected at the end of June. We have several speakers presenting today, after which we'll take questions, please, if you would like to ask a question, use the Q&A function within Zoom and as I mentioned, we'll get to those at the end. From Syntara today, we have the CEO, Gary Phillips, and the Head of Drug Discovery, Dr. Wolfgang Jarolimek. Joining them are our special guests. We've got Dr. Lynsey Bilsland. Lynsey's Managing Director of Parkinson's Research Ventures, and she's joining us from the U.K., where it's 3:00 A.M. right now, we thank her very much for that effort. We're also very grateful to have Professor Simon Lewis, who's a neurologist and also the principal investigator of the trial. To begin, I'll hand it over to Gary first. Thanks, Matt. Okay. I think Matt's just done a good job at just introducing the panelists today. It is a great group of people to be talking to you about the ongoing study that's going to reach a conclusion in the next month. Professor Lewis, obviously being a principal investigator of the Sydney branch of the study, and we had two centers, one in Sydney and one in Oxford. Dr. Bilsland as well, great for her to join us early in the morning for her. Obviously Parkinson's Research Ventures funded this particular study that we're reporting on, so it's great to have their perspective on this. Wolfgang's joining me here. Wolfgang's been with Syntara since 2010. This drug was one of the first ones that came off of the production line after Wolfgang joined us. Good to have us all on the call. We're going to run through an agenda, which is to basically describe a little bit about the background of SNT-4728, the drug that's being trialed in this study. Some background to the disease, from Dr. Bilsland, and then Wolfgang's going to explain a little bit how the drug works before going into the study itself with Professor Lewis. I'll wrap it up at the end. We're hoping that the presentation part of this would be about half an hour, and then we're happy to take any questions. In fact, we encourage you to ask questions. The purpose of this seminar, webinar today was really to provide more information about the study before the results come out. It's a chance to understand what we're looking for in the study, what the impact of this is on patients, and how to interpret the results when we see them towards the back end of June. Just briefly, SNT-4728. This is a rather unique drug in that, this came out of the Syntara Drug Discovery Group, back in 2012. Wolfgang, when was it? 2012. We put it into phase I clinical studies. It was primarily focused at being an inhibitor of an enzyme called SSAO. Really its role in inflammation was where we were going with it. We quickly attracted interest from several companies, one of them being Boehringer Ingelheim, who then licensed the drug from us halfway through phase I in 2015. At this stage, they were very interested in SSAO as an enzyme, and they put it into two studies, one of them in fatty liver disease, so NASH. That phase II study actually showed the drug worked in that indication when dosed for three months in those patients versus the placebo. Also during their development of the program, they also saw that it inhibited MAO-B in the brain. That meant that it perhaps had some flags against it for development for liver disease. When we then discussed more widely with neurologists as a group, and Simon in particular, its role in neuroinflammation became very prominent. The fact that Boehringer had already done a lot of development on the asset after licensing it from us meant that it had a really strong safety profile, which makes it ideal for going into a disease, in effect, a prodromal Parkinson's disease, where in fact one of the most important things is that the drug that you're using is safe because these patients are not exhibiting much in the way of symptoms when you start going into them. It's a drug which tackles two different enzymes, SSAO and MAO-B. Wolfgang will give us much more background on that and its role in neuroinflammation and its neuroprotective effects as well. With that, I'll hand over to Dr. Bilsland for a bit of a background on the disease. Thanks, Gary. Good morning, everyone. Yes, I'm Lynsey. I'm the managing director of Parkinson's Research Ventures, and I'm going to tell you a bit more about that in a moment. Next slide, please. First, I'm going to start by telling you a bit more about isolated rapid eye movement disorder, or iRBD. This is a sleep disorder that is characterized by people acting out their dreams during REM sleep, and this is often violently. It's now recognized that iRBD may represent a prodromal stage of Parkinson's. What we mean by prodromal is that there's things happening with inside the brain, so changes happening to the dopaminergic neurons, for example, but there's no outward signs in terms of motor or cognitive symptoms. Approximately 70% of people with iRBD go on to develop Parkinson's and related alpha-synuclein deposition disorders, dementia with Lewy bodies, and multiple system atrophy, or MSA. Over 8% of people between the ages of 70 and 89 years old have iRBD. There's a significant unmet need for iRBD. There's no currently approved treatments, and the standard of care is melatonin. This also offers a huge opportunity to intervene early in Parkinson's, too. If we can identify and treat people that will go on to develop Parkinson's up to 20 years before a standard diagnosis could happen. This could be clinically transformative. By the time someone is actually diagnosed with Parkinson's, more than 50% of the dopaminergic neurons have already been lost. If we can intervene at a significantly earlier time point, then we've got the opportunity to save those neurons and change the trajectory of the disease. We saw real potential in the trial being run by Syntara. Next slide, please. I've worked for Parkinson's U.K., which is based in London. It's the largest European funder of Parkinson's research. In the U.K., someone is diagnosed with Parkinson's every 20 minutes. By 2050, the number of people living with Parkinson's worldwide will double to 25 million, and there's no approved disease-modifying treatments, nothing that will stop, slow, or reverse progression. We do have some treatments for motor symptoms, but there's over 40 different motor and non-motor symptoms, and many of these are still very poorly controlled. In the U.K., we have a very strong Parkinson's community that engages with our funded research. This is a statement from Joe on what it's like to live with iRBD. Joe says, "I depend on my wife telling me of the restlessness and sometimes violent outbursts that have resulted in injury to her, myself, and a few broken windows. I now have to make sure that I have a safe sleeping environment to help reduce the risks of any damage done to myself, my wife, and my surroundings." Next slide, please. PRV is a wholly owned subsidiary of Parkinson's U.K. It can be considered as the drug development arm of Parkinson's U.K. Our goal is to accelerate the development of new drugs for the treatment of Parkinson's. We provide funding and investment to academics and companies around the world that are developing new drugs for Parkinson's. This can be at a pre-seed, seed, or Series A level. We can support both preclinical and clinical programs, both disease modifying and symptomatic, and we are mechanistically and modality agnostic. Importantly, we operate as a venture philanthropy, so it means our venture decisions are driven by the potential of projects to have an impact on the lives of people with Parkinson's rather than their potential for a financial return. I'm now going to hand over to Wolfgang. Thank you. Thank you, Lynsey. It's always a pleasure to talk about our drugs and the mode of action that are developed here in Frenchs Forest. SNT-4728 is no different. It does reduce inflammation, and I'm showing you a little bit of evidence that it reduces inflammation in the brain and by which mechanisms it's actually reducing cell death and hopefully helps Parkinson's patients and potential Parkinson's patients. SNT-4728 is a truly small molecule with well-balanced properties, has excellent oral bioavailability, and a good tissue penetration. That is actually important. Many drugs that are supposed to act in the central nervous system failed because they did not reach the site of action or not at high enough concentrations. SNT-4728 is clearly different. As Gary mentioned, Boehringer Ingelheim has run a clinical imaging study demonstrating that at a dose of 10 mg per day over four weeks, more than 70% of the Monoamine Oxidase-B receptors in the brain are occupied and blocked functionally. Now, Boehringer also demonstrated that the SSAO at that concentration, the SSAO semicarbazide-sensitive amine oxidase, the second enzyme, is also strongly blocked. In this study that Simon is going to report about, we have increased the dose to 50 mg just to ensure that we get a complete inhibition of Monoamine Oxidase-B receptors in the brain, and we have also obviously that in periphery with SSAO. So we feel very confident that we actually have the right measurements in place to demonstrate that a combination of SSAO and MAO-B should actually be anti-inflammatory. Before I dive into the mechanism, I would like to discuss a vicious cycle of inflammation and cell death in the brain, if you can go to the next slide, please, which is depicted on the right-hand side of this diagram. Various factors can stimulate the production of small, unstable molecules. They are called reactive oxygen species. The most famous one everyone knows is bleach, hydrogen peroxide. These reactive molecules that actually don't have a very long half-life because they are so quickly binding to other proteins, cause a dysfunction of cell energy factories, left-hand side, they are called mitochondria, or the cells itself. Reactive oxygen species also activate the brain's immune system, which is the microglia depicted on the right-hand side. There's a strong interaction between cell function and microglia activation in the brain, and ultimately, that results in neuroinflammation. Neuroinflammation is a further stimulus to actually kill very sensitive neurons in the brain, which is called neurodegeneration, the loss of neurons. Such a loss of neurons is irreversible and needs to be prevented by all means. The only way to do that at the moment is by reducing neuroinflammation. That's where our strategy actually comes from. Once these neurons are dying, they actually cause further release of substances that activate microglia to clean up the debris. That causes further stress to neighboring cells as well as microglia. That is a self-reinforcing mechanism. Essentially, once this cycle started that I've depicted here, each problem feeds into each other and makes the brain damage progressively worse. In the next slide, I show you the mechanism by which SNT breaks the cycle. Gary already mentioned SNT-4728 blocks two different molecules. They are called monoamine oxidase B and SSAO. They have similar but also distinct functions. Importantly, the increased levels of these enzymes seen in patients with Parkinson's disease are thought to be significant factors in the disease progression. Both enzymes metabolize primary amines, for example, like neurotransmitters, and form the toxic products that I already talked about, reactive oxygen species. Can you get to the next slide, please? In addition to this generation of oxidative stress, SSAO, which also is in the cells in the vasculature, helps to move immune cells from the periphery into the brain. These immune cells then directly contribute to the neuroinflammation and microglial activation. In addition, the reactive oxygen species, and if you can go to the next one, have further effects also from MAO-B. As I mentioned before, obviously, they do cause cytotoxicity and mitochondrial damage. More importantly, they also are triggers for protein aggregation in cells. In the case of alpha-synuclein, the aggregation is a hallmark of the beginning of cell dysfunction, which ultimately leads to the death of neurons. Cell death is therefore a very strong driver for microglial activation and enhanced inflammation in the brain. In the next one, please. SNT blocks these different pathways. As I mentioned before, we know that the inhibition of this enzyme is complete. Therefore, we can expect the maximal efficacy of these mechanisms in the clinical trial. The clinical trial itself is based on very compelling preclinical data that Professor Bailain and Dr. Becky in Sydney have provided. They have studied the anti-inflammatory roles of SSAO, but also MAO-B, in various animal models that are relevant for Parkinson's disease and have published these in high-ranking journals. They have applied locally in the brain a very strong trigger of neuroinflammation, which is lipopolysaccharide product from bacteria. Once they have applied these lipopolysaccharides, they have seen a very strong activation of the inflammation in the brain, and they have measured that by histology. What they have found, that is the microglia is activated, as well as that this LPS actually has promoted the influx of vascular immune cells into the brain, into the areas that are more sensitive, for example, into substantia nigra. These studies, these effects were reduced by SSAO inhibitor, and you can see the very strong effect on the left-hand side. You can also see that these green cells are studying the background of the neurons, and then there is a strong inflammation in purple. Importantly, the measurement of this immune cell activation demonstrated very high efficacy of our inhibitor. The targeted proteins that were measured in this histology are markers of inflammation, and they are similar proteins that are actually measured also by neuroinflammation in patients using optical measurements. In both cases, they show the same thing, which is activation of microglia. On the right-hand side, you see actually the foundation of our studies is that in healthy volunteers, where the blue one, there's less activation of microglia, as you can see in Parkinson's patients, which are purple. Coming together, we have shown that we have a strong anti-inflammatory drug. These enzymes that are inhibited by this drug are relevant for Parkinson's disease, and the measurements that we are using can translate from what we have seen in the animal studies to what can be seen also in the humans. We feel very comfortable that that actually is a very conclusive study. At this point, I would like to introduce Professor Simon Lewis, with whom we have been collaborating for many years, and he obviously stimulated this particularly interesting study. Well, thank you so much, Wolfgang, and perhaps Gary can put on to the next slide. Thank you. We've heard there the evidence around Parkinson's disease and inflammation. Around the time that Syntara approached me regarding the potential use of this agent, there had been some data that had come out in the field that I'm quite linked to, which is around prodromal Parkinson's disease, and that is this isolated REM sleep behavior disorder, which Lynsey spoke about. A study had been published to show that actually not only in Parkinson's disease patients, but when you look at these prodromal patients against healthy age-matched controls, there was evidence on imaging of increased neuroinflammation, and particularly in regions of the brain that we might think would be important of future development of Parkinson's disease. For those of you who aren't necessarily familiar with these images, you will see there is a label there pointing to the substantia nigra. Substantia nigra is the main part of the brain that has the dopaminergic neurons that are the ones that are dying and taking the biggest hit in Parkinson's disease. In this initial study on the left in The Lancet Neurology, you can see that patients with prodromal Parkinson's had increased neuroinflammation. Shifting over to the right panel, probably again helping to close this loop. This is a prospective study of patients with isolated REM sleep behavior disorder over three years that demonstrated in those patients with more microglial activation, there was actually more significant loss of that dopaminergic innervation in the pattern one sees in Parkinson's disease. Here we have this very clear, if there is inflammation, it might predict dopamine cell loss. I think that gave us a lot of confidence around targeting the isolated prodromal cases because we're hoping that, if we intervene early, we'd have the most effect for our neuroprotective strategy. Perhaps if we go to the next slide, I can just walk you through the trial that we designed. This is a study, phase II, really aimed at showing a few things without overreaching. What we wanted to do was to demonstrate that the product could actually reduce neuroinflammation. The way that we did that was to recruit a highly phenotyped group of patients with isolated REM sleep behavior disorder, that is to say, confirmed on a sleep study and demonstrating features that might give you more confidence that these are the patients that would go on to develop a neurodegenerative disease. As well as dream enactment, patients who lose their sense of smell, and also patients who lose their ability to discriminate between pastel shades or color discrimination, are also at increased risk of getting our diseases. The patients recruited into this study had confirmed isolated REM sleep behavior disorder, not enough physical changes to make a diagnosis of Parkinson's disease or other conditions, and these other features, the losing the sense of smell, the color discrimination. The study was set up really not to prove that it was a drug that was better than placebo, but just to see if there was a signal that we could then use to put into a phase III for our power calculation. You'll see that we randomized 40, actually turned out to be 41 participants, three to one drug to placebo. The placebo arm is not there to show efficacy, it's there to maintain the blinding. That's kind of important in the land of Parkinson's disease patients. These patients were recruited and studied at baseline, where they underwent a PET scan, looking for the level of neuroinflammation, and then had 12-week exposure to the IP or placebo, and then had a follow-up scan at 12 weeks to see whether we could see a reduction in the neuroinflammation on this PET imaging. As well as that, participants underwent a number of other rating scales and digital and biomarker work, which I'll talk about perhaps on the next slide. Participants were followed up just for a watch out for safety up to 24 weeks. Next slide, please, Gary. As we alluded to, we are hoping that by the end of this month, we will have the primary outcome. That is to say, in those participants exposed to the IP, was there a significant reduction in neuroinflammation? We'll obviously have a look at the placebo to see what the variance is like, but essentially by the end of this month, we are hoping that we'll have that data. That will give us a very clear signal around the imaging and the basis for why we studied this group. Obviously, we'll also be able to report on safety and tolerability at that stage. In addition to that, the subjects will actually have had their spinal fluid characterized. As people may on this call know, there are new ways of looking to see whether people have evidence for alpha-synuclein protein. There's a CSF, a spinal fluid assay, that we will actually apply to the participants in this study, which might help us to work out, well, okay, was this drug more effective in those who had a negative or a positive readout? In addition to those markers, we're also having digital biomarkers. People will know that even before patients develop Parkinson's disease, there are some elements of motor slowing, we have wearable devices and a smartphone technology looking at physical symptoms beyond the simple rating scales, as well as cognitive testing. Also, in addition to the spinal fluid I mentioned, we'll also have a range of biological markers. From blood and spinal fluid, we'll be able to look at things like measures of neuroinflammation, whether we'll have markers of cell death. People might be familiar with biomarkers like neurofilament light. We should be able to have a look at those studies. That's expected about quarter three, quarter four this year. With that, Gary, I'm happy to field questions, but perhaps I'll throw back to yourself. Thank you, Simon. Yeah, I guess when we're closing the formal part of this webinar before we open up for Q&A, just what happens next. This is a rather unusual study, for us at least, in that not all the endpoints come at one particular point in time. The primary endpoint of the inflammation measures the PET scan of the brain, we do expect to see before the end of June. The other endpoints, which Simon has talked through, we expect to see later on in the year. It may be that we need to see all of those things before we can draw an absolute conclusion to the study. Certainly we're extremely interested to see what happens in those primary endpoints coming out in just a few weeks. What do we do next once we see that? Well, obviously, we need to wait and see the results. I think as Simon introduced it quite well is that, when this study was designed, we didn't want to overreach. This was really seen as a way of exploring the impact of this drug and those two enzymes on these patients. We've been careful to try and select a group of patients which we think will be suitable and be able to show what the drug can do when it reduces neuroinflammation. As Wolfgang's talked through, there was very strong preclinical evidence of the impact of this drug on the brain, and a strong link through into the clinic. There's two separate potential indications going through. I think Lynsey, it was great to see her present the patient case study there, a statement from a patient who's suffering from iRBD, obviously it has a huge impact on patients' lives. Not only the patient, but also of their partners and their families as well. There's clearly a role here for a drug if it could be developed to treat iRBD. The only standard of care at the moment is actually melatonin, which I'm sure helps a little, doesn't really address the key issues of these patients going forward. There's a clear need for that. The other one, obviously, is the one that we all hope for is that if you can reduce neuroinflammation with this drug, it may well slow the progression to Parkinson's and be somewhat in the way of disease modifying. We'll wait and see what the results are, but there's two very strong potential routes forward for a drug that could work in these areas. I think it's fair to say that, at Syntara, we don't see this as a journey that we will take on our own once we see the results. We would be talking very closely and in detail with Parkinson's U.K. and other philanthropic organizations to see about the appetite to explore further what this drug can do forward. Also with potential commercial partners, maybe bigger companies that are focused in central nervous system diseases and Parkinson's, and neurodegenerative diseases in particular. Not a role that we'll be picking up and going on our own. In just finishing off, where does this sit in the overall Syntara pipeline? We are blessed at the moment with a pipeline with three different programs, with five different clinical studies that are due to read out within the next six to nine months. It's a very strong position that we find ourselves in. The recent capital raise that we completed gives us the runway to see us well through all of these endpoints to see whether we have value in this pipeline that Wolfgang and his team in Drug Discovery have developed and taken forward and we've put into the clinic. Our lead asset, amsulostat, in myelofibrosis and myelodysplastic syndrome, as well as now some solid tumors, will deliver further results towards the end of the year. We've got a skin scarring program in two different studies, which also we expect results in the second half of the year. The first cab off the rank, the first of those opportunities that we're going to be exploring is the one that we've been discussing today, and we were very keen to make sure that there was an opportunity for people to understand the significance of this study. We haven't talked about it a lot as we've gone through it, but now is the time to focus on this, and we will see what the results turn out within the next few weeks. With that, I'll hand it back to Matt, our facilitator, and happy to answer any questions that you have. Thanks, Gary, and to everyone who's presented today. Again, a reminder, if you have a question you'd like to submit, please do so by typing it in the Q&A panel within Zoom, and I will jump to those now. The first one I have is, how does SNT-4728 differ from mofegiline, forgive pronunciation there, which is also a dual SSAO/MAO-B inhibitor? Ceased trials before approval for human use. Yeah, happy to answer that one. Mofegiline was a lead molecule when I joined the company 15 years ago. It is a SSAO and MAO-B inhibitor with very similar potency. It has a disadvantage that it's more lipophilic, and that's what we characterized very early on in cell health assays that it does cause some cell death in these assays. Just as an indicator of off-target effects, we have been able to reduce that. As I mentioned, SNT-4728 is well-balanced. It's more hydrophilic and has less off-target effects. One of them is that we don't actually see any cell toxicity anymore. We improved on mofegiline from a side effect profile. I think the primary pharmacological profile being, SSAO MAO-B inhibitor is unchanged. Just to put that into context, if we were to take this forward in treating prodromal patients with iRBD who are still maybe some years away from developing Parkinson's, one of the key aspects of the drug is that it is well-tolerated because you're potentially giving a drug to people who don't yet have the symptoms. They are asymptomatic, so you don't want to be giving them problems at this stage. I don't know, Simon, whether you've got anything to add to that in terms of the profile of the ideal drug that you want for iRBD and Parkinson's. Safety, then safety, then safety. I think that's the watch word. These are people that are working every day, generally, and they're sort of not retired and active. For them to make a commitment is quite big. It has to really have that sort of rubber stamp of safety. Yeah. Thank you. Thank you. The next question is, given the size of the trial and control arm, is the trial adequately powered to deliver statistical significance? I'm happy to field that one. I think the bottom line is, yes, because what we weren't trying to do was prove that it was better than placebo. What we really want to know is there a statistically significant within subjects result that we could then say, "Okay, well, does that give us confidence to move on from here? Thank you. The next question is, thanks for the presentation. Can you please elaborate on the signal that you're hoping to understand from the PET imaging? Could this inform potential progression into phase III? Yep. Again, probably easier for me to say this. This is a carbon-11 PK11195 ligand, which people who are familiar with that would know, it binds the TSPO or the translocator protein, which is on the outer membrane of the mitochondrion within the cells. The exciting aspect of that, try saying that three times quickly. It's how you do your warm-ups. The exciting thing about this marker is that it gets activated when neuroinflammation is in play. Essentially, it gets upregulated in terms of the uptake of the ligand. What we're very much hoping here is that this ligand will show a clear reduction as the IP effects a reduction in the neuroinflammation, and that will hopefully reduce the signal. In terms of how we would've loved to have done the study, and we argued about this long and hard, but basically couldn't get enough money out, was, well, okay, why don't we do the rebound where effectively people have to wash out and then see if the signal goes back up? Unfortunately, I think it was a financial decision. Obviously, as you know, this was funded by philanthropic partners. The hope is we'll have enough here to give us confidence to go on and do those sorts of studies. The next question is, if this can help dopaminergic neurons for Parkinson's, does this show promise for other dopaminergic conditions such as ADHD? I might jump in. I think ADHD is an interesting condition, mainly because it isn't really regarded as neurodegenerative. Although it's thought to operate a little bit like schizophrenia through a dopaminergic axis, there isn't really a telltale neurodegenerative signal. Having said that, of course, there is evidence out there with PK11195, the same ligand here, that ADHD patients may indeed have evidence of neuroinflammation. It's a big question as to the company here, whether you take a look at things like Alzheimer's dementia, which has also got a neuroinflammation prodrome as well. I don't know that we would see it as clearly as ADHD, but certainly in the other synucleinopathies like dementia with Lewy bodies, which is second only to Alzheimer's dementia, big market out there with absolutely no disease-modifying treatment available. Things like multiple system atrophy, which is a little bit more boutique, one in 100,000 people. Again, no proven treatment to slow the disease progression, especially before they get the disease. The hope is that if you can target things upstream and stop other cascades coming in, a little bit like what Wolfgang was showing in the slides, you're kind of hoping that you'll actually push everything down the track and hopefully never see these degenerative diseases get diagnosed. Yeah, and I'd just add to that, when we first had the drug back from Boehringer and were exploring the neuroinflammation aspects that the drug had, it clearly had the preclinical work that we'd already done. We were guided by neurologists, including Simon, as to what would be the right way of exploring which diseases would work with this kind of mode of action. I think the combination of the advice we got from the neurologists, as well as the tremendous enthusiasm we had from the philanthropic organizations, being primarily Parkinson's U.K., was what led us into this study which, as we've described, is somewhat of an exploratory study in that it really will help us understand the impacts on neuroinflammation in the brain. Where we go from there is open. I think we will see what the impacts are and then explore with, again, other philanthropic partners, other companies, where this takes us. It's an exciting point to be at. Obviously, before we see the results, we hope we see something strong coming out the other side. Thank you. The next question is, how long is the IP for the drug? Is it possible to extend that IP duration? Can I have Wolfgang? Yeah. It goes up to 36. It started, as Gary said, 2012, we applied for the first patent on that one. We do have ideas about salt formulation and also the 50 milligram dose gives us new opportunities for filing if we can proceed in these indications. Yeah. Thanks, Wolfgang. Yeah, 2036 already, but this study is obviously breaking new ground, so we'll see. Thank you. The next question is, was neuroinflammation measured in the historical BI trials? If so, to what extent do those trials relate to the PET imaging in your iRBD trial? Neuroinflammation was not measured in these trials. It was only measured as a site pharmacology to see whether monoamine oxidase B was actually occupied in the brain, but they have not enrolled any patients with neuroinflammation at that stage. That was study in healthy volunteers. Thank you. The next question is, from a clinician perspective, what is the most important to see in the phase II trial, given the complexities of the disease? Following on from that, what does a phase III trial look like? I guess the bottom line is that we are going to get a few bites at the cherry with the way that we're collecting data. I think obviously we're very keen to see whether neuroinflammation as our primary outcome is impacted. This is a bit different to a disease that's already established where you say, "Well, did their cognition get worse? Did their physical rating scale get worse?" These are people that are prodromal. In actual fact, we don't have that sense of, okay, what would we measure in these people? Having said that, some of the sensitive markers, like the markers of neuroinflammation and neuronal death, like neurofilament light and the inflammatory markers from spinal fluid and blood, will also give us a signal. Although you examine these people, they really don't look as though they've got anything physical going on. Digital biomarkers are giving us more insight. I think that there are, as I say, a number of ways that we'll be able to look at the outcomes. In terms of what a phase III looks like, I think it's fair to say that it would need a larger number of participants. It would need to have a longer duration of exposure. The question really is, okay, these are still healthy people. Researchers have looked to say, well, okay, if you enrich the sample and say they've got these problems at the baseline, how many of them will get the disease over the next, let's say, three years? You can do the power calculation right now and say, well, you might need, I don't know, 500 or 600 participants worldwide to do that kind of a study over three years. That's one way of doing it. The other way of doing it is to say, well, okay, as I mentioned in the talk, we see that there is a loss of dopaminergic neurons in these participants before they get a diagnosis. As Lynsey very nicely pointed out, by the time somebody comes to see me for a diagnosis, they've lost about half of their dopamine cells. That doesn't mean to say their dopamine cells are normal. It may well be that what you would do in terms of a longer phase III study is say, well, let's do a baseline dopamine scan and then repeat that at, let's say, 18 months or 12 months. People have started looking at that as a model. Other people have suggested doing fluorodeoxyglucose PET scanning as a model of how you might look at a biomarker for disease change. I think there are a number of nuances, and I think that what we'd like to see is enough confidence to go forward into that kind of a study. There's plenty of ways we could design the trial to be very effective very quickly. Simon, could you add what you think an iRBD study would look like as the next stage? I think it would look very similar to what I've just outlined. The reason I say that is because when we see these participants clinically, what we can actually do, because research has done this previously, is to say, okay, we did a dopamine scan of this patient. Their dopamine scan was normal. That doesn't mean to say their dopamine system is normal, because the dopamine scan is down to, say, 1 mm or 2 mm. The cell death is down at the microscope level. Of those people with a normal scan, 6% will convert at three years. If you have an abnormal scan, you still don't have Parkinson's disease. You examine normally, you look as though you're functioning fine. If you have an abnormal scan at baseline, that risk goes up to about 20% over three years. Suddenly you can start saying, well, it doesn't actually have to be a transition to Parkinson's disease. What you're saying is, if we can map cell death, dopamine being the obvious system that's impacted by Parkinson's, and the majority of patients with dementia with Lewy bodies, then you'd have a biomarker readout that you wouldn't have to be worrying about, well, is that Parkinson's? You basically say, well, look, the hard value is at baseline, you had this much cells. At 18 months, you lost this many. It was better in the treatment group than the placebo group. Then you extrapolate the findings, hopefully, into stopping people going on and getting these terrible diseases. Thank you. Okay. Next we have, I believe SNT-4728 was discontinued development by BI because of a drug-drug interaction. Will that same DDI be an issue for this indication? No. They call it a drug-drug interaction because the patient population that Boehringer Ingelheim targeted were obese patients with MASH or liver fibrosis. The concern was that they would be on other drugs, in the CNS drugs that would interfere with the MAO-B component. At the 10-milligram dose, there was actually no indication that that actually would ever happen because 70% is too low in general to be considered as a drug-drug interaction. It was coming from the angle that these patients that are obese have additional drugs that would interfere with it. The population that Simon mentioned, obviously, iRBD is very different in that respect, and I think there's no risk to consider that there's a drug-drug interaction in this particular group. Yeah, I think Boehringer's view when they handed us back the drug was to emphasize that they actually thought the drug was safe. It was something specific to fatty liver disease that they felt was an issue. I think in context, they were just about to face the decision to put the drug into a phase III, probably two phase III studies of 1,000 or more patients would have cost many hundreds of millions of AUD to do. At that point, the fatty liver disease was a very hot space clinically. There were lots of drugs going into trials and very competitive, and they just didn't feel that the SNT-4728 with this potential drug-drug interaction might cause a few development issues going forward for that and would just make it more difficult for that drug to succeed in the end, which is why they stopped it. Right. Thank you. Next question is, the growth of the longevity field has a lot of repurposing of existing drugs to stave off the harmful effects of aging. Could you see this molecule potentially playing this role in the future if the safety profile is good enough? Simon, would you like to take a stab? I'm happy to take a stab. I thought from a company point of view, you might like to have a go first. I think the problem with the longevity field is that it's difficult to know how tightly regulated it is in terms of how you design an outcome measure for a study that shows you have delayed the onset of aging, or you prolong. I think, unfortunately, a lot here is the amount of evidence you need to sell a product is low because the hype is high. I think that in Syntara's world, I think that they probably are focused on, if you like, much more biological outcomes that you would put through rigorous testing and trials rather than these repurposed longevity products, which often don't have to meet the same standards. Thanks, Simon. Yeah, Syntara has never described itself as a CNS company, a company that's focused on this area. We're very much guided by the experts in the area as to where we go with this. As I said, I think we're encouraged by the preclinical to clinical links that there are in this neuroinflammation, neurodegeneration space. Based on the results that we see later this month and then the second half of the year, we will be checking back. I think one of the great things about this study and the way it emerged was the very collaborative approach that we had with key opinion leaders like Simon and Michele Hu, the professor in Oxford, who's the other principal investigator on this study, and the philanthropic organizations, including Parkinson's U.K. When we all sat together, the science behind this and the data that we had was stacked up against other opportunities that obviously these organizations had in terms of choosing where to put its funding. This study rose to the top through a peer review process, looking at the science and looking at the clinical need that was there, and eventually it was funded on that basis. I think we'll go through the same process once we see the results from this study and see where it stacks up against the huge amount of research which is going on in these fields. Also, the fact that this is a well-developed drug that's been largely de-risked and proven to be safe before in a large number of patients really makes it an opportunity to go quickly into the next stage of studies and perhaps make a difference for patients in the short term. Thanks, everyone. That's all the questions that have come through. Gary, I'll hand it back to you to provide a closing comment. Thank you very much. I think, first of all, thank you to our guest presenters today. Sorry, Simon, but particularly to Lynsey, who's got up at 3:00 A.M. in the U.K. to join us. We really appreciate the support that we've had from Parkinson's. It hasn't just ended, actually, with the funding. Right the way through this, they've been really with us all the way, that we had a few delays as we had technical challenges with setting up the study. I think as Simon has talked through, this is a technically challenging study where we're producing a radiolabeled ligand that has to be produced very shortly before the patient actually goes into a PET machine and has their brain scanned and with the infusion of this at the same time. It was technically challenging and we've all held each other's hands as we've gone through it, and we're delighted to get to this point where we're going to see results in just a few weeks. Thank you. Thanks, Gary, and thanks to everyone for joining.