Good morning and welcome to the Cognition Therapeutics KOL event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Cognition website following the conclusion of the event. I'd now like to turn the call over to your host, Lisa Ricciardi, Chief Executive Officer of Cognition Therapeutics. Please go ahead, Lisa. Thank you. Good morning and welcome, everyone, to Cognition Therapeutics KOL event on the evolving landscape in Alzheimer's disease. Thank you for joining us today. In today's session, our guest speakers will present their assessment of the current treatment landscape for Alzheimer's disease, as well as the gaps that remain and where new therapeutic options are required. Please take a look at our forward-looking statements. We may be making forward-looking statements, and actual results could differ materially from those stated. Review, please, this forward-looking statement and cautionary statements in our filings, including our recent 10-K. Now, before introducing our speakers, let me provide a brief overview of Cognition Therapeutics and the very important catalysts we are looking forward to this year. Our lead asset, CT1812, is designed to restore impaired cellular damage response functions. We are advancing this drug into mid and late-stage clinical trials and anticipate reading out proof of concept, phase 2 data, in mild to moderate Alzheimer's patients, that's our SHINE trial, and we look forward to presenting this data at the AAIC meeting in July of this year. Later in the year, we will read out our phase 2 proof of concept SHIMMER trial. This is a study in patients who have dementia with Lewy bodies. As you are probably aware, AD and DLB are two underserved treatments which reflect very large commercial opportunities. With regard to financial discipline, we have been extensively supported by NIH grants in excess of $170 million, Michael J. Fox Awards on several occasions, and last, a long partnership with the Alzheimer's Drug Discovery Foundation, where their venture philanthropy has supported significant work, particularly our biomarker research. So turning again to our SHINE study that's reading out: based on our earlier clinical, structural, electrophysiology, and biomarker data, we believe we will see a positive impact on cognition in our SHINE trial. And in connection with this study, we have a deep program of biomarker research. Planned studies include assessments of canonical or amyloid-related biomarkers, synaptic biomarkers including synaptotagmin, neurogranin, and neuroinflammatory biomarkers as well. Today's session will be focused on the broader treatment landscape in Alzheimer's disease, touching on the anti-amyloid monoclonal antibody launches, commercial uptake, and unmet needs of existing therapies. We are so pleased to be joined by experts in these areas: Dr. Martin Sadowski of NYU Grossman School of Medicine. Martin is an associate professor in the departments of neurology, psychiatry, biochemistry, and molecular pharmacology. He is a recognized expert on amyloid beta metabolism, the interaction between amyloid beta and APOE, and therapeutics for Alzheimer's disease and prion diseases. Dr. Anton Porsteinsson is the director of the University of Rochester's Alzheimer's Disease Care, Research and Education Program. Anton has devoted his career to the care and study of individuals with memory disorders and is internationally recognized in clinical research and considered a leading expert in Alzheimer's disease and dementia. Dr. Jort Vijverberg is a staff neurologist and CNS trial specialist at the Alzheimer Center Amsterdam. He has dedicated his career to finding novel ways to treat Alzheimer's disease, and he's the founder of the CANDIDATE Centre, a research unit dedicated to the treatment of central nervous system diseases targeting drug discovery and development. Turning to our agenda today, we're going to begin with Dr. Sadowski. This will be followed by a prerecorded session with Dr. Porsteinsson, who I mentioned is presenting at the American Academy of Neurology this week. After the prerecorded segment, we will continue with Dr. Vijverberg's presentations, and following these presentations, we will open the event to your questions and instructions for participating. With that, I'd like to turn this over to Dr. Sadowski. Martin? Good morning. Thank you for this introduction. My name is Martin Sadowski, and I'm a professor of neurology, psychiatry, and pharmacology at NYU Grossman School of Medicine, and I focus on developing therapeutics for Alzheimer's disease. I would like to give this introductory talk focusing on an overview of the current treatment landscape and current unmet needs for Alzheimer's therapeutics, which are in development. So for most of you, you realize that Alzheimer's disease is not a short disease. It is a condition that usually spans about 30 years of patient life and can be divided into five relatively simple stages, including preclinical Alzheimer's disease, mild cognitive impairment, and dementia due to Alzheimer's disease, which is then divided into mild, moderate, and severe stages. The preclinical stage of Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease, where the first signs of the disease due to Alzheimer's pathology in the brains are becoming apparent, usually takes about 15 years, and dementia takes about a course for under 10 or 15 years. Currently, Alzheimer's disease is one of the biggest social problems in our country and in the developing world. In the United States, it's estimated that there are 6.7 million patients with dementia, not exactly with Alzheimer's disease because many of them don't have a biomarker confirmation, but the number is staggering. It is expected that due to aging of the population, the number of patients with Alzheimer's disease will increase by 2050 to 14 million, and the costs of the care related to Alzheimer's disease, which is split between caregivers, Medicare and Medicaid, will rise from $400 billion to $1.1 trillion in 2050, provided nothing is done to slow down the progression of the disease or to prevent disease from happening. Alzheimer's disease has an extremely complex biology, and the disease starts from a neuron and eventually takes the full circle and destroys the neuron. The primary culprit of Alzheimer's disease is imbalance in production and clearance of soluble beta-amyloid, as soluble beta-amyloid is a small peptide that is released by the nerve cells and secreted to extraneuronal space. That monomeric beta-amyloid has to be promptly removed from the brain, and if it doesn't, it starts forming oligomers, protofibrils, and fibrils in the setting of increased local concentration, and eventually that is being deposited in the plaques. What happens with the plaques are the microglia cells which are trying to remove the plaques, and initially, microglia cells have a protective phenotype in Alzheimer's Disease, which is called disease-associated microglia. But while the beta-amyloid builds up and the tau protein starts accumulating within the nerve cells, those protective microglia change their phenotype into less favorable, called neurodegenerative microglia, and those microglia are toxic due to their pro-inflammatory character. Chronic accumulation of beta-amyloid and the effect of various forms of beta-amyloid, and also chronic neuroinflammation caused by microglia, take a toll on the nerve cells, which starts accumulating tau protein inside dendrites and inside the body of the cells. Over time, accumulation of the Tau protein inside the nerve cells leads to the demise of those cells, and they are dead, and further stimulates neuroinflammation coming from activated microglia cells. There are several areas therapeutics are being developed for Alzheimer's disease, and I simplified them into three different groups. Therapeutics which would target the accumulation of primary misfolded proteins associated with Alzheimer's disease, namely beta-amyloid, which is extracellular, and Tau protein, which is primarily intracellular. Therapeutics which would target secondary biological processes associated with Alzheimer's disease, namely neurodegeneration, neuroinflammation, and neuroregeneration. By this, we understand a drug which would target neurodegeneration would be any type of drug which would insulate a nerve cell from any type of insult. So, for example, a drug which would protect a nerve cell from the effect of toxic A -beta oligomers, or, for example, a drug which would protect mitochondria in the nerve cell from a toxic effect of intracellular tau protein. Neuroinflammation are all the approaches that would target microglia cells and make microglia cells less inflammatory and more phagocytic. And there are neuroregeneration approaches that have to do with anything that would allow the brain to rebuild itself and counteract the neurodegeneration process. There are also areas for symptomatic management, including cognitive enhancers and antipsychotic medications. Therapeutic groups which are highlighted by this little frame indicate those which we have therapeutics already approved by the FDA. As you can see on this slide, there are not that many therapeutics approved for Alzheimer's disease, although Alzheimer's disease is an extremely prevalent condition. The first group of symptomatic therapeutics are cognitive enhancers concerning improvement of choline metabolism and/or glutamatergic transmission, which were approved between 1993 and 2003. For the following 20 years, nothing has happened in the Alzheimer's field from the FDA side, although over 200 clinical trials have been launched. In 2001, the FDA gave accelerated approval to aducanumab, the first monoclonal antibody which was designated to clear beta-amyloid from the brain, and that antibody was shown to be extremely effective on biomarkers of Alzheimer's disease, but due to certain design flaws, it did not demonstrate sufficient clinical benefit for this drug to secure traditional approval. We had to wait until July of 2023, when lecanemab was the first disease-modifying therapeutic that has been fully approved, which received traditional approval of the FDA for Alzheimer's use. So, as you can see, between approval of lecanemab and approval of the first drug for Alzheimer's disease, tacrine, it has been 30 years and about 20 years between approval of memantine and lecanemab. Lecanemab is a monoclonal antibody which is targeting beta-amyloid that is deposited in the brain, both in its soluble and insoluble forms. And as it has been shown in a phase 3 clinical trial, patients who were treated with lecanemab and received lecanemab infusion every other week for 18 months benefited from significant clearance of beta-amyloid from the brain, as you can see on the PET scan. Above, you can see a PET scan from someone who was treated with placebo, where you don't see the distinction between white and gray matter, which indicates accumulation of beta-amyloid in the brain cortex. In the lower picture, you can see that the edge of the brain becomes darker again, and this is indicative of clearance of A beta from the brain cortex. Clearance of beta-amyloid plaques from the brain resulted in improvement of other biomarkers, including soluble tau in the spinal fluid. However, it didn't normalize those biomarkers to non-Alzheimer's patient levels. Although treatment with lecanemab in patients with MCI and mild Alzheimer's dementia was shown to be extremely effective on reducing biomarkers, the clinical effects were modest. Treatment with lecanemab did not stop the disease from progression. Unfortunately, it only slowed the rate of progression by about 30% at 18 months' time point, but the benefit has been confirmed on numerous scales, and I have shown only two here: clinical dementia rating and ADAS-Cog14. The area of anti-beta-amyloid antibodies is probably the most advanced and the most crowded area in Alzheimer's therapeutic development, and notable examples include aducanumab or Aduhelm, which was the first drug approved by the FDA using the accelerated approval process. The development of Aduhelm by Biogen has been put on hold due to company priorities and investment in other Alzheimer's therapeutics, where the company is doing very well. Then, Leqembi is the first traditionally approved disease-modifying therapeutic for Alzheimer's disease. They are currently developing subcutaneous Leqembi, which is under regulatory review. There is donanemab, another monoclonal antibody given intravenously, which is way more potent than Leqembi, and unlike Leqembi, it focuses on only one epitope, which is an epitope exclusively found in beta-amyloid plaques. This is an antibody which, as far as it is, provides the most robust clearance of pre-existing amyloid beta plaques but doesn't do anything to soluble amyloid beta, and it's currently under regulatory review. There is a derivative of donanemab, remternetug, currently in a phase 3, which is an even more improved antibody. There is a lot of attention paid to another antibody called trontinemab. That company comes from Hoffmann-La Roche and is a reiteration of the older antibody called gantenerumab. What's new about trontinemab? Trontinemab is the first antibody that is being developed based on the Brain Shuttle technology. This antibody is equipped in the receptor that allows this antibody to be actively transported into the brain. Therefore, greater reduction in amyloid beta accumulation can be achieved with a much lower amount of the antibody. Surprisingly, positively surprisingly, patients treated with trontinemab suffer from the least number of side effects compared to any other antibody targeting deposited beta-amyloid. Other therapeutics in development from that pipeline include ACU-193 from Acumen Pharmaceuticals and PRX-012 from Prothena, and those are monoclonal antibodies specifically developed to target beta-amyloid oligomers and beta-amyloid protofibrils, respectively. They are in phase 1, so we probably will need more data to assess their benefit. How do antibodies clear beta-amyloid plaques? Donanemab, aducanumab, and lecanemab are given in large amounts intravenously every 2 or every 4 weeks. The amount of the antibody given with each infusion ranges from about 10-20 milligrams per kilogram, and from that mass of the antibody that becomes available in the bloodstream, a small amount of antibodies penetrate the blood-brain barrier and get into the brain. In the brain, they found amyloid beta plaques, as you can see here, surrounded by microglia cells which try to remove those, but they are not particularly effective. Beta-amyloid plaques are a reservoir of soluble beta-amyloid species that are surrounding them. Antibodies induce activation of microglia and make microglia cells to. They essentially bring microglia cells to the plaques and make the microglia cells to clear the plaques. Some antibodies, like lecanemab, in addition, target soluble A beta species oligomers, protofibrils, and directly target them for destruction. Treatment with antibodies is unfortunately associated with certain types of novel side effects, and they are known as amyloid-related imaging abnormalities. They include brain edema, and they include microbleeds, and they happen during a very prespecified time of the treatment, usually between the second and fourth or second and fifth treatment. However, they happen in between 20%-40% of patients treated, depending on the antibody used. In most of the cases, those amyloid-related imaging abnormalities are clinically asymptomatic. Patients do not experience any symptoms. However, because they can progress, we have to closely monitor the patient, and patients undergoing treatment receive numerous scans during especially the first months of the treatment. And when we identify patients who develop amyloid-related imaging abnormalities, we usually ask those patients to stop the treatment, take a recess, and then, after amyloid-related imaging abnormalities are resolved, we can put patients back on the treatment. There are some cases where patients cannot go back to the treatment, but likely that fraction of patients is relatively small. So, where does this advance in Alzheimer's therapeutics take us? On the left-hand side, you can see brain and schematic depiction of Alzheimer's pathology before plaque clearance. On the right-hand side, you can see the brain in someone in whom we completely removed beta-amyloid from the brain, and we're getting more and more patients. So, we're getting a type of patients who have Alzheimer's disease and who continue progressing clinically, but they don't have any more beta-amyloid plaques. And so, as you can see, amyloid, as I pointed out at the very beginning of this talk, Alzheimer's disease is a very complex condition, and by removing plaques from the brain, we only have removed only one aspect of the treatment. The primary culprit in Alzheimer's biology, which is imbalance between production and removal of monomeric A beta persists. So, those patients, even if you remove beta-amyloid plaques from their brain, keep accumulating A beta oligomers, experience toxicity of A beta oligomers and protofibrils. They also keep accumulating tau protein inside the nerve cells and spread the tau from one nerve cell to another using the tau oligomers. So, removal of the plaques in patients in whom Alzheimer's disease biology went under full swing changes things a lot, but it's not enough. So, there is a lot of discussion on how should we take things forward and how should we improve the outcome of anti-beta-amyloid therapies. We are, of course, doing this by developing better antibodies and moving that field, moving those antibodies into earlier stages of the disease. However, we believe that, as a field, that beta-amyloid antibodies as a monotherapy may not be enough, and we would need to have some other agents that can be given in tandem with beta-amyloid therapies or as a sequel to beta-amyloid therapies. So, the goal of improved therapy includes improved clinical outcome, maintenance of treatment benefit from the antibodies, stronger reduction of tau, better side effect profile, and what is not included on this slide is that we would like to deal with drugs which are way more used to give to the patients. So, preferably, oral drugs would be better as antibodies require intravenous infusions every other week or every month, and drugs which would be significantly cheaper than the antibodies because of the cost of the, as you know, the cost of lecanemab alone is $26,500 a year, including the infusions and associated MRIs that come to about $50,000 per year. With this, I would like to thank you for your attention, and I think there will be some questions which I can address in the later part of this conference. Thank you very much. Good morning and welcome. My name is Dr. Anton Porsteinsson, and I'm the William B. and Sheila Konar Professor of Psychiatry, Neurology, Neuroscience, and Medicine at the University of Rochester School of Medicine in Rochester, New York. My presentation will focus on treatment development considerations in early symptomatic Alzheimer's disease. Basically, when you look at the pathophysiological continuum of Alzheimer's disease, the first thing to change, the first measurable change, is change in the amyloid cascade or what we refer to as cerebral amyloidosis. This change is present in even preclinical Alzheimer's disease, and we're talking about 20-30 years before the onset of any clinical symptoms. So, this is a very early-stage development that then evolves over decades, and it's identifiable in life through elevated beta-amyloid, the plaque burden on the amyloid PET, or on fluid biomarkers, then looking at soluble beta-amyloid species both in the cerebrospinal fluid as well as in blood. In addition to the amyloid cascade, we see a tauopathy, that is, a tau cascade that is actually triggered once we have a critical amount of amyloid built up. In addition to the tau cascade, we also see neuroinflammation, and we see oxidative stress. What does all of this lead to? It leads to loss of synapses, so the neurons, they cannot communicate well with one another, and that leads, obviously, to dysfunction in terms of communication between neurons. It has an impact on the brain cells that ultimately may atrophy and die. And with that, we see changes in neurotransmitters, both a decrease in neurotransmitters such as acetylcholine or an increase in certain neurotransmitter activity such as the excitotoxic glutamatergic system. The ultimate consequence of all of this is cognitive and functional decline. In this presentation, I want to highlight the pathological hallmarks of Alzheimer's disease in more details, and in particular, there, we are looking at the amyloid cascade. So, the amyloid cascade starts with the processing of amyloid beta precursor protein. And what happens in patients that get Alzheimer's disease is that the APP is snipped in the wrong fashion. So, instead of ending up with A beta 38 or A beta 40, we end up with A beta 42. And what does that do? Well, the A beta 42 monomers or the single strands, they are not cleared easily, and they have affinity for each other, so they form oligomers. These oligomers basically become more and more complex, and they end up forming protofibrils, then fibrils, and finally amyloid plaque. So, the amyloid plaque production is actually late in this cascade. We know that the oligomers and protofibrils are neurotoxic, and they are toxic in multiple ways. On one hand, they can influence the synapse. They can bind within the synapse and cause synaptic dysfunction. They can also interfere with microglia and bring about neuroinflammation. And furthermore, they have direct neurotoxicity and lead to the death of neurons. Ultimately, like I said before, this leads to synaptic dysfunction, neuroinflammation, and neuronal death. And what I want to do next is basically look at where we are in terms of therapeutic interventions within the amyloid cascade. Well, we have three humanized monoclonal antibodies all targeting the N-terminus of A beta 42, which preferably targets amyloid plaques outside of lecanemab that targets not only amyloid plaques but also fibrils and protofibrils. But basically, we have three medications that either have gotten provisional approval, full approval, or are likely to be approved this year. Aducanumab got accelerated approval in 2021, but this year, it was actually withdrawn from further development as well as from commercialization. Lecanemab is the first medication to get not only provisional approval but full approval by the FDA. And the indication is basically patients with early symptomatic Alzheimer's disease, that is, patients that have mild cognitive impairment or mild dementia due to Alzheimer's disease. Donanemab specifically targets the pGlu formulation of A beta, which is really only seen in amyloid plaques. Donanemab probably does not bind much to soluble species. So, lecanemab is given by infusion every 2 weeks. Donanemab is given by infusion every 4 weeks. They're both associated with fairly complex clinical and radiographic monitoring and a meaningful side effect profile. I'll get back to that in a minute or two. But what do they bring to the table? Let's start with lecanemab. The Clarity AD study was the pivotal phase 3 study for Clarity and had almost 1,800 patients enrolled, again with early symptomatic Alzheimer's disease, and basically appeared to slow decline, did not improve the disease, but slowed decline by about 30%-50% depending on the measure you looked at. If we look at what exactly the changes were, then basically we saw a 0.45 adjusted mean difference in the so-called CDR, or Clinical Dementia Rating Scale, sum of boxes. This is a scale that has a range from 0 to 18. The mean score in the Clarity study was about 3.17. The change there has to be seen as modest. What about the ADAS-Cog14? That is a scale that preferably looks at cognitive function. It is a scale with a range of 0 to 90. We saw a 1.44 adjusted mean difference in the ADAS-Cog14. The mean score of participants was about 24. The functional scale, the ADCS-MCI-ADL, showed about a 2-point adjusted mean difference between drug and placebo. There, we have a range from 0 to 52 with a mean score of 41. Lecanemab also showed the impact on downstream biomarkers. In terms of safety and tolerability, the main findings were that about 25% of participants had low-grade to medium-grade infusion reactions. Then there were what we refer to as the ARIAs, ARIA-E or edema and swelling seen in about 13% of participants, and ARIA-H, microhemorrhages or superficial siderosis in about 17% of patients. What about donanemab? The data for donanemab comes from the TRAILBLAZER-ALZ 2 study, which is currently under FDA review. There, we had just over 1,700 people with early symptomatic Alzheimer's disease that were stratified at baseline by how much tau they had, so low to medium tau tangle burden versus high tangle burden. And the primary outcome was a change in the so-called iADRS, which is a combination of the ADAS-Cog and the CDR. Basically, there, we also saw a 30%-50% slowing of decline, but no freezing of disease or improvement. On the CDR Sum of Boxes, in the population, low to medium tau population that had the best response, we saw about a 0.67 difference. On the ADAS-Cog14, a 1.52 point difference, and on the functional scale, a 1.83 point difference. So overall, a modest impact as well. We saw a pretty remarkable clearance of beta-amyloid plaques with both medications. In fact, about 85% of participants have fully cleared beta-amyloid plaques in 18 months. What about Donanemab, though, in terms of safety and tolerability? Well, there were some infusion reactions in close to 10% and higher rates of ARIA E at 24% here versus 13% for lecanemab and ARIA H at 31%. And also for Donanemab, when the ARIA Es were symptomatic, it was slightly more common in about 6% of participants. There were significant symptoms, and they were more severe. So basically, if you look at the patient population in the clinic, and you look at how many of them are appropriate for treatment with a humanized monoclonal antibody. Well, the Mayo Clinic looked at this and published their findings in 2023. And at that point, they used the lecanemab trial criteria and aducanemab trial criteria. They looked at patients aged 50-90 years old in their clinic with early symptomatic AD, and between 43%-47% met inclusion criteria for the studies, but only 5%-8% met all enrollment criteria. The point I'm trying to make here is that even if the humanized monoclonal antibodies targeting beta-amyloid plaques become well-established, they won't meet the need of all patients with early symptomatic Alzheimer's disease. We have to have options. And when you think about the amyloid cascade, you want to think about the soluble species. One medication targeting the impact of oligomers and other soluble species is CT1812, the medication from Cognition Therapeutics. It is a once-daily oral brain-penetrating small molecule that targets the sigma-2 receptor complex. It's well-behaved in terms of pharmacokinetics with peak plasma concentrations or Cmax 2 hours after dosing, linear pharmacokinetics, highly protein-bound, and mean half-life of a single dose at 11.5 hours. Dosing for CT1812 has been calculated to get at least 80% receptor occupancy at the sigma-2 receptor. So what do we know about the sigma-2 receptor and about does amyloid beta or Aβ 42 either as monomers or oligomers actually bind within the synapse? We have now good evidence that there is an Aβ oligomer binding site and that CT1812 can bind basically interfere with the binding of Aβ oligomers. And they do that by modulating the sigma-2 receptor. And with that, it basically boots out oligomers or prevents them from binding to neurons, clears them to the cerebrospinal fluid, and through that prevents the synaptotoxicity and the synaptic neurotoxicity and the impact on neuronal function. In fact, in preclinical models of Alzheimer's disease, it was able to restore cognitive deficits. This finding was recently that is actually the publication was this year reaffirmed by a UK research group that basically found that the A beta oligomer binds to the oligomer receptor complex in the synapse, which is basically right next to in close proximity to the sigma-2 receptor complex, and that the A beta oligomer appears to bind or bridge those two receptor complexes. So it binds both to the so-called prion protein as well as TMEM97. And basically, that is part of the sigma-2 receptor. CT1812 has undergone an ambitious preclinical as well as clinical program development. We have proof of concept studies that focused on mechanism and engagement. Now we have impact on disease pathology study. I want to highlight two of them. The SHINE study that we will see full results from soon and the preliminary data showed actually trend in cognitive improvement with about a 3-point difference in the so-called ADAS-Cog11. You can put that in context with what we spoke about earlier, as well as the START study, which is an NIA-funded study. In fact, one of the largest NIA grants to fund clinical research in Alzheimer's disease that will recruit 540 participants through the ACTC Clinical Trials Consortium. I'm a steering committee member of that group where we will target the early symptomatic Alzheimer's disease with either a 100 mg or a 200 mg once-daily dose versus placebo for 18 months. This study just started. So what we do know from animal studies and basic science studies is that CT1812 restores downstream membrane trafficking deficits back to normal. And we hope to see this translate into humans in the clinical studies, that is the SHINE and the START study. And in fact, the next presenter will talk more about the details from the SHINE study. So with that, I want to end my presentation. Thank you for your attention and have a great day. So yes, thank you. My name is Jort Vijverberg. I'm a neurologist in Amsterdam, where I conduct many clinical trials. And for me, the honor to talk more about the CT1812 drug and the clinical trials that we conduct here in Amsterdam. So in Amsterdam, we set up a nice clinical trial platform called the Brain Research Center, where it was designed to include patients in clinical trials in a very comfort environment. So what we did, we did the SEQUEL and the SHINE study for Cognition Therapeutics. And the recent clinical results from those studies show a beneficial effect on the synaptic health and function. And I, in a couple of slides, will talk about those results. So the SEQUEL, not named in the previous presentations, but the SEQUEL was a single-site quantitative EEG study performed here in Amsterdam in adults with mild to moderate Alzheimer's disease. So here you see an overview of the well-designed trial that we did. It was a two-group crossover design. And the inclusion was more or less the same as lecanemab and donanemab, only the stage of the disease was a little bit more advanced. So in comparisons, we did the mild to moderate patients and the previous antibody trials did MCI and mild. We checked on the biomarker profiles. We did MRIs and cognition for the inclusion. Then they were randomized in 2 groups. 1 group was started on the drug for 4 weeks on 300 milligrams and 1 group on placebo. Then they had a washout period, and we turned it over. So that was the crossover design. In the end of the relatively short trial, we, of course, looked at safety and PK and the EEG. What's the EEG? EEG is a measurement where we can measure the brain activity, what reflects synaptic health. In Alzheimer's disease, we can really see a decline in synaptic health on EEG. I will come back later on that. Also, we did CSF tests and plasma biomarkers in the end, and we looked at cognition. Of course, it was exploratory because in a short period, moving those biomarkers is optimistic. But still, we checked them. So if you look at the results of the SEQUEL study, we saw on the primary endpoints on the EEG a positive trend. That was very exciting. Here you see three figures that show that we normalized in a short period of time those measurements. A little bit more focused on the global alpha, the connectivity, you see a normalization. So the green part, patients on the drug versus patients that were off the drug. In a short period, we showed more connectivity between brain activity measured by this EEG. So very excited about that, that we showed in a short period again a normalization on these markers that reflect synaptic health. Moreover, we saw a very safe and well-tolerated drug. So the patients that were all my patients were included in this trial. We're very excited about the drug, taking the drug, and were a little bit disappointed when the trial was finished. It was well-tolerated, no serious adverse events, and some mild, and it healed like nausea or diarrhea, but no one discontinued on the adverse events the trial. So overall, we saw a favorable treatment difference for CT1812 on the EEG, on the synaptic health, on all the measures that we specified. Also, the acuity impact on the synaptic activity makes us very confident that this drug does what it needs to do. I previously explained the mode of action. It keeps the synapses healthy. If we go further, so the SHINE, also previously by the previous speaker, is a phase 2 safety efficacy study in the same population as the SEQUEL. However, a little bit different design. The same population. Again, a little bit more advanced in the Alzheimer's disease. Well-phenotyped before randomization. In this trial, we had 3 groups. Patients on CT1812 on 300 milligrams, the same as the SEQUEL study, a group on 100 milligrams, and of course, a placebo group. It was 6 months treatment, and we pre-specified also a cohort A with 24 patients to do a preliminary analysis that I show later. In total, 144 patients participated in the study. This phase of the drug development, we really want to look at the cognition that we see movement in a positive way, but also on the biology of Alzheimer's disease on different levels. Let me talk more about that design. Of course, again, safety and tolerability is in this phase very important. Efficacy measure is in this phase also very important. We used the ADAS-Cog11, explained also about the previous speaker, where we look at memory, language, and praxis. Here we really think that Alzheimer's disease is all about, so cognition, but also function and behavior. That is on the top of the slide. We see the global impact scale and also the activities in daily living scale. If we see movement on these scales, we really know that we are moving Alzheimer's disease with this drug. Of course, we do other measures like the Mini-Mental State Examination. It's a short screening cognition scale, which is more for safety. We can use different elements for composite scores. But I think if we can move like lecanemab and donanemab on these scales in the right direction, patients on the drug, we have good results. More about the other objectives. Of course, we look at the pharmacokinetics. So what is the drug doing in the body, how it moves in the body on different levels, so on CSF and plasma? And we look, of course, what the drug does with the body, but also with the disease. On that aspect, we look at different levels. You see some different biomarkers. We can measure some in the CSF, but also in the blood. And what this means is the first three amyloid, total tau, phospho-tau are really Alzheimer's biomarkers. Neurogranin and SNAP-25 are all markers of SNAP-25. In short, are all markers for synaptic health. We also measure them in CSF, and it is also possible in plasma. Neurofilament light chain, NfL, is really a marker of neurodegeneration. Also, if we can move this in the right direction, then it's, of course, very excited that CT1812 can change the disease of the course of Alzheimer's. Other markers are more on the oligomers, was already explained a lot, and other biomarkers to see if we can move the disease in the right direction. So I previously explained the design of the SHINE trial, where we used 24 patients that finished the drug to see primary data. And also mentioned, we see in the 24 patients that we already analyzed that there was a 3-point difference on the ADAS-Cog11. And that's more or less the double that we see in Leqembi trials. Of course, it's primarily, however, together with the SEQUEL that we saw quick response in synaptic health and this group of patients, we see also on cognition the right direction excite me very much. Also with this difference, it's clinically meaningful for me and for the patient. How do we experience the drug development here in Amsterdam and Europe? Of course, we're not that advanced yet in like the U.S. We don't have approval for lecanemab or donanemab. It's very exciting times if it gets approved in Europe. In the scenario, it is approved and it lands in the Netherlands, in Amsterdam, then we did a little bit the same like they did in the U.S. We looked at our cohort in Amsterdam in our memory clinic, where we see in two years around 1,300 new patients. Then we used the inclusion criteria from lecanemab, a little bit from donanemab. It's a little bit the same. We did it very conservative way. We also exclude microbleeds, E4 carriers, because that are risk factors for the amyloid-related imaging abnormalities. We exclude co-meds, like medications that influence cognition. Then in the end, we had only 7% of that that can be treated with antibodies that target amyloid. 7% as eligible. Also, the patients in my daily clinic ask for these drugs, and then I explain what it does, what the risks are, and what the logistics around that drug are. 50% that were eligible declined that treatment. So I agree. If we have lecanemab in Europe, it will not be the answer for Alzheimer's disease. It's a positive sign, but there will be a small group of patients that can benefit from this treatment. I did more or less the same for CT1812. The same population. So we had 40% mild-to-moderate dementia in that group, excluding the co-meds that maybe influence CT1812. Then in the end, around 80% were eligible for treatment. Of course, with the experience of all the other medication that can be given orally, I think not many, with also the side effect profile, will decline this. But this is also future talk. But I think it will be more the answer and more patients will be willing to take an oral drug for Alzheimer's disease than the IV. Also, from the perspective of the burdens on the healthcare system, so in Europe, every country has a little bit different healthcare system. But if you look at the left graph, you see a very complex flow chart if lecanemab and donanemab lands. So the general practitioner refers to local memory clinics, and then we think only three or four centers will give that treatment. Those will do the assessments. There are going to be multiple visits to this team that discuss the start of those treatments. The follow-up is very extensive with MRIs, what I already explained. Also, the infusion centers are not commercialized in Europe, so it must be in the hospital. We're understaffed already. So this is very impactful for the healthcare system. If you look at the small molecule that maybe has the same efficacy and a nicer profile, that will be less burden for the patient and the caregivers that are already burdened by the disease, less burden for our departments, not only neurology, but also the radiology departments or other departments, and indeed for the society because of the price of these drugs. And small molecules are by definition mostly cheaper. So hereby, I want to thank you for your attention and give it over to Tony, I think. Great. Thank you. And thanks to each of our speakers for a nice introduction to the basic pathophysiology of Alzheimer's disease, the treatment landscape, and then a good introduction to CT1812 and our current studies. Dr. Thorsten Steen could not be with us for questions and answers, so we asked him to comment on the effect size of the results from the lecanemab trial, thinking particularly about how traditionally we have viewed effect size as a number on a scale, whereas now we're really beginning to look at time saved or a slowing of disease by even almost 30% in these trials. So here is his prerecorded answer. So if we start with the effect size, we hear different opinions. Like I pointed out, we have a 30%-50% slowing of decline. We have somewhere about 0.45-0.5 if we look at the total groups, a difference on the CDR sum of boxes, which is a very clinically relevant scale. In my opinion, this is actually a great start for the first interventions that gun for disease modification. If we take into account oncology and chemotherapy to get to where we are today, which is a remarkable change in the impact of cancer, going from 25% overall survival about 30 years ago to about 75% now, we have to understand that all of this was incremental and that no single drug brought about complete magic. It also means that when we look at cancer right now, we're mostly seeing combination treatments. I expect that that's exactly what's going to happen in Alzheimer's disease, that we will have to target the amyloid cascade not only on the plaque end, but also on the soluble species end, that we will need to target tauopathy, that we will need to target neuroinflammation, and probably metabolic derangement as well. So we will have to look at patients. We will have to stage them. We will have to typify them by biomarkers to see, are we looking at the kind of amyloid dysregulation only, or in addition to the amyloidopathy, do we have tauopathy present? Do we have neuroinflammation? Do we have oxidative stress and metabolic derangement? And this really has to be incremental. And one thing that you want to see is that drugs can not only be used maybe alone, but also in combination treatment or sequential treatment. If we look at donanemab, the goal in the donanemab trials was to clear out amyloid beta plaques and then stop treatment. But we know that it isn't enough to clear just the plaque burden. We have to look at the soluble species. They start building up right away and having a near-term impact through synaptic dysfunction. And ultimately, they will build the plaques up again. So how do we intervene there? That is actually an important question. Great. So I think we can go to the live Q&A. So please hold for a brief moment while we pull for questions. So our first question comes from Charles Duncan at Cantor Fitzgerald. Please go ahead, Charles. Can you hear me? Yes, we can. Okay. Super. Thank you, Lisa and team, for hosting this very informative webcast and to the KOLs for sharing their perspectives. I had a question for Dr. Sadowski, considering the SHINE study that's upcoming in terms of a readout. It has a 6-month endpoint. And I guess I'm wondering, with the mild and moderate patient population, would you anticipate meaningful change over the course of the 6 months in terms of clinical parameters? And would you anticipate perhaps greater effect of 1812 in a more mild population than the moderate population? Well, that's difficult to say. Okay. I think that the drug may play either way. Okay. I think that depending on the outcome, I mean, we will appreciate and better the impact of the drug on the disease. I don't think I can give you a straight answer to this. Okay. I think that the drug can have. It's possible that the drug is going to have a stronger response in milder patients. And that would simply mean that the drug has a very strong response on just relieving synapses from oligomers. While if it would have a good response in moderate patients, then the drug would have a good that would simply to me, that would mean that it does have a more stronger prolonged effect protecting the nerve cells likely from building up the tau protein inside the nerve cells, which is more involved in that stage of the disease. So I would expect that the drug might have an effect in either stage of the disease. But in terms of the biology, I would have a different readout on the spinning. That makes sense to me. Then one additional question for you, Dr. Sadowski. With regard to a future treatment paradigm, given that Dr. Thorsten Steen, as well as a second or a third KOL, mentioned that very few patients actually are candidates for use of monoclonal antibody therapy based on what the current drugs show in terms of the profile, what can you imagine to be the future treatment paradigm? Would you start with an 1812, or would it be used in tandem or in sequence, as you mentioned might be the case in the future if it achieves its target product profile? So I think that if the 1812 achieves the product profile, and given the fact that it's an oral molecule, given the fact that the drug is relatively safe, doesn't have major side effects, I think that this would be something which would be the first line, truly first line of treatment, okay, which would be very easy to apply or a wide range of patients, right? And then you can have a conversation with the patient that perhaps you should address other mechanisms of action. Perhaps you should clear amyloid beta plaques as well. And if you're a candidate and if you're willing to take the risk, there are antibodies for you, right, which we will and we will be happy to put you through the regimen of 18 months or more required to treat the plaques, okay? But you will start with 1812, and you will continue with 1812 along with the antibodies. And once we clear the plaques, we know that the disease process doesn't stop, and you should continue being treated with 1812. So remember that we don't have agreement. We don't have a consensus. How are we going to use Leqembi? Right? It is in the way the FDA label has been written. Once you put a patient on Leqembi, you can continue Leqembi indefinitely. Many physicians are skeptical to consider Leqembi being lifelong treatment because you still have to give infusions every other week. It's a very complicated treatment. That thing and the reasons to treat for life with Leqembi is essential to target those oligomers. Okay? So if you do have a drug that would target oligomers, okay, equally to Leqembi, wouldn't be easier to give someone a pill once a day and then commit someone to an infusion every other week, okay, to receive the prolonged benefits of Leqembi? So again, I think that should CT1812 live up to its expectations. It can be very easy. It can be very easy disease-modifying therapeutics, which might become the first line of treatment and can be used in conjunction with any other treatments and in people who can afford who, for medical reasons, can tolerate more drastic treatments. Would your perspective change if there was a subcutaneous version of Leqembi or another antibody? The same thing. Subcutaneous injection of Leqembi requires your injection every week, right? You still have a number of patients you cannot put on Leqembi, right? And then depending on so medically, you will not put about 20%-25% of patients, okay, general populations of patients on Leqembi, okay, for medical reasons, right? Then you assume that you're going to have another 25% of patients who would not be able to take the risk. And they are not taking the risk at the moment, okay? We are including them into other clinical trials that test drugs which are not causing vasogenic edema at this very moment, okay, because we have Leqembi in clinical trial to offer the patients. And then you're left with the remaining 50%, okay, who can take both. Got it. One last question, Tara, for the company, either Anthony or Lisa, if you could clarify with regard to the SHINE study and the sample that has been enrolled, excuse me, are those patients all monoclonal antibody naive patients? And then can you give us a sense of the history, obviously on a blinded basis across the sample, what is the use of other orals, either Aricept or Namenda in that study? Are they allowed concomitantly, or is there a history and a washout? Just give us a little bit more understanding of what that sample looks like. Thanks. Sure. So individuals who have been on antibody therapies are prohibited from being in the SHINE study. So they have not been on antibody therapy. As far as other medications go, they are allowed to be on acetylcholinesterase inhibitors, memantine, and other standard medications used in Alzheimer's disease. Like most studies, we have restrictions around how long they need to have been with the disease, if there were adjustments in medications that came frequently. And of course, we encourage folks to maintain a stable regimen. Now, obviously, we can't prevent them from changing regimens as these are approved drugs. But that's how we handle it. And we know that in the interim read that we had in the first 24, the vast majority of individuals were on acetylcholinesterase inhibitors. Got it. Thanks. Thanks, Tony, for that clarification. Thanks for taking my questions. Thanks for the questions, Charles. Our next question comes from Mayank Mamtani at B. Riley. Please go ahead, Mayank. Mayank, you might be on mute. Mayank might be having difficulty, so we'll go to the next question. Can you hear me now? Yes, we can. I apologize. I was having trouble unmuting. Yeah, good morning. Thanks for the helpful overview. Maybe just on the Dr. Sadowski, good to hear from you again. Could we please talk to the field's understanding on the mechanism of ARIA brain swelling in light of perhaps what we are going to see at the upcoming AdCom and also what data we've seen with the next generation A beta antibodies? I think you mentioned Brain Shuttle. And then how does that framework apply to the 1812 mechanism of clearing oligomers off of the neurons, for example? It would be helpful to understand the field's knowledge of ARIA. And then I have a follow-up for the company. All right. So what we understand, we don't exactly know how the ARIA happens, okay, because we don't have a good model for it, although there are some attempts to recreate ARIA in mice. What we know about the ARIA, that there are certain prerequisites for ARIA, okay? Firstly, the beta amyloid has to be present in the brain vessels. And the antibody that you use has to bind the beta amyloid that is deposited in the brain vessels, all right? So we assume that there is some form of the immune reaction triggered by antibodies directed toward the brain vessels. We know that treatment of the animals, transgenic mice with anti-beta amyloid antibody, clears beta amyloid both from the brain, parenchyma, and from the vessels. And it also causes those mice to have some microbleeds. We understand that by observing humans, that the timing event of ARIA, which is usually between the second and the fourth month of the treatment, suggests that it's a transient phenomenon. It's related to the process of clearing and immune reaction around the clearing of beta amyloid from the vessels. Once that process is completed, then vessels regain their own integrity, and they are no longer leaky or they are no longer at risk, and patients are no longer at risk of ARIA, both edema and hemorrhage, okay? This is our understanding. We understand that ARIA is a transient phenomenon associated, caused by some form of immune reaction around the clearing of beta amyloid from the vessels, which makes the vessels temporarily leaky. What is interesting from the observation of trontinemab, that if you take an antibody and if you get that antibody, move this antibody from the blood vessel, okay, into the brain, then you're seeing much less ARIA. That simply suggests that it are not the cells that are causing the immune reaction, and they are damaging the brain vessels. Those are not cells that come from the brain, but rather the cells that come from the periphery, okay? So if you shift the compartmental presence of the antibodies from the bloodstream into the brain, leave less antibody in the bloodstream and more antibody into the move more of this antibody into the brain, you're getting stronger clearance on the plaques. And while you're going to get less ARIA. This is a very interesting observation, which Roche has contributed to the field, and it can be a game changer. I think the number of other companies right now are considering using the brain shuttle mechanism, developing their own brain shuttle. There are a number of other ways you can get antibodies into the brain. The second part of your question is a very good one. What's going to happen to the antibodies once you apply 1812? So 1812, as far as we understand, doesn't clear the antibodies, okay? It just essentially reshuffles the antibodies. It moves the antibody around. So either those, I'm sorry, move oligomers. So you have a situation that there is a certain pool of oligomers that are being produced, and this pool of oligomers is either being destroyed or goes into the protofibrils and into the plaques, where they essentially are less toxic, or they sit on the synapses. When they sit on the synapses, they are the most toxic, okay? So what 1812 would do will essentially displace oligomers from the synapses and move them into extraneuronal space. And the company has very nicely demonstrated this in the published data, both in mice and in the humans, that application of 1812 increased the concentration of oligomers. They are not binding anymore to the synapses. Therefore, they are no longer synaptotoxic. What happens to them, we don't know, but we can assume that either they are going to go into the protofibrils and plaques, and therefore, they're going to become less toxic, okay, when they accumulate in the plaques, or they will be available for microglia clearance, and therefore, they would be more and therefore, they would be more also, you're going to reduce toxicity. Since you asked the question, so let me speculate the following. So previously, we had the questions, should we use 1812 and Leqembi at the same time? And your question provides an answer in this. If you're going to use 1812 and if you're going to dislodge oligomers from the synapses and make those oligomers freely present in the brain parenchyma, and at the same time, you're going to apply the antibody that is targeting oligomers and has microglia effector function, then the microglia will effectively clear those released oligomers and protofibrils that will form from the oligomers. So there is theoretical explanation that how 1812 and Leqembi can work very well in a concert. Super helpful. Thank you, Dr. Sadowski. Then for the SHINE study specifically, and this could be for the KOLs and the company, what subgroup analysis are we most interested in? At least from my vantage point, statistics are important, but it's also important any particular biomarkers that should be of high or low interest that corroborates the drug's differentiated mechanism. I also asked this in context of the updated FDA guidance document that stresses on biomarkers over some of the clinical surrogates that we've been looking at. I think investors are also interested in the read-through to the DLB study. As you guys know, that readout is later in the year. Any commentary on the relevant subgroup analysis and the biomarkers within them would be very helpful. Thanks again for taking our questions. Sure. And thanks for those questions. We obviously will be doing a lot of subgroup analyses. We'll be dividing individuals by those who are more severe or more mild based on their MMSE score. We'll be looking at folks with different APOE statuses, whether they're non-carriers, hetero, or homozygous around APOE4. We'll be looking at folks who have been on other medications, obviously, by age, gender, and every other subgroup that you might look at. As Dr. Sadowski mentioned earlier, we believe based on the mechanism of CT1812 that we should have effects in those who are more mild as well as those who are more moderate. However, the data will tell us that when we see it. Now, as far as the biomarkers go, we have a nice, robust program of biomarkers. Up to now, we have very nice, smaller datasets telling us what we can expect to see. I think, in general, what I would expect is that we'll see the biomarker profile which supports that CT1812 is protecting the brain in Alzheimer's Disease. So things like reduced GFAP in the CSF or reduced fragments of synapse proteins like neurogranin and synaptotagmin. Ultimately, it would be nice to see a reduction in phosphorylated tau as we think that's a reflection of amyloid pathology and then downstream effects that propagates on its own as we went through earlier today. So those are the things that I would like to see and I'd expect that we'll see when we read out the SHINE data. Very helpful. Thank you, Tony. You're welcome. Thanks for the questions, Mayank. So our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay. Oh, hey. Thank you so much for providing this update. Super informative. I had a couple of questions for the experts, if I could. Can you talk about any particular biomarker that you think is especially important to demonstrate neuronal health and synaptic function and could be relevant as demonstration of disease modification and potentially to support an accelerated approval? Yeah. Thanks, Jay. Jort, perhaps you could address those questions. So which biomarkers do you think would be indicative of a biologic effect and positive effect of the drug? Yeah. So thank you for the questions. I think very important questions. So the FDA approval, I park, and maybe in the US, KOL can tackle that question. But for the mode of action of 1812, I think the SEQUEL was a perfect example of that. So we really use the EEG that the EEG reflects the synaptic health. And we know that in Alzheimer's disease, in the MCI and mild and moderate, the endpoints on EEG goes for the theta band reflects the progression of the disease. So that gets more dominant in your EEG. And we know that reflects synaptic loss, and we know that correlates well with cognition. So if you modify that biomarker, what we showed, a positive trend, then I think you have a disease-modifying effect. Of course, it was a small group, and it was not statistically significant. However, in the short period, we saw on more endpoints on EEG, a positive trend. So that's partly tackling your question, I think. Of course, you want to really have on amyloid p-tau or tau to see some movement in the right direction. And that will show us in SHINE, I think. But that's, I think, really our AD biomarkers. But also, the secondary downstream biomarkers, the synaptic injury in your plasma and CSF, is very important because that's also reflecting your synaptic health. And I think on neurodegeneration overall, so total tau or NFL, if you stabilize or even in a normalized direction, that will also prove the disease-modifying effect. But still, I think because the mode of action of 1812 EEG, it's not included in the SHINE, but we have the SEQUEL. In the SHINE, it's CSF and plasma on ED markers or synaptic markers will show us the effect. For the FDA approval, yeah, we had a lot of discussion about can we use EEG also as accelerated approval, but we're not there yet, not with the European agency or with the FDA. Maybe Tony or other can elaborate on that. Great. Thank you. Perhaps Dr. Sadowski, perhaps you could comment on what you think are the important biomarkers to see coming out of trials to support a biologic effect. Of course. Hi, Jay. Nice to see you again. Nice to see you, Dr. Sadowski. So look, I think that I fully agree with what was said, okay? I think that the EEG, quantitative EEG, all the forms, quantitative EEG, is an extremely sensitive biomarker, okay? But you're also looking into the this is the 1812 is the first drug of its kind, okay? It's truly the first synaptoprotective drug in Alzheimer's disease, all right? And I think that our biomarkers in the field of synaptotoxicity in Alzheimer's disease are a little bit behind our ability to detect an amount of disease-specific proteins, all right? So we are quite good in measuring A-beta-40, 42, the ratio, different forms of tau. But remember that this came after 40 years of research, all right? That anything that we do to synapses is just something which we are st arting, okay? So I think that if we would be able to show any benefit and consistent benefit in CSF synaptic markers, okay, in PET synaptic marker, okay, that would be great support to the drug, okay? So I think that in the situation of this particular drug, we would like to see a consistent cognitive effect, okay? That's the first thing. We would like to see a consistent EEG effect. We do have some preliminary data about the brain volume, okay? And at least we got a first study which the brain volume behaves in a logical way, all right? Okay? In the antibody studies, I mean, the patients are getting better, but their brain shrinks, okay? And everyone is scratching their head, "What does this mean?" All right? Here, I mean, we're getting the proper behavior of that particular metric, okay? We know that hippocampal volume can be a very sensitive marker of neurodegeneration and synaptotoxicity, okay? And it directly correlates with synaptotoxicity. I would like to remind you, we used to have a trial called Generation 1 and Generation 2 from Novartis of BACE inhibitor. And that trial was stopped in 2019 due to synaptotoxicity, specifically due to synaptotoxicity. And those patients in this trial showed a drop in cognitive performance and reduced hippocampal volume. And all of those findings completely reversed, okay, once they were taken off the drug, all right? So I realize that there is a lot of discussion about what the volumetric change in all of the studies means. But I think that in this particular case, it simply makes sense and goes in the right direction, all right? Looking into more finicky markers of synaptotoxicity, like fluorodeoxyglucose uptake, like other PET markers that directly target synapses, this hasn't been widely studied and analyzed, okay? Whatever we can get here and in support of the drug mechanism would be a great bonus because we are also the company is also trailblazing, okay, those biomarkers, okay? Remember that you don't should expect great change in the fluorodeoxyglucose uptake in the hippocampus, okay? Because comparing to the other parts of the brain, hippocampus doesn't have that much basic activity of fluorodeoxyglucose, okay? You should look in other areas that we know in the cingulate cortex and the frontal lobe, which we know they are affected early by beta-amyloid and that there are plenty of oligomers there. Perhaps segmented analysis of fluorodeoxyglucose from different parts of the brain would be better than global, okay? But here, the company will have a lot of fields to play and to create different answers, all right? So again, this is a new drug. Target synapses, okay? And we yet don't have a fully determined set of the biomarkers, okay, to determine effect. It's not another monoclonal antibody targeting plaques that you can simply compare what's the reduction in the plaque load after six months, okay? And that allows you to predict how this behaves, okay? So development of the refinement, let's put it this way, refinement of synaptic biomarkers and drug development, in this case, will go like hand and glove. Great. So Dr. Sadowski, we were wondering perhaps we can get you to clarify some comments from earlier where you were talking about how we had observed displacement of oligomers in the cerebrospinal fluid, which presumably would lead to clearance. But also, you mentioned reincorporation into plaques and how this would also be a beneficial effect of not having free oligomers. Could you comment a little more on that because I think perhaps that's not as obvious to the non-neurology population? Of course. So look, the oligomeric story came to light in the early 2000s when those oligomers were studied. And there was, at the time, the fibril theory has been proposed, okay? And well, observation has been made, okay, that the beta-amyloid, the plaque formation, okay, is a natural protective mechanism, the mechanism through which the brain protects itself from toxicity of oligomers, okay? The amount of free oligomers that are present at a given time in the brain is only the fraction of the oligomers that would be present in the brain should they will not be deposited in the plaques, okay? They are essentially packed by microglia, partially digested by microglia, but partially packed and formed into the protofibrils in the plaque. So essentially, what the plaque formation mechanism is essentially the same mechanism that we use in the big cities to collect garbage. We put in one place outside the city where we compact, okay, all the waste in one area. That's what the plaque formation does. It's a temporary protective mechanism. So what is going to happen again with 1812? We're going to displace oligomers, okay? And this is good because once the oligomers are bound to synapses, they are toxic. They are the most toxic. They are not toxic when they are floating around, but they are toxic when they bound and associated with synapses. And once they engage with the synapses, they don't disengage until the cell clears those oligomers or kill the synapse, okay? If we block oligomers from binding to the synapse, the oligomers can do one thing, either being degraded by microglia directly, or microglia can pack those oligomers into the form of protofibrils and fibrils and form the plaques where they are becoming less of the toxic species to the brain. Great. Thank you. Unless, as we discussed, we use 1812 in concert with some other plaque or oligomer clearing antibody, okay, which probably is going to work in concert. Great. I think we're going to move on to some of the written questions now. Great. Thanks, Tony. We had a question coming in in the portal from Tom Shrader at BTIG. His question: several proteins have been identified as binding oligomers. In your mind, KOLs, what is the best dataset from sigma-2 and 1812 that kind of moves 1812 to the front of the list as far as oligomer binders? Great. Perhaps Dr. Sadowski, you want to start, and then Dr. Vijverberg, if you have any thoughts to add to those? Well, I think that the list of the protein that can bind to oligomers is as long as 500, all right? There are 500 different the proteins claimed by different people and different companies to interact with the oligomers, okay? The association with oligomers and with oligomers and those proteins have been somehow shown. But I think that the 1812 I mean, the studies on sigma-2 receptors and prion protein are probably the most established two proteins through which those the oligomers bind. Proteins can bind to some proteins. Oligomers can bind to multiple different proteins because they are hydrophobic in nature, and they can bind very nonspecifically, all right? I think that in the case of sigma-2 receptors and prion protein, we do have quite strong and established interactions through a number of different number of different studies. So from this list of 500 different proteins that are being proposed, for some of them, of course, we know that likely the binding is nonspecific, okay? For something, the binding is specific, but it's not weak and probably may not be ongoing in biology. But I think that the most convincing for me in experiment is that how significant the Sigma-2 receptor is, is just simply displacement of oligomers from Sigma-2 receptors in vivo, using microdialysis studies in humans and in mice. So that essentially, those studies confirm that target engagement by that interaction between Sigma-2 receptor and oligomers is specific, okay? And the 1812 essentially engages the target. Great. Thank you. Great. I know we're up on time, so we'll just ask one more. Rohit Vanjani from Senator Investment Group had a question for the KOLs. What do you think the target in terms of what do you think in terms of targeting toxic oligomers over targeting A-beta plaques, so comparing and contrasting of the two? Well, there is a different I mean, there is a different benefit of targeting both, all right? I think that targeting oligomers provides you immediate benefit, positive benefit on synaptic health, reduces synaptotoxicity, and also works as a form of neuroprotective mechanism, insulating a nerve cell, okay, from an effect of beta-amyloid, an effect of beta-amyloid, and preventing the cell from attenuating the accumulation of the tau inside the nerves, okay? That's what the anti-oligomer the agent that displaces oligomers from the synapse would do. Plaques are, as we discussed, something that the brain uses as a protective mechanism, to such an extent is a protective mechanism, but it also has its downside. Presence of plaques changes the metabolism of beta-amyloid in the way that soluble beta-amyloid is no longer so easily removed from the brain, but more likely to deposit to the plaques. Plaques seed new plaques. There are daughter plaques quite often seen. So in order to get a strong effect of therapeutic effect, you really have to, at some point, clear the plaques, okay? So the mechanism of 1812 and the mechanism of the blockbusters are the primary mode of action different, but they are symbiotic. Great. I'm going to turn it back to Tony and Lisa for concluding remarks. Perfect. Great. So let me first thank each of our speakers, Dr. Sadowski, Dr. Thorsten Steen, and Dr. Vijverberg. We had a really nice introduction to the basic pathophysiology of Alzheimer's disease, some of the different mechanisms of disease leading to different therapeutic approaches. We drilled down into some of the nuances of both the lecanemab and donanemab treatment, and then a nice introduction to how CT1812 and its ability to displace oligomers might work on its own as well as complementary to other therapies in development. So we hope this was a nice introduction. Obviously, next for us is the data from our SHINE study, which we'll be reading out this year. And hopefully, this puts some of that data or will put some of this data in context for you. So thank you very much, and I'll turn it over to Lisa now. Great. Thank you, Tony. I want to echo your comments thanking all our speakers. Martin, what a pleasure. I think you took in a short period of time, all of us, through the 30 years of work since Tacrine. That was excellent. Your consideration around patients, which we know from talking to you, is outstanding. Keep doing what you're doing because you're going to help lead the field ahead. Thank you. Anton had fabulous remarks about the biology of Alzheimer's disease, a review of toxicity, his focus on the soluble species. Very much appreciated. Jort, we thank you for your leadership in multiple clinical trials. Your focus on what is happening in Europe and the complexities for patients there getting care is really important. Takeaway for all of us, this disease doesn't stop. By no means have we solved it. There are lots of fantastic opportunities before us for new drugs, oral drugs, combination drugs. We look forward to all of that. As Tony said, we very much look forward to seeing you interacting with all of you in July at the AAIC, where we're going to be talking about the results of our SHINE trial. Our thanks to all of you.