Good morning, everyone. Welcome to the Anavex 2-73 blarcamesine AD-004 phase 2b/3 clinical study results review conference call. My name is Clint Tomlinson. I will be your host for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session. During this session, if you would like to ask a question, please use the Q&A box or raise your hand. Finally, note that this conference is being recorded. The call will be available for replay on Anavex's website at www.anavex.com. With us today is Dr. Christopher Missling, President and Chief Executive Officer, and Dr. Ed Hammond, Chief Medical Officer. Also with us are two distinguished professors with backgrounds in Alzheimer's disease. From the University of Texas, Professor George Perry, PhD, is Dean of Sciences and Professor of Biology at the University of Texas at San Antonio. He is a former president for the American Association of Neuropathologists and the editor-in-chief of the Journal of Alzheimer's Disease, as well as the editorial board of over 150 other journals. Professor Perry has no affiliation with Anavex Life Sciences. From the Technical University of Munich, Professor Dr. Timo Grimmer is a board-certified psychiatrist and psychotherapist and an associate professor working as a specialist registrar at the Department of Psychiatry and Psychotherapy at the Technical University of Munich School of Medicine, Munich, Germany. Dr. Grimmer is head of the Center for Cognitive Disorders, which specializes in early and differential diagnosis of patients with cognitive impairment. He also served as a national coordinating investigator for the Anavex 2-73 blarcamesine phase 2b/3 study. Before we begin, please note that this conference call, the company will make some forward-looking projections and forward-looking statements. These statements are only predictions based on the current information and expectations and involve a number of risks and uncertainties. We encourage you to review the company's filings with the SEC. This includes, without limitation, the company's Form 10-K and Form 10-Q, which identify the specific factors that may cause actual results or events to differ materially from those described in these forward-looking statements. These factors may include, without limitation, risks inherent with the development or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights. With that, I would like to turn the call over to Dr. Missling. Thank you, Clint. We appreciate everyone joining us on today's conference call to review our most recently reported Anavex 2-73 blarcamesine AD0004 phase 2b/3 clinical study results and provide an update with the next steps. Top-line data of the randomized double-blind placebo-controlled phase 2b/3 study of Anavex 2-73-AD-004 for the treatment of early Alzheimer's disease was presented in a late-breaking oral presentation at the Clinical Trials on Alzheimer's Disease CTAD Congress 2022 last week, December 1, 2022, at 4:30 P.M. Pacific Time in San Francisco. Let me start by saying that our aim for scientific advancements is to help patients. They deserve the utmost respect and dignity. Alzheimer's is a cruel and devastating disease. It takes away a person's past and future. Today, we would like to take the opportunity to provide clarity on some questions and comments we have received. At this point, we can confirm that all efficacy data as presented at CTAD are accurate. The objectives and endpoints assessment using appropriate statistical analysis were performed by an independent expert team. I would like to walk everyone through the details of the primary endpoints, benchmarking the data with 2 Aβ antibodies, Aduhelm, which had received approval by the FDA, and lecanemab, which recently reported full data. Before I do that, I would like to emphasize that the data is even better than anticipated. We know from our previous 2 dementia studies, namely the Anavex 2-73 Alzheimer's disease phase 2a and phase 2 dementia study in Parkinson's, that we have a strong therapeutic candidate. To succeed in the pursuit of addressing this very difficult indication, which so many others have struggled to solve, confirms our tenacity to go after Alzheimer's disease, one of the most challenging and highly complex indications of modern time. We are doing everything in our power to bring this convenient oral once daily treatment to patients as soon as feasibly possible. I'd like to run you through the presentation. If I might ask to show the next slide, please. The forward-looking statement was just read to you. I wanna point out in this summary slide that we are in our aim of Anavex 2-73 trial, we have aimed for showing a drug which improves patients' lives. That means we're aiming for improving the efficacy of the drug in patients' lives. For that reason, we moved the also the doses was pre-specified for all patients in all doses. That is consistent also with reaching this for the co-primary objective, which is to show and evaluate reduction in cognitive and functional decline assessed from baseline over 48 weeks. Compared to placebo using the ADAS-Cog and the ADCS-ADL scale respectively. What is very important, the co-primary endpoints, however, ADAS-Cog and ADL, were analyzed using generalized linear modeling to write and evaluate the clinically meaningful treatment effect, since this is our goal to improve patients' lives of Anavex 2-73 on cognition and function compared with placebo at the end of the treatment. These outcome variables are now expressed for ADAS-Cog and ADL as binary outcomes, and this is called the odds ratio. The ADAS-Cog binary outcome variable is a meaningful improvement in cognition and is defined by something which is above the improvement threshold. In this case, it is minus 0.1 points or better, versus not improved. For the ADL, the binary outcome variable is a meaningful improvement in function by 3.5 points or better versus not improved. The CTAD slides, to repeat this, contain accurate statistical calculations. For increased clarity, we added footnotes and one non-material typo was corrected in the version which you can download on www.anavex.com. Preliminary benchmarking indicates that Anavex 2-73 is better, has better efficacy combined with convenient oral administration versus the current Aβ antibodies. More details will be shown here. I also like to remind this is the top-line data. We've received just the data, a day before the presentation and the full analysis, including pre-specified biomarkers of response as well as MRI, whole genome exome sequencing, DNA data and full RNA exome expression data collection and collection data on biomarkers of neurodegeneration like Aβ tau, NFL and so forth, are ongoing and will be published in a peer-review medical journal. Next slide, please. As indicated before, the primary objective was to estimate the efficacy of Anavex 2-73 entirely for all doses compared to placebo in patients with Alzheimer's disease. The study design specifically allowed for up-titration to target those with provision for down-titration as well based on tolerability and in line with the study objectives to have Anavex as a treatment group combined in the top-line analysis, basically all exposed to Anavex 2-73. That's why all patients are in the top line pre-specified primary endpoint analysis. Next slide, please. Regarding the co-primary endpoints, the co-primary endpoints were analyzed using generalized linear modeling to evaluate clinically meaningful treatment effects of Anavex 2-73 on cognition and function compared with placebo at the end of the treatment. The co-primary endpoints were ADAS-Cog and ADCS-ADL. These outcome variables were expressed as binary outcomes. The ADAS-Cog was defined as a binary outcome variable by showing a meaningful improvement in cognition by at least minus 0.5 points or better versus or not, or not improved. The ADCS-ADL binary outcome variable is a meaningful improvement in function by at least 3.5 points or better versus non-improved. I also like to point out the co-primary endpoints do not require adjusting for multiplicity. That means each endpoint requires to just surpass, exceed the bar of 0.05 statistical significance and not anything less. The outcome measures now are expressed as odds ratios of improvement in cognition and function associated with Anavex 2-73 treatment compared to placebo. You will see now how these odds ratios have been also used in other clinical trials, which is quite standard. Next slide, please. The ongoing analysis is going on beyond the top line findings. These analysis will include pre-specified biomarkers of response, including Sigma-1, magnetic resonance imaging, MRI, outcome measures of response, whole exome sequencing, DNA data, as well as full RNA exome expression, which we, for example, showed already for the Parkinson's disease dementia study with extreme intriguing features of improving the biological response of pathologies suppressed in Alzheimer's disease. As well as biomarkers of neurodegeneration, which includes all the ones including CSF collected samples as well as blood collected samples of Aβ, Tau, NFL and so forth. We plan to submit the complete data for publication subsequently in a peer-reviewed medical journal. Next slide, please. I mentioned the odds ratio hasn't been used prior, and I have found, we found a very distinct example recently used in the package of Aduhelm. In the analysis of odds ratio, which is a measure of association between treatment, placebo versus drug and outcome, which is commonly used measure in efficacy analysis in clinical trials. The example here is from the phase 3 EMERGE study, the successful study of Aduhelm, which was approved by the FDA recently. I'd like to only point out to the items which have been highlighted in red, we will show them in the next slide, highlighted again. Next slide, please. We made a comparison slide here of Anavex 203 in which addresses the co-primary end outcomes measure using odds ratio to the Aduhelm data. I'd like to go through this line by line. First of all, the study duration of the trial for Aduhelm was 78 weeks, much longer. More time to show a separation between placebo and active arm in practice. Our trial was 48 weeks long, shorter trial for Anavex 2-73. The ADAS-Cog responder threshold, the bar, so to speak, was set for Aduhelm, is smaller than 3 points for ADAS-Cog. As a reminder, since ADAS-Cog is an inverse scale, basically a lower number is an improvement and a higher number is a decline. The bar is set as a lower bar cognitively by cognitive impaired threshold of 3 points or better. While our bar is set as -0.5. In order to have a patient to reach that bar, which is higher, he needs to already have been improved absolutely from baseline to end of trial after 48 weeks in order to even come above this bar. The ADAS-Cog odds ratios were calculated for Aduhelm as 1.25, which is still lower than 1.839 in our case, despite the much lower bar for Aduhelm. In its interpretation, Anavex 203 is 84% more likely to improve cognition by -0.4 points on the ADAS-Cog or better compared to placebo. The next line is the ADCS-ADL responder threshold. For Aduhelm, it is larger than -3. For Anavex, is larger than close +3.5. The threshold interpretation is that the bar set for Aduhelm is at lower bar for a functionally impaired, starting as a functionally impaired level. Since -3 at the ADL points or better, is already including patients which are impaired. The bar, however, at Anavex 203 study, which we set for our primary endpoints, is set as a much higher bar, is set as a net improved level of +3.5 points. The ADAS-Cog, ADL odds ratio for Aduhelm is still lower despite the lower bar set for Aduhelm than Anavex 203 at 1.6, while Anavex 203 odds ratio comes out as 2.67. The Anavex 203 data is 167% more likely to improve function by 3.5 points or better compared to placebo. In summary, the threshold for Anavex 203 is clinically meaningfully set in patients who are cognitively declined. We have allowed a net improvement in cognition. Shorter duration of Anavex 2-73-AD-004 trial in patients shows statistically significant improvement in cognition and function, the co-primary endpoint. The oral once daily administration of Anavex 203 has also favorable efficacy hence. Next slide, please. Let's go through the top line data of efficacy discussed at the CTAD meeting. Next slide, please. The AD0004 co-primary endpoints consisted of ADAS-Cog and ADL. Let me start with the ADAS-Cog. The Anavex 203 treatment was 84% more likely to improve cognition compared to placebo by ADAS-Cog score change of -0.5 points or better at 48 weeks. The interpretation is among patients who improved with Anavex 203 treatment, the mean ADAS-Cog score improvement was -4.03 points. This was significant with 0.015 P value. Next slide, please. The second co-primary endpoint, ADCS-ADL, the Anavex 203 treatment was 167% more likely to have improved function compared to placebo at clinically significant ADCS-ADL score change of +3.5 points or better at 48 weeks. Clinically significant response categorization function defined as ADCS-ADL larger than +3.5 points change from baseline. The p-value of this co-primary endpoint is 0.0255, statistically significant. Next slide, please. The secondary endpoint, see there some of the boxes, demonstrated that Anavex 203 treatment slowed clinical decline in cognition and function assessed by 27% compared to placebo. The Anavex 203 treatment difference in mean score change was 0.42 points. The p-value of 0.04 is statistically significant. I'd like to point out to a comparison, because we were asked, you know, how does this data compare to other data out there, the most recent antibodies? I provided a comparison for Aduhelm at the odds ratio. Let me give you a comparison to lecanemab using their primary endpoint, which you see there some of the boxes. The endpoint of lecanemab was 12, 18 months. The presentation from lecanemab, the full data allows for extrapolation also because they have a score point measure at 12 months to extrapolate the comparable time point where the Anavex 2-73 study finished at 48 weeks. Do the participants in the Anavex 2-73-AD-004 study entered the study with more advanced AD than in the Clarity AD study from lecanemab that was showed by measures by MMSE baseline, which were slightly lower for Alzheimer for the Anavex study than the lecanemab study. However, they reached a similar delta in CDR Sum of Boxes and in Clarity AD. In our case, -0.42 and 27% slowing the decline over placebo in 48 weeks, while Clarity AD showed a -0.45 slowing decline over placebo in 18 months. However, that already much earlier for Anavex at 11 months, which represents 48 weeks, and with a simple oral once daily capsule. Participants in the AD0004 study, Anavex study, did not require expensive and hard to find MRI monitoring for ARIA adverse events. A look at the chart of lecanemab of CDR-SB, which scored -0.5 at 18 months, allows for a rough comparison. Around the same time of the end of the trial period of 48 weeks or 11 months, lecanemab approximately is -0.3. Based on that result, Anavex 2-73 would be approximately, when you calculate that difference and divide it by the 0.3, approximately 40% better than lecanemab. Again, based on this exploratory analysis, is approximately Anavex 2-73 is 40% better than lecanemab at the same time point. Let me move forward with the slides. Next slide, please. Additional analysis we did on this top line data were the following. Next slide, please. We measured also the ADAS-Cog co-primary endpoint over the time of the course of the duration of the trial, in addition to the previously described co-primary endpoint. The Anavex 2-73 treatment slowed cognitive decline by 45% compared to placebo at 48 weeks. The mean difference in ADAS-Cog score change was minus 1.85 points. The p-value was 0.033 and statistically significant. Next slide, please. In summary, we reached at clinically significant levels of improvement in cognition, ADAS-Cog score threshold change of -0.5 points or better with in patients on Anavex 2-73 treatment were 84% more likely to improve cognitively compared to placebo. At clinically significant levels of improvement in function, ADCS-ADL score threshold change of +2.5 points or better. Anavex 2-73 treatment was 167% more likely to improve function compared to placebo. Compared to placebo, Anavex 2-73 reduced clinical decline of cognition and function by 27% as measured by the CDR-SB score. The Anavex 2-73 treatment slowed cognitive decline by 45% compared to placebo at 48 weeks. In summary, totality Anavex 2-73 was safe and well-tolerated. Next slide, please. I wanna also explain to you how is it possible that we have patients who improve. We knew from previous trial and our mode of action that we are restoring homeostasis by activating sigma-1 receptor, which is an endogenous ligand we all have in the body, which only gets activated if there are cellular stress. Anavex and Alzheimer pathology is causing tremendous cellular stress on multiple fronts. This impaired sigma-1 function also is known to cause destruction and cellular stress and even Alzheimer's disease. The opposite is, for that reason, confirmed sigma-1 activation could be beneficial in countering the Alzheimer pathology. Next slide, please. We have described the way the mechanism works by activating now sigma-1 endogenously, not sufficiently activated because of chronic stress. Chronic stress. The ability to activate from the outside with Anavex 203 would be the compensatory mechanism to support the biological compensation in the body to counter this cellular attacks. Next slide, please. That's been also described in many several papers that Anavex 203, with the activation of Sigma-1, is able to reduce Aβ pathology, but also is able to reduce Tau pathology, but also is able to restore homeostasis and mitochondrial function. It is also showing to reduce inflammation, and also was able to demonstrate autophagy increase if it's impaired. Very complex pathology where the Sigma-1 endogenous activation is able to counter the very complex Alzheimer's pathology. Next slide, please. On top of that, recently, sigma-1 activation was demonstrated to be even further upstream involved in chromatin remodeling, in preventing RNA gene transcriptions, toxic gene transcription before and after RNA gene transcription to prevent toxic RNA to be expressed and hence toxic proteins to be expressed, which further increase the cellular stress in asthma pathology. Next slide, please. What are the next steps? Our next steps are the full analysis, including pre-specified biomarkers response, as well as MRI, whole exome sequencing, DNA data, and full RNA exome expression data collection, data of biomarkers of neurodegeneration. These are ongoing and will be published in a peer-reviewed medical journal. At the same time, the open-label expansion study, ATTENTION-AD, will continue to follow participants over 96 weeks. Now we plan to meet with regulatory authorities to determine the next steps. The next slide, please. We like to acknowledge at this point, the principal investigators and all clinical trial staff, site staff, study staff for their tremendous accomplishment. We also like to thank the Data Safety Review Committee for their work. We also like to thank Anavex Scientific Advisory Board. Most of all, we really like to be thankful and grateful and acknowledge the contribution of the participating asthma patients and their caregivers. Also, I'd like, at this point in time, thank all our supporters and shareholders for their support. Thank you. Next slide, please. I'd like to now move to a question and answer panel with Professor Dr. Grimmer and Professor Dr. Perry. If I could kindly start with the first question. Let me start out by saying, Professor Grimmer, maybe starting with you since you have been involved in the study. Then I'd also like to ask the same for Dr. Perry, obviously. Can you please discuss your thoughts regarding the top-line results from this AD0004 study and what it means from your clinical perspective? Christopher Missling, thank you so much for representing. I've had the opportunity to be present at CTAD and watch the original presentation. Of course, we have still not seen the whole data set, and I think this is also reflected in your question and answer chat, which I read in between. I think what can already be stated at that moment is that, of course, what you're seeing with your compound is appears to be an improvement. You'll be able that patients perform better even after a year during a progressive disease, which of course is things we are highly needed. We only have these anti-dementing drugs, small effect sizes yet, everything on top is highly appreciated. We have not seen whether or not your compound is able to show hints of disease-modifying. I'm excited to learn about this in the future. Currently, I think the main thing is you really improve patients as compared to what you've, for example, shown these disease-modifying agents that only will slow down the course of the disease. Thank you very much. Dr. Perry, would you like to share your thoughts? I share, Dr. Grimmer's enthusiasm that patients are actually improving. To just note that you have a change in the slope of decline, as has been shown with Aduhelm, as well as other amyloid vaccines, is not very inspiring. Further, which I think is even more important, is that you're seeing the positive effect with patients that are frankly already demented. The vaccine approach has been directed primarily to patients that are pre-dementia, either in mild cognitive impairment or maybe even earlier stages when you can detect amyloid and the value of that. Finally, I think the most important thing is that you, at least so far, have no reported major side effects, none that are life-threatening. This has certainly become a concern with the vaccine, where at least two patients, as well as probably others that have not been reported, have had, well, beyond life-threatening, actually have died from the approach. I appreciate it. Thank you. Based on your expert opinion, if patients or caregivers had to choose between an IV injection every two weeks or an oral once daily capsule with a simple refill, which do you propose would be their preference? You're asking me? Yep. Oh, Dr. Grimmer would be best. Dr. Perry first, and then Dr. Grimmer. Okay. Well, I do not treat patients personally, but I think the whole issue of the vaccine approach as opposed to an oral is very simple, that patients will choose an oral medication. To have to go to an infusion center, to have to have as many side effects, even if they're not life-threatening, the headaches, the many of the other problems associated with it. I think that an oral medication with very few side effects and not requiring MRI imaging, to follow them will make it available to a much greater number of patients. Thank you. Dr. Grimmer. Yeah, I can only echo Dr. Perry's comments. Of course, it is much more convenient for patients, for healthcare professionals to provide a drug which can be taken orally and is generally safe and does not require any elaborate serial MRI examinations for safety, which does not require patients to travel somewhere, which does not block offices of physicians for infusions. I think this is absolutely clear, this oral formulation with a safe drug is clearly preferred. Oh, great. Another question. In the clinic, for Dr. Grimmer. Do you see more patients expressing concern about their Alzheimer's risk than in years past? In other words, are individuals seeking to understand their Alzheimer's risk earlier than before, for example, using genetic screening? Yes. Of course, it is not representative what's seen at my specialized unit, but in principle, awareness has substantially raised, including by all the news that have been brought up by these disease-modifying agents. Persons, elderly persons that presume that they might experience forgetfulness are much more likely to show up at the clinic and seek for advice and diagnosis. Right. Thank you. The next question is, Aduhelm is currently processing. We mentioned that we are in the middle of this, analyzing now the biomarker samples and data for the AD-004 study. Suppose near-term future biomarker tests are available to measure, you know, risk factors for Alzheimer's and reach the clinic and help predict future AD risk in individuals. Would prescribers consider using next generation AD medications in a preventative manner? Maybe Dr. Perry first. I don't know about exactly the biomarkers that are available now having great predictive value. That said, a drug that could be, with low side effects, relatively low cost, really would be a major godsend to the field, because then it could be used in patients that are having, like they have APOE4 genotype and are at high risk of transitioning into Alzheimer's disease and those that are in mild cognitive impairment, administering it. I think that this would be. If you have to apply something like the vaccine approach, you put those patients at high risk of problems and cost and burden for families. I think that an oral medication is really critical for changing the public health scene. Right. Thank you. Next question. Given the recent developments, would combination therapies for Alzheimer's disease, for example, small molecule therapies and antibody anti-amyloid therapies, be potentially synergistic? Dr. Grimmer, what are your thoughts? Yeah. Probably every expert needs to state this since several decades that combination therapy is probably the best approach. One could imagine, of course, yeah, given your clearly different mode of action as compared to these anti-amyloid antibodies, that both therapies, yours and anti-amyloid immunotherapy, could work synergistically. Yes. All right. Assuming, Dr. Perry, what are your thoughts? I think that approach is definitely called for, but not just, the small molecules that you're talking about or the vaccine, which I think right now isn't clearly efficacious. Even if it has statistical efficacy, I don't think it has clinical efficacy. But I think Alzheimer's is moving along the line of heart disease, where you have multiple approaches, both lifestyle approaches, therapeutics that hit various different pathways, and all of that makes a tremendous difference in the outcome. And you don't have to have a cure to have incredibly effective therapeutics. Appreciate it. Let me round out because we also like to have some space and time for some Q&A. In conclusion, bringing the discussion back to the AD-004 study, what is your perspective on how you think these top lines can affect treatment in Alzheimer's disease? Dr. Grimmer first, maybe. This of course depends. First, we need to see the whole data set and, maybe you can convince regulators, to make an exception to already approve your compound based on this one study. This probably is high hope, but I wish you for, we hope sooner or later to have this available in clinic. As a well-tolerated, easy to administer drug, probably it will find its way into market. Thank you. Dr. Perry? I think as you stated, I think that this drug, as well as some others that are not as far along the pipeline, mark a tremendous change in how people are approaching the treatment of Alzheimer's disease to work with the biology of Alzheimer's disease rather than against it. You know, the removing of pathology has not been therapeutically efficacious so far, but working with the biology as you're doing, now we see patients actually improving. Thank you very much. Thank you, Professor Dr. Grimmer and Professor Dr. Perry, very appreciated to joining us today. This is an exciting time in neuroscience in rare disease drug development, and we are committed to bringing potentially life-improving treatment options to patients with Alzheimer's disease, a condition with significant unmet need and high economic burden, for which there are only limited approved pharmacological treatment options. We'd like now to turn the call back to Clint for a Q&A with the investors, analysts. Thank you, Christopher. The question and answer session is open. Please either raise your hand or put a question in the Q&A box. We'll start with Pete Stavropoulos from Cantor. Let me allow you. You should be good to go, Pete. Hello, Christopher, and thank you for the hosting the call and the additional analysis. Question I have is there any way to tie back efficacy or safety to the phenotype of patients, you know, sort of like, you know, less severe patients based on MMSE or ADAS-Cog, age, and any possible concomitant drug, use? Very good question, Pete. The analysis exactly of that is part of the follow-up, which we're now doing, which is a detailed analysis. We are proceeding with that, and we hopefully will have intelligence on that very soon. Okay. You know, in terms of, you know, concomitant medications, you know, when I went through ClinicalTrials.gov, you know, for the Rett program as well as for the AD program and PD programs, you know, what I did see was that one of the exclusion criteria in the Rett program was CYP3A4 and CYP2C19 inhibitors and inducers. Is there a possibility that, you know, there's some type of drug interaction that may be affecting the PK and possibly tie that back to safety or efficacy? These are all cell line experiments which indicate that there could be some effect on those CYPs with our drug in presence of other ones which also are processed through this CYP, but I think the these are drugs which often are often not used in patients. You mentioned is more a theoretical, you know, bullet point, if you like, with exclusion criteria, which does not exclude really standard concomitant medications. We didn't have any exclusions because some drug was used at the same time. Okay. Then, in terms of the safety observations, dizziness and confusional state, you know, can you give us any sense of time course, you know, when these events sort of happened within the dose, dosing course, you know, the severity and possible functional blinding? Yeah. No, the functional blinding is not really the case because it was a small group of potential population, but it was equivalent in our patients in Alzheimer doing uptitration in placebo in an active arm. In the active arm was slightly higher, not by much, but that was also a little bit like, we have had a protocol which required that the patients take the drug in early in the morning. Early in the morning is the time we probably are naturally more trending towards some, you know, slight dizziness when you just wake up, get out of bed, you have automatically some higher level of dizziness, also, probably lack of liquids. That can be also addressed very conveniently by, for example, if the label that requires that you take the drug at bedtime, so you don't even notice. If there was some temporary dizziness, which was only a question of getting used to the drug. That's been shown in many CNS drugs to have that profile. It's relatively benign, actually, compared to other adverse events of other CNS drugs, which we didn't have, for example, diarrhea levels or ARIA mentioning the antibodies. That's very manageable and was really noticed mostly during uptitration. Again, because we forced the patients to take that early in the morning to be on the schedule, we almost did not address the potential of doing that in a much more softer way by bedtime administration. Okay. Similar question for the for the doctors. You know, what's your perspectives on the AE profile, you know, dizziness and confusional state? If you're referring to me, I would absolutely agree. Probably it would be worth considering taking this at bedtime in order to oversleep this, has not been much of an issue during the course of the clinical trial. So I think it's a rather benign aspect which probably would not result in any patients to be put off the drug. Okay. thank you, for taking our questions. Yeah, thank you. Thank you. The next question is from Soumit Roy at Jones Research. Hello, everyone. Congratulations on this clearly positive data. Thank you for presenting the data in context with the Aduhelm's data. One question which you haven't presented, probably it's coming in the future, is what's the time course looks like when you look at ADAS-Cog or ADL at 6 months and 12 months? When do you start seeing the separation, how the standard deviations look like? Any color would be appreciated. Yep. This is really exactly intriguing for us to look at because we noticed in the Parkinson's dementia study a cognitive improvement already after 14 weeks, as you might recall. We're also very intrigued about seeing that data points. We measured the scores at every 3 months, so we will have that available 3 months, 6 months, 9 months, up to the, you know, 48 weeks. We don't have that yet. It will be all part of the follow-up analysis as we speak. Got it. The ADL score, was that you turned it sort of into a responder because of the powering issues or the trial needs to be a larger size to see the difference? No. Let me just back up here. That's very important to understand. The CDR-SB, the ADAS-Cog and the ADCS-ADL co-primary endpoints of odds ratio were pre-specified specifically in the SAP, in the statistical analysis plan. The reason why that is because we are aiming for showing an improvement for patients. That's something which we knew from previous phase 2a trials and the Parkinson's dementia trial that we should go after that also for differentiation of the drug and for label reasons, labeling reasons. That is really the key here to understand. We are aiming for that, and we pre-specified explicitly that analysis of improvement over a threshold of clinically meaningful improvement even in the clinical study, the statistical analysis plan. that is not in any shape or shape, anything else but the pre-specification of this methodology in, for the study, given the effect of a drug and the interest of showing a differentiated profile. Got it. Thank you for clearing that. Christopher, can I say more? Yes, please. You know, this is there's several ways in which this is an incredibly innovative study. One is it works for the biology. Other people are doing that. It's one of the first, if not the first, to really show patients improving. If you think about this in terms of your family member, we already have a drug that changes the slope of decline at best, Aricept. It's highly effective in that sense. This changes the whole expectation of the disease. When you administer it, you have a good probability, not 100%, that you've actually changed the course of the people improving and that the people are already demented to begin with. All this is very revolutionary, if it holds up in future studies. Got it. Thank you, Dr. Perry. One last question. Do you expect, given the clear clinical benefit, this trial to be stopped ahead of time and either you move into a full phase 3 or accelerated approval when? Any thoughts on that? Yeah. We plan to very aggressively now to engage with regulatory authorities, both FDA as well as EMEA, U.K. and Pacific Asia, to aim for through interaction in EMEA's scientific advice, is the conditional marketing authorization procedure, which is the analogy of accelerated approval in the U.S., as well as engaging with the community, the scientific medical community, with payers, patient advocacies in the key geographies around the world, to really aggressively seek this path forward because of the benefit and the unmet need which is existing in, for this pathology. Ultimately, it really will be down to the full data and the discussion with these authorities how the next stage will play out. This is the step we are doing to be very aggressive. Thank you, and, congratulations again. Thank you. Great. The next question, will be from Yun Zhong at, BTIG. I think you can go ahead, please. Hi. Great. Thank you very much for taking the questions. I understand the benefit of showing improvement, but have you disclosed the actual number of patient or percentage patient that showed improvement as compared to baseline? On the odds ratio as the format of primary endpoint analysis. I believe that probably the rationale behind that is to show improvement, but given the clear benefit of the oral compound, as long as you can show separation from placebo in delaying maybe deterioration from baseline, that should be sufficient to support your discussion with the FDA. Do you have any comments on that, please? Yeah, I mean, you saw that the secondary key endpoint, CDR sum of the boxes, which is really a very strong global measure of cognition and function, and it's used for that reason in the other Alzheimer's studies as primary endpoint, has been significant and improved over the course of the trial from placebo active versus placebo. In a way, we show that effect and in that, in that, global score. The package is really strong from that perspective that we show an improvement in the co-primary endpoints, function and cognition separately, and then we show an improvement over placebo in the global score CDR sum of the boxes. Okay. Maybe my next question to Dr. Grimmer and Dr. Perry, please. I guess the again, the benefit of oral therapy for Alzheimer's is very well established, I think, cannot be argued. Just what do you think about the mechanism of action of the compound? Do you think it makes a big difference whether it's a disease-modifying versus maybe more symptomatic treatment? Also, what kind of evidence do you think will be strong enough to prove that this is actually through the activation of sigma-1 receptor? I believe the compound also has a muscarinic receptor binding affinity. Interesting question. First, from a patient perspective, it absolutely does not matter which mode of action is present. I think from a patient perspective, the idea to have a symptomatically working compound is much more appreciated because patients are already symptomatic and like to see a relief. As you already implied, the question of disease modification only turns out if it goes to several years of treatment when you then expect the delta between active drug and placebo to become larger and larger. From a symptomatic, already demented patient perspective, and then being an elderly person, I think a symptomatically working compound is clearly favorable. The mode of action, of course, I cannot comment on this, but the only thing I'm aware is that as far as I remember, the vast majority of patients has already been on a background medication, butyrylcholinesterase inhibitor. I'm not sure how much of this mechanism is already or still be left. Yeah, hopefully we will see or get much more insight seeing the full data set, including all biomarkers. If I can jump in on that last part, Yun, we have done experiments in preclinical with the drug and to see what the relatively contribution of the sigma-1 and the muscarinic target is. We noticed when we use a sigma-1 antagonist in presence of the drug, the beneficial effect of the drug goes entirely away. That's really clearly sigma-1 driven. When we do the same with the muscarinic receptors, if we block them or mute them, then the effect is not really going away as much. We believe there could be a synergistic play between the Sigma-1 and muscarinic, really the clearly dominant factor, contributing factor is clearly the Sigma-1 activation, that's why we're basically having this also shown in the slides as a majority of the contributing factor for the effect of the drug. Great. Thank you very much for taking the questions. Thank you. All right. That's all the questions for now, Dr. Missling. Great. Thank you. Thank you again very much for... We look forward to advancing our novel approach to therapeutic development, and are excited about the company's growth potential as we continue to build on biomarker-driven precision medicine studies with significant unmet medical need and economic burden. We will continue to work on developing accessible, easy-to-administer treatment options for patients with Alzheimer's disease and to advancing our rare disease franchise in pediatric Rett syndrome and Fragile X syndrome. We will live in a future where dementia and other neurological diseases are no longer an element of human suffering, and I would like to thank the patients and families who make this research possible. To all of the amazing community-based groups and nonprofit organizations who continue to collaborate with us to make our envisioned future a reality. Thank you very much. Ladies and gentlemen, we sincerely appreciate you joining and participating in our call today. Thank you very much. This concludes today's conference, and it will be posted on the website today if you want a replay. You may now disconnect.