I think that just about looks like everybody's joined us who was going to join. It is my pleasure as the Chief Executive Officer of Actinogen to welcome everybody here today. We are very thrilled to have Professor Sabbagh from the U.S.A., who is a very experienced investigator, academic, and expert in the field of Alzheimer's disease, having published nearly 500 or more or so publications in the field. He is joining us in a discussion with Dr. Dana Hilt, our Chief Medical Officer and expert neurologist as well. The proceedings will be shared in a sort of fireside chat format by our Chief Commercial Officer, Andy Udell, based in Connecticut. As you all know, we are developing Xanamem as a potentially safe and effective oral therapy for Alzheimer's disease that we hope can stabilize or even, meaning halt the disease or significantly slow it, to a greater extent than anything anybody else has developed previously. That is the result we are looking forward to in our pivotal trial results coming out in November. More about that later. If we go to the next slide. This is our usual disclaimer that is available on the website, and I will not pause on that, but we will be making forward-looking statements as always. Next slide. Just a little reminder about the Q&A, which I will manage. We will prioritize questions that are based on the content from today's webinar. Hopefully there will be plenty of time, as there usually is, to answer all questions. They will be grouped, and we will take Q&A in the chat during the presentation, but we will not actually group those together and answer them until the end of the presentation in the Q&A section. With that, my pleasure to hand over to Andy Udell, for the next and main part of the session. Thank you, Steve. Let me stop sharing there. I assume you can see me now. Thank you, Steve. Marwan and Dana, great to have both of you here. It is clear that we are in an interesting time in Alzheimer's disease. We have the first disease-modifying therapies now being used in clinical practice. The diagnostic landscape is changing quickly, particularly with the blood-based biomarkers, and there is a tremendous amount of science continuing to advance across the field. At the same time, we know that enormous unmet need remains. Rather than spend the next 30 minutes talking about individual products, I would like to take a broader look at where Alzheimer's disease care is today, what we are learning from the real-world experience, and perhaps most importantly, where the field may be headed from here. Marwan, I am going to start with you. How has the Alzheimer's diagnosis and treatment evolved with the introduction of the anti-amyloid therapies? First, I want to say thank you to you, Andy, and to Steven, and to Dana for including me tonight. I am honored to be included in this discussion. Alzheimer's has changed dramatically in the last five years. The first major change was we went from a clinical phenotypic diagnosis, meaning a description of the symptoms, to a biological diagnosis, now using amyloid, tau, and neurodegeneration, the A/T/N criteria. We are now using in- vivo diagnostics, PET, CSF, and blood to increase our accuracy and improve the time from presentation to a diagnosis. That is major change number one. Major change number two is now we have a class of drugs called amyloid-targeted therapies, or ATTs. These are monoclonal antibodies. These drugs bind only one of the proteins, which is amyloid, and remove it out of the brain. The drugs do not make you better. They make you less worse. We still struggle to explain why 85% removal only causes a 27% clinical effect. The uptake has been pretty much, much lower than expected. The uptake worldwide was maybe 5%, 10% of what was expected or projected. There are safety issues. There are frequent monitoring. These are intravenous drugs that require frequent MRIs. They are infused drugs, so there is not an oral pill. You have to do frequent MRIs because of a concern about a complication called ARIA. We use them in my practice and in our clinic here, but I will tell you that they did not become the panacea that everybody had hyped or worried about, that this would bankrupt our Medicare. None of that has happened. It is a niche drug. A few thousand people, Andy, I will tell you something, the estimates are like 25,000-30,000 people take these drugs. I think globally it is like 50,000. Far, far less than the millions that were projected to take these drugs. They have a niche. They serve a purpose, but they have not been the panacea that we expected. Great. Well, thank you for that perspective. Dana, anything you would add from your perspective, particularly as you think about how the science and the treatment landscape are evolving Well, just to emphasize one point that Marwan made. Back when I was taking care of these patients and we based our diagnosis on clinical diagnosis, even if we were experts in taking care of these patients, we were wrong 30%-40% of the time. This is the biomarkers, the imaging, this has really refined our ability to characterize the patient. And that's important both for prognostic reasons, to tell the patient what they have and what they might be facing, but also to do clinical trials, try to decrease the heterogeneity of the patients in the clinical trial, which is a real problem. I think the biomarker field is rapidly evolving. I think Marwan's very well described the benefits of the antibodies, which are modest, and then some of the safety side effects, and I'll get to that in a second. The biomarkers are getting to the point where I think in the very near term, we can have individual practitioners not send patients for PET scans or invasive CSF analysis and do laboratory-based testing. The biomarker that is probably the laboratory-based biomarker of choice and will evolve to be the standard is p-tau217. That's at least one of them. I think in the future, as we get more therapies, maybe safer therapies, maybe oral therapies, I could envision the scenario where primary care physicians or primary neurologists, community neurologists, can see the patients, make a careful assessment, do these plasma-based biomarker analyses of patients, and put them on therapies. The other thing that I think has really occurred is that people recognize, as Marwan suggested, that you can almost quantitatively remove the amyloid plaques in patients, yet you see a very modest improvement. Part of that is maybe we need to move earlier in treatment, but part of it is Alzheimer's disease is not dependent upon one pathology. It's not just amyloid. It's probably not just amyloid and tau. There are many pathologies, neuroinflammation, other factors that are involved in this disease, and I think Xanamem is focusing on blocking cortisol production in the brain. That may be one that might be beneficial. I think the more we learn, the more we understand that Alzheimer's is even more complex than we originally thought it was. Yeah. Thanks, Dana. We clearly entered a new era in Alzheimer's treatment, but the significant unmet need remains. Marwan, I want to talk a little bit about how these advances are translating into your practice, into your clinical practice. You talked a little bit about it, obviously, from a global level and knowing the numbers, but take us through when you see a patient, how would you deem them appropriate for an anti-amyloid therapy? What's the perfect patient for you? What happens if you discuss it? How does that conversation go with them? Tell us about the whole process, please. In the initial consultation, the first thing I am doing is determining their condition. Is it mild cognitive impairment or dementia? Then looking for the etiology, meaning Alzheimer's or another pathology, Lewy body, et cetera. I tell them at the beginning, at the initial consultation, what are my concerns. I order some tests, including plasma test, as Dana said, p-tau217. I will order, in round one, neuropsych testing, MRI, and then the first follow-up visit, talk about what the findings are, if it reinforces my concerns. At the end of round one, I'll order amyloid PET and APOE genotyping. By the time I'm talking about an amyloid-targeted therapy, a monoclonal antibody, I already have established a preliminary diagnosis, I've already discussed this preliminary diagnosis, I already confirmed that they have the presence of amyloid, I've genotyped them, I've discussed the risks and benefits of symptomatic therapy versus monoclonal antibody therapy versus a clinical trial, the consequence of a decision and the consequence of a not decision, what we call a shared decision-making model, and talk about what the prognosis and future looks like. Andy, let me just say, this is not a five-minute conversation. Not like a- Yeah, no, it doesn't sound like it. Yeah, it's not a five-minute like, "Oh, you have Alzheimer's," and walk out the door. These are- It's a 45-minute conversation. It is a 45-minute conversation. Do you get into the efficacy and time and those kind of topics with them, or is that too personal and, obviously there's variable. Do you want to set expectations with something like that, or are you just- Yes. Yes, I do. I do. I actually talk about what are the benefits or the limitations of the symptomatic meds, that they are to Alzheimer's what Tylenol is to arthritis, and I say it just like that. If you have arthritis and you take Tylenol, your knee pain, back pain might go away, but you still have arthritis. That's what donepezil, rivastigmine, galantamine, and memantine do. I talk about the fact that Go ahead, sorry. Oh, no. Keep going. I talk about the fact that amyloid-targeted therapies are going to not make you better. They're going to make you less worse, around 30%, but coming with a lot of surveillance and monitoring and MRIs and infusions. Then I talk about clinical trials and the possibility of placebos. I'm at a research center. That's why I have the third option always. Dr. Google, by the way, I want to point out, is not my friend. So by the time a patient walks in the door, they already have a stack of papers of everything they read. They're experts. They're experts. Not you and me, Dana, whose whole life's career, this is our entire career, but they are the experts. Well, I can see that being a challenge with something like this. From an access standpoint, particularly in the U.S., let's say you've made the decision to offer them, even if it's not a joint decision, you make the recommendation, whatever it may be, or even if it's a joint decision, they say yes. Tell us about from that time, from that minute till they actually go on the treatment and what do you have to do while they're on treatment, and how cumbersome is it? I'm looking forward to your solution because it'll be much less complicated than what I deal with in my current practice. We have to register the patient with Medicare. It's called the CMS Registry. You have to get authorization from the insurance company and Medicare, so if they have a supplemental Medicare policy. You have to find an infusion center. You have to pre-schedule the MRIs. We actually have nurse practitioners whose whole job, only job it is to set up, monitor, surveil our patients getting infusion therapies for the practice, not just for me, but for the entire practice. Yeah. Because we have about 250 people on these treatments now. It's a lot of work. It's very laborious. We set it up so that if they get an MRI, they cannot get their next infusion until one of us signs off on their MRIs, because there's a lot of safety monitoring that goes along with it. It's not easy. It's not like I just write a script and say, "Here, take this pill and see you later." I wish it was, but it's certainly not. It's much more complicated than that. Just a quick addition, that every 80-year-old Alzheimer's patient I took care of had an 80-year-old spouse. Getting people out of the house across town to an infusion center for a one or two-hour infusion back and forth is a non-trivial challenge because most of them have comorbidities and other problems. This is a major issue when dealing with these types of therapies. Yeah. The paradox of this is that ideally we would love to have them infused at our medical center because we like to keep control over the surveillance and the monitoring, et cetera. But of all the patients, to your point, Dana, prefer to be infused near their home. Right. Their infusion is our risk. It's not like just because they're getting infused somewhere else, I'm the one who wrote the prescription. I'm the one who's responsible if a complication occurs. Every time that happens, to your point, Dana, we're holding our hands, making sure nothing bad happens. You do the MRIs, and yes, you can see an obvious hemorrhage, obvious edema, but sometimes some of these findings are relatively subtle, and you have to have experience reading these types of complicated, sophisticated imaging studies. Anyway, there are challenges. Yes. Marwan, if you had to guess, out of every 10 patients that you discuss and recommend this, how many actually say, "Okay, I'm going to go for it," or how many resist, and who is it that resists usually? The number I typically quote, Andy, is about 20% of people walking in the door are going to get an anti-amyloid therapy. The other statistics quote something more than 8%-12%. My point is, it is not as many as you think. People are scared. They read about this and they are scared. People are not convinced that it works. People, they do not think they are bad enough to qualify, and by the time they are, they are going to not qualify. It is a paradox like, "Oh, I am going to kick the can down the road," thinking that is a fine solution when it is not. It is less than you think. My estimate was about 20%, but it might even be less than that. Okay. Look, while anti-amyloid therapies, they represent an important therapeutic advance. Absolutely. We have learned a lot from them, but the key is many patients still remain untreated and obviously, it still has a huge unmet need. May I add one comment to that, Andy? Sure. That sets up the conversation that we're having today because we're now moving to the idea that Alzheimer's is treatable. Okay? Yeah. We need to get away from the idea that Alzheimer's is not treatable. It is treatable, and maybe that's not the ideal first step, but it is a first step. Now we can move toward the idea that we see better drugs, oral drugs, safer drugs, moving forward because Alzheimer's is treatable. Great. Before we go to there, I do want to transition. I'm going to start with Dana on this. I want to talk about the impact of blood-based biomarkers. Dana, in the clinical practice, you've seen the evolution of these biomarkers firsthand through the clinical development process over the last few years. Maybe just give us a brief perspective on how the use has evolved and what you're seeing in clinical trials and clinical work. These biomarkers, and there are a number of them, to simplify it a little bit, I think p-tau217 is the leading candidate for blood-based biomarker to confirm the diagnosis of Alzheimer's disease. Initially, they were used in patients with early AD, MCI that had PET scan abnormalities, known amyloid, and the correlation between the elevated p-tau217 or p-tau181 and positive amyloid by CSF or PET scans was very high. The focus of this antibody treatment is to move the treatment earlier and earlier. Now these, we can, I think, see in the future the notion of using these biomarkers in patients who are functionally normal, maybe even don't even have MCI. There are studies going on in patients who have amyloid but don't even have minimal cognitive impairment, let alone Alzheimer's disease, to see whether the antibodies can prevent the onset, and the biomarkers are the way you diagnose patients. Clinical trials now are using elevated biomarkers to characterize the patients and to qualify them for clinical trials, which is much simpler than doing a spinal sampling, spinal tap, lumbar puncture, or doing a PET scan. I think in the not-too-distant future, this is going to be almost standard. Now, caveats. I think there are seven p-tau217 assays on the market. If I have a patient and I do a plasma potassium, I get a standard value. Doesn't make any difference which assay I use. Many of these p-tau assays are going to give different normal ranges, different values, and this is going to require some education of the clinical practitioner to understand which test they're using, what's normal, what isn't. The other point about the p-tau test is it may be abnormal. If it's very high, it's probably predictive of a more rapid progression in these patients versus borderline elevated. I think we're learning a lot about these biomarkers. They're rapidly evolving, and if you told me today, two years ago, that we would be where we are today, I would've said that would've been impossible to make that much progress. It is going at very rapid speed, and by the time we get to the end of this year, it'll be different yet again. That's my perspective. I think Marwan's in practice and takes care of these patients. Dana and I were in London at the CTAD conference, and now not only from what Dana has said, they're even positing the possibility that these blood tests are predictive, not just diagnostic. Yeah. Right. But predictive. We went from waiting and waiting and waiting, now the bullet train, and we're all just trying to hold our breath and keep up because it's been really fast. Marwan, let's take these into the actual clinical practice now. How do you see them changing the diagnosis and management, and are they going to reshape the patient journey? Are we going to just be able to detect much more patients and have them grow? Are primary care physicians going to start making this diagnosis? Tell us what your thoughts are on where we're going. The answer is yes. There'll be some nuances to that yes, but we will use p-tau as a diagnostic, particularly because we would teach primary care physicians to use the p-tau217, kind of like a PSA or a hemoglobin A1c. So if your A1c is, you know what to do with it. If your PSA is elevated, you know what to do with it. So a primary care physician will have a kind of a roadmap, like, "Okay, this is abnormal. I know to refer, I know to work it up." So I feel like that will help the PCPs, but I don't necessarily lay it on them that they need to make a diagnosis. I just need them to say, "Okay, we can't ignore this. We need to do something about it." Beyond that, of course, the questions that are being posited, not necessarily by whether we're going to talk about this drug today, but is whether would we use it instead of a PET or a CSF, and that is a debate that it still hasn't settled. I think it's going to be very useful as a rule-out in the primary care setting. You come in, it's an older person, 75 years old. They're well. They don't have a functional issue. They may have some perhaps very mild memory problems. You're not sure whether they have the early stages. If you do a p-tau and it's normal, the likelihood of them going on to have AD is pretty low. If you have an elevated p-tau, probably the primary care physician, as Marwan suggested, if a primary care physician sees a patient with a high PSA, they don't go into the treatment of prostate cancer. They refer the patient to a urologist or an oncologist, confirm the diagnosis, but then they pass off the treatment of the patient to a specialist, which is where I think these therapies need to belong. They need to belong with a neurologist, psychiatrist who are treating these patients. Well, I think that's a good segue to the next topic, which is what physicians and patients are going to expect from Alzheimer's therapies as the treatment landscape continues to evolve if more people are getting diagnosed early by primary care. I really want to put on your futuristic hat here, and we'll start with you, Marwan. As you look to the future, what do you think physicians are going to be looking for in the next generation of AD therapies, and what role might differentiated mechanisms and potentially multiple therapeutic approaches play in this evolving treatment landscape? Many topics laid into that question. Number one, I think we are on the precipice of converting Alzheimer's disease from a terminal disease to a chronic disease. This is the diabetes and HIV of our time. A generation ago, if you had HIV, you were going to die. I remember being in medical school. If you got diabetes, for sure you were going to be on dialysis, blind, and amputated. Now people live normal life with HIV and a normal life with diabetes. We're going to see the exact same thing. We're going to make Alzheimer's a chronic disease. The idea that we're going to prevent it or cure it, I think is aspirational, but we will make it a chronic disease. That's number one. Number two is we will be able to detect the Alzheimer changes in the brain before onset of symptoms. There's now a big push to go to a time where we would treat before onset of symptoms. That is a whale of an idea, but it is being floated in our field. The third idea is that we can't be reductionist simplistic. The future of Alzheimer's treatment is a polypharmacy, a chemotherapy, a drug cocktail approach. Amyloid therapies is just one drop in the bucket, but we're going to probably have tailored therapy. I've actually read a grant a few months ago that said there are 16 endophenotypes for Alzheimer's disease. An idea that we would actually find what is your endophenotype and then give you your cocktail like cancer time and again. We expect to see the route that was laid out by cancer to come to Alzheimer's as well. Dana, let me bring you here and get your thoughts from the scientific. I think, Marwan has touched on a lot of the points that I wanted to make. I always have the maxim that I never treat a patient with a chronic disease with a single drug or single mechanism. A patient has hypertension, you approach it from many different angles. You use drugs in combination. You use drugs at different stages of disease. I think Alzheimer's is going to be a chronic disease, which is like all other chronic diseases, and we're learning more about these different mechanisms. So it's not just amyloid and tau, it's mitochondrial oxidative stress, lysosomal dysfunction. We're working on a drug to block cortisol production in the brain, which has many deleterious effects in the brain. So we're coming at this now, learning more about the basic science of the brain and Alzheimer's disease and approaching it from multiple mechanisms. I think that's going to be synergistic. Treating patients with different drugs, with different mechanisms is probably going to be synergistic. Back to the amyloid therapies briefly. On the horizon are new forms of these amyloid antibodies that are going to be safer to administer, shorter treatment courses, probably have less side effects, and may even remove more amyloid. So I think even that type of therapy is going to be transformed within the next five years, I would predict. Great. Marwan, any final thoughts? We're running to the end of our time here. No, it's an exciting time. You've touched on a lot of the key points that are relevant to the state of the science at this moment. Great. Well, Marwan, Dana, thank you so much. Thank you. I think what comes through clearly from this discussion is that Alzheimer's disease care has made progress, but we're still at the beginning, let's say, of what we can imagine being a much larger evolution in how we certainly this disease. Seems like we're identifying patients differently. There's going to be new treatment options and the expectations for future therapies to deliver are continuing to evolve and maybe be additive. What I'd like to do now is spend a few minutes putting some data around several of these themes that we just discussed, the scale of the remaining unmet need, talk about what physicians are telling us about the changing treatment landscape and where we believe continued innovation could take Alzheimer's care from here. I'm going to start sharing my screen. Okay, that should do it. See my screen? Okay, so before we talk about treatments, biomarkers, and clinical trials, it's really important to ground us to remember what Alzheimer's disease really means. This is a disease that affects not only the person diagnosed, but families and caregivers around the world. That's ultimately why continued progress in Alzheimer's matters so much to us. There we go. The scale of the challenge is enormous. There are 57 million people worldwide living with dementia in 2021, with AD accounting for approximately 60%-70% of those cases. Nearly 10 million new cases of dementia occur each year, and that number is projected to grow substantially to close to 140 million by the year 2050. The growing global burden reinforces the need for continued innovation in Alzheimer's disease. At the same time, we really are entering a new era in Alzheimer's disease. Disease-modifying therapies have begun to reshape the treatment landscape. Blood-based biomarkers have the potential to simplify diagnosis and identify patients earlier, and our scientific understanding continues to expand across multiple biological pathways. So together, earlier diagnosis and new treatment approaches may allow us to improve care for more patients. There's clearly been meaningful progress, but we're still early in this evolution. You heard it from Marwan and Dana, and the need for continued innovation certainly remains. The recent advances, we talked about this in targeting amyloid, have provided real hope for some patients, but they've also highlighted the challenges that remain. It is progress, as we talked about, but as you heard from Marwan, there are a lot of challenges with efficacy and with just getting and monitoring the treatment for these patients. They aren't appropriate for every patient, and the monitoring can be complex. Most importantly, we're learning more and more that Alzheimer's is a biologically complex disease that's going to likely require multiple therapeutic approaches. Our understanding of Alzheimer's biology continues to evolve. It's increasingly clear that we are going to need new mechanistic approaches to address the diverse needs of the patient. That view is very consistent with what we heard directly from neurologists in our market research. We conducted primary market research, and it was with close to 100 neurologists. These neurologists in the U.S. all treated, on average, over 250 dementia patients each. So they're seeing a huge population. These are on the front lines. 91% told us there remains a high unmet need for additional disease-modifying therapies. Interestingly, what surprised me a little bit was 86% expect the treatment of Alzheimer's disease to change over the next five years. That optimism is great, and some of them may be involved in clinical trials and things, so that's encouraging. I think the neurologist's quote on this slide captures the point particularly well. The future is unlikely to be about one mechanism alone. It's likely to involve multiple approaches targeting different aspects of the disease, just like Dana told us with other chronic diseases, as well as Marwan. We're really just at the beginning of this journey and understanding the biology more and more. So when asked neurologists what they value most in future Alzheimer's therapies, well, obviously meaningful clinical benefit, slowing or halting disease progression clearly matters, but it's not the only consideration. I guess based on what they've seen so far, really, they value favorable safety tolerability profiles that are simple, convenient. These were really highly ranked compared to efficacy, and I think that's based on what they've seen today and been exposed to. Ultimately, the future of these therapies are going to need to deliver not only some benefit, but also fitting seamlessly into clinical practice, and ease of use is going to be extremely important. So when we look at those attributes and compare them with Xanamem's profile, there's certainly encouraging alignment. We've certainly have seen some encouraging phase II clinical efficacy signals, and Xanamem's been consistently well-tolerated in all clinical trials to- date. It's a once-a-day oral tablet, which is certainly convenient, and there's no monitoring that infusion or routine MRI monitoring, I should say, that's going to be required most likely. So Xanamem's profile really is aligning with what we saw on the last slide, the characteristics that neurologists are considering important for future Alzheimer's disease therapies. That brings us to what makes Xanamem mechanistically different, what makes our mechanism different. So what makes Xanamem different is its mechanism again, and rather than targeting amyloid, Xanamem's designed to control brain cortisol levels by inhibiting the enzyme 11-beta HSD1. So based on the extensive scientific literature, reducing this excess brain cortisol has the potential, really, to influence several processes associated with Alzheimer's disease, including cognition and memory, neuroinflammation, synaptic function, and tau biology. So targeting excess brain cortisol represents a unique and promising approach to treating Alzheimer's disease. That brings us to XanaMIA, our pivotal phase II-B trial in 247 participants with mild to moderate Alzheimer's disease. Top-line results are anticipated in November. If successful, Xanamem has the potential to expand the therapeutic options for patients living with Alzheimer's disease, further validate brain cortisol control as a therapeutic mechanism, and certainly contribute to the next generation of Alzheimer's disease treatment. So XanaMIA really represents an important milestone for patients, physicians, and caregivers, and for the future of the disease. It's at that point I'm going to stop this point and remind everyone I'm going to turn it back over to Steve for questions. And remind you how to ask questions, and I'll stop sharing the screen so Steve can start. Right. Thanks, Andy, Dana, and Marwan. That was a great tour through what is actually an exciting time for Alzheimer's disease. And Marwan, it is great to see something happen that makes the disease treatable. I saw a really interesting presentation in London where somebody had done proteomics, dividing Alzheimer's into five different subtypes. It's kind of like the beginning of, I don't know, breast cancer research 50 years ago, where breast cancer was just breast cancer, and now it's many different diseases treated with many different cocktails of therapies. So hopefully we can go fast in the next five or 10 years and solve that for the majority, at least, of patients. Anyway, my job is to put together the questions that we've received to- date. And the first one just pertains to Australia, really. What of these diagnostics, new diagnostics, blood diagnostics are available actually in Australia? I will just answer that one. So p-tau181 was approved one and a bit years ago, I believe. General practitioners can order that. It is done by the Florey Institute in Melbourne every two weeks. It has, as Dana said, if it is negative, it pretty much rules out Alzheimer's disease. If it is positive, there is roughly a 50% predictive value that the patient will have Alzheimer's disease. A general practitioner in Australia should, with a positive test, refer that patient on to an expert memory clinic or a neurologist with the expert to use in Alzheimer's disease. Just a few weeks ago, the p-tau217 was approved, and I am not exactly sure where that is processed, but I believe it was the Roche version of that test. Both of those blood tests are available to general practitioners in Australia, but they are not necessarily reimbursed by the health system here just yet. They probably will be in the near future. That is just that one question. Somebody asked, Tim asked, cortisol control potentially is very anti-inflammatory. Are there other diseases, or is there a myriad of diseases that Xanamem could be used to treat assuming we continue to get positive data from our clinical trials? I do not know, Dana, do you want to take that one? Yeah, sure. I think that just to comment first on cortisol's role or corticosteroids' role in the periphery versus the brain. Physicians administer corticosteroids to suppress inflammation in systemic inflammatory diseases, autoimmune diseases. Paradoxically in the brain, cortisol has the opposite effect. It promotes neural inflammation. The enzyme which makes cortisol is expressed in microglia. As microglia get activated and release toxic cytokines, the level of cortisol synthesized and released goes up. If we think about systemic diseases outside the brain, there may be a number of diseases with elevated 11-beta HSD1 activity. That is the enzyme that makes cortisol. There are diseases such as metabolic diseases. There is depression. We have already done a study at Actinogen showing the drug may have antidepressant effects, and that may be a useful indication outside of Alzheimer's disease. Comment, about 50% of AD patients have depression and apathy, so that may be useful, another effect of the drug in that patient population. There are some geriatric conditions such as muscle wasting and other conditions that may involve excess cortisol production by 11-beta HSD1. There may be other opportunities. Even in the CNS space, because this drug is not directly aimed or targeting amyloid or tau, it could be useful in other neurodegenerative diseases with cognitive impairment. I think that is for the future for us to look into if we are successful in this Alzheimer's trial. Great. Thanks. Thanks, Dana. I'll stick to inflammation for the moment. Somebody also asked, will we be looking at inflammatory biomarkers in the Xanamem pivotal trial that we're conducting currently, such as GFAP and neurofilament light? We are looking at those, and we have some plans to look beyond that if those show an indication of activity. Those are more exploratory. The primary endpoint of the trial is a clinical one. The CDR-Sum of Boxes and the ADL scales and other clinical scales, see if we can produce a clinical benefit. But we're mindful of this potential to block toxic cytokine production by 11-beta HSD1 inhibition. So we will be looking at that at a second level, if you will. Yep. Okay. Thanks very much. Marwan, maybe this is a good one for you. Somebody asked about the next generation of amyloid antibodies, such as trontinemab from Roche, that are using Brainshuttle technology to get across the blood-brain barrier without binding to the blood vessel amyloid, and thus reduce side effects to a certain extent. David was wondering, what's the likely impact of these antibodies clinically? Then obviously, does it have any major impact on the potential use of an oral therapy like Xanamem? The short answer is no. It should have zero effect on Xanamem's development or uptake. The fact is, trontinemab, remternetug, and a couple of other drugs are in the, what I call, third-generation monoclonal antibodies. They've perfected them to the point where we will remove amyloid out of our brain in 180 days. They're just faster, more efficient, but not necessarily a better clinical effect. No matter how fast you remove amyloid, you're still only going to get about a 28% effect. Why? Because amyloid is not a huge driver of clinical progression. It's tau that drives clinical progression. So my point is, even if tronti works, and we assume it will, and you remove amyloid in 90 to 180 days, you're still only going to get about a 28% effect. So there's always a market and opportunity for Xanamem. Yep. Thanks very much for that answer. Hopefully, that was helpful. We've got a few questions about the current clinical trial design. Dana, I might just pitch a couple of these to you. Dev asked about the inclusion and exclusion criteria for the current Xanamem trial, and how were they designed to optimize the chance of seeing a signal, seeing success in the trial? Well, we're first of all requiring a clinical diagnosis, a rigorous clinical diagnosis of Alzheimer's disease, and then we're using p-tau181, elevated p-tau181 as an inclusion criterion. That's going to, first of all, pick out patients who most likely have Alzheimer's disease, but also patients who have a cognitive impairment and a clinical deficit that have elevated biomarkers like p-tau181 are more likely to progress over the observation period of a trial. If a patient progresses during the trial, that gives us a better chance to show a treatment effect. We're also excluding patients that have or are on corticosteroids, other common illnesses, patients who have insulin-dependent diabetes. We're also excluding patients who've been previously treated with monoclonal antibodies, and that's, as Marwan has suggested, is not dramatic in the fraction of patients we've excluded with that. Because when patients are treated with monoclonal antibodies, it impacts their plasma biomarkers. They're depressed for a long period of time after that. So they may not meet the criterion. Those are some of the factors that we're using to include or determine eligibility of patients in the study. Yep. Thank you. In a related question somebody asked, is there any significant impact of having used 181 versus the 217 species of p-tau for selection? We use p-tau181 because that was actually the first one, as you've suggested, that was approved in Australia where part of the trial was being done. By the time we started the trial, p-tau217 was also approved, much to our surprise. We're doing both of them in the trial. We're formally using p-tau181 as the eligibility. I know, Marwan, what's your thoughts about the two biomarkers? We've sort of suggested, I think, that p-tau217 will be the standard. I don't know what your thoughts are. Remember, we're using it for the selection of patients with progressive Alzheimer's in this trial rather than a super accurate diagnostic. But Marwan, please answer the question. Feel free. To Dana's point, the p-tau217 and people have coalesced around it for its positive predictive value. People are also coalescing around the concept that p-tau181 has strong negative predictive value. If your p-tau181 is normal, you do not have Alzheimer pathology. If you have both, you are in good shape. I mean, from a clinical trial standpoint. Trial perspective, right. I do not mean that if both are positive, you are not in good shape. Right. Yeah. Thanks. There was another question around the relevance of the cortisol control mechanism to the population of Alzheimer's patients in general. In other words, can we think about is Xanamem potentially a therapy that would apply to all patients, or would there be subgroups of patients in whom we would expect the therapy to be confined to subgroups or work better in subgroups? Well, that is an excellent question to which I do not have an answer yet. I think this trial is going to really allow a pretty large data set for us, or moderate size data set for us to characterize that. I think that the epidemiologic data from the literature shows that patients with APOE4 have elevated cortisol. Patients that have elevated CSF cortisol have a higher risk of AD. I think right now, our present thinking is this could be applicable to the majority of patients with Alzheimer's disease. Also, the trial we are doing is not in MCI. It is not in very early Alzheimer's disease. It is in mild, moderate Alzheimer's disease. We think that it would be applicable or useful, over a broad range of patients. But that is to be determined. Yep. Thanks, Dana. Broadly speaking, I think we have designed the Xanamem program to be applicable to all patients with Alzheimer's and potentially MCI, and potentially even other forms of dementia, such as dementia with Lewy bodies that Marwan mentioned just briefly, and frontotemporal dementia, for example. Of course, the safety looks really good, meaning it could be broadly applicable to many patients in the elderly age groups across those types of diseases. But we will be data-driven and follow the science. We will see what we see in this initial trial of 247 patients with mild to moderate disease. We will be doing the genomics such as APOE4, as Dana mentioned. We will be looking at milder versus more moderate patients. We will be exploring all of those things. We will follow the data. But to our knowledge right now, pretty much everybody is potentially a candidate for Xanamem therapy. A couple of last questions. I know we are a little bit short on time, so I am going to keep it brief. I think we have nearly answered everybody. David asked a question about the effect size in the current pivotal trial. I will answer this one because I am basically the company. You are a statistician. In the pilot data where we had 34 patients from the previous phase II-A study with elevated p-tau, using a different assay than we used in this current trial. We were able to correlate the cutoffs very well. We know exactly where we are with the patients we selected. We saw about a 0.6 difference between active and placebo over 12 weeks. Meaning Xanamem slowed the progression in the CDR-Sum of Boxes, which we are currently using as the primary endpoint, by a bit over half a point in just 12 weeks. The Eli Lilly drug did that in 18 months, meaning 72 weeks. If we saw that result again in this trial, we would be over the moon. It would be a dramatically positive effect in a 36-week period. The simple answer to the question is, the question was actually what would you be disappointed? We would be disappointed if we saw our drug was less effective than the antibodies, as adjusted for the period of treatment. Because of its improved safety, if it was just as good as the Eli Lilly or Eisai/Biogen antibodies, but much safer and easier to use with much lower costs for monitoring, I think we would be very pleased. The trial is basically designed to show that over a 36-week period, we will have a greater effect size than the amyloid antibodies have during that same time period. That is the answer to that one. There was a quick question on how many people are opting into the open label study. As a direct rollover rate, we reported a few weeks ago an 88% enrollment, from those people who are finishing the trial and going straight into the open label. That is a very enthusiastic participation rate, which we are pleased about. We do not have any updates to the numbers. The last update from a few weeks ago was more than 80 people are currently participating. One last question. This is a good one I guess. If the top line results in November are successful, when would Xanamem be available? I guess, as a company, we will do our very best to bring Xanamem to as many patients as quickly as possible, as we can. We have treated more than 500 people to- date. We are planning a second pivotal phase III study to start in the middle of next year. That will go ahead no matter what. Is it possible that regulators could give us an accelerated approval so that patients could get the drug on market faster? While always possible, it is a bit of a long shot, but we will certainly give it a try. Of course, the stronger the results in November, the more likely that would be. We will just have to see. We will do the best thing we can do for patients, by bringing it to as many people as quickly as possible. Do not know if you want to say anything else. Andy, I might just hand it back to you to finish off. Well, no, I just wanted to thank Marwan for joining us. I appreciate your perspective and I think this was a productive session to really describe the market today and what we have to look forward to. Certainly, as Steve said, we are very optimistic about the potential of our product. When we see the clinical results in November, we are very excited to see how they perform. I think I will close with that, and thank you everyone for joining us. Thank you for including me. Thank you, guys. All right. Thank you. Thanks everybody. Thanks. Bye.