Good morning and welcome to the Cognition Therapeutics Conference Call. 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. As a reminder, this call is being recorded, and a replay will be made available on the Cognition website following the conclusion of the event. I'd now like to turn the call over to Lisa Riccardi, Chief Executive Officer of Cognition Therapeutics. Please join us. Thank you. Thank you, Sarah. Good morning, everyone. Thank you for joining us. First comment, please see our forward-looking statement. I'm Lisa Riccardi, President and CEO of Cognition Therapeutics. I'm joined this morning by my colleague, Dr. Tony Caggiano. Tony is the Chief Medical Officer of Cognition. We are so pleased this morning to be discussing the results of our SHIMMER trial in patients that have dementia with Lewy bodies. It is often referred to as DLB, has been called the most common dementia no one has ever heard of. Now, to clarify any misunderstandings or lack of knowledge, and to provide you with a deeper understanding of both the disease and the import of our results, we are joined by one of the foremost experts in DLB, Dr. James Galvin, Director of the Comprehensive Center for Brain Health at the University of Miami Miller School of Medicine, is joining us today. Dr. Galvin is the PI for the SHIMMER trial. He'll give us an overview of DLB and patient experience. And following that, Tony and Dr. Galvin will present and discuss the SHIMMER results. Finally, we're going to talk about what these results mean to the patient, the caregiver, and the clinician treating the DLB patient. One note, please type your questions in the chat box, and if we have time, we'll address them as we have time to do so. With that, let's begin. Dr. Galvin, Jim, good morning. Please tell us about your practice and how you became interested in treating patients with DLB. Sure. Excuse me, everybody. I have a little bit of laryngitis today because I was so excited about presenting the data this morning. So I'm a neurologist, Professor of Neurology at the University of Miami, and I've been taking care of patients with dementia with Lewy bodies for almost 30 years. I came into the field as my grandfather developed the disease, and it really led me to think about what we could do to improve the care of our patients. DLB is, as Lisa mentioned, a very common cause of dementia only after Alzheimer's disease. There are approximately 1.5 million Americans who are living with the disease. And one of the things that's really important, it's characterized by a number of features. And those features are dementia, but the dementia looks a little bit different than the dementia we see with Alzheimer's disease. And it has a number of other features, which both make it difficult to make a diagnosis and leads to a number of therapeutic challenges because you have to balance the effects of medication on each of these individual symptoms. So the core features of DLB are what we call fluctuating cognition. These are spontaneous changes in alertness and attention, neuropsychiatric symptoms, particularly visual hallucinations, anxiety, depression, and other mood disturbances, and delusions. This disease is more common in men. There's often a tremendous delay to diagnosis, and that's problematic because DLB has a faster rate of decline than we see in Alzheimer's disease. So it requires patients to have a number of visits with a number of physicians roughly over a year and a half before they're correctly diagnosed and offered any therapy. Here's the key: there are currently no approved medications in the United States to treat patients living with Dementia with Lewy bodies. Jim, that's excellent. Thank you. I believe you're the one that coined the phrase, "Lewy body dementia is the largest dementia," that no one has ever heard about it. Why? After all the challenges these patients have, doesn't anyone know about it or understand it? Yeah. Again, I think it comes down to really the collection of symptoms. And so it's often misdiagnosed. It might be misdiagnosed as Alzheimer's disease. It might be misdiagnosed as Parkinson's disease. And while those are not technically correct, they're not terribly wrong diagnoses because it's depending on the way the patient presents. But 25% of the patients are diagnosed with a geriatric psychiatric disease, like geriatric schizophrenia or bipolar disease, and 25% of the patients never get a diagnosis. So this has caused a tremendous burden and stress for the patient and for the family. Excellent. Thank you for that clarification. In your practice, how do you make the differential diagnosis: DLB, Parkinson's, AD? Right. So the key really is what we do in our practice is we focus on trying to first interview the patient and do the exam on the patient. But we also listen to the caregiver. So we do separate interviews with the caregiver that really allow us to understand what were the first symptoms, how did they progress, and how are they interacting with each other in order to affect the patient's everyday functioning. And it helps us understand what medicines might be the right ones to use for these patients who are living with this sort of large collection of diverse symptoms, which is very unique. It's very different than a lot of other diseases such as Alzheimer's disease. Sounds quite complicated. Let me ask you this, Jim. How many new patients do you see a year? How often do you make a DLB diagnosis? So in my clinic, we're currently following about 150 patients with Dementia with Lewy bodies from the very mildest stages all the way through the later stages of disease. We do a very comprehensive assessment at the first visit, and then we try to tailor the visits for follow-up depending on what the patient and the family needs. So patients that are very mild and have mild symptoms might need to be seen less frequently. Patients with behavioral symptoms in particular need to see more frequently. So we try to personalize the schedule of visits based on the patient's presentation and the family's distress. Excellent. Now for the heartbreak questions. What do you tell patients to expect when you tell the patient and their caregiver about DLB, and what are the biggest concerns patients have? I think it's important to remember that when we see a patient, we're seeing that patient, and each patient's different. But in general, we really want to try to prepare the family and the patient for some of the symptoms that may appear. Now, again, one of the challenges is all of these core features of Dementia with Lewy bodies may not appear all the time. So while the dementia is present all the time, the fluctuations may come and go. The hallucinations may come and go. The sleep disturbances may come and go. And so this can be a real challenge because it's often hard for the patient and for the family to determine is the patient getting worse or not. We do know that the patients progress much faster. And so from diagnosis to death, the median time is roughly between four to seven years. It's a much more progressive disease than we see in Alzheimer's disease. It's important to make an early diagnosis and then to intervene as early as possible so that we can provide the best quality of life for our patients. Thank you for that. What would be helpful, Jim, is to understand how you use these different scoring tools in your observation and treatment of patients? Sure. So as the slide actually nicely says, it's like a buffet of symptoms, and the important thing is not all patients will have all symptoms, and patients that have symptoms will not have those symptoms all the time. What is consistently present is the cognitive decline, the dementia, so when we think about how we're going to review these different symptoms, we can put them into little buckets, so for behavioral symptoms, this will often include visual hallucinations, delusions, particularly something called Capgras delusion, where people believe their loved ones have been replaced by an identical imposter, and anxiety, and then they have other symptoms. They can be agitated, irritable, depressed, and so we have to think about what tools we would use to try to determine this. One of the assessment tools that's commonly used both in clinical trials and in clinical practice is the Neuropsychiatric I nventory or NPI. As part of that, we collect a rating on how distressed the caregiver is based on these symptoms. You might have a mild symptom, but it might be very distressing to the patient and to the caregiver. It's important to capture not just the severity of the symptom, but how much it's affecting the caregiver or the care partner. For cognition, we want to be able to capture all the different aspects of cognition, so memory, executive function, attention. We use a large number of tools to do this. These can be pencil and paper tests, such as the Montreal Cognitive Assessment or MoCA, or they can be computerized tests, such as the Cognitive Drug Research System. And so these are valuable because it allows us to capture snapshots of how the patient is performing, and then we can look and see how the patient is doing over time. We can also use a scale to try to capture these fluctuations. And so we can ask questions as to how often they occur and how long that episode lasts. And that's called the Clinician Assessment of Fluctuation Scale. But it's not just cognition and behavior. You have to think about the patient as a whole. So how are they functioning in their everyday activities? So they're bathing, they're toileting, going out into the community and shopping or interacting at a community event, meal preparation. So we capture these on an activity of daily living scale. And that allows the caregiver to actually report how much change they're seeing in their loved ones. And the last, and this is what makes DLB also very unique, is the movement problems, the symptoms of Parkinsonism. So very slow in initiating a movement, continuing a movement, lots of problems with gait and balance, very stiff, a change in facial expression, a change in their voice, a change in their handwriting, and sometimes tremor. So we can use a standardized scale called the Movement Disorders Society or MDS, Unified Parkinson's Disease Rating Scale or UPDRS. So the combination of these very powerful clinical and clinical research tools allows us to make a correct diagnosis and follow our patients over time. Excellent. It sounds extremely challenging to integrate all this information to look at a patient holistically as you treat them over a series of years. How challenging is it to design then a clinical study in this population where there's so much variability? It's very difficult because, one, there's lots of different symptoms, two, not all the patients have the same symptoms other than the dementia, and three, they tend to fluctuate, so they're there sometimes and may not be there other times, and last is that often any intervention on one bucket may have a negative consequence on another bucket, and that's made it very difficult in the clinical setting to treat these patients, so there's a tremendous unmet need for symptomatic and disease-affecting therapies that can address each of these buckets without having negative consequences on the patients. Excellent. That's so helpful. Thank you, Jim. Last question before I turn it over to Tony. What did you want to see coming out of the SHIMMER study? The things I want to see as a clinician and as a researcher is, one, is the medicine safe and well tolerated? Because these patients are very sensitive to medications and therapeutic manipulation. Very, very sensitive. And two, do we see signs of efficacy? In an early phase trial, like a phase IIA study, it's most important to try to understand, is there a signal in our primary and exploratory outcomes? And two, is there a movement of direction that promotes further development of the medication? So I want to see a medicine that's addressing each of these buckets without adversely affecting one of the other buckets. And that has been the great challenge in trying to do any clinical trials in DLB. So well said. Thank you, Jim. Not easy to do, but extremely well said. Tony, over to you. Perfect. So thanks for the introduction, Jim, and despite your trailing voice, I'm going to ask you to comment on the data as we go through it and give a little perspective around what this means for people with DLB and also what it means for your practice, so as a little introduction to the trial, the SHIMMER trial or COG-1201 was a phase II trial. It was our first trial with CT-1812 in dementia with Lewy bodies. This was a placebo-controlled randomized trial where individuals were evenly randomized to one of three different groups receiving either 300 or 100 milligrams of CT-1812 or placebo. Individuals were treated for six months with daily dosing of CT-1812 or placebo, and then we followed the symptomology throughout the course of the study. Now, the primary objective of the study was to confirm safety and tolerability of CT-1812, but also to explore signals of efficacy of CT-1812 in improving the symptomology of these people with DLB. Now, as Jim described, because DLB has diverse symptomology, we look at a range of outcomes ranging from measures of behavior, cognition, function, and motor symptoms. And those are the assessments that Jim described just a few minutes ago. And we'll go through those data now. So overall, we're incredibly excited to see that we're able to slow progression of disease as measured by all of these outcome measures. So here are the same buckets of symptomology that Jim showed just a few minutes ago. What you can see is whether we're looking at behavior, cognition, function, or movement, we're able to slow progression as measured by those scales between 50% and 90% in these individuals. Not only that, but their caregivers, as indicated by the NPI Distress Index, also saw the improvement in these individuals. We'll go through those data now. The first group of data we're showing you are the results of the NPI or the Neuropsychiatric Inventory, which Jim described. As Jim described, these neuropsychiatric or behavioral symptoms are a great burden in individuals with DLB. This scale is a combinatory total score based on the symptomology of 12 different particular items. Those are shown on the right. What you can see here in the total score on the left, those people in the study treated with placebo, as shown in red, continued to decline throughout the course of the six months of the study, whereas those who are treated with CT-1812 progressed much more slowly. In fact, they had a progression that was 82% slower than those treated with placebo. This is really a remarkable finding from the study. As Jim described, this score is based on individual items such as anxiety and hallucinations and delusions. Shown on the right are the mean difference of each of these items from placebo, with differences favoring CT-1812 on the left and differences favoring placebo on the right. And what you can see based on these four slides, which show the mean difference and the 95% confidence interval, is that the preponderance of data clearly is on the side favoring CT-1812. So Jim, perhaps this is a good time where you can comment on some of these particular symptoms and how they impact people and your practice. Yeah. So thanks, Tony. So as I mentioned, the behavioral symptoms are very prominent features of the disease. And these are perhaps the most disturbing symptoms to the family. So while the cognition problem is consistent in all patients, in fact, once the family recognizes the patient has a cognitive problem, it's not as disturbing. What is disturbing and often forces people out of their homes is poor behavior, particularly psychotic behaviors like delusions and hallucinations. So what I think is really important is that most medicines that address these types of symptoms, the antipsychotic class of medication, one, has a black box warning, and it's not approved for use in patients with dementia. And two, is that they often worsen the other symptom buckets that I discussed before. So you give a medicine to try to reduce hallucinations, and their movement gets worse, or their blood pressure gets worse, or their cognition gets worse. So it's really important to be able to demonstrate this decline or reduction in the progression of these very, very disturbing symptoms. Yeah. Thanks, Jim. So speaking of disturbing symptoms, along with the NPI comes a measure of their caregiver distress related to each of these symptoms. So what we are showing you here are the total caregiver distress scores on the left. And again, much like the previous slide, what you can see is that for the caregivers whose loved ones receive placebo, their distress continues to worsen or decline throughout the course of the study. Whereas those whose loved ones receive CT-1812, their distress level actually was unchanged or even a little bit better at the end of the study than it was at the beginning of the study. So this, again, much like the observations we saw within individuals, was a remarkable finding. And again, just like we showed you on the previous slide, the magnitude of that response for each of the individual items is plotted here with means and 95% confidence intervals. Again, with favoring CT-1812 on the left and favoring placebo on the right. Do you have any more comments around behavioral symptomology, or should we move on? I think we could move on, but I just want to stress it's very rare that a caregiver 182 days later is not going to report worsening distress from a disease that's neurodegenerative and progressive. So this is quite notable. Great. Thanks, Jim. So as Jim mentioned, cognitive issues are also a feature of DLB. And we looked at a range of different measures of cognitive function in these individuals, looking at the CDR as Jim described, the Montreal Cognitive Assessment, and the assessment of fluctuations, all of which Jim walked us through a few minutes ago. And what you can see when you look across these assessments of cognition is that, again, individuals treated with placebo, shown in red, continued to worsen throughout the six months of the study, whereas those treated with CT-1812 have really, again, a remarkable slowing ranging from 60%-90% compared to those treated with placebo. So Jim, perhaps you can tell us a little bit about these different assessments and the different things that they measure within the participants in the study. Right. So many people may be familiar with the MoCA. So the MoCA is a 30-point scale, pencil and paper test that includes a bunch of sub-tests. And this is a commonly used test in clinical practice for evaluating and following patients. And so it is generally reflective of being able to demonstrate a treatment effect across many, many different categories. The CDR, episodic memory test, is really focusing more on their ability to learn and recall items after a delay. And so we often see a little bit of slowing in the memory test. But I think the last component is really important because these patients fluctuate. And because they fluctuate from moment to moment, second to second, hour to hour, day to day, they may seem very, very different in terms of their ability to attend. Right? So if you're testing someone who's fluctuating, they're going to score poorly. But you test them 10 minutes later when they're not fluctuating, they maybe do a little better. So what I think is really telling here is by essentially almost totally slowing the fluctuations, you're seeing a true effect on memory. And you can see that the separation between the two groups on the CDR episodic memory test reflects the tremendous slowing of the fluctuations. And I think that's really critical because, again, this makes it very, very difficult to treat these patients. Great. Obviously, we have highly complex tools to measure these specific things like memory recall and anxiety. However, what individuals with disease, what we as developers, what physicians, and surely regulatory bodies are interested in is how do these changes in symptoms affect people in their everyday life? So one of the measures of this is the ADCS, Activities of Daily Living. And as the name implies, it's an attempt to assess how folks are able to deal with the everyday activities that occur during life, such as bathing and dressing and eating and shopping and making your appointments. So here, again, we're showing the scores of individuals treated with placebo and CT-1812 on the Activities of Daily Living scale. And again, shown in red are individuals treated with placebo. And then shown in blue are individuals treated with CT-1812. Like the other observations, you can see that those treated with CT-1812 declined 52% slower over the course of six months than those treated with placebo. So this was really a great observation that indeed, not only can we measure specific symptomology, but it's really reflected in these people's lives. Similarly, as Jim mentioned before, being in Alzheimer's disease and having some symptomology similar to Parkinson's disease, these individuals have motor symptomology, which is very troubling. The components of the UPDRS, as Jim described, are shown here on the right. We measured this throughout the course of the study in all of our individuals. Again, like the Activities of Daily Living, you'll see here, those treated with placebo, shown in red, continue to worsen or continue to decline throughout the six months of the study, whereas those treated with CT-1812 declined 62% slower. Again, really remarkable finding in this trial. So one thing that we want to look at is all of the outcome measures in whole. And again, what you see here is that there's a clear indication that those treated with CT-1812, shown in blue, are progressing more slowly than those individuals treated with placebo, shown in red. A few other observations, and some from our advisors pointed out, is these outcome measures are participant-reported, caregiver-reported, clinician-reported. So really, the effect is being seen across the community of those affected by this disease. And then another thing to point out is that in many of these outcome measures, the difference or the magnitude of effect is continuing to grow throughout the six months, which makes us very excited to see what this drug could do as we treat people for a longer period of time. So obviously, this drug is not approved, and we're looking forward to advancing this in the future studies. But Jim, assuming that one day we're able to show a favorable benefit-risk profile and there's a drug like this approved, what would this mean to people and your practice? Tony, I think for people in my practice and in every practice, a medication that can holistically address all the different domains of the patient and the family will have great benefit because you can see that there's a slowing, but a slowing across all the different domains. At the end of the day, this is a really important question. At the end of the day, are we as physicians doing better for our patients by treating them? I think this type of global approach where we can see the cognitive benefits, the motor benefits, the movement benefits, the behavioral benefits, the activity of daily living benefits gives you a global sense that we can make a difference in our patients' lives. Great. So we'll run through the rest of the study. And obviously, this is a safety and tolerability study, so we'll highlight some of the observations around safety and tolerability. And then Jim, we may ask you to make a few more comments here as we go. So this study was supported by a very nice $30 million grant from the NIA. One of the notable features around this study was this study was initiated on the heels of COVID. So indeed, we received approval for this grant during COVID and then really were unable to start the trial until mid-2022. And then as we started this trial, opening the trial in March, the first patient wasn't dosed until June of 2022. I think we, our investigative sites, our CROs, and our vendors were really surprised at the hangover from COVID and just how disruptive it was to executing clinical trials. But really, once 2023 hit, this trial recruited wonderfully. Our last patient came in in May of this year. Our last patient's safety visit was the day before Thanksgiving, a few weeks ago. And we completed database lock within a few days of that. And as you can see now, we've been able to report data out within just a few weeks of the last person having the last visit. So we are incredibly proud of. Sorry to interject. I want to acknowledge the partnership with the LBDA, patient advocacy organization. Without these colleagues at the LBDA, this trial wouldn't have moved as quickly and efficiently as we did. We had academic sites, industry leaders. All were rowing in the same direction. But a bedrock for us was our partnership with the LBDA, and we want to acknowledge them. Absolutely. We ended up screening 293 individuals. As you saw before, 130 were randomized to the three treatment groups. The discontinuations, as we expected and as you expected, were highest in the 300-milligram dose group. In the end, we ended up with 130 individuals in the intent-to-treat population and 129 individuals in the safety population, and we'll go through that now, so looking at the baseline characteristics of the individuals who entered our trial, the mean age was about 73 years, as is common in most DLB studies. It was largely male, white, non-Hispanic. The mean MMSE, or Mini-Mental State Exam score, was about 24 for individuals. And notable here is really the great balance between the active and placebo patients, indicating that the randomization worked. So Jim, perhaps now is a good time to comment on how the participants in our study reflect what you see out in the real world. Yeah, Tony. Great question. So DLB is a male-predominant disease. So about a three to four to one difference between men and females for DLB. This is different than you see in Alzheimer's disease, which tends to favor or not favor, but tends to have more women in those studies. For a reason that's not entirely clear, across the board, we see this largely in non-Hispanic whites. We do have patients with other racial ethnic groups, but it seems to be more prominent in non-Hispanic whites. And I don't believe this to be solely an ascertainment bias. I think the same clinics that see DLB patients that are white and male see African-American, Hispanic, and Asian patients who are female. So it's not just access to care. I mean, I think there's some differences that we don't yet understand. Great. Thank you. So looking at the safety profile here, particularly at adverse events, we're very pleased to see that the safety profile really did not change with this study from our previous experience. Again, what you can see is that overall, the treatment emergent adverse events were relatively high in this population, as we know. They're older, very sick. And really, around 90% of individuals, whether treated with CT-1812 or treated with placebo, had reported adverse events. As we mentioned before, there is a slight predominance of adverse events in the highest dose group, 300, but not in the lower dose group at 100. Importantly here, if you look, the serious adverse events are not greater within the CT-1812 treated individuals. In fact, the number reported and the frequency reported is actually lower within those treated with CT-1812. There were three deaths in this study, two in active, one in placebo, so at an even ratio. None of these were deemed related to studied drugs. As we reported before, one of the adverse events that we're following are elevated liver enzymes, so these are elevations in AST or ALT that have been and always have been in this study and were in the past, mild and reversible on discontinuation of drugs, and you can see those reported here. Overall, when we look at all groups, the adverse events were predominantly mild and moderate, and all this information will be on our website so you can look at it more carefully. When we look at the types of adverse events that we see, again, a very pleasing outcome of this study was that it's very similar to what we've seen before and also very similar to what we expect in individuals with this disease state. So again, falls, one nice observation here again, is that the 100-milligram dose group, there's no indication of any increase in falls within individuals. And then again, the symptomology is very much like we've seen before, and you're expecting these individuals. One thing to point out is, as we've seen before, one of the features that is a bit more common in individuals treated with CT-1812 are abdominal symptoms of abdominal discomfort and, as reported, elevated liver enzymes. So those are here. Again, these details will be available on our website. We'll be going through much more detail around both the efficacy data as well as the safety data when Jim presents this information in January at an international conference. Looking at the totality of the safety information, again, very similar to what we saw before, adverse events around 90%, both in active and placebo-treated individuals. As we just noted, there is no increase in serious adverse events. In fact, in this study and the previous study we reported, whether real or not, there's a reduction in serious adverse events in those treated with CT-1812. Then also, again, as you look at the data, they're equally proportioned between active and placebo-treated individuals. Again, none of these were related to studied drugs. So a very similar picture to what we've seen before. So finally, as we look at what's next with CT-1812, obviously, we're incredibly pleased with the data that came out of this study demonstrating that we could have a real impact on the symptoms of people with DLB. Next will be a podium presentation. Jim will be presenting this data at the International Lewy Body Dementia Conference at the end of January in Amsterdam. Then we'll really be looking to prepare for an end-of-phase II meeting. We'll be talking to our advisors, our key opinion leaders, our regulatory experts to really think about what a study design would be, as well as what could be approvable. Then finally, we'll continue to be doing market research because, as Jim mentioned, there are no approved drugs here. And so we're excited about the possibility that, again, should this drug prove to have a beneficial or a favorable benefit-to-risk ratio, this could be the first approved drug within this field. So in summary, we're incredibly pleased to see really remarkable effects across a broad range of symptomatic domains impacting these individuals with dementia with Lewy bodies. And we really believe that we strongly support advancing this into the next phase of study. Lisa. I think we wanted to ask Jim if he has any further comments that he'd like to share. I just want to say that the importance to me, both as a clinician and as a researcher, is the safety and tolerability signals because it's very challenging to treat these patients, and the holistic global effects across all the different domains that favor treatment over placebo really offer tremendous hope and potential moving forward for patients that often we have very little to offer other than borrowing medicines off-label from other fields, so I think what we see here is something that provides great hope to the field, and that's what we want to do, is provide hope for the field as we continue, hopefully, to develop products such as these. Thank you, Jim. Next slide so before we turn to Q&A, there are many people to thank. Our gratitude goes to, first and foremost, the study participants and their care partners. It takes courage and patience to participate in a clinical trial. There were long visits. People traveled great distances. If patients weren't willing to do this, we would not have the results we see here today. Dr. James Galvin in the University of Miami team that served as our PI, guiding insights and if you don't know Jim, you're missing one of the most compassionate individuals in the field. Our thanks to you, Jim. Our NIH and NIA partners for providing funding. Cognition has benefited from close to $200 million of funding. And we can assure you there is no way a small company like Cognition Therapeutics can do not only this work, but Alzheimer's disease, five phase II trials without the deep and strong support from the NIA. Site investigators and their teams, as Tony pointed out, during COVID and at the end of COVID, everybody was on their back foot. These groups came together and delivered for patients and their families the opportunity to learn as we've done here. Our partnership with the Lewy Body Dementia Association and the New York-based Resource Center, these people better understand Lewy Body disease in patients than anyone. And they have helped to guide our thinking as to how we progress. I'd like to close by thanking our Cognition colleagues. Our colleagues at Syneos, our CRO partner, without all of these folks working together, we would not be where we are today of excellent results in a very well-executed trial. With that, we'll turn to Q&A. We will go back to Sarah to tell us if there are questions for us. That's great. Thank you so much, Lisa. So please hold for a brief moment while we pull for questions. So our first question comes from Mayank Mamtani at B. Riley. Please go ahead, Mayank. Yes. Good morning, team. Thanks for taking our questions. And congrats on a very strong data set here and impressive study execution here with your partners. So you reported pooled data analysis here. I wonder if you could maybe comment on the dose-dependent effect if you did see between the two dose levels you tested. And I was also wondering around the statistics if you could comment on some of the more prominent endpoints that we've seen done in the space, like CDR, MoCA's, and maybe UPDRS, if there was a statistical P-value analysis done there. And then I do have a follow-up for Dr. Galvin. Yeah. Sure. Thanks, Mayank. So interesting, like we saw in the SHINE study, which we reported out earlier this year, the 100- and 300-milligram dose group really behaved nearly identically, which is good as we reported out. The safety and tolerability at that 100-milligram dose is really quite favorable. So as we said before, we'll be proceeding with doses below that 300 milligrams. We'll be showing the individual dose information when Jim presents the full information in January. Related to statistics and P-value, so this was indeed a signal-finding trial, right, where we were looking at a broad range of symptomology, which is why we showed the statistics as means and 95% confidence intervals. Where you were asking about what is strongest, for sure, the Neuropsychiatric Inventory was one of the strongest observations here, obviously, as well as a few of the others. We'll get more into the specifics around the statistics and values as we present the full data in January. Great. Thank you. That's helpful. And for Dr. Galvin, if I could hear from him relative to peer studies that you've been part of or you've recently seen a lot of not very positive results. So if you could maybe, Dr. Galvin, put in context this data set and how novel and never-seen-before, unprecedented kind of data set this is. And maybe for the January medical conference presentation, should we be looking for some biomarker data also, just that, like you've done in Alzheimer's, at two medical conferences earlier this year, that story of target engagement and proof of mechanisms also come together with the clinical assessments? Thanks again for taking our questions. Okay. Thank you. I'll answer the second part first, is that lots of biomarkers were collected, and these are all still being analyzed. So Tony can comment, but the analyses are not completed yet. So it's hard to comment much on the way of biomarkers at the moment. But a lot of biomarkers were collected. Those are being analyzed. And we hope to be able to show data in the future. In terms of the other question, this has been a field that has had lots of disappointments. A number of clinical trials, both from big pharmaceutical companies and from smaller companies with very interesting compounds, just have failed to meet their primary outcomes or shown a significant efficacy signal to move forward. So there's been a lot of discontinuations of programs in the last couple of years on trials for DLB. I think what's really notable about this one is not only did our hypothesized domains show favor, but really, across every single domain we looked at, favored treatment, and so I think that that's a very promising signal for moving forward. Thank you. I'll jump back in to you. Thanks for the questions, Mayank, so our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay. Hey, congrats on these results. And thank you for providing this update. Maybe just to follow up on the biomarker question, are there any biomarkers that suggest evidence of disease modification with CT-1812 in DLB? And given the enormous unmet need in DLB, would you think it's possible to pursue an accelerated approval strategy using a biomarker? And then I have some follow-up questions, if I could? Yeah. Sure. So I'll start, and then we'll throw it back over to Jim. So as Jim suggested, we've collected plasma from these individuals and are looking at a wide range of biomarkers. We have analyses on alpha-synuclein in the cutaneous nerve fibers, which is a measure of overall alpha-synucleinopathy within these individuals. So we know how many individuals have elevated alpha-synuclein. We ran tests, the blood tests confirming amyloid pathology, right, looking at amyloid monomers as well as ratios of plasma P-tau and total tau. And then we have a range of other neurodegenerative inflammatory biomarkers, which you would expect to see. Now, obviously, the field of biomarkers in DLB is very different than AD, right? This is Alzheimer's disease. The biomarker changes have been studied extensively. And we know a lot of what to look for. But maybe we'll let Jim comment on what things will be interesting to look at as these data come in from our plasma biomarkers. Yeah. So Tony, I think you hit the nail on the head. We know a lot about how Alzheimer biomarkers change in Alzheimer's disease. We don't know how much Alzheimer and neurodegenerative biomarkers change in dementia with Lewy bodies. So we'll be able to explore that. I think it's also difficult to quantify synuclein. So most of the assays currently available for synuclein are qualitative, not quantitative, although those platforms are now expanding so we can get semi-quantitative data. So I think depending on what we see, there is the possibility of looking at, is there a signal that looks like a biomarker change? Now, I don't know what that's going to show yet. There are also some novel, interesting platforms that are proposed to look at to try to get plasma and other fluid measurements of synuclein. So I think there's a lot of interesting things that we could find, but I don't know that we will find them at this point because those analyses haven't been done yet. Great. Thank you. That's super helpful. And then can you please talk about your plans for further clinical development of CT-1812 in DLB in terms of the doses that you plan to take forward? Will you continue to pursue both 100 and 300-milligram doses or maybe look at another intermediary dose? And also, what would you propose as the primary clinical efficacy endpoint in DLB for future studies? And what would be a meaningful improvement in that primary endpoint that you would consider? And maybe finally, as you look ahead to further clinical development, will you continue independently, or do you think you might seek a partner? Thank you. I'll take that. Yeah. So thanks for the question. We've had this data for hours, right, adding up to just a couple of days. So clearly, we haven't really planned the details of what's next. Having said that, we certainly will be pursuing an end-of-phase II meeting to talk about those plans with FDA after we've had time to meet with our advisors, our other KOLs in the field, our regulatory consultants to discuss this. I mean, I think clearly that these data suggest, again, that this could be a really beneficial drug for these individuals, again, assuming we can show an adequately sized trial that is a favorable benefit-risk ratio. So you asked a bit about the dosing. I think much like we told everyone after the SHINE study, given that the data with the 100 milligrams and 300 milligrams is really quite identical, which is why we presented it together, it's very unlikely we'll pursue a 300-milligram dose given that the troublesome adverse events and discontinuations are really higher in that group and not worth pursuing. Now, we haven't decided whether we would pursue a 200-milligram dose as we are in our early Alzheimer's trial and in our MAGNIFY trial of dry AMD, but certainly something less than 300 and definitely will include 100. Now, as far as outcome measures go, again, I think all of these are reasonable. Now, again, as we discussed with Mayank, really the Neuropsychiatric Inventory is really incredibly strong here. And using that, perhaps paired with something like the Activities of Daily Living, could be a really compelling case, which again, we'll have to discuss with FDA. Now, it's a little bit harder to predict right now than, say, in Alzheimer's disease, right? There have been so many trials and so many different companies who have met with FDA, and we understand their guidance and what could be approvable. But I think a pairing of the symptomatic outcomes like the Neuropsychiatric Inventory with the Activities of Daily Living could be really compelling. Jim, any comments on what you might suggest with those trials? Yeah. Again, I think what's interesting is, one, DLB has really a buffet of symptoms that occur. And two, that buffet was sampled very well during the trial so that we could see effects. So it might be co-primary in the future. I also potentially could see a composite being developed like the ADCOMS or the IADRS, where you're taking scales that move forward. And asking a really important question is, at the end of the day, is the patient better for being treated across all these different domains? So I could see a couple of possible strategies going forward, but that'll depend on conversations that Cognition Therapeutics has with regulatory and FDA. Yeah, and if I can add on just one additional comment, is that regardless of what that next study looks like, it will certainly be after discussions and after agreements on what the study should be, how we'll analyze data, the size, and so forth, so that regardless of what that next trial is, it could be one of our pivotal registrational trials to move towards approval. And then last, Jay, I'll address your question. Good morning. And thank you for your question, Jay. As we have told investors many times, since Tony and I started working together five years ago, we have made it a practice to engage with pharmaceutical companies, large, middle, small size, and keep them apprised of our progress. The goal was always for us to understand them and for them to see, in my estimation, the rigor and ability to execute demonstrated through Tony's leadership here at Cognition. So these are not new conversations. And certainly, since the summer when we reported our AD data and then our CTAD data, we've had a lot of interest in meeting and talking at JPMorgan. So what I can tell you is there's lots of excitement in the pharmaceutical community. As to your specific question, will we take our program forward with a partner? All that is in front of us. We don't have that answer today, but we're eager to talk to skillful groups that can help amplify our work. Excellent. It's super helpful. Thank you so much for taking all the questions. And congrats again on these data. Thank you, Jay. Yes. Thank you for the questions, Jay. So our next question comes from Boobalan Pachaiyappan at H.C. Wainwright & Co. Please go ahead, Boobalan. Hi. Good morning, team. Congrats on the progress. Can you hear me? Yes. Yes. Good morning, Boobalan. Yeah. Hi. Thanks so much for organizing this call. This is very informative. So I have a few questions for the team as well as for Dr. Galvin. Maybe starting with Dr. Galvin. So just curious, when we look at the DLB market, especially the patient segmentation, so there's a school of thought that suggests that there's a certain segment of patients who have their disease pathology limited to basal forebrain. And then there's these advanced patients who also exhibit AD symptoms plus DLB. And in that case, the DLB extends to the hippocampal region. So I'm curious whether this school of thought has already been applied in your current phase II SHIMMER program, or this is something you're planning to do? Because clearly, as the disease expands into the hippocampus, it's going to be very harder and tougher to treat. So obviously, I would love to hear Tony's views as well. But I wanted to start from your view first. Yeah. So roughly 80% of patients with DLB have concomitant Alzheimer's disease. And so this trial encompasses people with mild and moderate disease. So we're well outside the hippocampus itself. So there's no way of imaging Lewy bodies currently in a living person. So we're relying on assays to try to get a sense of the synuclein burden. But based on the clinical features of the people, this is a cortical and subcortical process with both brainstem and peripheral effects. So the target population in this study really would encompass people with the more restricted pathologies all the way to people with more diffuse pathologies with concomitant Alzheimer's disease. All right. Thank you. And then I have a couple of clarifications. So were any of the SHIMMER patients on background therapy, like were they on acetylcholinesterase drugs or any of the other drugs? Yes. So the vast majority, over 80% of individuals were on acetylcholinesterase inhibitors or memantine. So all of these data are on top of already standard of care. And Jim, I don't know if you want to comment on other standard of care, but that was one that obviously we tracked very carefully. Yeah. I mean, so there's no approved medicines, excuse me. So everything is off-label. But in the dementia world, the standard of care for a DLB patient is a cholinesterase inhibitor. And they tend to be more robust responders to cholinesterase inhibitors than you see in Alzheimer's disease. The evidence on memantine is much, much less clear. There were fewer people in the study on memantine, but memantine and DLB is not well. The signal is not very clear. Patients might have been on the other symptomatic medications for the other buckets of symptoms that they had. So we did have a list of concomitant medicines in the inclusion-exclusion criteria. But I think what Tony said, about 80% or so on a cholinesterase inhibitor, that's what you would see in the general clinical practice. All right. Sorry. Go ahead. I think we're at the hour, Boobalan. We'll have an opportunity to take more questions from you offline. But I believe, Tara, we're at the hour. I'd like to give some closing comments. First of all, Dr. Galvin and Tony, thank you. Thank you. From my perspective, this trial delivered the results and insights that exceeded everyone's expectations. We've now shown that CT-1812 has a consistent and clinically meaningful therapeutic benefit in six months of treatment in two separate neurodegenerative diseases. We showed in our Alzheimer's trial the ability to particularly impact patients that have lower levels of p-tau217. And as you've seen here today, SHIMMER-delivered SHIMMER, the drug CT-1812 in this trial delivered outstanding results. We believe CT-1812 should be pursued in larger studies in dementia with Lewy bodies. There is an enormous unmet need to be filled. With that, our thanks, and we'll close.