Cognition Therapeutics, Inc. (CGTX) Earnings Call Transcript & Summary

Good morning, and welcome to the Cognition Therapeutics KOL event. [Operator Instructions] 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 therapy 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 II 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 II 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 2 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 ventures of 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 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 the New York University, NYU 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 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 specialists at the Alzheimer's Research Center in Amsterdam. He has dedicated his career to finding novel ways to treat Alzheimer's disease, and he's the founder of The CANDIDATE Center, 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 professor of neurology, psychiatry and pharmacology at NYU School of Medicine, and I focus on developing therapeutics for Alzheimer's disease. I would like to give this introductory talk focusing on overview of the current treatment landscape and unmet needs -- current unmet needs for Alzheimer's therapeutics, which are in development. So for most -- most of 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 5 notably simple stages, including preclinical Alzheimer disease, mild cognitive impairment and dementia due to Alzheimer's disease, which is then divided it into mild, moderate and severe stages. The preclinical stage with Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease were the first signs of the disease due to Alzheimer's pathology in the brains are becoming apparent. Usually, it takes about 15 years, and dementia takes about course for under 10 or 15 years. Currently, Alzheimer's disease is one of the biggest social problem in our country and in developing world. In the United States, it's estimated that there are 6.7 outpatient 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 population, a number of patients with Alzheimer's disease will increase in -- by 2050 to 14 million. And the cost of the care are related to Alzheimer's disease, which is split between caregivers. Medicare and Medicaid will raise from S400 billion current 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 is extremely complex biology, and the disease starts from a neuron and eventually takes a full circle and destroys the neuron. The culprit -- the primary culprit of Alzheimer's disease is imbalance in production, the clearance of soluble beta amyloid. 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 happen with the plaques are the microglia cells, which is trying to remove the plaques. And initially, microglia cells have protected 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 amyloids and various -- and affective various form of beta amyloid and also chronic neuroinflammation caused by microglia take a toll on the nerve cells, which starts accumulating tau protein inside the -- inside dendrites and inside the barrier of the cells. And over time, accumulation of the tau protein inside the nerve cells leads to demise of those cells and their death and further stimulates neuroinflammation coming from activated microglia cells. There are several areas therapeutics are being developed for Alzheimer's disease, and I simplified this -- them into 3 different groups. Therapeutics, which would target accumulation of primary misfolded proteins associated with Alzheimer's disease, namely beta amyloid and -- which is outside -- 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. And by this, we understand a drug, which we know 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 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 the -- all the approaches that would target microglia cells and make microglia cells less inflammatory and more phagocytic. And there are neuroregeneration approaches that has to do with anything that would allow the brain to rebuild itself and counteract neurodegeneration process. There are also symptomatic -- areas for symptomatic management, including cognitive enhancer and antipsychotic medications. Therapeutic groups, which are highlighted by this little frame indicate those which we have therapeutics already approved by FDA. As you can see on this slide, there are no that many therapeutics approved for Alzheimer's disease, although Alzheimer's disease is extremely prevalent condition. The first group of symptomatic therapeutics or cognitive enhancers concerning improvement of [indiscernible] metabolism and/or glutamatergic transmission were approved between 1993 and 2003. And 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, 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 biomarker of Alzheimer's disease, but due to certain design flows did not demonstrate sufficient clinical benefit for this drug to secure a traditional approval. And we had to wait until July of 2023 and -- when lecanemab was the first disease-modifying therapeutic that have been approved -- fully approved, which received traditional approval of FDA for Alzheimer use. So as you can see, between approval of lecanemab and approval of the first drug for Alzheimer's disease stacking, 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 deposit in the brain, both in its soluble and insoluble forms. And as it has been shown in a Phase III 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 PET scan from someone who is treated with placebo, where you don't see distinction between white and gray matter, which indicates accumulation of beta amyloid in the brain cortex. In the lower picture, you can see the edge of this -- of the brain becomes darker again, and this is indicative of that -- 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 level. Although treatment with lecanemab in patients with mild -- with MCI and mild Alzheimer's dementia was shown to be extremely effective on reducing biomarker, the clinical effects were modest. Patients -- 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 2 here, clinical dementia rating and ADAS-Cog 14. The area of anti-beta amyloid antibodies is probably the most advanced and the most crowded area in Alzheimer therapeutic development, and notable examples include aducanumab or ADUHELM, which was the first drug approved by 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 therapeutics, which -- where the company is doing very well. Then LEQEMBI is the first traditionally approved disease modifying therapeutic for Alzheimer disease. They are currently developing subcutaneous LEQEMBI, which is under regulatory review. There is donanemab, another monoclonal antibody given intravenously, which is way potent than LEQEMBI. And unlike LEQEMBI does, focuses on only one epitope, which is an epitope exclusively found in beta amyloid plaques, and this is an antibody, which thus far provides the most robust clearance of beta -- of preexisting beta amyloid plaques, but don't do anything to soluble beta amyloid and is currently under regulatory review. There is derivative of donanemab, remternetug currently in a Phase III, which is even more improved antibody. And there is sort of attention page to another antibody called trontinemab. That company comes from Hoffmann-La Roche and is reiteration of the older antibody called gantenerumab. What's new in about trontinemab, trontinemab is the first antibody that is being developed based on the Brainshuttle technology. This antibody is equipped in the receptor that allows this antibody to be actively transported into the brain. Therefore, greater reduction in beta accumulation can be achieved with much lower amount of the antibody. And surprisingly, positively surprising, patients treated with trontinemab suffers from the least number of side effects with any other -- comparing to any other antibody targeting deposited beta amyloid. Other therapeutics in development from that pipeline include ACU193 from Acu (sic) [ Acumen ] Pharma and PRX012 from Prothena. And those are monoclonal antibody specifically to develop -- developed to target beta amyloid oligomers and beta amyloid protofibrils, respectively. They are in Phase I, so we probably will need more data to assess their benefit. How the antibodies clear beta amyloid plaques? Donanemab, aducanumab and lecanemab are given in large amount intravenously every 2 or every 4 weeks. The amount of the antibody given with each infusion ranges from about 10 milligrams to 20 milligrams per kilogram. And from that mass of the antibody that becomes viable in the blood stream, small amount of antibodies penetrate the blood brain barrier, get into the brain. And 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. And beta amyloid plaques are a reservoir of soluble beta amyloid species that are surrounded -- that are surrounding them. Antibodies induced activation of microglia and 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 type of novel side effects, and they are known as amyloid-related imaging abnormalities. They include the brain edema and they include micro bleeds. And they have been 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% to 40% of patients treated, depending on the antibody use. 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 received numerous scans during the especially first months of the treatment. And those -- 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 -- what does this advance in Alzheimer therapeutics take us? On the left-hand side, you can see brain and schematic depiction of Alzheimer pathology before plaque clearance. On the right-hand side, you can see 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 type of patients in whom -- 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 the plaques from the brain, we only have removed only one aspect of the treatment. The primary culprit in Alzheimer biology, which is imbalance between production and removal of monomeric A-beta persist. 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 to the tau from one nerve to another using the tau oligomers. So removal of the plaques in patients with -- in whom Alzheimer's disease biology went under full-swing changes. Changes thinks a lot, but it's not enough. So there is a lot of discussion how should we take the things forward and how should we improve the outcome of anti-beta-amyloid therapeutics. We're, of course, doing this by providing -- developing better antibodies and moving that field -- moving those antibodies into earlier stages of the disease. However, we believe that as the field that beta amyloid antibodies as a monotherapy may not be enough, and we would need to have some other agents that would -- can be given in tandem with beta amyloid therapies or as a sequel to beta amyloid therapies. So the goal of improved therapy include 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 patient. 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 and -- including the infusions and associated MRI that comes to about $50,000 per year. With this, I would like to thank 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 of 20 to 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 identical -- it's identifiable in life through elevated beta amyloid, the plaque burden on 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 synapsis. 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 increase in certain neurotransmitter activity such as the cytotoxic 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 beta amyloid 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 strand, they are not cleared easily, and they have affinity for each other. So they form oligomers, and these oligomers basically become more and more complex, and they end up forming protofibrils than fibrils and, finally, amyloid plaques. 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 3 humanized monoclonal antibiotics, all targeting the end terminus of A-beta 42, which preferably targets amyloid plaques outside of lecanemab that targets not only amyloid plaque, but also fibrils and protofibrils. But basically, we have 3 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 [indiscernible] 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. And they're both associated with a fairly complex clinical and radiographic monitoring and a meaningful side effect profile, and I'll get back to that in a minute or 2. But what do they bring to the table? Let's start with lecanemab. And the CLARITY-AD study was the pivotal Phase III 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 slow decline by about 30% to 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. And the mean score in the CLARITY study was about 3.70. So the change there has to be seen as modest. What about the ADAS-Cog 14? And that is a scale that preferably looks at cognitive function. It is a scale with a range of 0 to 90. And we saw a 1.44 adjusted mean difference in the ADAS-Cog 14, and 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. And there, we have a range from 0 to 52 with a mean score of 41. Lecanemab also showed impact on downstream biomarkers. And in terms of safety and tolerability, the main findings was that about 25% of participants had low-grade to medium-grade infusion reactions, and 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 cirrhosis 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 tao 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% to 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-Cog 14, a 1.52 point difference and on the functional scale of 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, the -- 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 humanized monoclonal antibody, well, the Mayo group looked at this and published their findings in 2023. And at that point, they used the lecanemab trial criteria and aducanumab trial criteria. They looked at patients age 50 to 90 years old in their clinic with early symptomatic AD. And between 43% and 47% met inclusion criteria for these studies, but only 5% to 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. And 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 alpha 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 the -- does a beta amyloid or A-beta 42, either as monomers or oligomers, actually bind within the synapse? We have now good evidence that there is an A-beta oligomer binding site, and that CT1812 can bind -- can basically interfere with the binding of A-beta 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 synaptic toxicity 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 U.K. researcher 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 2 receptor complexes. So it binds both to the so-called prime 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. And now we have impact on disease pathology study, and I want to highlight 2 of them. So 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-Cog 11. And 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. And I'm a steering committee member of that group where we will target early symptomatic Alzheimer's disease with either a 100-milligram or a 200-milligram once daily dose versus placebo for 18 months, and 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 study, 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, it's an honor to talk about more about 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 shows beneficial effect on the synaptic health and function. And I -- in a couple of slides, we'll talk about those results. So the SEQUEL, not 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 2-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 comparison, 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. One group were started on the drug for 4 weeks on 300 milligrams and one group on placebo. Then they had a washout period, and we turned it over. So that was a cross overdesign. In the end of the relative 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 that reflects synaptic health. In Alzheimer disease, we can really see a decline in synaptic health on EEG. I will come back later on that. Also we did CSF taps and plasma biomarkers in the end, and we did cognition. Of course, it was exploratory because in a short period, moving those biomarkers is optimistic. But still, we checked them. So if we look at the results of the SEQUEL study, we saw on the primary endpoint on the EEG a positive trend that was very excited. And here, you see 3 figures that show that, that we normalized in a short period of time those measurements. A little bit more focused on the global alpha, the cognitivity, you see a normalization, so the green part, patients on the drug, first patients that were off the drug. In a short period, we showed more talking between brain activity measured by this EEG. So very excited about that, that we showed in the 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 we're a little bit disappointed when the trial finished. It was well tolerated. No serious adverse events, and some milds that feels 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 synaptic health, on all the measures that we specified. Also the activity impact on synaptic activity, what makes us very confident that this drug does what it needs to do. I have previously explained the mode of action that it keeps the synapses healthy. If we go further, so the SHINE, also by the previous speaker, is a Phase II safety and efficacy study in the same population as the SEQUEL. However, a little bit different design. The same population. So again, a little bit more advanced in the Alzheimer's disease. Also -- well, phenotype before randomization. In this trial, we had 3 groups. So patients on CT1812 on 300 milligrams, the same as the SEQUEL study, a group on 100 milligrams and, of course, in placebo group. It was 6 months treatment, and we prespecified also a cohort A with 24 patients to do a preliminary analysis that I'll show later. In total, 144 patients participated in the study, and this phase after 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. So let me talk about more about that design. So of course, again, safety and tolerability is, in this stage, very important. And efficacy measure is in this phase also very important. And we used the ADAS-Cog 11, explained also by the previous speaker, where we look at memory, language and [indiscernible]. And here, we really think what Alzheimer's disease is all about. So cognition, but also function and behavior. And this is -- on the top of the slide, we see the global impact scale and also the activities in daily living scale. If we see movements on these skills, 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, and we can use different elements for composite scores. But I think if we can move like lecanemab and donanemab on these skills in the right direction, with patients on the drug, we have good results. More about the other objectives. Of course, we look at pharmakinetics. So what is the drug doing in the body, how it moves in the body on different levels, 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 of different biomarkers. We can -- some measure in the CSF but also in the blood. And what this means is the first 3 amyloid total Tau. Phospho-Tau is really Alzheimer biomarkers. Neurogranin, and synaptosomal 25 are all markers of SNAP25 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. Other markets 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 SHI trial, where we use 24 patients that finished the drug to see preliminary data. And also mentioned, we see in the 24 patients that we already analyzed that there was a 3-point difference on the ADAS-Cog 11 and that's more or less the double that we see in [ chemi ] 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 connection, in the right direction, excite me very much. And also with this difference, it's clinically meaningful for me and for the patient. So how do we experience the drug development here in Amsterdam, in Europe? Of course, we're not that advanced yet like the U.S. We don't have approval for lecanemab on donanemab. And it's very exciting times if it gets approved in Europe. But 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 look at our cohort in Amsterdam in our memory clinic, where we see 2 years around 1,300 new patients. And then we used the inclusion criteria from lecanemab and a little bit from donanemab, it's a little bit the same. But we did a very conservative way. We also exclude microbleeds, E4 carriers because that are risk factors for the [ amyloid ] image abnormalities, and we exclude co-meds like a medication that influenced your coalition. And then in the end, we had only 7% over that can be treated with antibodies that target amyloid. 7% as a clinical trial list and also the questions of the patients in my clinic, daily clinic, patients ask for these drugs. And then I explain what it does, what are the risks and what is the logistics around that work. 50% that were eligible declined the treatment. So I agree if we have lecanemab in Europe, it will be not the answer for Alzheimer's disease. It's a positive sign, but it will be a small group of patients that can benefit of this treatment. I did more or less for CT1812. The same population. So we had 40% mild dementia in that group, excluding the co-meds that maybe influence CT1812. And then in the end, around 80% are eligible for treatment. And of course, with the experience of all the other medications that can be given orally. I think not many with also the side effect profile will decline. But this is also -- and this is future talk. But I think it will be the -- more the answer more patients were willing to take an oral drug for Alzheimer's in the IV. Also from the perspective of the burden on the health care system. So in Europe, every country has a little bit different health care system. But if you look at the left graph, you see a very complex flow chart if lecanemab, donanemab lands. So the general petition refers to our local memory clinics, and then we think only 3 or 4 centers will give that treatment, those will be the assessments. There are going to be more multiple teams that discussed the start of those treatments. The follow-up is very extensively with MRI, what I already explained. Also the fusion centers were not -- are not commercialized in Europe, so it must be in the hospital. We're under staffed already. So this is very impactful for the health care system. If you look at the small molecule and maybe has the same efficacy and a nicer profile that will be less burden for the patients 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, per definition, mostly cheaper. So hereby I want to thank you for your attention and give it over to the -- 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 in our current studies. [ Dr. Thorstenstein ] 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 view -- 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% to 50% slowing of decline. We have somewhere about the 0.45 to 0.5 if we look at the total group's 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 -- done for disease modification. If we take into account the 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. And 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 a kind of amyloid disregulation only or in addition to the amyloidopathy, do we have tauopathy present? Do we have neuro inflammation? 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 the drugs cannot 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 the clear out beta amyloid 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 poll for questions. So our first question comes from Charles Duncan at Cantor Fitzgerald.

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 the 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 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 drug is going to have a stronger response in milder patients. And that would simply means that the drug has a very strong response on that -- 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 means that it does have more stronger prolonged effect protecting the nerve cells likely from building [ capital ] protein inside the nerve cell, which is more involved in those -- in that stage of the disease. So I would expect that the drug might have an effect in either stage of the disease. But I would -- but in terms of the biology, I would have a different readout in our understanding.

That makes sense to me. And then one additional question for you, Dr. Sadowski. With regard to a future treatment paradigm given that Dr. Thorstenstein 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 SEQUEL, 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 oral molecule, given the fact that the drug is what we say, it doesn't have a major side effects. I think that this would be something which would be the first line to the first line of treatment, okay, which would be very easy to apply, okay? All 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 that amyloid plaques as well. And if you're a candidate, and if you're willing to take the risk, there is -- that are antibodies for you, right, which 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 your will continue with 1812 along with the antibodies. And once we clear the plaques, we know that the process of the disease process doesn't stop. And you should continue, okay, 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 that to consider LEQEMBI being live long 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 also ligamers. 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 injection every week, right? You still have a number of patients you cannot put on LEQEMBI, right? And then the depending somatically, you will not put about 20%, 25% of patients, okay, general populations of patients on LEQEMBI, okay, for medical reasons, right? And you assume that you're going to have another 25% of patients who would not being able to take the risk. And they are not taking the risk at the moment, okay? We set -- we are including them into other clinical trials that don't -- 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. But -- and then you're left with the remaining 50%, okay, who can take both.

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, 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 in a wash out? Just give us a little bit more understanding of what that sample looks like.

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 on disease, if there are 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.

So our next question comes from Mayank Mamtani of B. Riley.

Maybe just on the -- Dr. Sadowski, good to hear from you again. Could you please talk to [ few ] understanding on the mechanism of ARIA brain swelling in light of perhaps what we are going to see at the upcoming [ outcome ] and also what data we have seen with the next-generation a beta antibodies? I think you mentioned Brainshuttle. And then how does that framework apply to the 1812 mechanism of clearing oligomers of the neurons, for example. Would be helpful to understand the field's knowledge of ARIA. And then I have a follow-up for the company.

Right. So what we understand, we don't exactly know how the ARIA happens because we can have a good model for it. Although there are some attempts to recreate ARIA in eyes. What we know about the ARIA that there are certain prerequisites for ARIA, okay? Firstly, the better amyloid has to be present in the brain vessels. And the antibody that you use has to bind the better amyloid that is deposited in the brain vessels, right? So we assume that there is some form of the immune reaction triggered by antibodies directed toward the brain vessels. We know the treatment of the animals, transgenic mice with anti-beta amyloid antibody, clears better amyloid both from the brain parenchyma and from the vessels. It also causes those mice to have some micro bleeds. We understand that by observing humans that the event -- the timing event of ARIA, which is usually between the second and fourth month of the treatment suggests that it's a transit phenomenon. And it's related to clearance, to the process of clearing and immune reaction around the clearing of beta amyloids from the vessels. And once that process is complete, 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. So we understand that ARIA is transient phenomenon associated -- caused by some form of immune reaction around the clearing of back amyloid from the vessels, which makes the vessels temporarily leaky. What is interesting from the observation of trontinumab 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 you have -- those 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 compartment of the compartmental presence of the antibodies from the bloodstream into the brain, leave less antibody in the blood stream and more antibody into the -- 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 conservation, which Hoffmann-La Roche has contributed to the field, and it can be a game changer. And I think the number of other companies right now are considering using the Brainshuttle mechanist, developing their own Brainshuttle, there are a number of other ways you can -- different ways you can get antibodies into the plaque. The second part of your question is a very good one. What's going to happen to the antibodies once they are -- 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 antibodies around. So either those -- I'm sorry, moves 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 blood [ fibers ] and into plaques, where they are essentially less toxic or they sit on the synapses. And 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 external space. And the company has very nicely demonstrated this in the published data both in mice and in the few months that application of 1812 increased the concentration of oligomers. They are not binding any more to the synapses, Therefore, they are no longer synaptotoxic. What happens to them, we don't know, but we can assume that either you -- they are going to go into the protofiber and plaques, and therefore, they're going to become less toxic, okay, when they accumulate in the plaques. Or they will be viable for microglia clearance and therefore, there would be more -- also, you're going to reduce toxicity. And since you asked the question, so let me speculate the follow-up. So your -- the pros -- we have the questions, should we use 1812 and LEQEMBI at the same time. And to your question provides an answer in this. If you're going to use 1812 and if you go into these large oligomers from the synapses, and makes us -- and makes those oligomers freely present in the brain parenchyma. And at the same time, we're going to apply the antibody that is targeting oligomers and has microglia effector function, then microglia in the microglia will effectively clear oligomers -- those released oligomers on protofibers that will fall from the oligomers. So there is theoretical explanation that how 1812 and LEQEMBI can work very well in the concept.

Super helpful, Dr. Sadowski. And 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? And 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. And 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. So any commentary on the relevant subgroup analysis and the biomarkers within them would be very helpful.

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 [ MSC ] score. We'll be looking at folks with different AOE statuses, whether they're noncarriers, 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. And up to now, we have very nice smaller data sets 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 [ symbiont ] protein like neurogranin and synaptotagmin. Ultimately, it would be nice to see the 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 things that I would like to see, and I'd expect that we'll see when we read out the SHINE data.

So our next question comes from Jay Olson at Oppenheimer.

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?

Yes. Thanks, Jay. [ Jord ], perhaps you could address those questions, which biomarkers you think would be indicative of biologic effect and positive effect of the drug?

Yes. So thank you for the questions. I think very important questions. So the FDA approval part and maybe in U.S. KOL can tackle that question. But for the vote of action of 1812, I think the SEQUEL was a perfect example of that. So we really use the EEG, the EEG reflects the Synaptic Health. And we know that in Alzheimer's disease in the NCI and mild and moderate, the endpoints on EEG goes for the [indiscernible] reflects the progression of the disease. So that gets more dominant 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 was not statistically significant. But 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 an amyloid beta or tau to see some movement in the right direction. And it will show us in SHINE, I think. But that's, I think, really are [ AD ] biomarkers. But also the secondary downstream biomarkers, the synaptic ureaplasma and CSF is very important because that's also reflecting a Synaptic Health. And I think on neurodegeneration overall, so total Tau or NFL, if you stabilize or even in the normalized direction, that will also prove the disease monitoring 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. And in SHINE in CSF and plasma on immune markers or [indiscernible] markers will show us any effect. For the FDA approval, yes, we had a lot of discussion about if we -- can we use EEG also as accelerated approval, but we're not there yet, not with the European agency or with the FDA, but 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 biologic effect?

Of course. Jay, nice to see you again. Look, I think that -- I fully agree with what was said, okay? I think that the EEG -- probably the EEG in the [indiscernible] for quantity of EEG is extremely sensitive biomark, okay? But you're also looking into the -- this is the -- 1812 is the first drug of its kind, okay? It's the truly first into protective drug in Alzheimer's disease, right? And I think that our biomarkers in the field of synaptoxicity in Alzheimer's disease are little bit behind our ability to detect amount of disease specific projects, right? So we are quite good in measuring a better 40, 42, the ratio different forms of Tau. But remember that this came after 40 years of research, right? That anything that we do to synapses is just something which we are starting, okay? So I think that if we would be able to show any benefit and consistent benefit in CSF synaptic markets, okay, in PET synaptic market, 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 consistent [ coated ] effect, okay? And 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, antibody studies, I mean, the patients are getting better, but their brain shrinks, okay, and everyone is scratching the head, what does this mean, right? Here, I mean, we're getting the proper behavior of this particle metric, okay? And we know that hippocampal volume can be a very sensitive marker of neurodegeneration synaptoxicity, okay? And indirectly correlates with synaptoxicity. I would like to remind you we have -- we used to have a trial called Generation 1 and Generation 2 from Novartis of BACE inhibitor. And the trial stopped in 2019 due to synaptoxicity, specifically due to synaptoxicity. And those patients in this trial should drop in a cognitive performance and reduced hippocampal volume. And all those -- all of those findings completely reversed, okay, once they were taken off the track, all right? So I realize that there is a lot of discussion about what a volumetric change in all of the studies mean. But I think that in this particular case, it simply makes sense and it goes in the right direction, right? Looking into more finicky markers of synaptoxicity like fluorodeoxyglucose uptake, like uptake other PET's markers that directly target synapses, this hasn't been widely studied and analyzed, okay? And whatever we can get here and in support of the drug mechanism would be great bonds because we are also -- the company is also trailblazing, okay, those biomarkers, okay? Remember that you don't should expect a 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 single cortex frontal lobe, which we know they are affected early by the amyloid and that there are plenty of oligomers there. And 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 field to play and to create a different [ transfers ], right? So again, this is 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 6 months. And that allows you to predict how this business, okay? So development of the refinement is a refinement of synaptic biomarkers and drug development in this case, will go like hand in glove.

Great. So Dr. Sadowski, we're 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 cerebral spinal fluid, which presumably will be 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 starting. And there was -- at the time, the fields theory has been proposed, okay? And well, observation has been made, okay, that the better amyloid, the plaque formation, okay, it's a natural protective mechanism. The mechanism through which 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 are -- that will 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 form into the protofiber in the plaques. So it's -- so essentially, what the plaque -- when the plaque formation mechanism is essentially the same mechanism that we use in the big cities to collect garbage and we put in one place outside the city where the -- 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 synapses, okay? If we block oligomers combining to the synapses, oligomers can do one thing, either being degraded by microglia or -- directly or microglia can pack those oligomers in the form of protofibers and fibers and form the plaques where they are becoming less of the toxic species to the brain. Unless as we discussed, we used this in our 1812 in concept with some other plaque or oligomer clearing antibodies, okay, which probably is going to work in a concept.

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 bio oligomers. In your mind KOLs, what is the best data set from sigma-2 and 1812 that kind of moves 1812 to the front of the list as far as oligomers 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 combine to oligomers is as long as 500, right? The 500 different -- the proteins claimed by different people in different companies to interact with the oligomers, okay? The association with oligomers and those proteins have been somehow shown. But I think that the 1812, I mean, the studies on sigma-2 receptors and in protein is probably the most established 2 proteins to 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 have -- they can bind it [indiscernible] specifically, right? I think that in the case of sigma-2 receptors and plant protein, we do have quite strong and established interactions through a number of different starts. 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 not specific, okay, for something which binding is specific but it's not weak and probably may not be ongoing in biologic. But I think that the most convincing for me an experiment is that how significant the sigma-2 receptors is just simply displacement of oligomers from synapses -- from sigma-2 receptors using in vivo, using microdialysis studies in humans and in mice. So that essentially, those study confirms that target engagement by that interaction between sigma-2 receptor and oligomer specific, okay? And the 1812 essentially engages the target.

Great. I know we're up on time, so I'll just ask 1 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 2.

Well, there's a different -- I mean there is a different benefit of targeting both, right? I think that targeting oligomers provides you immediate benefit -- positive benefit on synaptic health, reduce synaptoxicity and also ask -- works as a form of neuroprotective mechanisms, insulating a nerve cell, okay, from an effect of beta amyloid and preventing the cell from reduced -- attenuating the accumulation of the Tau inside the nerves, okay? That's what the anti oligomer, the agent the displaces oligomers from the synapses would do. Plaques are, as we discussed, is something that brain uses as a protected mechanic. To a certain extent, is protective mechanism, but it also has its downside. Presence of plaques changes metabolism of beta amyloid in the way that [ solve ] beta amyloid is no longer so easily removed from the brain, but more likely to deposit to the plaques. Plaques seat new plaques. There's some -- that are [indiscernible] plaques quite often seen. So if you -- 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 mechanism of the blockbusters are the primary mode of action are 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. [ Thorstenstein ] 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 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 is 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 put 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 [indiscernible] 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. Jord, we thank you for your leadership in multiple clinical trials and 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. And 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. So our thanks to all of you.