Good morning, and welcome to the CervoMed KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded, and a replay will be made available on the CervoMed website following the conclusion of the event. I'd now like to turn the call over to John Alam, Chief Executive Officer at CervoMed. Please go ahead, John. Thank you, Tara, and thank you to everyone joining us. Thank you for your interest and taking the time for this, what I hope will be a tremendous event. I will thank Professors Taylor and Nixon as well for being with us today. We'll point you to our various filings otherwise, and I'm going to open up with a few introductory comments and just an overview of the agenda and the discussion topics. For those who are new to the story, I have a couple background stories on the company as well. CervoMed is a public company trading on NASDAQ under the ticker symbol CRVO. We're formed from a merger between a private company, EIP Pharma, and Diffusion Pharmaceuticals, a public company, but Diffusion Pharmaceuticals just about a year ago. Our lead program, our focus is on CNS therapeutics, but in particular, our lead program is an oral drug, neflamapimod, for the treatment of dementia with Lewy bodies, where we are with our published data, and that we have—we are the only company with positive clinical data. In terms of, again, on the background, on the clinical program in neflamapimod with dementia with Lewy bodies, our published data is out of a phase II-A trial called the ASCEND-LB trial. We have fully enrolled, are in the midst of a phase II-B trial, the REWIND-LB trial, which is to confirm the results from that initial trial, ASCEND-LB, in dementia with Lewy bodies. This study, REWIND-LB, is anticipated to read out top-line clinical results in December of this year. With positive data here, we would go to the FDA in the first half of 2025 and initiate phase III in dementia with Lewy bodies by the middle of 2025. Our discussion today is to really go through all the data and the thinking that's gone behind designing the REWIND-LB trial. In the end, why we believe a lot of the work that we've been doing to try to identify the right path forward and to be in a position where we can have positive data in that trial, what the science, what both preclinically and clinically, as well as the clinical data, how all of that informs to being where we are today. The agenda and the way of talking about it is really meant to address what has been the challenges in CNS drug development, where in many cases, the mechanism of action of drug was not well defined, the disease population was diffuse, too broad. Out of that, over and over again, we get clinical signals that are, at best, modest and often just uninterpretable because we don't know how all of it fits together. What we've been working on over the last few years is to find, give, understand our mechanism of the drug, match that with the right disease, match that with the right patient, the right stage of disease, and then be able to run clinical trials that give clear answers to whether the drug works in the way it's supposed to work in the patient population. And our agenda today, with Professor Taylor and Professor Nixon, who have, whose work and their thoughts have shaped this program and where we've come to, is to really convey that thinking to you, of why we're in DLB, why we believe this is the right drug for dementia with Lewy bodies, and why we are in the right stage of patients, as well as in the right clinical trial to demonstrate, clinical efficacy, and why we believe, ultimately, the REWIND-LB trial, will be positive. And then, answer your questions, and then at the end of the day, let you decide whether you agree with us or not. So, John-Paul Taylor's talk will be about the... Well, underlying all of this is that what ties all of this together is that the drug is acting on a very specific part of the brain, the basal forebrain cholinergic system. And Professor Taylor will describe this part of the system, the cholinergic complex, as well as its role in dementia with Lewy bodies, and otherwise, to talk about the, to describe the disease, and how it clinically all connects back to the cholinergic system. Professor Nixon will then talk about the preclinical data and scientific data that demonstrates, indeed, we work on disease in the cholinergic system, and then underlying it-... In what's a common theme in both our conference and presentations, is that the disease process, if you have the right mechanism, which in the case of neflamapimod, is through acting on p38 alpha and this protein Rab5, that disease process can be reversible. And then my talk will be about which stage of patients within the disease population has that reversible component of the disease. And the short answer is that it's the patients where the disease is confined to the basal forebrain cholinergic system, ahead of where they have significant neurodegeneration and neuronal loss in the hippocampus. So for the moment, this means there's a lot I've just thrown at you, but I'll come back, and we'll come back to this, and as we go through it, I'm hoping that it will all become very clear-cut. So with that, let me introduce John-Paul Taylor. And I'll just say that, I think the short introduction is he is truly a leading authority in dementia with Lewy bodies, and Newcastle is really the world leader in understanding, particularly from a translational clinical science standpoint, the disease of dementia with Lewy bodies. And I think it's a privilege for me, certainly, to have him here, and I think you will agree that, for you as well, that it's actually great to have singularly John-Paul Taylor to talk about dementia with Lewy bodies. Thank you. That's incredibly kind of you. Thanks, John. Great introduction for me. So I think I've got charged now the slides. So, welcome, everybody, and I'm very much tasked to give you a hopefully a gentle introduction to dementia with Lewy bodies or DLB, and then the cholinergic system. My focus, in terms of overview, is very much to present to you DLB as a health challenge, then more specifically, some of the symptoms that people with DLB experience. I will then discuss the impacts of core pathology in DLB and then move to look at the cholinergic system and what it does, and then more specifically, how it's disrupted in DLB. So in terms of DLB, it is a major health challenge, and it sits under the umbrella term of Lewy body dementia, which also includes people with Parkinson's disease who go on to develop dementia, and that's up to 80% of people with Parkinson's disease. Now, I'm not going to be speaking to PDD specifically, but it is important to say that there's huge overlaps in the underlying pathology as well as the clinical symptoms, and undoubtedly, therapeutics will span across, not just DLB, but also potentially PDD as well. Now, the core pathology within Lewy body dementias are Lewy bodies, and more specifically, the aggregation of abnormal alpha-synuclein. Now, Lewy bodies in themselves are. So Lewy body dementia is the second commonest cause of late-life dementia, and there's estimated to be over 1.4 million people living with LBD alone in the U.S. It's associated with poor quality of life, significant morbidity, and increased mortality, and indeed, from point of diagnosis, people with DLB have a much shorter survival compared to Alzheimer's patients. There are significant care costs and economic burden associated with this condition as well, with estimates of two to three times that of Alzheimer's disease. Now, when we look at clinical trials in the DLB and also PDD space, there hasn't been many for, in, and certainly, two decades ago, although there has been an increase in the number of clinical trials more recently. But many of these have been negative, and furthermore, we don't have a disease-modifying therapy. So there is a real significant gap for therapeutics in this space and therefore a real opportunity. Now, when we speak to people living with DLB, their families and caregivers, they recognize it as a complex condition, as do clinicians, and patients present with a medley of wide-ranging and significant symptoms. Obviously, one of the major symptoms is cognitive impairment, but more specifically, patients can experience more cognitive fluctuations or variations in their concentration, their attention, and general function. So individuals can be quite loose at one moment but then confused or switched off on another occasion. And these fluctuations can occur on a minute-by-minute basis, over hour- by- hour, and across days to even weeks, and have very significant sequelae for individuals themselves, as you might imagine, and their families. DLB patients can also experience significant psychiatric symptoms, depression, anxiety, delusions, and complex visual hallucinations where they might see animals, children, people. These can be very distressing. There's also variable degrees of Parkinsonism, so tremor, stiffness, rigidity, problems of gait, tendency to fall. It's also important to recognize that DLB is not just a brain disease, but also is a body disease and can affect autonomic function. What I mean by this is that patients with DLB might experience problems with blood pressure regulation control, so that they might feel faint when they stand up, or they might have a tendency to fall. They can also experience severe constipation, urinary difficulties, problems with regulating their temperature. In addition, many experience severe sleep disturbances. An example of this is the REM sleep behavior disorder, where people thrash out and kick out in the night with vivid nightmares. Insomnia is another feature, and excessive daytime sleepiness. So with all of these symptoms, as you might imagine, it can be incredibly difficult and burdensome for patients and their families. Turning now to core pathology in DLB. As I've indicated, the core pathology is abnormal alpha-synuclein, but we are increasingly recognizing that DLB patients also express other pathologies in their brain, including amyloid and tau, those things which are more typically seen in Alzheimer's disease. Now, different patients express this level of core pathology, variably, but approximately half of DLB patients will have some level of Alzheimer's core pathology. Why is this relevant? Well, certainly, patients who have got DLB as well as the Alzheimer's core pathology, have more cognitive and memory difficulties, a faster decline and shortened survival. Many may experience more symptoms, including hallucinations, and most importantly, they may also experience more neurodegeneration or brain shrinkage, particularly in those areas which are opposite to Alzheimer’s, such as the medial temporal lobe. Turning things a little bit on its head, looking more towards individuals who have got Alzheimer’s disease and looking then at the core pathology of alpha-synuclein. I just draw your attention to the Swedish BioFINDER study. In this particular study, they looked at memory clinic patients, individuals presented to memory clinics, who would have a degree of cognitive impairment, and they conducted lumbar punctures and looked at the cerebrospinal fluid and specifically alpha-synuclein seed amplification, as a biomarker of alpha-synuclein Lewy body pathology. Now, as you can see here on the graph, you can see that the majority of patients had evidence of amyloid and tau, as you might expect, because there may be a predominance of Alzheimer's pathology here, but it's notable that just under a quarter had evidence of alpha-synuclein core pathology. So really, the take-home message is that Lewy body pathology is probably a lot more common than we first thought. So I will turn now to the cholinergic system and very briefly introduce this. So acetylcholine is a core neurotransmitter as part of the cholinergic system. As John presented earlier, there is a number of different cholinergic nuclei in the brain. The main ones are the Nucleus Basalis of Meynert, which sits at the base of the brain, the NBM, but there's also other nuclei as well, including the pedunculopontine nucleus, the PPN, which sits in the brain stem. Now, these are pretty small nuclei, I mean, about the size of a peanut for the NBM and a garden pea for the PPN, but they have incredibly strategic importance to the brain, as I will come on to. Projections or axons from these nuclei spread out right across the brain. So what does the cholinergic system do? Well, it's involved in cognition, attentional focus, memory, shaping how we walk or gait. Also, on a simplistic level, the cholinergic system is a bit like a radio, tuning in the brain to the right station at the right time. So improving that signal-to-noise ratio, particularly when we're receiving sensory information. So it is really strategic in the overall function of our brains. Now, the cholinergic system has axons up to 100 meters in length. And if you were to sort of project and imagine that the brain cell body of a cholinergic neuron in the NBM was the size of a basketball, really to just sort of take home this message, its axon would be over 1,000 km long. Now, there's estimated to be 200-400,000 neurons in the human NBM. That seems like quite a lot, but it's really to sort of, again, on the right, this is a tiny fraction of the total number of neurons which are present in your brain. Yet fundamentally, this particular system has such major implications on how our brain works. Each cholinergic neuron has over 100,000 contacts or synapses. So let's look at the cholinergic system in DLB and its deficits, and I'll first focus in very much from a clinical and imaging perspective. We know that when there's disruption to the cholinergic system, it can impact upon gait and also potentially lead to falls and problems when people are coordinating their gait function and separating their attention. To really sort of demonstrate this, is to take a look at what happens when you try and remediate the dysfunctional cholinergic system in DLB using traditional drugs such as cholinesterase inhibitors. And I'll draw your attention to this study from Emily Henderson. This is in Parkinson's patients, but has relevance to DLB, is that treatment groups have less falls compared to placebo groups. So evidence underwriting the relevance of the cholinergic system for gait function.... We've looked at the cholinergic system in DLB in relation to psychiatric symptoms such as hallucinations. In this case, looking at the brainstem PPN or Pedunculopontine cholinergic nucleus, and its projections to a key area in the center of the brain called the thalamus. When this pathway is disrupted, which occurs in DLB, you have a greater chance of hallucinations. So again, evidence underwriting the cholinergic system and centrality in the clinical symptoms in DLB. When we treat people with DLB with cholinesterase inhibitors, in this case, donepezil, this can improve hallucinations as well as delusions. When we take a look at the NBM, and again, looking at the projections outwards from the NBM, in this case, the lateral pathway, as we call it, we find that there is when there's disruption to this particular pathway, more damage in these projections, that correlates with worse cognition, more rapid decline, and worse decision making. Treating the cholinergic system, again, with cholinesterase inhibitors, which are not brilliant, I hasten to add, that can lead to a symptomatic improvement in fluctuations and attention. What about the pathology? I appreciate this is a busy slide, but I'll just say that there's a lot of evidence underpinning pathology in the cholinergic system in DLB. Firstly, there is more evidence to suggest that there is much more loss or damage to the cholinergic system in DLB compared to Alzheimer's. Furthermore, there are changes in receptors, muscarinic receptors, and nicotinic receptors, as I will present, and these are the cholinergic receptors, so the postsynaptic elements which are relevant for the cholinergic system. That then is associated with visual hallucinations and delusions. So further underwriting that clinical data and imaging data that I showed you previously. There's associations with the fluctuations, and there's also associations, again, with some of the nicotinic receptors. So really take-home messages is that the cholinergic system is deeply disrupted in DLB. There are significant receptor changes. These associated with changes in key symptoms, and the deficits are much greater than Alzheimer's disease. What about early changes and compensation? Well, when one moves to prodromal or pre-dementia groups, and the left-hand side here is a study which we conducted in MCI or mild cognitive impairment, there is evidence that there is pathology in the NBM, so shrinkage of the NBM, even at an early stage. And this is further underwritten by work done in the Mayo Clinic, the right-hand side, looking at basal forebrain degeneration. However, this does represent a window of opportunity, which I'll come on to a little later. Looking across the Lewy body disease spectrum and using other imaging techniques, in this case, PET imaging and a particular tracer called FEOBV, which is a surrogate marker for the integrity of the cholinergic system. What is intriguing is that the uptake of this radiotracer is higher in prodromal or pre-dementia states, such as REM sleep behavior disorder. This is a condition which can predate the onset of Parkinson's disease or DLB. So we're seeing an upregulation, which means that potentially there's an increased level of cholinergic system activity. Looking to the right-hand panel here in Parkinson's disease, individuals who do not have cognitive impairment in Parkinson's disease also appear to have an upregulation as well. That compares to Parkinson's disease patients who have got cognitive impairment. So perhaps this represents a degree of compensation in response to very early changes. So this is a very simple cartoon or graphic to try and perhaps speculatively consider what is going on. Clearly, within the basal forebrain, we are going to have a number of neurons and cholinergic neurons which are dead, which are lost. Nevertheless, there's also other neurons which are potentially stressed or dying. We know potentially that a number of the neurons themselves, there may be changes within the, the projections themselves, but the cell body is still very much alive. Yet other neurons within the cholinergic basal forebrain may be compensating, increasing their activity. Nevertheless, with time, compensating neurons may decompensate, may become stressed, may begin to die. So there is this window of opportunity that we could be moving things away from this particular scenario and stopping the neurons, particularly dying within the cholinergic system. Functionally restoring those neurons which are under a state of stress, where there's peripheral changes, and normalizing those cholinergic neurons which are being compensating or being overactive. So I'm going to stop there, and I appreciate that's a fairly high-level discussion and overview of things, and happy to get down to the more granular detail if there's more specific scientific questions. Thank you, JP. If we can move to the next slide, and we're gonna move right to Professor Nixon at the NYU Grossman School of Medicine, as well as the Nathan Kline Institute for Psychiatric Research. Ralph is a close, I think, has become a colleague to us and to myself. We were introduced originally now about 7 years ago, and we've worked very, very closely together in really defining further the mechanism action with neflamapimod in terms of the cholinergic system. And otherwise, I'll just say that he's really been the key person over the last 20, 25 years in understanding the disease mechanisms in AD, particularly and in particular or more specifically, in relation to the cholinergic system. But it's really much more broadly in terms of understanding Alzheimer's disease. And I think as much as it's a privilege to have John-Paul Taylor here, I think you will agree when he's done that it's a real privilege to have him come and speak to us here today. Thank you. Ralph, turn it over to you. So, thanks, John, for that very nice introduction. What I will be trying to do, as big a picture level as I can, is to discuss the brief history of a very long investigative journey that has implicated Rab5 in Alzheimer’s disease and beyond, because of its connection to cholinergic degeneration. The image on the right is the subject we’ll be talking about, which is the endosome, in particular, the signaling functions of the endosome that are diverse. But, for the purpose of this discussion, the most important signaling from Rab5 is its involvement in mediating the neurotrophic effects of nerve growth factor, NGF, that has to be taken up and delivered to the nucleus to induce a program of neurotrophic growth and maintenance. Without NGF delivery and action, the cholinergic neurons die. And, back in the 1990s, my colleague, Anne Cataldo, discovered that endosomes, Rab5 endosomes in particular, were enlarged grossly in Alzheimer's disease, and more notably, were enlarged at a very early stage of disease before plaques and tangles developed. But around the time that cholinergic dysfunction could be detected stereologically. This enlargement is a feature of both Alzheimer's and DLB, and it is mimicked by most of the well-known AD models, as well as Down syndrome, where a lot of the work has been done by us and by Bill Mobley at UCSD. What we were able to show collectively is this association with basal forebrain cholinergic degeneration, and the fact that the enlargement was due to the hyperactivation of Rab5 primarily, and I'll be talking about what the implication of that is to the cholinergic system and its failure. Let's see. So, one of the most compelling arguments for its linkage to Alzheimer's disease is the fact that the genetics strongly support its disruption by both the autosomal dominant genes that cause Alzheimer's, but also the risk factors, including things like APOE4, which is what Anne Cataldo was able to show is an accelerant of the enlargement process that is partly to explain its linkage to the cholinergic degeneration. But you can see that there are a variety of risk factors that are involved in Alzheimer's disease increasing risk. There's an interesting relationship that's developed, in which the risk factors that, if you look on the right side, the risk factors that favor the entry of substrates and increase endocytic uptake are the ones that are most involved, and those enlarge the endosome. And the ones that are in red that are the recycling functions from the endosome are actually lowered, and the genetics aren't as strong, but the biochemistry is strong, to show that the recycling is lowered even as the endocytic uptake is increased. And that should clue you into the fact that this is the basic mechanism of enlargement. Enlargement itself is a surrogate of the fact that Rab5 is activated. That one of the functions of Rab5 is to accelerate and fuse internalized clathrin-coated vesicles into early endosomes, and that enlargement is a very striking early surrogate of what's happening to the endosomal system. The other, as you could tell from the previous diagram, APP is central to the dysfunction in Alzheimer's disease, and it's mediated by Beta-CTF, not by A beta. The evidence is quite significant. I'm just showing one study on the left that indicates that experimentally increasing Beta-CTF levels... I should explain that Beta-CTF is the C-terminal fragment of A-Beta of APP, that is the first cleavage product of APP, and it then is metabolized to A-Beta. But all of the effects that I'm talking about are actually mediated by CTF and not A-Beta. And elevations, you can see here, slow the speed of vesicles down back from the terminals to the cell body, and that includes the NGF that regulates cholinergic maintenance. And even some of these vesicles get stuck for longer periods of time as a result of the increase in Beta-CTF. One of the things that does this is actually a gamma-secretase inhibitor, which curiously blocks A-Be ta and increases Beta-CTF. So this is one of the strongest pieces of evidence that this is really a Beta-CTF effect, and not A -Beta. The consequence on the right is that you don't deliver NGF back to the soma of the basal forebrain neuron efficiently, and it fails to induce the program to maintain the function and the integrity of the cholinergic neuron, and it results in atrophy. John-Paul indicated that the early stage is the axon starts to fail, and ultimately the cell body is lost. Another piece of really, I think, compelling evidence that Rab5 is central to the mechanism is our study that showed that Rab5, when it's overexpressed to a level that matches what is seen in Alzheimer's disease and activates the Rab5 complex, has this panoply of pathogenic effects. On the right, I've summarized a lot of data, but you can see from the list here, that this is a true model of the phenotype of Alzheimer's disease in many respects, including synaptic loss, LTP, and LTD deficits, and cognitive deficits, and, of course, cholinergic neurodegeneration. So even bypassing the Beta-CTF stimulus that we know is involved in Alzheimer's disease... activating Rab5, and this is important, activating Rab5 by any possible mechanism would promote the kind of phenotypic and pathogenic effects that we're seeing in this model. I keep going to... I put this slide in, even though this paper is about to be published, it isn't available now. But this is another link to... and it explains why Beta-CTF actually does what it does. It doesn't bind to Rab5 and activate it directly. It recruits this other protein, unfortunately, called APPL1. It's a very long name, and it's unrelated to APP. But the interest here is that it's recruited, and its function is to specifically stabilize the activated form of Rab5 on endosomes. It's also notable because it's a signaling molecule in its own right, and it's involved in the signaling of the important players in this talk, TrkA and TrkB, which is a BDNF carrier. It also interacts with some Alzheimer's risk factors that are activators of Rab5. What we were able to show on the right side here is that a mild overexpression in neurons phenocopies the model that I just showed for Rab5. So it underscores the fact that there is this complex and that CTF may be the tip of the trigger, but the complex of Rab5 and APPL1 are the clues to how transport to the nucleus takes place. And part of the clues as to why it fails, based on genetic and other factors that may include synuclein as well, and in fact do include synuclein, which has many of the same properties in disturbing axonal transport as Beta-CTF and APOE and the other factors that slow the retrograde transport that would include NGF transport. This is the flip side of hyperactivation is the capability of a drug such as neflamapimod to block the process of overactivation. And at least one mechanism that we think is relevant is the inhibition of the p38 MAP kinase that is regulating the association of either active or inactive Rab5 on the endosome. And what p38 does pathogenically is to preserve the active form on the endosome, so it is aberrantly hyperactive. What neflamapimod does is to block that process so that inactive Rab5 occupies the endosome, and that down regulates it. And we could show in a mouse model, Ts2 is a Down's mouse model, chromosomally or similar to the trisomy 21, that is the human form of Down syndrome, and has a very early onset of cholinergic dysfunction. The effect of neflamapimod is to attenuate the hyperactivation of Rab5. And those yellow neurons show the normal hyperactivation in this mouse model and the effect of the drug in attenuating that activation. More importantly, the bottom shows that the decline in the cholinergic neurons in the basal forebrain that you see in that mouse model are reversed by the drug. And it was already pointed out that part of the reversal, if the neurons are dead, they're not going to regenerate, but many of the neurons are dysfunctional because they're being metabolically compromised and impaired, and this causes them to lose their cholinergic identity, even though they are still capable of being rescued. And this is part of the promise of a drug to be able to restore a significant function of a cholinergic neuron that looks like it is not ever going to come back to normal. Another feature, which John may be talking about, is that the phenotype in these mice is also a tauopathy that is reversed by the treatment and the inhibition of p38 by neflamapimod. This occurs, by the way, at a very low concentration in fibroblasts derived from individuals with Down syndrome. So that this was also very encouraging early on, that even at concentrations lower than what were used to treat inflammation, this effect in attenuating Rab5 activation was a very striking and complete effect. So this brings me to the final couple of slides, which are more than just a proposal for a molecular pathway to cholinergic neurodegeneration. I think that there literally is a linear pathway that is tipped off, in one case, by Beta-CTF in Alzheimer's disease. But as I explained, it can be tipped off by activating Rab5 directly, which happens with a not quite clear mechanism right now, but by APOE4, independently of Beta-CTF, and it can be tipped off by overexpressing experimentally APPL1. And any of these effects result in the failure of the transport of this complex with carrying the NGF neurotrophin to the nucleus and maintaining that program of survival. The flip side, or I, I don't know if it's a flip side, but it is a, the other aspect, is that all of these black arrows are able to intervene in a very meaningful way in exerting therapeutic effects. Most of these are, have been demonstrated in vivo, some in our laboratory, some in other laboratories, and notably, that UCSD team has done a lot of work in this respect. And, you'll note that the treatments are in many cases, genetic treatments, lowering APP genetically, which reduces Beta-CTF, deleting BACE, one allele of BACE to reduce its activity in produc- producing Beta-CTF. And, of course, blocking Rab5 activation directly with the p38 alpha inhibition. TrkA as well is able to an agonist of TrkA that promotes the signaling in ways that I don't think are fully understood or even replacing NGF are modalities that improve not only the endosome function, but all of these downstream effects that we know from our models are outcomes of the original failure of the endosome to signal. So this is just a smattering of the emerging literature that argues that something that we in the field have known for quite a long time, that alpha-synuclein has properties in many of the functional respects that I just mentioned in as APP does. And those include interactions with... with APP and, in some cases, beta C, not Beta-CTF, but A-Beta. But the studies of its interaction with Beta-CTF have not been as well studied. But what is known is that overexpressing alpha-synuclein has the same downstream consequences as I just described for Rab5 activation by Beta-CTF. And it is thought that there's probably a similar mechanism going on, even though it hasn't been as well studied. And if, as you can imagine, if you combine several factors that activate Rab5, you're going to synergize the toxicity of those effects. In the clinical realm, that seems to be likely that there's co-pathology that is worsened by the co-presence of alpha-synuclein and A-beta and tau, and probably CTF, which is starting to be studied more vigorously. And that the co-presence of these factors in neurons, which is quite common, is a synergistic effect on the neurotoxicity and the loss of neurons. There's actually a talk coming up in the AAIC meeting next week by Dietmar Thal that shows that hippocampal neurons that have both alpha-synuclein and APP markers are lost at a much higher rate. Even though the mechanism hasn't been fully elucidated for the synergism, there is a wealth of evidence that this synergism exists. And finally, this is something that John has already shown, and I think he'll be following up with it. But we see that Rab5 is the center of this convergence of various factors that, on the one hand, are very implicated in Alzheimer's disease. But for very similar reasons, we would imagine are implicated in synucleinopathies. And both Parkinson's and Lewy body have effects on Rab5 and on endosome trafficking that are very parallel to what I describe for Beta-CTF. So I'll stop there, and, I'm sure there'll be questions at the end. Thank you. So if I can get the controls back. Thank you. So I have a few kind of closing comments and slides that pulls this together and brings it back to the clinical program. To begin with, that, to tie back to John-Paul Taylor's talk, one of the key you know, all the... I'm not gonna go through all of the clinical data and the program, but you know the clinical data. But what is important, relative to what we've been talking about, is that all the endpoints that we've seen as John-Paul pointed out, the effects on cognition and function, on gait, on attention, the visual hallucination severity, they can all be tied back to the cholinergic system, in particular, in the DLB patient population. So that's kind of the fundamental argument for why this mechanism, DLB, and we see the readout, the effect of that, directly in the phase II-A data. The other part of, as you know, within the clinical data, is that we do see a more specific and much, actually more better effect in the patients with early stage DLB, who have lower levels of this blood biomarker phospho-tau. Now, what the reason for that, it relates then to go to, is, I'll explain in a couple slides, but from a patient perspective and what the right patient then is, it's the combination of the patient who has defined cholinergic dysfunction and degeneration, and that inherently, actually, the DLB patient population and the clinical criteria define that aspect of the disease. What p-tau181 is doing is actually excluding patients who have disease in addition to that. So it ends up being the combination of the two. A DLB patient population who does not have elevated p-tau181 is defining a patient who has a pure cholinergic deficit- ...as you've heard, that deficit is intrinsically, if you are in that right stage of patient, is going to be reversible and rescuable. So this slide just gives you some more recent data that actually makes the argument about what p-tau181 and that cutoff is telling us. That in our original paper that was published in Neurology in October, we used a cutoff that was based on actually an Alzheimer’s disease patient population, where it defined patients with amyloid and tau pathology by CSF as well as having dementia. So it’s really an A+, T+, N+ population, for those of you who know that designation. But in the DLB patient population, it’s actually very recently, even in the last few months, that publications that really tell us what specifically that cutoff is around. And the bottom line is, what it translates to is either tau pathology or medial temporal lobe atrophy by MRI. And it's fundamentally, what it's telling us is that patients who are above that cutoff level have more extensive and above a certain threshold level of neurodegeneration in the hippocampus. Those are the advanced disease patients. While the early-stage patients are the ones who have the cholinergic deficit, which is defined intrinsically by the diagnosis of DLB, but they don't—they only have limited neurodegeneration in the hippocampus. And that's what allows for the type of effects we're seeing. As Ralph was talking about, allows for that reversal of disease, allowing in the cholinergic system, and with it, actually restoration of function. The basal forebrain cholinergic system, as John-Paul said, is actually not responsible for the actions of tasks themselves. It regulates other parts of the brain, and a critical node there is the hippocampus, where the cholinergic system either tunes, modulates, fundamentally allows the hippocampus to work better, and its role in attention, memory, spatial navigation, or gait. When you have disease here, and this is intact, and you have, which is the early-stage population, with treatment, this hippocampus is going to work better. If there's significant neuronal loss, which are the patients with advanced DLB, elevated p-tau181 in the hippocampus, what you do to the basal forebrain, in effect, doesn't matter, because you can't make the hippocampus work better if it's too far advanced in terms of neuronal loss within the hippocampus. That's the fundamental reason why p-tau181 matters, and that early in that early-stage population, if you are ahead of where there's significant hippocampal neuronal loss, you have this ability to actually reverse clinical progression, see a clinical signal within a phase II study, which are typically three to six months in duration. Actually, in the long run, as we've talked about, gives you the opportunity in this patient population to get, to run, to go to the market with a six-month duration phase III trial. Just a few slides on that actually reinforces that from our data, from, again, from the phase II-A study with the biomarker GFAP, glial fibrillary acidic protein, which we presented at AD/PD. We actually have some more in-depth data on this, or another poster on this at the AAIC meeting. GFAP is a general and actually quite sensitive marker of neurodegeneration. It shows up in all ranges of neurodegenerative diseases. In DLB, in the early stages, what it seems to be is when, in the context where, the patients actually do not only have cholinergic degeneration, it's actually elevated, which would argue that it is actually a direct marker of the cholinergic degeneration in that patient population. And it's supported by our phase II-A data, where we do see, a correlation between CDR Sum of Boxes and GFAP. It's actually quite a good correlation. If you looked at the pure DLB population or the early DLB patient population alone, the correlation is actually stronger than in the patients with more advanced disease, with elevated p-tau181. GFAP does go up as the disease advances because it also picks up the neurodegeneration in the hippocampus. But in this population, what it's really telling you is it's a marker of the cholinergic degeneration, and it's in that population where we do actually see a significant reduction, compared to placebo. It's actually a reduction relative to baseline as well, with neflamapimod treatment. This is comparing baseline to week 16. We don't see that in the patients with elevated p-tau181. And so it's again telling you, it's a direct evidence, that in this patients who have a pure cholinergic degeneration, dysfunction and degeneration, we are reversing the disease process.... We don't end up picking up that effect, in the patients with elevated p-tau181, because it doesn't have the effect, presumably, on the hippocampus. It may, in the long run, slow the neurodegeneration, but it's within a 16-week trial, what we do pick up is this reversal and improvement on a neurodegenerative marker. And that's that much more reinforced because we do see a correlation to the clinical outcome. Again, in that early DLB population, where the patients who have a reduction in GFAP, none of them worsened, and four out of the nine actually improve. We're actually making a direct argument that we are reducing the cholinergic degeneration, or the dysfunction as reflected by GFAP, and that is leading then to the beneficial clinical outcome. Now, as many of you heard me said, that, you know, this was a phase II-A study, it was an exploratory study, and we fully acknowledge that and the number of patients. Very consistent results, so we believe they are, as we've talked about, reflect on there is evidence of efficacy. But to actually claim efficacy, we have to do a confirmatory trial with a predefined hypothesis, and that's the REWIND-LB study. 80 patients per group of 40 mg TID against placebo, of matching placebo. But critically, we're excluding patients with the more advanced disease, focused on the patients with early DLB, with the pure cholinergic dysfunction, where our drug mechanism matches the patient, and we're using the CDR sum of boxes as a primary endpoint. The argument for the right trial ultimately is in the likelihood of success, probability of success. We actually originally, the 80 patients per arm, comes from... We originally were going to have the mixed population. But after our NIH grant review and feedback, we actually excluded the patients with more advanced p-tau181. And so, obviously, with a significant increase in activity, we have significantly more power, and that's demonstrated by when we do clinical trial simulations and look at the CDR sum of boxes with 80, 80 patients per arm using the data out of phase II-A, essentially, it hit on all 100 simulated clinical trials. So there's a if we are, you know, in the range of activity that we saw in phase two A in this population, this trial should read out positively, which would then set us up for phase three, again, to be initiated in the middle of next year, pending alignment with the FDA on a design in an end of phase two meeting that we plan for in the first half of this year. This trial will be very similar to the phase two B trial. We'll try to change as little as possible. The one add we plan on adding is to have all patients have MRIs and to look at basal forebrain atrophy, as John-Paul Taylor described. This is probably the most rigorous biomarker to track the actual cholinergic degeneration, degenerative process. We have a subset of patients in REWIND-LB who are actually being analyzed for effects on basal forebrain atrophy, but that's primarily to plan for phase three. And as many of you know, we have seen effects on basal forebrain atrophy in a study in AD we had otherwise done. So I will stop there and open it up to questions, but I hope what we've been able to convey is by the work we've done over the last few years and the advances in understanding DLB mechanism of drug and the clinical data, we really do believe we are in the right patient population with the right drug, and we've designed a trial that will confirm that effect. Great. Thanks, John. At this time, we'll be conducting a question and answer session with our speakers, so please hold for a brief moment while we pull for questions. Our first question comes from Sumant Kulkarni at Canaccord. Please go ahead, Sumant. Morning. Thanks to CervoMed and John for organizing this informative event and for the opportunity to ask questions. I have three, actually, one for Dr. Nixon, one for Dr. Taylor, and one for John. So for Dr. Nixon, is there an elegant imaging modality or assay to measure endosomal enlargement, to either utilize that as a screening tool for trials or as a biomarker for regulatory purposes? There's not been as much data on that, but there is some, and it's from Madeleine Potier from France, who has been using various blood elements and was able to measure enlargement in these studies. I don't... That was some years ago, and I don't know if it's been followed up or confirmed by others, but it was promising that a peripheral blood sample might be useful to as a surrogate. Yep. For Dr. Taylor, do you think that real-world diagnosis of DLB will be consistent with the opening of the window of time that treatment with neflamapimod may be most optimally started? In your view, is p-tau181 cutoff that's used specifically in this trial, sensitive enough to get the right patients into the trial? Okay. So, yeah, just the first point about, I suppose, the diagnostic sensitivity and specificity. I think that what we have established is the consensus criteria for DLB, which is predominantly clinically based, although it brings in biomarkers such as, say, the DaTscan within that. And they've been around for a little bit of time now and have been through several washes of validation against neuropathology, and hold up pretty well in terms of, you know, the specificity. The sensitivity is perhaps a little bit lower than the specificity, but that means, in essence, you're very much likely to get the right patients into the trial, rather than having, you know, misdiagnosed individuals. I think on top of that, clearly, we've got the SAA biomarker, which is now heading, hitting us at the moment, both on the CSF side and also skin biopsies. I think this is really opening up the frontiers, and again, the readouts on this are still nascent, but, you know, are looking very promising in terms of the sensitivity and specificity. I know data will be emerging on the Neuropath side on that as well, soon. So there is a building. So I would feel pretty confident that we can find the right patients. I think it has been a challenge in the past in terms of identification of patients, and there's always the challenge of recruitment in this particular complex group, as it were. But nonetheless, I think that the general direction of travel, because it is actually... there's much greater cultural awareness of DLB now in all sorts of jurisdictions, and in the U.S. in particular, I, you know, we have the LBDA's, you know, centers of excellence. This has raised the profile, so it is getting much more recognized, much more diagnosed, which means that there's a defined population now to recruit to trials. So I would feel pretty confident on that. But with regard to the cut-offs, you know, I think I'm not gonna... I mean, that's probably more in John's turf regard to, you know, that separation, because in a way, that is asking very much in regard to, as I was alluding to, this sort of Alzheimer's co-pathology question of whether that is present or not. And I think that, you know, clearly there's a degree of arbitration when one thinks about a cut-off rather than necessarily quantification, and I'm sure I won't, I won't speak to what John might say on this, but, you know, in secondary analysis, one will want to take a look at that from a quantitative perspective to understand, you know, what the expression is. But I think that, you know, it very much fits within the A/T/N framework on the Alzheimer's side as a cut-off. You know, we also have other emerging, that, you know, the AD biomarkers, the 217, which can also be examined. But I think as a marker here, I think it's a very sort of neat way to help identify and delineate those individuals who have perhaps a much more pure DLB clinical and pathological phenotype. You know, because clearly we do see, and I think John didn't get time to mention certainly some of the data, and when I showed some of it, where the pathology, the co-pathology really does modify the clinical course and the overall projection of how people change. And certainly as well, will have implications about clearly how therapeutics are looked at for this population group. I don't know if that's answered your question, but... It does. Thank you. One for John before I hop back into the queue. So we know your plans are to conduct a phase III trial, but given you're following the science and the data here, in the event that you get an overwhelmingly positive result in the confirmatory trial, what would your next steps be, given the unmet need in DLB? Before I answer that question, I'll just add on to John-Paul's answer. It is that I think certainly in terms of early enough, everything argues it ends up being actually more similar than to what we're seeing in AD. It's a tau signal that really defines whether or not you're going to have a response, a treatable patient, a responsive patient or not. And that's what the p-tau, plasma p-tau cutoffs are telling us. And then, too, can you identify them? I can just say that in our screening data in phase IIa, you know, you were at AAIC, we were together at AAIC, and we were wondering, like, how it was going to play out going forward. But in our screening data, you know, the 65, about two-thirds of the patients who had a CDR 0.5 or 1, so very mild or mild dementia with Lewy bodies, met clinical criteria. Two-thirds of the patients were below that cutoff that we're applying in the phase 1b trial. So I think it's actually, as we had suspected, we're seeing this data now that DLB just presents with more patients ahead of when they are too far advanced in terms of their disease process. You know, if we get great results in phase II-B trial, I think the best way to approach that is, you know, we go to the FDA, we'll be in the phase 2 meeting, we'll see the data. Be prepared for that contingency, and we are, you know, this hasn't been actually a quiet time, quiet summer at all for us on, within the company. We're really actively, fully gearing up the development program on the side you don't see, on the non-clinical and the CMC side, et cetera, to be prepared if there is an opportunity to move forward with the, with the phase 2B trial. But I think it's hard to handicap that today without the data. Thank you. Could I just quickly follow up my answer, which was that there is a very promising avenue regarding extracellular vesicles and markers within them that are instructive for Alzheimer's disease and could equally be instructive for synuclein. And there's a huge interest in developing that as an early marker that would be applicable to DLB, I'm sure. In that case, Dr. Nixon, I'll squeeze in one question for you. On a biomarker, what do you consider the best biomarker for pure DLB that could be used as an endpoint in clinical trials? Would it be GFAP or basal forebrain atrophy or something else? I think it would be more something related to the contents of the endosomes that are recovered via their surrogate, the exosomes that are released into the blood. I mean, if you're talking about brain itself as a biomarker, again, I would be looking at more specific endosomal lysosomal markers as opposed to inflammatory markers, which are more general. I think it depends on, Sumant, on a biomarker for what? If you want the biomarker in terms of the pathogenic mechanisms, et cetera, then I would agree with Ralph. I think if you're really talking about a surrogate endpoint of the disease process, you have to go back to, like, what is the closest marker of the underlying true pathology, which is neuronal loss. And maybe I'm just marked by my experience with MS many years ago, but at the end of the day, that should be MRI and looking at atrophy measures. And there, that's the reason why we're we would anticipate building in basal forebrain atrophy, because that in the end we're talking about slowing the underlying disease process, it is fundamentally our long-term goal is towards slowing neuronal loss and preventing neuronal loss. Our most sort of pathology, like true pathology, our most direct measure of that is MRI. Thank you. Can, can I just add to that? I, I agree. Certainly, the MRI is a great marker, and again, you can nuance that by adding a volume functional PET tracers, and I presented the FEOBV, which is a pretty good marker of cholinergic integrity. There's other PET tracers as well, which could be applied in that way. And people have also looked at rather clever ways of looking at metabolic imaging with FDG PET, which is more widely available. So there are ways to look at that and I suppose triangulate across the board if you're wanting to get some surrogate of cholinergic response. And I know we've also looked at EEG as well as another route in as well. And me and John have had conversations about the utility of that particular modality. Yes, we are looking at EEG in the phase II-B study. We're exploring actually some work and looking at FEOBV to look at. But those are... I would say that they help you understand more of the drug, and they are biomarkers that are, and perhaps better described as pharmacodynamic markers of actually confirming drug action. And my comment, the more aggressive comment, perhaps, was around to think about surrogate endpoints, which is really: Could you use that to actually demonstrate disease progression and a claim around disease progression? And I think there it is actually atrophy is in some part of the brain, whole brain, cholinergic system, hippocampus or wherever, is probably the only one that would hold up. There are, yes, there are other imaging techniques in particular to look at drug effect, and are you impacting the underlying disease process? Thanks. I'll hop back in the queue. Thanks for the question, Sumant. Our next question comes from Soumit Roy at JonesTrading. Please go ahead, Sumit. Hi, everyone, and thank you to all the speakers to take us through the mechanistic aspect of this cholinergic system. Possibly one first question is for Dr. Taylor. It looks like, DLB is quite a heterogeneous patient population with multiple co-pathology signs of Parkinsonism and Alzheimer's disease. Using that cutoff, or in the real-world scenario, what percent of DLB patients at diagnosis do you think are really pure DLB patients without any AD or Parkinson's disease pathology? Is it 25%, a third of the patient, half the patient population? What's the real-world scenario look like? Yeah, I mean, I think I'd refer back to John's comment on this and their screening data from which is, you know, as close as we can say to real world, and particularly in the context of a clinical trial. And I think, John, you indicated that in essence, 60% of individuals fell within the pure DLB domain. And I think that, you know, again, the evidence is certainly suggesting about a 50/50, so one in two patients will have evidence of, you know, the raised, you know, evidence of tau pathology as an example. So I think that is perhaps a rough rule of thumb that one would take away with that. And apologies, I've forgotten the second part of your question. No, I think you addressed that. The other question probably for, for John is, it's a, it's a tall ask you're going after from neflamapimod is, to reverse this disease pathology. Going back, one of the earlier questions I've asked is, is 4 weeks enough, long enough time point now that the trial size is significantly 5 times larger than the phase II-A? There is inherent patient variability by age, by other markers. What is the plan if at 16-week you do not see, or is the goal is to start another trial with a, 52-week, or do you think it... You can completely change tack and use a combination approach, use one of these approved drugs, which targets the amyloid plaques and combine it and expand the enrollment criteria, because from Dr. Nixon's. I don't think it's a tall order. What we're not saying reversing, you use the term reversing the pathology. We're not saying that. What we're saying is, it's functional improvement. These are, as both, you know, John-Paul and Ralph both showed in their presentations, the neurons are still there. You don't need to bring them back. They are sick, they're stressed, they're not expressing cholinergic markers, and they, you know, and, and it is a... and, and they come, you know, they can revert. And it's not four weeks either. It's 16 weeks is the placebo-controlled period. Right, 4 months, sorry. We saw that effect within 4 weeks in the preclinical data. And it is that if you have a direct effect on and can actually restore function, then it's going to show up relatively quickly. And we saw that in the clinic in our phase II-A study. We saw separation on attention test. We only measured the cognitive testing at 4 weeks. We saw a difference from placebo at 4 weeks in our phase II-A study. On CDR Sum of Boxes, there was a clear difference from placebo at the first time point it was assessed, which was at 8 weeks. Again, I refer you back to what I showed in the, you know, in this diagram. The trajectory we're seeing is we're where it's not about slowing of progression, but it is actually showing that improvement and restoration of function, which actually shows up relatively quickly. And everything, particularly given our 6 phase two A data, there is no reason it's not gonna show up at 16 weeks. The reason to go longer is to be able to show, in addition to that, a slowing of progression and stabilization, over a longer period of time. And that, I think, is something we can consider at some point, but if we have this kind of improvement and restoration, I don't think it's... and you can go to the market with 6 months, I don't think it's ethical to run placebo for much longer than that. Certainly, you would have to have some sort of rescue program provision if someone has had, does progress. And if you look at this window of opportunity before you've advanced too far in terms of neurodegeneration, you know, in terms of hippocampal neurodegeneration, and look at the survival curves, I'm not sure it would be correct to go much longer than that. Again, fundamentally, we don't need to go longer than that because we've already shown that in the clinic, that we see effects as early as four weeks. Perfect. Thank you again for taking the questions. Thanks for the question, Sumit. Our next question comes from Tyler Bussian at Brookline. Please go ahead, Tyler. ... Yeah, thank you very much. It was a great talk all across the board. I've got about 3 quick questions here. Hopefully, they're quick. But I wanna start with, John, you had kind of talked a little bit about, loss of neurons in the MRI being a readout or potentially a surrogate readout for, you know, phase 2, phase 3, your phase 3 trial. Where is your opinion on some of the other research being used, like plasma neurofilaments, as a readout for neurodegeneration, or how does that play into potential clinical trial plans? I think if you look at in DLB, in particular, NfL is elevated along with GFAP, but in most analyses that have been published, and there is one that just came out, recently out of the Amsterdam UMC, GFAP is more sensitive and more discriminant. If you look in, for example, in MCI or prodromal DLB, there's one paper that they're both elevated, which I think was from Newcastle, but again, the specific statement is that GFAP is more discriminant. But in the Mayo study, you know, NfL was not elevated in MCI due to DLB, and neither was p-tau181, obviously. But the only biomarker that was elevated was GFAP. I think the other thing is that more consistently GFAP is correlated to cognitive outcome and rate of cognitive decline, and this is now including AD and DLB. If you look across a range of data, GFAP performs better. A little bit of that is, and the one exception is FTD. FTD, clearly NfL has a bigger signal. Mm-hmm. But in AD and DLB, GFAP, in my mind, consistently performs better. Great. My second question is for John-Paul. So you were part of the 2017 McKeith consensus report that kind of is the basis for DLB diagnosis, and that report, I think, is now closing on 7-8 years old. I just kind of wanted to get a sense of how is the field kind of generally thinking about DLB diagnosis after that period of time. What do you think might be parts of that kind of next diagnostic criteria? How is CervoMed trials going to work? That's an excellent question, and actually, you're probably alert to the fact that there's been two proposals put forward for biological frameworks in the Parkinson's disease and DLB space. One from Michael J. Fox Foundation, the neuronal synuclein disease as a proposal and staging system. And then there's one from a Canadian group, SynNeurGe, it's called, and a lot of those are predicated on a very much biological definition of the Lewy body disease spectrum, diseases, that it is. I'm not gonna go into the details. It is relatively complicated, but in essence, that is all pivoting around the synuclein amplification assays and their utility as being, I suppose, the sort of the gold standard for the detection of alpha-synucleinopathy. So I think that... I mean, there are still many, many questions about that, and it's very live and very dynamic at the moment. But I suppose there is a sort of question of how that will then impact back to the consensus diagnostic criteria for DLB. We are having our international meeting, where the DLB consortium and community comes together in Amsterdam in January, and it's undoubtedly gonna be a topic of that. Now, forward directions, if I was, and again, this is crystal ball gazing, I would guess that there is an intention, given it's been quite a hard pathway to raise the profile of DLB, that we will not be wanting to make major changes to the criteria. But it's potentially that within the indicative biomarker section, that a something like SAA would be embedded, whether that's, you know, from CSF or, or skin-based. So I think that would be the sort of forward direction to potentially include that, but I think it would not be-- we would not be predicating a diagnosis, or, or, you know, or mandating the, the use of of SAA as a biomarker, given that it's not, you know, it's not easy to acquire, it's not ubiquitous. And certainly, we know that the the clinical criteria, combined with the existing indicative biomarkers, tunes in very well to what's happening from a neuropathology perspective. So I think that that would be my thoughts, although that is speculative thoughts, 'cause the the field, I have to say, is is moving quite rapidly. I suspect that, you know, from a CervoMed perspective, there will be views to take a look to see how people map across to these other biological frameworks. But I think that, you know, from a community and patient perspective, from a regulator perspective, from a, you know, I suppose a delivery of these treatments clinically on the, you know, the, at the real coal face, it will be about clinical diagnosis of DLB. What else do I need to do to, you know, introduce drugs such as lecanemab? Do I need to do anything else, a blood test? Okay, I'd need to do p-tau to determine whether somebody should or shouldn't have this drug. Then I think that will be sort of a relatively more easy ask. Hope that— Does that answer the question? Yeah. No, that, that gives me some insight. It seems like things are basically gonna stay the same, but there are some indications that might be footnotes, that these would be a better indication or diagnosis criteria if you have access and ability to. Is that a fair kind of summary? ... Yeah, I think that's, so that's with the additions, but it perhaps not necessarily changing the structure of the diagnostic criteria, but maybe adding in, as I say, SAA, as one of the indicative biomarkers, and then that would open up the possibility for further validation of this as an additional biomarker modality. Yeah, Tyler, I would add to that, just from a, you know, just, and I went through it a little bit quickly, but from our perspective, you know, if you use the AD analogy, it is, you know, it, they're using amyloid PET or other amyloid markers because they have anti-amyloid therapy. Mm-hmm. That's how they're matching the patient. Inherently, with our mechanism and drug, because of the specificity of the criteria for actually defining a patient with a cholinergic deficit, inherently, the clinical criteria actually get us to that, the match we want to do. And it is, if we go back to actually much earlier data out of the National Alzheimer's Consortium, et cetera, that, you know, the specificity of the DLB diagnosis is substantially higher than in AD. Mm-hmm. If you're gonna market against ultimately amyloid plaque or not. And so there is, like, from a drug development standpoint, with our mechanism, there is actually less of a need to define the disease biologically, because inherently, the biology goes with the diagnostic criteria. Great. Well, thank you guys very much. I appreciate the time. Thanks for the questions, Tyler. Our next question comes from Boobalan Pachaiyappan at Roth. Please go ahead, Boobalan. Hi, everyone. Can you hear me okay? Yes, we can. Yes, we can. All right, great. So in the interest of time, I'll be asking only one question, but I would like, I would love to ask more. But, so anyway, at a high level, maybe to you, John, so brain disorders have gained significant traction, especially in the last couple of years. So just to mention some examples, maybe on the regulatory side, we witnessed the approval of lecanemab and donanemab, and also on the M&A side, we saw, AbbVie taking over Cerevel for a little shy of $9 billion, and BMS taking over Karuna for $14 billion. So I'm curious, how do you expect to leverage this uptick in market activity into your playbook as you think about designing your long-term strategy for several shareholders? Thank you. So I think the CervoMed acquisition is probably the best example of this, but it ties into lecanemab and donanemab as well. It's again, that diagram that I showed. The appetite is for context, et cetera. And ultimately, what it-- well, ultimately, what you need to be able to do is to deliver value to patients and to the system. And I think it's actually what works is, if you can do it within relatively short period of time. I think that a pure disease progression effect is just inherently difficult to demonstrate clinically, and it's difficult to actually demonstrate substantial value. What sets apart lecanemab and donanemab is that they target the oligomeric forms of A-beta, or the more complex forms, and they actually, underlying it, they have a certain symptomatic effect, that relative to a lot of the other drugs, they see some separation of, from placebo in the curves relatively early in the timeframe as they're clearing plaque. That's what allowed them to get a better efficacy signal. That's what allows them to actually make a better, result in, in, in the end and, and more successful. It's the same thing with Cerevel. The approaches there are, they went after symptomatic approaches that actually do improve, and you can get the signals in phase two, you can get the... and, and just simply confirm it in phase three. That's what we're trying to do, and I believe this is everything we're, what we were talking about here is to do that. In CNS, what's reproducibly successful is if you can get a clear efficacy readout, actually, you can call it a symptomatic improvement, but it's actually a symptomatic effect, but it's actually restoration of function, giving benefit to patients in the near term, then that translates, you can get efficacy in phase two, that translates in phase three. That's more value to patients, more value to caregivers, more value to patients, to, to the system. And this patient population we've defined in DLB, actually, that's the fundamental therapeutic drug development and commercial opportunity, is that you can actually restore function, you can improve, you can deliver benefit in a six-month phase three trial. That's what we've been attempting to do, and it meets in this disease, in these patients, and we believe we're gonna show that very clearly in the REWIND-LB trial when the results come out. All right. Great. Thank you. PJ at LSA, I think we're gonna take one more question that you're going to read out at this point, or Karen. Correct. Yeah, I'll take the last, written-in question from Jeff Hung, from Morgan Stanley. And John, I think you're most suitable to answer this, but, can you talk about your expectations on compliance rates in pure DLB patients? And then, would you expect a meaningful difference in the real world, and how does the TID dosing impact compliance rates, in pure DLB? We would not expect any substantial impact. You have to remember that they're early, but they're symptomatic. I mean, they have. This is not preclinical AD. This is symptomatic. This is patients with dementia with Lewy bodies, and if you look at the data, as I think John-Paul alluded to, but there's clear-cut data. If you look in these early populations, on the CDR sum of boxes, the functional deficits and impairments are actually on those domains, they're consistently worse than in an AD patient. So there's an impact that caregivers see. And so there is a drive for treatments, you know, to provide to these patients. This is the very reason, again, of why you want to be able to have, again, a disease-modifying drug actually have a symptomatic effect because patients see it. We haven't had problems with adherence and compliance in our Phase 2A trial. We don't expect it here. It's a highly motivated patient population. There's a tremendous medical need. And what works with our TID regimen is that it has to be given with food. That's substantially better than if it were fasting. And, you know, the TID regimen is, you know, you just take it with every meal. It's not every 8 hours. So that's important also. There are certain advantages actually over BID in that if you miss a dose, what our advice is and what patients and caregivers do is they double up on the next meal, on the dose. If you miss on a BID regimen, you go 24 hours without a dose. So there's, again, in this context, it's not an issue. I will say that, as we've talked about, we could match the same C trough, which seems to be the PK parameter that drives efficacy based on our full set of analyses, including our AD data, with 80 milligrams twice a day. We didn't incorporate it in the phase II-B because we didn't have any PK data, pharmacokinetic data, with giving two 40-milligram capsules. We are... But it is a possibility within the Phase 3 to have that as an additional arm. We would not expect any difference in efficacy with that, because the C trough would be the same. To be determined, actually. That's the reason to do the PK study first. But it may give an option for patients if they don't want to go with the TID regimen. So we will stop there. We are a little over time already, but I'm actually very glad that we had the opportunity to bring in the questions and the further discussion. I want to first thank you, Ralph and John-Paul. Again, thank you very much. Your talks were great. I actually personally learned some more again. Every time I read your papers or listen to you speak, it's both of you, I learn more. But that was great, and I'm sure the audience is very much appreciative of your talks and your comments as well. So thank you again, and then thank you again to everyone who was listening. There were some questions in the queue. We will follow up with people individually, our LifeSci Advisors, or we will directly follow up in that regard. And I look forward to seeing you at some of the upcoming conferences, and continued discussions otherwise directly with many of the people in the audience today. Thank you very much to all, and have a good day.