Syntara Limited ($SNT)

Thank you for standing by, and welcome to this Syntara Investor Webinar and Q&A, which is intended to provide further information on the ongoing Phase II trial of 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. [Operator Instructions] From Syntara today, we have the CEO, Gary Phillips; and the Head of Drug Discovery, Dr. Wolfgang Jarolimek. Joining them are our special guests. So we've got Dr. Lynsey Bilsland. Lynsey is 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. So we thank her very much for that effort. And we're also very grateful to have Professor Simon Lewis, who is a neurologist and also the principal investigator of the trial. But to begin, I'll hand it over to Gary first.

Thanks, Matt. Okay. So I think Matt has just done a good job at just introducing the panelists today. It's 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, we have 2 centers, one in Sydney and one in Oxford. And Dr. Bilsland as well, great for her to join us early in the morning for her, but obviously, Parkinson's Research Ventures funded this particular study that we're reporting on. So it's great to have their perspective on this. And Wolfgang is joining me here. Wolfgang has been with Syntara for -- since 2010. And this drug was one of the first ones that was -- came off of the production line after Wolfgang joined us. So 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 4728, the drug in -- that's being trialed in this study, some background to the disease from Dr. Bilsland, and then Wolfgang can explain a little bit about how the drug works before going into the study itself with Professor Lewis. And then I'll wrap it up at the end. We're hoping that this -- 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. But the purpose of this seminar -- webinar today was really to provide more information about the study before the results come out. So 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. So just briefly, 4728, this is a rather unique drug in that this came off of the -- out of the Syntara drug discovery group back in 2012 when we put it into Phase I clinical studies and was primarily focused on being an inhibitor of an enzyme called SSAO and really its role in inflammation was where we were going with it. And 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. And at this stage, they were very interested in SSAO as an enzyme, and they put it into 2 studies, one of them in fatty liver disease and NASH. And that Phase II study actually showed the drug worked in that indication when dosed for 3 months in those patients versus the placebo. But also during their development of the program, they also saw that it inhibited MAO-B in the brain. And that meant it was -- perhaps had some flags against it for development for liver disease. But when we then discussed more widely with neurologists as a group and Simon, in particular, its role in neuroinflammation became very prominent. And 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 fact, 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. So it's a drug which tackles 2 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. So with that, I'll hand over to Dr. Bilsland for a bit of a background on the disease.

Thanks, Gary. Good morning, everyone. So 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. So 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. And it's now recognized that iRBD may represent a prodromal stage of Parkinson's. And what we mean by prodromal is that there's things happening 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. And 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 treatment and the standard of care is melatonin. But this also offers a huge opportunity to intervene early in Parkinson's, too, because 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, then 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. And so 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. And so we saw real potential in the trial being run by Syntara. Next slide, please. So I've worked for Parkinson's U.K., which is based in London, and it's the largest European funder of Parkinson's research. And 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 treatment, nothing that will stop, slow or reverse progression. We do have some symptoms -- some treatments, sorry, for motor symptoms, but there's over 40 different motor and nonmotor 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. And 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. So 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. And our goal is to accelerate the development of new drugs for the treatment of Parkinson's. So we provide funding and investment to academics and companies around the world that are developing new drugs for Parkinson's. And this can be at a pre-seed, seed or Series A level. And we can support both preclinical and clinical programs, both disease-modifying and symptomatic, and we are mechanistically and modality agnostic. And 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 Ventures for us. And 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 those mechanisms, it's actually reducing cell death and hopefully helps Parkinson's patients in total and 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 milligrams a day over 4 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, SSAO, semicarbazide-sensitive amine oxidase enzyme is also strongly blocked. In this study that Simon is going to report about, we have increased the dose to 50 milligrams, just to ensure that we get a complete inhibition of monoamine oxidase B receptors in the brain, and we have also obviously that in symmetry with SSAO. So we feel very confident that we actually have the right measurements in place to demonstrate that the combination of SSAO and MAO-B should actually be anti-inflammatory. Before I dive into the mechanism, I would like to discuss the 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 dysfunction of cell energy factories. left-hand side, they are called mitochondria or the cells itself. At the same time, the active oxygen species also activate the brain's immune system, which is a 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 then 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. And the only way to do that at the moment is by reducing neuroinflammation. That's where our strategy actually comes from. Now when these neurons are dying, they actually cause further release of substances that activate microglia to clean up that debris, but that causes further stress to neighboring cells as well as microglia and that is a self-reinforcing mechanism. Essentially, once this cycle started that's depicted here, each problem feeds into each other and makes the brain damage progressively worse. So in the next slide, I show you the mechanism by which SNT breaks this cycle. Gary already mentioned, SNT-4728 blocks 2 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. Now both enzymes metabolize primary amines, for example, like neurotransmitters and form the toxic products that I already talked about reactive oxygen species. In addition to the -- 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. And these immune cells then directly contribute to the neuroinflammation and microglial activation. In addition, the reactive oxygen species and if you can go to next one, have further effects also from MAO-B. As I mentioned before, obviously, they do cause cytotoxicity and mitochondrial damage. But more importantly, they also are triggers of protein aggregation in cells. And in the case of alpha-synuclein, the aggregation is a hallmark of the begin of cell dysfunction, which ultimately leads to the death of neurons. Cell death is therefore a very strong driver for microglial activation and hence inflammation in the brain. So the next one, please. SNT blocks these different pathways. And as I mentioned before, we know that the inhibition of the enzyme is complete. Therefore, we can expect the maximum efficacy of these mechanisms in the clinical trial. The clinical trial itself is based on very compelling preclinical data that Professor Balleine and Dr. Becky in Sydney have provided. They have studied the anti-inflammatory roles of SSAO 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. When they have applied these lipopolysaccharide, they have seen a very strong activation of the inflammation in the brain and have measured that by histology. What they have found that 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 areas of 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 are measured in this histology are markers of inflammation and there are similar proteins that are actually measured also by neuroinflammation in patients using optical measurements. And in both cases, they show the same thing, which is activation of microglia. So on the right-hand side, you see actually the foundation of our studies is that in healthy volunteers with blue on, there is less activation of microglia as you can see in Parkinson's patients, which are purple. So 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 humans. So we feel very comfortable that, that actually is a very conclusive study. So 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. So we've heard there the evidence around Parkinson's disease and inflammation. But around the time that Syntara approached me regarding the potential use of this agent, there had been some data that have 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. And the study has 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 for future development of Parkinson's disease. So for those of you who aren't necessarily familiar with these images, you'll see there's a label there pointing to substantia nigra. Substantia nigra is the main part of the brain that has the dopaminergic neurons that are the ones that are dying, taking the biggest hit in Parkinson's disease. So in this initial study on the left in The Lancet Neurology, you can see that patients with prodromal Parkinson's has increased neuroinflammation. And then 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 3 years that demonstrated in those patients with more microglial activation, there was actually more significant loss of that dopaminergic innovation in the pattern one sees in Parkinson's disease. So here, we have this very clear if there's inflammation, it might predict dopamine cell loss. And 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. So perhaps if we go to the next slide, I can just walk you through the trial that we designed. So this is a study with Phase II really aimed at showing a few things without overreaching. So what we wanted to do was to demonstrate that the product could actually reduce neuroinflammation. And 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. So 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. So the patients recruited into this study had confirmed isolated REM sleep behavior disorder not enough any physical changes to make a diagnosis of Parkinson's disease or other conditions and these other features that are losing the sense of smell, the color discrimination. So 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 can then use to put into a Phase III for our power calculation. So you'll see that we randomized 40 -- actually turned out to be 41 participants, 3:1 drug to placebo. So the placebo arm is not there to show efficacy. It's there to maintain the blinding and that's kind of important in the land of Parkinson's disease patients. And so these patients were recruited and studied at baseline where they underwent a PET scan looking to 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 washout for safety after 24 weeks. Next slide, please, Gary. So 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 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 have been 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 that alpha-synuclein protein, so there's a CSF 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 have a negative or a positive readout. In addition to those markers, we're also having digital biomarkers. So people will know that even before patients develop Parkinson's disease, there are some elements of motor slowing. And so we have wearable devices and a smartphone technology looking at physical symptoms beyond the simple rating scales as well as cognitive testing. And also, in addition to the spinal fluid, I mentioned, we'll also have a range of biological markers. So 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 and we should be able to have a look at those studies, and that's expected about quarter 3, quarter 4 this year. And so with that, Gary, I'm happy to field questions, but perhaps I'll throw back to yourself.

Thank you, Simon. So yes, I guess in closing the formal part of this webinar before we open up for Q&A, just what happens next. So we're -- this is a rather unusual study for us, at least in that not all the endpoints come at one particular point in time. So the primary endpoint of the inflammation measures, the PET scan of the brain, we do expect to see before the end of June. And then the other endpoints, which Simon has talked through, we expect to see later on in the year. And it may be that we need to see all of those things before we can draw an absolute conclusion to the study. But certainly, we're extremely interested to see what happens in that -- 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. So this was really seen as a way of exploring the impact of this drug and those 2 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. And as Wolfgang 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. So there's 2 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 and obviously has a huge impact on patients' lives and not only the patients, but also of their partners and their families as well. So 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 bit but doesn't really address the key issues of these patients going forward. So 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 at least somewhat in the way of disease modifying. So we'll wait and see what the results are, but there's 2 very strong potential routes forward for a drug that could work in these areas. And I think it's fair to say that Syntara, we don't see this as a journey that we will take on our own once we see the results. So 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 actually can do forward and also with potential commercial partners, maybe bigger companies that are focused in central nervous system diseases and Parkinson's and neurodegenerative diseases in particular. So not a role that we'll be picking up and going on our own. But in just finishing off, where does this sit in the overall Syntara pipeline. And we have -- we are blessed at the moment with a pipeline with 3 different programs with 5 different clinical studies that are due to read out within the next 6 to 9 months. It's a very strong position that we find ourselves in. And 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 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 2 different studies, which also we expect results in the second half of the year. But 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 presented today. [Operator Instructions] The first one I have is how does SNT-4728 differ from mofegiline, which is also a dual SSAO/MAO-B inhibitor [ disease ] trials before approval for human use.

Yes. Happy to answer that one. So mofegiline was a lead molecule when I joined the company 15 years ago. It's SSAO and MAO-B inhibitor with very similar potency. It has a disadvantage that it's more leukopenic. 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 and we have been able to reduce that. As I mentioned, SNT-4728 is well balanced. It's more lipophilic and has less off-target effect. And one of them is that we don't actually see any cell toxicity anymore. So we improved on mofegiline from a side effect profile. I think the primary pharmacological profile being SSAO and MAO-B inhibitor is unchanged.

And 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 mean I think that's the word. These are people that are working every day generally in their sort of not retired and active. And so for them to make a commitment is quite big. So it has to really have that sort of rubber stamp of safety.

Yes. 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?

So I'm happy to field that one. I think the bottom line is, yes, because what we weren't trying to do is prove that it was better than placebo. What we really want to know is, 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?

Yes. So again, probably easier for me to take this. So this is a Carbon-11 PK11195 ligand, which people who are familiar with that would know binds the TSPO or the translocator protein, which is on the outer membrane of the mitochondria within the cells. The exciting aspect of that, saying that 3 times quickly [indiscernible]. So the exciting thing about this marker is that it gets activated when neuroinflammation is in play. So essentially, it gets upregulated in terms of the uptake of the ligand. So 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. Now in terms of how we would have loved to have done the study, and we argue 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 watch out and then see if the signal goes back up. And unfortunately, I think it was a financial decision. And obviously, as you know, this was funded by philanthropic partners. So 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?

So I might jump in. I mean I think ADHD is an interesting condition mainly because it isn't really regarded as neurodegenerative. So 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. And 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. So I don't know that we would see it as clearly as ADHD, but certainly in the other synucleinopathy like dementia with Lewy bodies, which is second only to Alzheimer's dementia, big market out there with absolutely no disease-modifying treatment available. And then things like multiple system atrophy, which is a little bit more boutique in 100,000 people. But again, no proven treatment to slow the disease progression, especially before they get the disease. So the hope is that if you can target things upstream and stop other cascades coming in, like what Wolfgang was showing you 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.

Yes. And I'd just add to that, that when we first had the drug back from Boehringer and we're exploring the neuroinflammation aspects that the drug had, we clearly added the preclinical work that we've 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. And I think the combination of the advice we got from the neurologists as well as the tremendous enthusiasm we have from the philanthropic organizations, primarily Parkinson's U.K., was what led us into this study, which, as we've described, is somewhat of an exploratory study and that it really will help us understand the impact on neuroinflammation in the brain. And 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?

Yes. So it goes up to '36. It started, as Gary said, 2012, we have filed the first patent on that one. We do have ideas about solid formulation and also the 50-milligram dose gives us new opportunities for filing if we can proceed in these indications.

Yes. Thanks, Wolfgang. So yes, 2036 already, but this study is obviously breaking new ground. So we'll see.

Thank you. The next question is, was neuroinflammation measured in historical BI trials? If so, to what extent do those trials relate to the PET imaging in your iRBD trial?

Yes. So neuroinflammation was not measured in these trials. It was only measured as a side 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. It 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? And following on from that, what does the Phase III trial look like?

So 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. So in that sense, 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 in spinal fluid and blood will also give us a signal. And although we will examine these people, they really don't look as if they've got anything physical going on, digital biomarkers are giving us more insights. So I think that there are, 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, but these are still healthy people. Now people have -- 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, 3 years? And you can do the power calculation right now and say, well, you might need, I don't know, 500, 600 participants worldwide to do that kind of a study over 3 years. So 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. But that doesn't say their dopamine cells are normal. So it may well be that what you would do in terms of a longer Phase III study to say, let's do a baseline dopamine scan and then repeat that at, let's say, 18 months or 12 months. And 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 of disease change. So 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, but there's plenty of ways we can design the trial to be very effective very quickly.

Simon, could you add what you think an iRBD study would look like at the next stage?

I think it would look very similar to what I've just outlined. And 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 on this patient. Their dopamine scan was normal. Now that doesn't mean to say the dopamine system is normal because the dopamine scan is down to, say, a millimeter or 2. The cell death is down at the microscope level. So of those people with a normal scan, 6% will convert at 3 years. But if you have an abnormal scan, you still don't have Parkinson's disease, you examine normally, you look as they're functioning fine. But if you have an abnormal scan at baseline, that risk goes up to about 20% over 3 years. So suddenly, you can start saying, well, does that 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 have a biomarker readout that you wouldn't have to be worrying about, well, is that Parkinson's or is this -- how does the cognition? You basically say, well, look, the hard value is at baseline, this much cells at 18 months, you lost this many. It was better in the treatment group than the placebo group. And then you extrapolate the findings hopefully into stopping people going on and getting these terrible diseases.

Thank you. Next, we have, I believe 4728 was discontinued development by BI because of a drug-drug interaction. Will that same DDI be an issue for this indication?

No. Not quite a drug-drug interaction because the patient population that Boehringer Ingelheim targeted were obese patients with NASH or liver fibrosis. And the concern was that they would be on other drugs, the CNS drugs that would interfere with the MAO-B component. Now 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. But 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.

Yes. I think Boehringer's view when they handed us back the drug was that they actually thought the drug was safe. So it was something specific to fatty liver disease that they felt was an issue. And I think in context, they were just about to face a decision to put the drug into a Phase III, probably 2 Phase III studies of 1,000 or more patients would have cost many hundreds of millions of dollars to do. So -- and at that point, the fatty liver disease was a very hot space clinically. There are lots of drugs going into trials and very competitive. And we just didn't feel that the 4728 had -- with this potential drug-drug interaction might cause a few development issues going forward for that and would just take -- make it more difficult for that drug to succeed in the end, which is why they stopped it.

Thank you. Next question is, the growth of the longevity field has a lot of repurposing of existing drugs to save 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 have liked going first. And 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 prolonged. So I think, unfortunately, a lot here is the evidence -- so the amount of evidence you need to sell a product is low because the hype is high. And so 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 repurpose longevity products, which often don't have to meet the same standards.

Thanks, Simon. 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. And I think we're encouraged by the preclinical to clinical links that there are in this neuroinflammation, neurodegeneration space. And based on the results that we see later this month and then the second half of the year, we can again -- we will be checking back. I think one of the great things about the 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. I mean we all sat together and the decision, and it was the science behind this and the data that we had was stacked up against other opportunities that obviously that these organizations had in terms of choosing where to put its funding. And 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. And 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, but also the fact that this is a well-developed drug that's been largely derisked 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. So Gary, I'll hand it back to you to provide a closing comment.

Thank you very much. Well, I think, first of all, thank you to our guest presenters today, particularly -- sorry, Simon, but particularly to Lynsey, who's got up at 3:00 in the morning in the U.K. to join us, and we really appreciate the support that we've had from Parkinson's. It hasn't just ended actually with the funding. We're right the way through this, they've been really with us all the way that we had a few delays as we -- 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 scan and with the infusion of this at the same time. So 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.