Anavex Life Sciences Corp. (AVXL) Earnings Call Transcript & Summary

Good morning, everyone, and welcome to the ANAVEX 2-73 blarcamesine AD-004 Phase IIb/III Clinical Study Results Review Conference Call. My name is Clint Tomlinson, and I will be your host for today's call. [Operator Instructions] 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 2 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. And from the 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 IIb/III study. Before we begin, please note that this conference call -- the company will make some forward-looking -- some 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 Forms 10-K and 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. And 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) AD-004 Phase IIb/III clinical study results and provide an update with the next steps. Top line data of the randomized, double-blind, placebo-controlled Phase IIb/III 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 of 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 endpoint 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 Abeta antibodies: Aduhelm, which had received approval by the FDA; and lecanemab, which recently reported full data. But 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 IIa and Phase II 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. Now I'd like to run you through the presentation if may I ask to throw the next slide, please. So the forward-looking statement was just read to you. So I want to point out in this summary slide that we are in this -- in our aim of ANAVEX 2-73 trial, we have aimed for showing a drug which improves patients' life. That means we're aiming for improving the efficacy of the patients -- of the drug in patients' lives. For that reason, we moved the -- also the doses were prespecified for all patients in all doses. That is consistent also with reaching this for the co-primary objectives, 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 evaluate the clinically meaningful treatment effect since this is our goal to improve patient's 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 is binary outcomes, and this is called the odds ratio. The ADAS-Cog binary outcome variable is the 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 nonmaterial 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 Abeta antibodies, and 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 prespecified 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 Abeta, tau, NFL and so forth are ongoing and will be published in a peer-reviewed medical journal. Next slide, please. So 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, and that's why all patients are in the top line prespecified 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 effect 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 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 exceed the bar of 0.05 statistical significance and not anything less. The outcome measures now are expressed as odd ratios of improvement in cognition and function associated with ANAVEX 2-73 treatment compared to placebo. You will see now how these odd 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. And these analyses will include prespecified biomarkers response including SIGMAR1, 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 Abeta, tau, NFL and so forth. We plan to submit the complete data for publication then subsequently in a peer-reviewed medical journal. Next slide, please. So I mentioned the odd ratio having been used prior, and I have found -- we found a very distinct example recently used in the package of Aduhelm. In the analysis of odd 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. And the example here is from the Phase III EMERGENT 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 because we will show them in the next slide and highlight it again. Next slide, please. We made a comparison slide here of ANAVEX 2-73, which addresses the co-primary outcomes measure using odds ratio to the Aduhelm data. I'd like to go through this line by line. So first of all, the study duration of the trial for Aduhelm was 78 weeks, so much longer, so more time to show a separation between placebo and active arm in practice. Our trial was 48 weeks long. So 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. And as a reminder, since ADAS-Cog is a negative -- is an inverse scale. So basically, a lower number is an improvement and a high number is a decline. So the bar is set as a lower bar cognitively by cognitive impaired threshold of 3 points or better while our bar is set as minus 0.5. So 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. So in -- as an interpretation, ANAVEX 2-73 is 84% more likely to improve cognition by minus 0.4 points on the ADAS-Cog or better compared to placebo. The next line is the ADCS-ADL responder threshold. For Aduhelm that is larger than minus 3. For Anavex, it's larger than plus 3.5. So the threshold interpretation is that the bar set for Aduhelm is a lower bar for functional impaired -- starting as a functional impaired level since minus 3 at the ADAS -- at the ADL points or better is already including patients which are impaired. The bar, however, ANAVEX 2-73 study, which we set for our primary endpoint is set as a much higher bar, is set as a net improved level of plus 3.5 points. The ADAS-Cog, ADL odds ratio for Aduhelm is still lower despite the lower bar set for Aduhelm than ANAVEX 2-73 at 1.6, while ANAVEX 2-73 odds ratio is set as -- comes out at 2.67. So the ANAVEX 2-73 data is 167% more likely to improve function by 3.5 points or better compared to placebo. So in summary, the threshold for ANAVEX 2-73 is clinically meaningful -- is clinically meaningfully set in patients who are cognitively declined to evaluate a net improvement in cognition. Shorter duration of ANAVEX 2-73 AD-004 trial in patients show statistically significant improvements in cognition and function, the co-primary endpoints. The oral once daily administration of ANAVEX 2-73 has also a favorable efficacy, hence. Next slide, please. Now let's go through the top line data of efficacy discussed at the CTAD meeting. Next slide, please. The AD-004 co-primary endpoints consisted of ADAS-Cog and ADL. Let me start with the ADAS-Cog. The ANAVEX 2-73 treatment was 84% more likely to improve cognition compared to placebo by ADAS-Cog score change of minus 0.5 points or better at 48 weeks. So the interpretation is among patients who improved with ANAVEX 2-73 treatment, the mean ADAS-Cog score improvement was minus 4.03 points. This was significant with 0.015 p-value. Next slide, please. The second co-primary endpoint, ADCS-ADL, the ANAVEX 2-73 treatment was 167% more likely to have improved function compared to placebo at clinically significant ADCS-ADL score change of plus 3.5 points or better at 48 weeks. Clinically significant response categorization in function defined as ADCS-ADL larger than plus 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, CDR sum of the boxes demonstrated that ANAVEX 2-73 treatment slowed clinical decline in cognition and function assessed by 27% compared to placebo. The ANAVEX 2-73 treatment difference in mean score change was 0.42 points. That p-value of 0.04 is statistically significant. Now I'd like to point out to a comparison because we were asked how does this data compare to other data out there, the most recent antibodies. I provided a comparison for Aduhelm at the odds ratio. Now let me give you a comparison to lecanemab using their primary endpoint, which is CDR Sum of Boxes. The endpoint of lecanemab was 18 months. However, the presentation for 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. So 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 shown by measures by MMSE baseline, which were slightly lower for Alzheimer's 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, minus 0.42 and 27%, slowing the decline of a placebo in 48 weeks, while Clarity AD showed a minus 0.45, slowing decline of a 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. Also participants in the AD-004 study -- ANAVEX study did not require expensive and hard-to-find MRI monitoring for ARIA adverse events. Now a look at the chart of lecanemab of CDR Sum of Boxes, which scored minus 0.5 at 18 months, allows for rough comparison around the same time of the end of the trial period of 48 weeks or 11 months. Lecanemab approximately is 0.3 -- minus 0.3. Based on that result, ANAVEX 2-73 will be approximately when you calculate that difference and divide it by the 0.3, approximately 40% better than lecanemab. So again, based on this exploratory analysis, approximately ANAVEX 2-73 is 40% better than lecanemab at the same time point. Let me give you -- move forward with the slides. Next slide, please. So additional analysis we did on this top line data were the following. Next slide, please. We measure 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 endpoints. The ANAVEX 2-73 treatment slowed cognitive decline by 45% compared to placebo at 48 weeks. And the mean difference in ADAS-Cog score change was minus 1.85 points. The p-value was 0.033 and significant -- and statistically significant. Next slide, please. So in summary, we reached at clinically significant levels of improvement in cognition, ADAS-Cog score threshold change of minus 0.5 points or better, in patients with 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 plus 3.5 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 Sum of Boxes score. And the ANAVEX 2-73 treatment slowed cognitive decline by 45% compared to placebo at 48 weeks. And in summary, totality ANAVEX 2-73 was safe and well tolerated. Next slide, please. So I want to also explain to you how is it possible that we have patients who improved. We knew from previous trials and our mode of action that we're restoring homeostasis by activating SIGMAR1 receptor, which is an endogenous ligand we all have in the body, which only gets activated if there is cellular stress, and Anavex and Alzheimer's pathology is causing tremendous amount of stress on multiple fronts. And this impaired SIGMAR1 function also is known to cause destruction and cellular stress and even Alzheimer's disease. So the opposite is for that reason confirmed SIGMAR1 activation could be beneficial in countering the Alzheimer's pathology. Next slide, please. We then have described the way the mechanism works by activating now SIGMAR1 endogenously, not sufficiently activated because of chronic stress. The ability to activate it from the outside with ANAVEX 2-73 would be the compensatory mechanism to support the biological compensation in the body to counter these cellular attacks. Next slide, please. And that's been also described in many -- several papers that ANAVEX 2-73 with the activation of SIGMAR1 is able to reduce Abeta pathology, but also is able to reduce tau pathology but also is able to restore homeostasis and mitochondrial function. It's also showing to reduce inflammation and also was able to demonstrate autophagy increase if it's impaired. So very complex pathology where the SIGMAR1 endogenous activation is able to counter the very complex Alzheimer's pathology. Next slide, please. On top of that, recently, SIGMAR1 activation was demonstrated to be even further upstream involved in promoting 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 Alzheimer's pathology. Next slide, please. So what are the next steps? Our next steps are the full analysis, including prespecified biomarkers response as well as MRI, whole exome sequencing DNA data and full RNA exome expression data collection, data on biomarkers of neurodegeneration. These are ongoing and will be published in a peer-reviewed of medical journal. At the same time, the open-label extension study ATTENTION-AD will continue to follow participants over 96 weeks. And now we plan to meet with regulatory authorities to determine the next steps. Next slide, please. We like to acknowledge at this point the principal investigators and all clinical trial 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. But most of all, we really have to be thankful and grateful and acknowledge the contribution of the participating Alzheimer's patients and their caregivers. And also, I'd like at this point in time, thank all our supporters and shareholders for their support. Thank you.

Next slide, please. So 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. And then I also like to ask the same for Dr. Perry, obviously. Can you please discuss your thoughts regarding the top line results from this AD-004 study and what it means from your clinical perspective?

Yes. Dear Dr. Missling, thank you so much for representing, and I've had the opportunity to be present at CTAD and watch the original presentation. And 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. But I think what can already be stated at that moment is that, of course, what you're seeing with your compound appears to be an improvement. So it'll be able that patients perform better even after a year during a progressive disease, which, of course, is -- things we are highly needed. So we only have these anti-dementing drugs, small effect sizes yet. So everything on top is highly appreciated, and 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. But currently, I think the main thing is you really improve patients as compared to what you, for example, show these disease-modifying agents that only will slow down the course of the disease.

Thank you very much. Dr. Perry, do 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 by 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 the amyloid and the value of that. And 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, and this has certainly become a concern with the vaccine where at least 2 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 2 weeks or an oral once-daily capsule with a simple refill, which do you propose would be their preference?

You're asking me or -- Dr. Grimmer would be the 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 many side effects, even if they're not life-threatening, the headaches, 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?

Yes, 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. So I think this is absolutely clear. This oral formulation with a safe drug is clearly preferred.

Great. Another question, in the clinic, do you see -- for Dr. Grimmer, do you see more patients expressing concern about their Alzheimer's risk than in years past? Or 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, but seen at my specialized unit, but in principle, awareness has substantially raised including by all the news that have been brought up by this disease-modifying agents. So 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 Anavex is currently processing, and we mentioned that we're 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 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 but exactly the biomarkers that are available now having great predictive value. But that said, a drug that could be with low side effects, relatively low cost would be -- really would be a major God send to the field because then it could be used in patients that are having like -- to have ApoE4 genotyping or high risk of transitioning into Alzheimer's disease than those that are in mild cognitive impairment administrating it. I think this would be -- but if you have to apply something like the vaccine approach, you put those patients at high risk of problems and cost and burden for family. So I think that an oral medication is really critical for change in the public health scene.

Right. Thank you. Next question. Given that recent developments with 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?

Yes. Probably every expert needs to state this since several decades that combination therapy is probably the best approach. And one could imagine, of course, 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. So, yes.

All right, and assume 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 that's 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. So let me round out because we like -- 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 and how you think these top lines can affect treatment in Alzheimer's disease? Dr. Grimmer, first maybe?

This, of course, depend. 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. But this probably is high hope, but I wish you for. And so we hope sooner or later to have this available in clinic. And 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. The removing of pathology has not been therapeutically efficacious so far. But working with the biologies you're doing. And 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. So this is an exciting time in neuroscience and rare disease drug development, and we are committed to bringing potentially life-improving treatment options for 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. So I would like now to turn the call back to Clint for a Q&A with the investors, analysts.

Thank you, Christopher. [Operator Instructions] And we'll start with Pete Stavropoulos from Cantor.

Thank you for hosting the call and the additional analysis. A question I have is, is there any way to tie back efficacy or safety to the phenotype of patients, sort of like 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 are now doing, which is a detailed analysis. So we are proceeding with that. And hopefully, we will have intelligence on that very soon.

Okay. So in terms of concomitant medications, when I went through clinicaltrials.gov for the Rett program as well as for the AD program and PD programs, what I did see was that one of the exclusion criteria in the Rett program was CYP3A4 and CYP2C19 inhibitors and inducers. So is there a possibility that there's some type of drug interaction that may be affecting the PK and possibly tie that back to safety or efficacy?

Yes. 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 these are drugs which often are not used in patients. You mentioned, it's more a theoretical bullet point, if you select exclusion criteria, which does not exclude really standard concomitant medications. So we didn't have any exclusions because some drug was used at the same time.

Okay. And then in terms of the safety observations, dizziness and confusional state, can you give us any sense of time course when these events sort of happened within the dosing course, the severity and possible functional blinding?

Yes. No, the functional blinding is not really the case because it's a small group of potential population. But it was equivalent in patients in Alzheimer's, doing up-titration in placebo in active arm. But in the active arm, it 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 early in the morning. And early in the morning is the time we probably are naturally more trending towards some slight dizziness when you just wake up, get out of bed, you have automatically some higher level of dizziness, also probably lack of liquids. And -- so 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 that if there was some temporary, by the way, dizziness, which was only a question of getting used to the drug, and that's been shown in many CNS drugs to have that profile. So 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. So that's very manageable and was really noticed mostly doing up-titration. Then, 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. And a similar question for the doctors. What's your perspective on the AE profile, dizziness and confusional state?

If you're referring to me, then I would absolutely agree, probably it would be worth considering taking this at bedtime in over -- to over sleepers and 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.

The next question is from Soumit Roy at Jones Research.

Congratulations on this clearly positive data and 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 was it -- what 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.

Yes. 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. So we're also very intrigued about seeing that data points, and we measured the scores at every 3 months. So we will have that available 3 months, 6 months, 9 months up to the 48 weeks. So we don't have that yet. It will be all part of the follow-up analysis as we speak.

Got it. And the ADL score, was that you turned it sort of into a responder is because of the powering issues or the trial needs to be a larger size, do you see the difference?

No. Let me just back up here. That's very important to understand. So the CDR Sum of Boxes, the ADAS-Cog and the ADCS-ADL co-primary endpoints of odds ratio were prespecified specifically in the SAP, in the statistical analysis plan. And the reason for that is because we are aiming for showing an improvement for patients, and that's something which we knew from previous Phase IIa trials and the Parkinson's dementia trial that we should go after that also for differentiation of the drug and for labeling reasons. That is really the key to understand. We are aiming for that, and we prespecified explicitly that analysis of improvement over a threshold of clinically meaningful improvement even in the clinical study -- statistical analysis plan. So that is not in any shape, anything else, but the pre-specification of this methodology in -- for this study, given the effect of a drug and the interest of showing a differentiated profile.

Christopher, can I say more. This is -- there are several ways in which this is an incredibly innovative study. One is it works for the biology. Other people are doing that, but it's one of the first, if not the first, to really show patients improving. And 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, but 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. 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 III or acceleratory approval when -- any thoughts on that?

Yes. So 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, 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's advocacies in key geographies around the world to really aggressively seek this path forward because of the benefit in the unmet need which is existing and 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. But this is the step we're doing to be very aggressive.

Great. The next question will be from Yun Zhong at BTIG.

So I understand the benefit of showing improvement, but have you disclosed the actual number of patients or percentage patient that shape improvement as compared to baseline? And 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 for placebo in delaying maybe deterioration from baseline, that should be sufficient to support your discussion with the FDA. So do you have any comments on that, please?

Yes. I mean you saw that the secondary key endpoint, CDR Sum of 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 study as primary endpoint has been significant and improved over the course of the trial from placebo active versus placebo. So in a way, we show that effect in that global score. So 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 of a placebo in the global score CDR Sum of Boxes.

Okay. And maybe the next question to Dr. Grimmer and Dr. Perry, please. So I guess -- again, the benefit of oral therapy for Alzheimer's is very well established, I think, cannot be argued. But just -- what do you think about the mechanism of action of the compound? Do you think it makes a big difference whether it's disease-modifying versus maybe more symptomatic treatment? And also, what kind of evidence do you think will be strong enough to prove that this is actually through the activation of SIGMAR1 receptor? I believe the compound also has a muscarinic receptor binding affinity.

Interesting questions. So first, from a patient perspective, it absolutely does not matter which mode of action is present. And 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. And as you already implied, the question of disease modification only turns out if you go through several years of treatment when you then expect the delta between active drug and placebo to become larger and larger. But from a symptomatic already demented patient perspective and then being an elderly person, I think, a symptomatically working compound is clearly favorable. And 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 with a cholinesterase inhibitor. So I'm not sure how much of this mechanism is already -- or still be left, but 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. We have done experiments in preclinical with the drug and to see what the relatively contribution of the SIGMAR1 and the muscarinic target is. And we noticed when we use SIGMAR1 antagonist in presence of the drug, the beneficial effect of the drug goes entirely away. So that's really clearly SIGMAR1 driven. And when we do the same with the muscarinic receptors, if you block them or mute them, then the effect is not really going away as much. So we believe there could be a synergistic play between the SIGMAR1 and muscarinic, but really the clearly dominant factor, contributing factor is clearly SIGMAR1 activation. And that's why we're basically having this also shown in the slides is a majority of the contributing factor for the effect of the drug.

That's all the questions for now, Dr. Missling?

Great. Thank you. Thank you, again, very much and 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 believe 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. And to all of the amazing community-based groups and nonprofit organizations who continue to collaborate with us to make our envision 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.