Hello, and welcome to today's webcast with AlzeCure Pharma. With us presenting today is Professor Zetterberg and Martin Jönsson and Johan Sandin from AlzeCure Pharma. After the presentation, there will be a Q&A, so if you have any questions, you can send them in via the form to the right. And with that said, I hand over the word to you, Martin. Thank you so much, Ludwig. So welcome to today's session on Alzheimer's, and we have the pleasure to have Professor Zetterberg, a distinguished Alzheimer's person, who is well known all over the world for his expertise in Alzheimer's and biomarkers. He is active at the University of Gothenburg and also at University College London, UK. And then we also have the pleasure to have our AlzeCure’s CSO, Chief Scientific Officer, Johan Sandin, PhD, and also co-founder of AlzeCure. And then you have me, Martin Jönsson, who is the CEO of AlzeCure. The agenda we have for today's meeting is that we will look at Alzheimer's disease and amyloid hypothesis, where we stand today, and how the knowledge around the amyloid hypothesis has developed with the new evidence that has emerged. Then we will also look at Alzstatin, AlzeCure's small molecule, disease-modifying therapy against Alzheimer's, which is a so-called gamma-secretase modulator. Then we will also learn more about AlzeCure as a company and our pipeline. Then in the end, we will have a Q&A, where we will take questions from you as an audience. So please send in questions. If we begin to look at AlzeCure and just give a company overview and look at our pipeline. AlzeCure is focusing on Alzheimer's disease and pain, and we are a spin-out out of AstraZeneca. So the company was created when AstraZeneca left the CNS and Alzheimer's space. And we were initially funded from the Swedish Alzheimer's Fund, so a big thanks to the Swedish Alzheimer's Fund for all the funding we have had. Today, we are active at Karolinska Institutet, where we also started our activities. We have three project platforms with small molecule candidates with first-in-class properties. We have Alzstatin, which is an innovative, preventive, and disease-modifying treatment against Alzheimer's disease, which we will look at very much today. Then we also have NeuroRestore, which is a novel symptomatic treatment for cognitive disorders, where we are focusing on Alzheimer's disease and where we now also have data showing that NeuroRestore is potentially neuroprotective and also disease-modifying. Then we have the platform of the pain project. As a company, we are listed at Nasdaq First North Premier Growth Market in Sweden, which we have been since 2018. If we look at our pipeline of small molecule program, it looks like the following: We have NeuroRestore, which is, with our lead candidate, ACD-856, which is a positive allosteric modulator, upregulating NGF and BDNF signaling, where we are focusing on Alzheimer's disease. Here we have had positive phase I data, showing safety, tolerability, and target engagement, and where we are preparing for phase II. In Alzstatin, we have two programs, ACD-679 and ACD-680, both gamma-secretase modulators, and here we have both programs in preclinical phase. Last year, we selected a new additional ACD, ACD-680. Here we are now looking at what, which of the programs we will go ahead and bring into phase I. Of course, the new molecule can be beneficial with a better, even better, patent situation. Then we have our pain platform with two programs, ACD440, a novel TRPV1 antagonist against neuropathic pain. Here we last year had a positive readout in a phase IIa showing proof of mechanism with safety tolerability and efficacy on pain. Then we also have ACD137, which is TrkA NAM, a negative allosteric modulator, downregulating NGF signaling. Here we about three weeks ago showed ACD137, which we now are preparing, working on in preclinical phase, preparing for phase I. What's so nice when it comes to the Alzheimer's space is that we since the last 18 months really have seen positive progress. Of course, we have seen scientific validation, which we will talk about today, showing what the positive, positive benefits of reducing the amyloid load and also having positive phase III and approvals. And what we are now also are seeing is increased investment in this field with additional big pharma companies entering or re-entering the field, such as Bristol Myers Squibb, MSD, and AstraZeneca. And we also see more funds investing in the field of Alzheimer's. But still, if we have this positive development, we still do not have any curative treatment or cognitively effective cognitive-enhancing treatments, and this is what we at AlzeCure really would like to change. If we look at the antibodies today, based on current published data, we know that only about 5%-8% of the patients who come to the clinic is eligible for antibody treatment, and this really show the huge unmet need that still remains with all the patient that's out there. The way we are focusing on this from AlzeCure's point of view is that we have our two Alzheimer's platform. So Alzstatin, targeting amyloid production to reduce the production of the toxic amyloid Aβ42, and then also having NeuroRestore, Trk PAM, positive allosteric modulator, upregulating BDNF and NGF signaling. What's great here is that both our programs are being validated by, for instance, Roche and Eisai. Roche having a gamma-secretase modulator, and then we have Eisai having a TrkA PAM, which we will come back to. And if we begin to look at NeuroRestore, where we developed NeuroRestore to improve learning and memory capabilities, which now is in preparation for phase two. This program, NeuroRestore, our TrkA PAMs, are focusing on the neurotrophins, BDNF and NGF signaling, which we know are key in Alzheimer's. We know that these neurotrophins are key for brain health and cognition, and that when BDNF and NGF signaling are decreased, we also see negative effects with regard to cholinergic function and synaptic plasticity, and also that loss of NGF-dependent cholinergic neurons correlates with cognitive decline. We can also see that certain genetics, like, for instance, BDNF Val66Met polymorphism, where you see a lower levels of BDNF, are leading to a more rapid cognitive impairment and increased disease progression. And that's why we are focusing on these neurotrophins, since we know that reduced BDNF or NGF levels could limit the brain's ability to withstand pathological conditions. And if we look at NeuroRestore, which is a positive allosteric modulator, which is increasing the NGF and BDNF signaling, we initially focused on developing it as a symptomatic treatment with long-term benefits. What we have seen and generated data on and published on last year is also that we see the potential also for disease-modifying effects, where we have seen that NeuroRestore is improving neural proliferation, neuroprotection, stimulate neurite outgrowth, improve synaptic plasticity as measured by SNAP25, and also improves mitochondrial function. The preclinical data that suggests disease-modifying effect is that we see this neurite outgrowth in PC12 cells, which is with concentration similar to what is found in CSF in our SAD/MAD study. We also see increased level of synaptic markers in PC12 cells. We also see increased proliferation of Trk receptors. We see improved mitochondrial function and neuroprotection. We also see enhanced synaptic plasticity in the hippocampus, and we have also been able to demonstrate long-term plasticity effects after repeated dosings. So this data is really supporting also the potential with the NeuroRestore as a disease modifier. And our data is also validated by external parties like Eisai. Eisai has a TrkA PAM, E2511, and they have published data and also are stating that they see this TrkA PAM as a potential disease-modifying therapy against neurodegenerative diseases in general. So this data is also helping us at AlzeCure in increasing the interest in NeuroRestore. If we compare Eisai's compound E2511, which is a TrkA PAM, which is increasing NGF signaling, and then compare it to NeuroRestore, ACD856, our clinical candidate, we see that there is truly a difference. We can see that both compounds are showing signs of improving or showing potential disease modification. But what we also have with our compound, which we think is due to that we also increase BDNF signaling, is that we see a cognitive enhancement, and we also see an antidepressant and long-term effects, and also this when we add it to a SSRI. So this compound don't only have the opportunity in cognition, but also in depression. And if we look at ACD-856, we see that it can improve the ability to learn, to store, and remember, and this has been shown in a cognitive test in preclinical, where we have had young mice equivalent to age of 25 and old mice equivalent to 75, 80. We gave them one dose of ACD-856. We performed a memory test, and then we measured cognition. When we looked at cognition after 11 days, we saw that the old mice who had not received ACD-856 had more or less forgotten everything, while the young mice remembered everything, and this was also the case for the old mice who had received ACD-856. We have done a phase 1 study, where we have shown that the compound ACD-856 is safe and well-tolerated, excellent PK profile, which shows it is suitable for once daily with a half-life of 20 hours. We also see that it goes over the blood-brain barrier more than 37%. We also see a central target engagement as measured by quantitative EEG, where we show that we activate areas in the brain, which both are central in cognition, but also central with regard to antidepressant treatments. Now, this candidate, ACD856, is being prepared for phase 2. With this, I'm going to hand over to Professor Zetterberg, who will present to us on where we stand with regard to amyloid. So Henrik, please. Thank you very much. Good. Yeah, it's my pleasure to speak to you in this webinar, and I will talk about my favorite topic, recent developments in Alzheimer's disease, biomarkers and the therapeutic landscape. It's been such an exciting last few years in this field. Yeah, it will be interesting to go through this with you and also very happy to take questions during the Q&A session. If you start with the neuropathology of Alzheimer's disease, you all know that there are three neuropathological hallmarks characterized by amyloid plaque pathology, neurodegeneration, and tau tangles, and this has been known for a long time. But thanks to genetic evidence and biochemical data, the amyloid cascade hypothesis on Alzheimer's disease has been formulated. This is a relatively early version of the cascade hypothesis. It is a little bit modified, but you see that beta amyloid aggregation into plaques plays a key role in this process, and then tau pathology and neurodegeneration are downstream in this simplified cascade. The hypothesis is supported by genetic data in families with Alzheimer's disease and also by biochemical data indicating that oligomerized or fibrillized beta amyloid really can cause synaptotoxicity in cultured cells. And there are a lot of other evidence that supports this. It has been criticized because there are so many other changes in the brain tissue of Alzheimer's disease patients, and this is one of the more complicated picture on what's going on in an Alzheimer's disease brain. Amyloid is still a central player, but you see that there, in addition to tau pathology, there are also cellular imbalances, inflammation, mitochondrial dysfunction, a lot of evidence of neuronal cell cycle re-entry, and a lot of things that could contribute to the neural loss in Alzheimer's disease. But if one would summarize this, I think most researchers now, especially after the positive results on the anti-amyloid antibodies, would agree that Alzheimer's disease, the key trigger is amyloid pathology, but with a lot of susceptibilities in individual patients that might play in. Risk factors include high age. This is the key risk factor, but we all want to get old, so that's not anything you would like to do anything against. We have the genetics, of course, in sporadic Alzheimer's disease, the APOE ε4 allele is a really strong susceptibility gene, with each allele contributing an approximately 10 years earlier onset of amyloid deposition. And if you look at the... So basically, you get Alzheimer's disease earlier with this susceptibility gene. And it seems actually to be related to onset of amyloid aggregation in the brain tissue, although there might also be something in relation to the interplay between amyloid and tau pathology and neurodegeneration also. Then there are indications that some comorbidities and lifestyle-related factors might increase the risk for Alzheimer's dementia. I will come back to this very shortly, or I'll come back to it right away, actually. These are Swedish newspaper pieces on different ways through which you can escape Alzheimer's disease. So eat more fruit, escape Alzheimer's. If you eat Mediterranean food, you can also diminish the risk of getting demented. If you eat fast food, a lot of hamburgers, then you get increased, increased risk of Alzheimer's. If you do a lot of barbecuing, that increases the risk of Alzheimer's. Curcumin is good for the memory. If you eat chocolate, you can also reduce the risk of dementia. And I will continue now without translating this, and those of you who live in other parts of the world will recognize this from your general media. In Sweden, we drink a lot of coffee, and that's apparently good against Alzheimer's disease. If you drink juice, you reduce your risk of dementia. B vitamins are good against dementia. If you brush your teeth, that is also reducing the risk of dementia. If you do crosswords, it's the same thing. You can walk a lot and drastically reduce your risk of Alzheimer's. If you have many kids, you have increased risk of Alzheimer's. If you sleep badly, especially if you're a neurotic person, you also have an increased risk of Alzheimer's. If you live close to big electrical cords, that's not good for the brain, and if you live in polluted areas, that's also contributing to dementia risk. It continues like this. Sauna is good against Alzheimer's in the Scandinavian countries. With this, I would like to just reflect that many of the risk factors associated with increased risk of Alzheimer's disease are most likely confounded results from poorly designed studies, and it really looks like we need drugs against this disease. We can't just change our lifestyle in this confusing manner that one would have to do if one were to follow all these general advice for the public. So we need drugs, and we know a lot about the genetics and the pathophysiological process of Alzheimer's disease. AD pathology can be identified using biomarkers. So here is an amyloid PET scan showing, no, actually, this is both amyloid PET and also tau scans showing Alzheimer's disease in the brain tissue. And we can also measure Alzheimer's disease in cerebrospinal fluid samples, and now, since the last few years, reliably in blood. And blood tau and a beta levels can actually substitute. They can essentially replace the need for CSF diagnostics. So in terms of detecting, Alzheimer's neuropathology, we are in a very good place with very simple and easy biomarkers that can be done in regular blood samples. And then in some cases, we need to verify the results with CSF or PET imaging studies. There have been a new framework on how to diagnose Alzheimer's disease, which is based on the biomarkers, basically. And this is being revised as we speak here. The new framework will be released during the spring. But the centerpiece here is that you can have Alzheimer's disease in a preclinical, mildly symptomatic, moderately symptomatic, and severe stage, as long as you have biomarker evidence for amyloid pathology and eventually tau pathology and neurodegeneration. And then it has also turned out that approximately 30% of cognitively impaired elderly have brain amyloidosis, according to biomarker studies. If you follow them longitudinally, they will have a very high risk of developing Alzheimer's disease. So if you're 70 years old, cognitively intact, with positive biomarkers for Alzheimer's disease, the positive predictive value for getting Alzheimer's disease dementia within 10 years is around 96%, so it's a very high number. So it really looks like amyloid is a very important pathology in the brain, and it really is strongly, strongly associated with Alzheimer's disease. Also in cognitively impaired individuals, if they live long enough to have the time to develop the cognitive impairment. If we traditionally would have looked at clinical diagnosis of Alzheimer's disease and compared it with the reference standard of neuropathology, we would see that around 30% of Alzheimer's patients do not have the pathology, but a clinical phenotype that might resemble Alzheimer's disease. And this has likely contributed to some of the confounded results in regards to lifestyle and Alzheimer's disease, and also to some of the early negative studies on drugs that actually look quite promising now. And these patients most likely have other pathological changes, like hippocampus sclerosis or TDP-43-related disease called LATE, and so there are lots... and of course, cerebral vascular disease. But if one is interested in Alzheimer's disease, it's important to verify that there is amyloid in the brain, and that can now easily be done with a blood test. If we then look again at the risk factors for Alzheimer's disease, the epidemiological studies have not been based on biomarkers. And if one instead uses biomarkers to classify people and look what are the risk factors for amyloid pathology, none of the lifestyle-related factors show up. Instead, it looks like age and APOE epsilon four are the strongest predictors for who will get and who won't get Alzheimer's. With this, I should clarify that I don't mean that lifestyle is not important. It's not super important, according to me, but it might determine a little bit on how well your brain resists amyloid pathology. And this could also play into what Martin talked about earlier, about neurotrophins and other things that could help the brain maintaining its function, also in the presence of some pathological changes, which is super interesting. But I think one needs, also something stronger than a walk in the park to enhance, enhance those, processes. So again, I'm very much for that we need, we need drugs to, to, to help the brain, both in the presence of Alzheimer's disease with amyloid pathology, and also if you have other age-related brain changes. Drug treatment of Alzheimer's disease, we have approved drugs, but they are symptomatic drugs, and they work so that they improve basically the levels of acetylcholine in the brain, which is a neurotransmitter, but also a molecule that could help with brain cerebral blood flow and such things. And these drugs typically gives a bit of a cognitive improvement in most patients, but it's transient, and it's not dramatic either. So if you have Alzheimer's, a patient with Alzheimer's disease now in Sweden and elsewhere, you will treat them with these types of symptomatic drugs. Or for such drugs, and there are no magic pills, but they are not bad and should be tested, of course, but they don't slow down the disease process. So we have the symptomatic drugs, the cognitive enhancers. But now we also know a lot about how beta-amyloid is formed, and we know that it comes from an amyloid precursor protein, which is a type I transmembrane protein, highly expressed in neurons, and it's cleaved by different enzymes, and then eventually we get the release of beta-amyloid. And if you look carefully on this sketch, you will see that this beta-amyloid peptide sits in the phospholipid bilayer, and it's very hydrophobic in its C terminus. And the longer the C terminus, the more sticky the protein is, and this is most likely the basis for why some of us will age with aggregating amyloid in the brain tissue. Then, amyloid plaques eventually will form in the brain tissue, and this will disturb cognitive function, neuronal function, and give you cognitive symptoms in the end. These oligomers are small aggregates of beta-amyloid, which likely precede the plaques, and the plaques are likely surrounded by a halo of these oligomers, and they can bind to synapses. They can also activate microglia and astrocytes in a way which is synaptotoxic, and then eventually get tau phosphorylation and tangle pathology, and some inflammation and other things happening in the brain. One idea was that one would inhibit the production of beta-amyloid, and this was an old idea that came from the identification of the gamma-secretase complex as a key enzyme releasing amyloid from neurons. And the gamma-secretase inhibitor was developed and tested in mice, Semagacestat. And then, with acute treatment, one could really reduce the amyloid pathology. And one could also reduce the area of the amyloid plaques in the brain tissue over longer times of treatment also. So it really looked like gamma-secretase inhibition worked, but there were side effects, and these were actually seen in quite large studies where it was proven that Semagacestat didn't do anything good to cognition, but caused side effects, most likely because gamma-secretase also cleaves a lot of other proteins. But this was an inhibitor of gamma-secretase activity. I will come back to the relevance of this a little bit later. So this was stopped. Then eventually, the other enzyme responsible for producing beta-amyloid from the amyloid precursor protein is BACE1. BACE1 knockout mice look very good, at least the initial studies. Then the idea was to hit BACE1 hard and reduce amyloid production, thereby preventing Alzheimer's disease. The drugs worked to reduce both the beta 40 and 42 levels, dose-dependently. But in symptomatic clinical trials, they failed to give any cognitive benefit. Eventually, it was shown in different competing phase III clinical trials that the inhibition actually caused a little bit of a cognitive impairment that was dose dependent. It was reversible, but it was still not doing what one would have expected. So there is a lack of clinical effect, or there were side effects among the different approaches to, to inhibit beta-amyloid production by gamma-secretase and beta-secretase inhibition. There are still then options available, and they are in need of further study, and this here, Alzstatin comes in very good. Gamma-secretase modulation, that is not to inhibit gamma-secretase, but to modulate the function of gamma-secretase to produce less of the longer forms and more of the shorter forms without inhibiting other gamma-secretase dependent signaling, could really be something that could potentially be a primary prevention therapy against onset of amyloid pathology. One could also think about this approach as something one would initiate in parallel with or after brain clearance of amyloid by anti-amyloid antibodies. The other one is, of course, to continue to look at BACE1 inhibition, but not inhibit by 70%-90%, but perhaps inhibit it a little bit. If we look at the Icelandic mutation, which is a protective mutation against Alzheimer's disease, the effect of that mutation, which sits close to the beta-secretase, the BACE1 site in APP, is a 30% lowering of beta amyloid production, and that could give a lifelong protection against Alzheimer's disease. So both these options are really viable. I'm so happy that AlzeCure are doing this work, and that also the other companies that were mentioned in Martin's talk are looking into this. Because this could, from my point of view, be a little bit like a, and the name indicates that also, like a statin. If you think about the cholesterol-lowering treatments, something that would prevent from future myocardial infarctions, one could think about gamma-secretase modulation as something you could start when you are in mid-life and actually prevent you from getting onset of amyloid build-up, potentially. So that's extremely exciting. But then, of course, the drugs have to be very, very safe. And so, but with the modulation aspect and not inhibition, there is a good chance that that might work. Both these approaches have strong support from genetics as primary prevention strategies against amyloid build-up in the brain and Alzheimer's disease, and also as secondary prevention if one has removed the amyloid with antibodies. Here I just would like to now recapitulate a little bit what was seen in anti-amyloid antibody trials. This is gantenerumab, which was a monoclonal antibody against amyloid that really could remove amyloid pathology relatively well from the brain. But in this relatively early study, there was no cognitive benefit. So it really proved that anti-amyloid antibodies, given intravenously, can reduce plaque pathology in Alzheimer's patients. Then the cognitive benefit basically didn't appear for this particular drug. Then we have aducanumab that dramatically reduced the beta plaque loads. And as you know, here, this is what it looks like, a dose-dependent decrease in amyloid plaque pathology as determined by PET, comparing baseline and week 54 data. So again, the approach of removing amyloid with an anti-amyloid antibody really was validated here. Then eventually, this was given a breakthrough approval by FDA because of the link between amyloid pathology and, and, Alzheimer's disease dementia. It was reason that it's a clinic- it's a likely potential clinical benefit in the future. So this was accepted. As you know, it became very controversial, though. But then you also know that BioArctic produced this lecanemab. BAN 2401 was the first name, and this was renamed to lecanemab and co-developed by Eisai and Biogen. And now, this has been shown to give a clear amyloid removal coupled with a clinically meaningful benefit of slowing of disease progression, progression. So one could say that there is a difference during 18 months of around 30% slowing in the active arm. And there are some interesting data also, if you look at subgroup analysis, but that's of course scientifically less strong. But if one looks at people who are very early on in the Alzheimer continuum, the effect might be stronger. But that's, that needs to be proven also in future studies. So here we have the now a clear... If one looks at all the different trials that have been concluded, a pattern is emerging, that if an antibody can remove amyloid relatively quickly and a lot, then there is there is clinically meaningful benefit to the active arm. So this has now, as you all know, underwent the traditional approval by FDA, so lecanemab is now fully approved in the U.S. This is a synthesis of the literature by Eric Karran and Bart De Strooper that, to me, was really... I really thought that this was an interesting article to read, actually. Basically, it looks like one has to remove around 80% of the amyloid during 12-18 months in order for the drug to have the possibility of having a clinically meaningful effect. The drugs that have failed in regards to clinical outcomes have been a little bit slower. The downside, of course, is that giving anti-amyloid antibodies can give side effects, and the most well-known side effect is ARIA, amyloid-related imaging abnormalities. ARIA can be symptomatic, with headache, and basically brain inflammation, and that often happens during the first months of the treatment. So removing fast could also give a higher risk of ARIA, but one could potentially mitigate that in different ways. But removing slowly will not give the brain time to recover in the same way. So it's a balance, but I think we are starting to know how this works now, which I think is super positive to the field. But there are many other drugs in the pipeline also. This is a classical pie chart developed by Jeff Cummings, who is following this field carefully. Here is a reference that you could read if you're interested in it. In the center piece of this circle with different pie segments here, you see the drugs that are in phase 3. And many of them are also looking into neuroplasticity and other types of effects that might be related to, but not solely focused on amyloid. There are some tau approaches of the treatments on the way also. So it's a very exciting field, very many interesting results coming up. Good biomarkers with which you can objectively evaluate the clinical trials, which I think will be important, and also better ways to include the right patients for a certain drug target. There are problems with antibody-based removal of established amyloid pathology, and I talked about them before. We have ARIA. They are expensive. You have to give them also intravenously every second week or a little bit less often. Neural network damage may have already occurred-... And here we come, here we also have to think about neurorestorative treatments, of course. If you have removed the amyloid and you want to restore something, then it might be important to give something that helps with brain plasticity. Tau pathology might have taken off. There is a worry. I think it's a worry. It's a little bit scary, the idea that amyloid triggers tau, and that tau then could get independent in terms of disease progression. But it could also be that some of the tau effects that are not completely reversed by in the anti-amyloid treatment might become more visible if the treatments go on for longer or if they are initiated earlier. The gamma-secretase modulation case, it's one of my favorite approaches, I have to say, but that's that is because of this fact that we know so much about gamma-secretase, and we know that it cleaves sequentially along the APP molecule, releasing... And if it's very active gamma-secretase, it will chop down the amyloid into water-soluble pieces that will never aggregate in the brain tissue. And the longer forms are the more problematic ones, and the ones that tend to accumulate in the brain. And this is not a new concept. This paper is from 2013, and there are more in the literature, there are many more in the literature. And it looks like Aβ38, for example, a water-soluble form of beta-amyloid could even be a bit neuroprotective or have good effects. If you add Aβ 38 to Aβ 42, when you do Aβ 42 fibrillation kinetics in vitro, then you can inhibit Aβ 42 aggregation. So this balance, if we just modulate gamma-secretase a little bit without inhibiting it, to me, it feels like that could be a safe way of preventing onset of the amyloid cascade. There are many different biomarkers for Alzheimer's disease, and I will just very quickly state that this is possible to do now in also in with very simple tests. So we have CSF tests for amyloid pathology. We have PET test for amyloid pathology. There is a blood test for Aβ 42/40 ratio, which works relatively well. Then we can look at phosphorylated tau forms. The way we look at phosphorylated tau is that it's a biomarker that reflects an amyloid effect on neurons, leading to increased phosphorylation of and secretion of phosphorylated tau. Then we can also measure astrocytic activation in CSF and plasma by glial fibrillary acidic protein, and there is a possibility of measuring the blood-brain barrier function, which could be relevant for Alzheimer's disease, by measuring Alzheimer's disease-related side effects of the anti-amyloid treatments, the ARIA treatments, which most likely happens in the neurovascular unit, by measuring soluble PDGF receptor beta. GFAP could also be a potential marker for that, since the astrocytic end feet extend into the neurovascular unit. Then we have a general neurodegeneration marker called neurofilament light. We have neurogranin, and we have different ways of monitoring also presynaptic health. So the synaptic markers are really interesting also in terms of looking at, protective effects of, anti-amyloid treatment, but also of neurorestorative treatments. The plasma beta ratio is working really well in CSF, in the B panel. It works less well in blood because of peripheral beta amyloid, which is not affected by the pathology in blood, but there are group level differences. But the group level differences are so small, so we don't think that this test will make it into clinical practice, at least not broad scale or in a very... It will not be a very general test because you have to keep it very stringent to work in the plasma. This just illustrates it further. In the leftmost panel, you see how close the amyloid PET positive and negative groups are if you look at the plasma beta-42 ratio and how much better the separation is if you look into CSF. That plasma phospho-tau comes as a savior here for us in the lab, because phosphorylated tau reflects amyloid. So if you have amyloid pathology, neurons will phosphorylate and secrete tau, and you get an increased level of phospho-tau in both CSF and blood. This has been validated in neuropathological studies and across different cohorts, where you see a dose-dependent increase. The more amyloid pathology, the higher plasma phospho-tau levels. This has been seen across cohorts in other neurodegenerative diseases without amyloid. For example, in this slide, progressive supranuclear palsy and other disease groups to the right in the, in the upper middle panel, you see that there is no increase in phospho-tau. So we have really good ways of monitoring, Alzheimer's disease in the blood. Here is another study looking at different phospho forms of tau, and the most popular form is tau phosphorylated at amino acid 217, for which there are several really good assays now. And the marker starts to increase at the tiniest amount of amyloid pathology in the brain, according to PET, and then it, it increases stepwise further, the more advanced the disease is. And actually, phospho-tau 217 works as well as the CSF test. So we now start to enter a phase in this type of research where we actually could get molecular information on brain changes in simple blood tests, which will make it very easy for the study participants. This also shows that if we compare different biomarkers, phosphorylated tau at amino acid 217 comes out as the top marker. So we think that this will be available in clinical practice. We are setting it up here in Gothenburg as we speak, and we think there could be potentially two cut points above. If you have above a certain level, you have almost 100% certainty that there is Alzheimer's disease in the brain. And if you have a level below a certain cut point, you will not have Alzheimer's disease, basically. Then we could have an intermediate probability zone, where you could do a CSF test or a PET scan if you don't feel completely convinced on what's going on in the brain, if we are focused on Alzheimer's disease. Neurofilament light can work to detect general neurodegeneration. From a clinical chemistry standpoint, it's nice to have this type of alternative biomarker, because if you think that you are working in a memory clinic, you would like to know if there is neurodegenerative disease, then neurofilament light could tell you that. It works in plasma. If it's Alzheimer's disease, phosphorylated tau 217 could help with that. With that, you come a far way in. That's actually really, it, it's a nice combo of these two types of simple blood biomarkers. GFAP is an astrocytic activation marker that has turned out to be very reactive to amyloid pathologies. We don't know the mechanisms directly, but it looks like amyloid will be giving you an astrocytic activation that immediately is seen also in plasma by increased GFAP levels. And now we can do this in blood spots by fingerprint testing. So this is work led by Nick Ashton here in Gothenburg, where we evaluated different ways of collecting live plasma. And we can see that the biomarkers that we measure in regular venous samples can also be measured in these simple finger prick tests that can be collected using these types of devices. If you look to the lower right, you see how nice the correlation is for phospho-tau 217 in a home-collected blood drop that you can put on this device and then keep at room temperature and post to the lab. We also now know that the anti-amyloid antibody treatments lower phospho-tau levels. So phospho-tau levels can also be used to monitor treatment response in anti-amyloid treatments. So if we sum up the blood biomarkers to diagnosis, we have the amyloid marker, which is then passed maybe up to 240 or phospho-tau. And then I am much more for phospho-tau because the fold change in amyloid positive people are compared with negative people is much greater. And then we have the tau pathophysiology, which, to some extent, also could be monitored by plasma phospho-tau. But then it's more like a predictive marker of tangle pathology and a direct marker of an amyloid-induced tau disruption in the neurons. And neurofilament light works then to detect neurodegeneration across neurodegenerative diseases. Glial activation and inflammation, the plasma GFAP, and other inflammatory proteins. And then the vascular component of Alzheimer's disease and regular small vessel disease could potentially be monitored by a new biomarker discovered by the MarkVCID Consortium in the U.S. A very interesting protein called placental growth factor, for which there are also many interesting proteins. The therapeutic landscape, if we just return to that, we have antibody-based removal of existing amyloid pathology. This is clinically meaningful. No one would, very few would question that now, but there are side effects, and it's an expensive drug. When should one stop with the drug? Gamma-secretase modulation, to put this into context, could be a safe primary prevention strategy in high-risk individuals. For example, if I know that there is Alzheimer's in my family, I could consider when these treatments have been approved to start to take a gamma-secretase modulator when I'm 40 or 45. So before I am amyloid positive, according to the biomarkers. Potentially one could combine this with a polygenic risk score test, or if one just would focus on APOE ε4. And if you're a positive or a high-risk individual, one could then consider to do this type of treatment. Well, one, of course, would need to evaluate the gamma-secretase modulators also to check if they could prevent from symptom progression in or also early symptomatic amyloid pathology. One favorite thing is also if this would be a potential way through which one could follow up the amyloid clearing therapies with the antibodies, with the gamma-secretase modulation to prevent the disease from recurring, which is what I put in this last bullet point. The nice thing is that accessible biomarkers exist for all of the Alzheimer's continuum. So when it's very relatively, I shouldn't say easy, but one can now design trials of novel drugs depending on what hypothesis you would like to test for a drug. One could measure the effects quite reliably with relatively accessible biomarkers, I would say. With this, I would like to stop and thank you for the attention. I'm very happy to the questions during the Q&A. Thank you very much. Many thanks, Henrik, for this excellent overview of the Alzheimer and amyloid. It was really educational. My, my name is Johan Sandin, and I'm a CSO at AlzeCure, and I'm going to talk about Alzstatin, which is our small molecule disease-modifying therapy against Alzheimer's disease. Now, the Alzstatin program emanates from Big Pharma AstraZeneca, where we were part of the conception of the project at the time, and there's substantial investment that was already made into the program when we took this program over. The target here is the gamma-secretase, as we heard Henrik talk about earlier on, which is certainly a key enzyme producing A-beta. We also heard about this, this strong genetic linkage to disease, where the majority of all familial mutations are actually linked to the gamma-secretase complex, causing an early onset of disease. We have two drug candidates, ACD679 and ACD680, which are both in preclinical development phase, so we are currently conducting the safety and toxicology packages before moving into clinical studies. Both compounds potently reduce Aβ 42 production, and do instead produce these shorter peptides, which are not prone to aggregation. There are also suggested beneficial effects of these, as we heard Henrik mention earlier on. Now, this slide's just showing you the kind of classical amyloid cascade, if you will. Starting with the, with the cleavage and the formation of Aβ monomers, which over time and with the increase in concentration, starts to accumulate into larger and larger, larger aggregates, such as oligomers, protofibrils, fibrils, and eventually these amyloid plaques, which are so characteristic of the disease. Now, with Alzstatin, with the gamma-secretase modulator, we're actually targeting the production of the building block of these various amyloid aggregates to prevent the buildup of various toxic aggregates, such as oligomers and fibrils. And so this is really targeting the key initiation, if you will, of the amyloid cascade. Now, if you look at the right-hand side of the slide, this shows the actual cleavage that Henrik showed on his previous slide as well. How Aβ is cleaved out of the amyloid precursor protein, which is a sequential cleavage by first the beta secretase and then by the gamma secretase, releasing Aβ of various lengths. The aggregation-prone and toxic Aβ42 forming the core of the amyloid aggregates. The gamma secretase modulator, like Alzstatin, they will target the gamma secretase and modulate the cleavage pattern. So instead of forming these longer forms, the 40, 42 amino acid long Aβ peptides, instead forming increased amounts of the shorter fragments, the 37 and 38 amino acid long peptides. So what it, it essentially does is change the ratio between the long aggregation-prone and toxic forms towards the shorter forms, which actually have shown to have also added beneficial effects. So indeed, what it does is actually the reverse of what many familiar mutations do. Now, if we look at the left-hand side, you see the gamma-secretase complex, which actually consists of four different subunits. You have the presenilin, the PEN-2, the nicastrin, and the APH-1. And here we can also see the interaction sites that various drugs bind to. You have the gamma-secretase inhibitors, which bind to the active site and blocks the activity of the enzyme. And then you have also allosteric sites, which, again, modulate the enzyme's activity more specifically. And with Alzstatin, we bind to the classical imidazole gamma-secretase modulator allosteric site. Now, just to reiterate, obviously, the A-beta 42 peptide being and forming the kind of core of these amyloid aggregates being a really aggregation-prone peptide. The gamma-secretase modulators reduce the A-beta 42 and 40 and shift this towards shorter forms of A-beta, the 37- and 38-amino acid long peptides, which are not prone to aggregation, and as we heard earlier, can exhibit protective properties. Now, the Alzstatin compounds have been tested in vivo, in animals, and we've been able to show even after a single dose, that we get potent and dose-dependent reduction of the amount of toxic brain A-beta 42, as you can see here, with more than 60% reduction. It also behaves as a classical gamma-secretase modulator. It reduces the amount of the aggregation-prone A-beta 42 and 40, shown here in black and blue, and at the same time, it increases the amount of the protective 38 and 37 species. In fact, if you look at the total amount of Aβ, it doesn't change. So it just changes the ratio. It also has the benefit, if Aβ does have a physiological role in the brain, it's less likely to affect that, given that we're not affecting the total amount of Aβ, but just changing the ratios. Now, I think this, as Henrik pointed out earlier on, it's really important to notice the difference between the gamma-secretase inhibitors and the modulators, because it's really a different mechanism of action. And, as Henrik showed earlier on, the gamma-secretase inhibitors were really the first on the stage. The intent here was obviously to block enzyme activity and then block the production of Aβ. Now, it's since been known that gamma-secretase has some 100 different substrates, some of which, like Notch, plays a really important function in normal cell function. So, in inhibiting that cleavage is obviously of major importance. So, the clinical study showed major side effects with inhibiting the enzyme, so this was not a really good strategy forward. The next thing that the industry went for was BACE inhibition. We also heard there, BACE also has multiple different substrates. So again, inhibiting the enzyme will also affect the metabolism of these other substrates. Inhibition was clearly not the best way forward, and therefore, this idea about modulation came about, where the idea was to rather specifically try to modulate how the enzyme cleaves, specifically A-beta, and not inhibiting other gamma-secretase-related substrates, such as Notch. And here, you can see down to the right, that our compounds do not touch other gamma-secretase substrates such as Notch, but it's specific for A-beta. So it's clearly a much safer mechanism of action than an inhibitor. We also did a collaboration with Washington University, looking specifically at the effect of statin compounds in the brain of an established mouse AD model. Here you can see that the compound induces a rapid and long-term decrease of Aβ40, 42, here shown in blue, with about 80% reduction shown here and over quite a substantial time after a single dose. At the same time, as shown here to the graph to the right, you can see that it increases the shorter fragments, the Aβ37 peptide. We also did conduct a two-photon microscopy study, where you're able to actually monitor the appearance and growth of amyloid aggregates, such as plaques, in the living tissue, in the brain of living animals. This is also a mouse AD model called APP/PS1. Here we saw that 1-month treatment with a gamma-secretase modulator it attenuated a further plaque growth and actually decreased the appearance of new plaques and also induced a plaque regression. This is coming back to what Henrik mentioned earlier on with potential beneficial effects of these shorter Aβ peptides that are produced after gamma-secretase modulation. There are both clinical data showing that patients or populations with higher Aβ 38 levels have a-- seem to have a slower conversion into AD and also have a slower decline in MMSE scores. You have another paper also with Henrik as part of the team behind the publication, showing that indeed, these shorter peptides do seem to inhibit the aggregation of Aβ42, as Henrik mentioned earlier on, and also seems to have effects on important cellular processes, such as long-term potentiation, where again, Aβ38 reverses the kind of toxic effects of Aβ42. So clearly indicating that these shorter fragments do seem to have some neuroprotective properties and beneficial effects. So again, coming back to how does the Alzstatin differ from the antibodies? What are the... what do we see as advantages? Well, this being a small molecule therapy, it passes much more readily across the blood-brain barrier to reach its target site, the brain, than larger molecules such as antibodies. It also provides a more cost-effective treatment for chronic use than biologics do. And it's also suitable, as we heard from Henrik, as a standalone treatment, but also as a combination therapy together with anti-amyloid antibodies. And it's also something that you could take as a pill, as an oral formulation, which allows for home treatment, so you don't need to come into the hospital once or twice a month for infusions. So that's also helpful for this patient population. And we're not expecting to see this kind of side effects, the ARIA effects that we heard Henrik mention earlier on, with this class of drugs. Another stronghold and a strong value driver for the program is that you can establish proof of mechanism and central target engagement already in phase one. So besides looking at safety and tolerability after single and repeated administration, we can also explore the effects on biomarkers, as we heard Henrik mention earlier on, Aβ42/40, to show that we can reduce these Aβ species, and at the same time, we can show an increase of the shorter Aβ37 and Aβ38 peptides. This is a biomarker strategy we've seen previously employed by Pfizer, but also by, recently by Roche. And measurements can be done with existing technologies. And again, as I mentioned, we're not expecting to see the same ARIA side effects as seen with the antibodies. So with regard to the different target populations, and I think this is also something that Henrik talked about, we see this as it could be used as a maintenance therapy in patients with established Alzheimer's disease. So a treatment that you would start with after you've cleared existing plaques, with a monoclonal antibody treatment, so to prevent new buildup of amyloid aggregates in the brain, which was actually the original intent by Lilly, with their BACE inhibitor. You could also imagine this as a combination therapy together with monoclonal antibody treatment to both, prevent, new amyloid from forming and at the same time, clearing existing amyloid, so getting a very rapid effect. And as we heard from Henrik also, in the long term, I think this is obviously really interesting as a potential preventive therapy as well, based on genetic risk factors and biomarkers. And here you could imagine doing a study, for example, in familial forms of the disease, to, to look at its potential preventive effects, as a long-term potential possibility. But as a first step, we would be looking at the maintenance or combination therapies. And obviously, as we heard from Henrik earlier as well, there are well-established biomarkers in the field, and it's, it's currently evolving at a very rapid pace. And it's so much exciting data coming out, where obviously, Henrik has been really in the forefront of this, and it's, it's really exciting to see. So it's, it's certainly, I think, important for the whole field and, and certainly for us as a, as a drug development company as well. To summarize, with Alzstatin, the gamma-secretase modulators in the Alzstatin program decreases Aβ42 production, which also will then reduce the production of various amyloid aggregates, such as oligomers, fibrils, as well as plaques. It increases these shorter peptides, Aβ37 and 38, which are suggested to have beneficial properties. We do not block Notch activity as the inhibitors do, so we thereby spare important physiological signaling, which is certainly key for safety. It's also a genetically supported mechanism. It is its mode of action is the reversal most familial forms of Alzheimer's disease. It's also a small molecule compound, so it allows for oral administration, good CNS exposure, and we can achieve proof of mechanism data already in phase one clinical trials, which is an important value driver for the program. could be used together with other disease-modifying therapies, such as antibodies. It's also got the potential to prevent or slow disease progression, as we heard Henrik mention earlier. So I think this is a really interesting, really interesting program, a really interesting, mechanism of action, as we heard Henrik mention earlier on as well. So with that, I thank you for your attention, and let's then turn to the Q&A session. Thank you so much for the presentation here. We got a couple of questions that I think we should start right ahead with them. The first one is for Professor Zetterberg. What is the role of the amyloid in Alzheimer's disease, and how important is the amyloid in the development of the disease? Let's see. Should I, should I turn on the... There we have the mic. Exactly. Yo! This is a very important question. Amyloid looks, it really looks like amyloid is triggering the disease. So it is. But there is a little bit of a debate on, in regards to if it's also a disease driver, further on. But when new plaques form, it's very clear that surrounding neurons react to the, to the pathology by, phosphorylating and secreting tau. So it's an ongoing process. Everything that happens with, tau in terms of the biomarkers is amyloid dependent. And, so most likely, if one wants to go to the core of the disease, it is amyloid that you need to target. One could also think that there might be ways through which you can prevent amyloid from aggregating, but those, it's a little bit hard to know exactly how to do that, except for changing the stoichiometry of long versus short A-beta. So that's why I am so positive to the gamma-secretase modulation approach. Thank you. Another one for you, Professor. How early can we today predict if somebody's likely to develop Alzheimer's, and how do you expect the future will look like? Yep. That's an exciting question, too, because now the data tell us how this could be in a way that I think is reasonable. So we know, for example, a lot about genetic susceptibility of Alzheimer's disease. That has been quite well established now, also in relation to well-diagnosed patients. So we, there is a possibility now of getting a polygenic risk score for Alzheimer's disease. This is something you are born with, and it will give you your risk from the day you're born until you develop the disease, basically. If I would be very simplistic, it's often enough to look at APOE ε4, actually. It is a big risk, genetic risk factor for the common form of Alzheimer's disease. So if I think a little bit about myself also with some Alzheimer's in the family, I could, in the future, then do a genetic test and get my individual risk, and then I could monitor myself with biomarkers in blood when I go to the general practitioner or whatever type of healthcare system I'm in... and then when the biomarkers start to become abnormal, one could potentially initiate the treatment. With Alzstatin, we even have the possibility of going earlier. This depends on how safe the drug is. It could be that I know that I have family history of Alzheimer's disease, and then perhaps if the drug is very, very safe and not too expensive, perhaps I could start on the treatment and just make sure that I then I could monitor my biomarkers to make sure that the disease doesn't appear in my brain. But this is something that happens in midlife. So this is something which is relevant for the future 45-, 50-year-old people. One could also think about it later in life also, but if you want to do primary prevention and try to not get amyloid plaques growing on your brain, this is the age range, 40-60, 65, where one should look carefully. If it turns out that the drugs are effective when Alzheimer's disease pathology is starting to establish itself in the brain, then it's not that big rush, because then one could look at that at 60, 65, 70. And if it turns out that you can reverse pathology also in symptomatic individuals, perhaps combining it with some type of restoration therapy, then it's also less of a panic. A nice scenario is that established Alzheimer's disease pathology with mild symptoms could be mitigated or dealt with with an anti-amyloid treatment, and then you start with something that could be a window of treatment for 1-2 years, and then you would start on something that would prevent the disease from coming back. So the biomarkers work. Okay, the genetic risk can be detected from birth. The biomarkers will react to onset of pathology that most often happens in middle or late midlife. And then the degree of biomarker abnormality will correlate at least for the phospho biomarkers a little bit with how advanced and intense the disease process is, and that also works later in the disease process. Thank you. What role, what role do you think gamma-secretase modulators could play in the treatment of Alzheimer's? Yeah, I mean, from my point of view, they could play a major, major role as primary prevention treatments. And if they turn out to be safe and not too expensive, then this could really be something that people with some luck, this could be a primary prevention treatment for sure. So it could play a major role. And then we also have this more tangible role of evaluating it as a secondary preventive treatment after removal of amyloid pathology with antibodies. So it's quite interesting because then gamma-secretase modulation could have a role during the full continuum of the long Alzheimer's process. From before you have symptoms, if you know that you have high risk, and through the early symptomatic and symptomatic stages, and also after removal of amyloid pathology. It might also be that gamma-secretase modulation could make the plaques stop growing, which also could be beneficial. You have the plaques you have, but they don't continue to spread in the brain. So I, I think we need some more data on this, but, potentially, this could be major. Thanks. Another one for you, Professor. What are relevant reductions in amyloid levels when using a gamma-secretase modulator? It looks from the in vitro studies that you don't have to modulate that much, actually. Wow. So it looks like if you just change the relative composition of longer versus shorter forms with 30, 40% or so, which is clearly achievable with these compounds, then you really... It's like, then you have tipped the balance so that aggregation will not happen. It's pure biochemistry, actually, but in humans, then it happens in the brain tissue, and we can also do it at the bench. And it really looks like lowering the longer form, increasing the shorter forms, most likely, potentially, this could give you more water-soluble heterodimers that are not aggregating further. That could be enough. And this could also be an explanation for why Alzheimer's disease doesn't start early in people, because we are almost managing to keep Aβ42 in solution throughout life, but we fail in the later stage of life, some of us. And modulating gamma-secretase a little bit to give a different A beta milieu, almost, A beta composition, with a little bit less aggregation-prone and a little bit more aggregation, well, not prone peptides, that or inhibiting peptides, that, that really looks like, that could be the magic we are looking for. Professor Zetterberg, what is your comments to Roche result with their gamma-secretase modulator, RG6289? I haven't looked at the data carefully, but what I've heard, it looks really promising and supportive of the approach. Thank you. Moving on, to the subject Alzstatin a little bit more, and this question is for you, Johan. Mm-hmm. What are the potential advantages and differences of a gamma-secretase modulator versus gamma-secretase inhibitors and versus BACE inhibitors? Yes, as I mentioned earlier on, I think it's a very different mechanism of action in that we don't inhibit the enzyme, and thereby not inhibiting the cleavage of other enzyme-related substrates, such as Notch. So it is certainly a much safer mechanism of action, specifically than targeting the ratio, as we heard Henrik mention earlier on, the ratio between the shorter and the longer forms. That's the major focus of this mechanism of action, and not inhibiting enzyme activity whatsoever. So it's a very different mechanism of action, clearly with a much safer strategy to move on with. Thank you. And this is one for you, Johan, as well. What are the potential advantages and difference of a gamma-secretase modulator versus a antibody? Well, I think that's, that's again, relating to, you have the differences between the small and the large molecules. With a small molecule compound, such as Alzstatin, which have the advantage of being small and actually going through the blood-brain barrier much easier and reaching the target. So that's clearly an advantage. Also, as a- you can take it as a pill, as I mentioned, as an oral treatment, which certainly helps a lot with the patients not needing to get to a hospital. And it's also much more cost-effective to produce. So certainly, I think for... Given that so many people, so many million people are currently living with Alzheimer's disease, there's a huge population that needs to be treated. So a cost-effective treatment, I think, is going to be crucial, to lead, to, to reach a larger population. Obviously, there will always be a niche for, for antibodies. That's, that's clear. But I think, what we'll see more and more is actually combination therapies. We're seeing here now, maybe a, together with gamma secretase modulators and, and an anti-amyloid antibody as a maintenance therapies is, is maybe something we'll see as well. But I think, again, as, as Henrik mentioned, that gamma secretase modulators could also be used at, at a clearly earlier stage, thereby, being able to use as a, as kind of a, across the disease continuum, I think is, is really interesting concept, actually, with the gamma secretase modulators. Thank you. Professor Zetterberg, what is your view on combination therapies, for example, GSMs and AB antibodies, and what ways could they be combined? I think there's a huge potential for this because now we don't really know how to deal with the anti-amyloid antibodies. First of all, they're not approved yet in Europe. That's a problem. But in the U.S., where I also work, of course, patients are getting these treatments now. But no one knows really when to stop. So should one stop when a patient has gone amyloid negative according to PET scans, or should one then reduce the dose and continue to infuse these antibodies, but at a lower dose? Or could one... Because one problem with amyloid diseases is that misfolded proteins have a tendency of coming back. The pathology has a tendency of starting again. One needs to study this scientifically, of course. But removing amyloid with an anti-amyloid antibody, and in the later phase of this treatment, for example, during the last 12-18 months, perhaps starting up on a gamma-secretase modulator and then stopping the antibody and maintaining the patient on an overall anti-aggregation amyloid compound in the form of a GSM, to me, it feels very... I really like that thought, and it makes very much sense to me. So, we need to do those types of studies, I think. Thank you. Potential, I think. Mm-hmm. Thank you. Johan, what patient groups could potentially benefit from a gamma-secretase modulator treatment? I think, as I highlighted, I think the two populations that we would single out as kind of the first way in would be as a maintenance or combination therapy in patients that are being treated with anti-amyloid antibodies, either as a maintenance therapy, so after they've finished their and reached amyloid negativity, so to prevent the buildup of new amyloid, or, and I should say, as a combination therapy together with anti-amyloid antibodies, to prevent both the kind of formation of amyloid and at the same time clearing existing amyloid pathology to maximize the effect of the combination approach. Both of them are clearly ways forward based on what's currently out on the market or on the way to the market. As a long-term possibility, clearly, prevention, as we heard from Henrik, I think is a really exciting possibility. Based on its mechanism of action, this could clearly be a, a very interesting preventive therapy, for the disease. Because again, if you go in as early as you do with the preventive therapy, you don't need to lower A beta that much, 'cause you do it under such a long time, that you would expect that, a low dose of a gamma-secretase modulator would, over time, have a, a very beneficial effect and actually could prevent the disease, from developing. And that would also... I mean, a low dose of a gamma-secretase modulator would also then have, a much even better safety profile because it's so low doses. So I think it's also a very interesting concept. But again, we would start with maintenance and combination therapy. ... Thank you. When would it be optimal to start Alzstatin treatment if biomarkers and infrastructure is in place? I think that's for Henrik. Yeah. Yeah, I think the biomarkers will be in place in most parts of the world within the next few years, actually, through the blood tests. And so I think actually the biomarker side will almost... That will not be a problem, basically. That will be... So now it's about moving these trials forward. That's what I would say. Thank you. Here's a question for you, Martin. Mm-hmm. What is AlzeCure's business development strategy with regard to out-licensing? Sorry. Our strategy is to out-license 1-2 projects to finance our others, and our main strategy is to out-license our pain projects. As you saw earlier in this seminar, we have just had a positive phase 2 data, phase 2a data on TRPV1 antagonist. So that would be very suitable for out-licensing. Then we also have a TrkA-NAM, another pain project, which is also in a good position. So to out-license primarily the pain projects, to finance our Alzheimer's projects, that is our main strategy. Then, of course, we are in dialogue with various companies also on our Alzheimer's programs. So depending on the potential partner and depending on the setup, we are also open to partner or out-license on those. But the thing there is also, we have talked much about the gamma-secretase modulator program, Alzstatin. To drive a project like that isn't very costly. What we are preparing for is a SAD/MAD, and here we also expect to have proof of mechanism with showing how we can lower amyloid load, the production of Aβ40, Aβ42. And to be able to do that, and then really to generate generate that data would be a great value driver, which we are very keen to be able to do ourselves. And we already have done several SAD/MADs in the company, so we know we are very capable of doing that. So to go back to the question, our focus is to out-license our pain projects to drive our Alzheimer's projects. Thank you. Another question for you here, Martin. Mm-hmm. What will validate AlzeCure's gamma-secretase modulator and creates reasons to believe? I think that it's the phase one where we have shown how we can lower the production of Aβ40, Aβ42, and also increase the production of the potential beneficial forms, Aβ30 and 37 and 38. And then, then I think we have, in a good way, validated. But of course, we then later on need to take it into the patients. But also, as Henrik has talked about before, I mean, the patients who can be relevant to treat later on are not the patients who have cognitive deficits, et cetera. It's based on the production of Aβ42 and then also the risk factors. So that's why it's very interesting to define who's the patient and how do we look at this. So that's a very interesting question. But here we also think that the FDA and EMA will be very open to look at the biomarkers, and hopefully based on this, we can use Alzstatin just as a statin, as Henrik talked about before. So, interesting future. Thank you. We have two questions left here regarding NeuroRestore, and the first one is for you, Johan. What is the support of the role of TrkB, BDNF in the cognition? Well, there is plenty of support actually supporting the role of BDNF in cognition. So BDNF plays a really important role in synaptic plasticity in the hippocampus, which is the really important relay station in the brain, handling and putting together a lot of sensory information that the brain receives. So it really is in the key place where cognitive processing is taking place. It's also known that BDNF, for example, in the Val66Met polymorphism, so individuals which have about a 30% decrease in BDNF release, there you see that these individuals, when they do develop Alzheimer's disease, you have a much more rapid cognitive decline. So clearly indicating that this system is crucial for normal cognitive function, but also plays a really important role when it comes to sustaining cognitive function during pathological load. So it's clearly there's very much publications in around the role of BDNF in cognitive processing, in synaptic plasticity as well. Thank you. Moving on to the last question here, Martin, it's for you. How does AlzeCure's TrkA-PAM differ from Eisai's TrkA-PAM? So Eisai, as you say, have a so-called TrkA-PAM, and what that means is that they are increasing the signaling of NGF, and NGF is key to brain health. We also have this with NeuroRestore, but what we also have is we are increasing the signaling of BDNF, working on the TrkB receptor. And BDNF is key for the cognitive functions to improve learning and memory capabilities. And then also, what we have seen from preclinical work is that our molecule can also, as it looks, have an effect on, as an antidepressant. So there are several benefits and differentiation points. Thank you so much. This was the last question I had, so now I will hand over the word to you, Martin, for some concluding remarks. Okay. Thank you, Henrik. Thank you. Closing remarks and take-home messages. First of all, I can say it has been a great session. Thank you so much, Henrik, for taking time and present with us. So take-home messages, what we can say, and as Henrik talked about before, is that early detection of the risk of Alzheimer's can be found very early. And as Henrik said, actually it can be seen already more or less when you're born, based on your risk factors. And then you need to be able to monitor the pathology based on how you increase the production of Aβ 40/42 and other factors. But with this development, we're also seeing a need for new treatments that is aiming to minimize a toxic amyloid load. We can also say that even if we have had antibodies entering the market now in the U.S., in China, and Japan, there is still a huge unmet medical need since we know that it's only about 5%-8% of the Alzheimer's patients today that are eligible for the Alzheimer's treatment as they are indicated currently. And also, that there are still no curative or preventive Alzheimer's treatment approved, so this also signals the huge unmet medical need we have. And also, as we have talked about today, is that gamma-secretase modulator is a new and promising class of Alzheimer's therapies with several different target patient populations. Then on AlzeCure, AlzeCure is a clinical-stage Alzheimer's and CNS company with several novel first-in-class or best-in-class clinical assets. It is AlzeCure's ambition to develop Alzheimer's therapies that both can stop the disease progression of Alzheimer's and improve cognition, so we have a broad ambition. Also, that NeuroRestore ACD856, our clinical candidate, is in preparation for phase II, and it is being developed as a cognitive enhancer with potential neuroprotective and neurodegenerative properties. Neuroprotective properties, I should say. Then, that Alzstatin in our AlzeCure's gamma-secretase modulator program is currently in preclinical phase and is planned to initiate phase I studies in 2025. That we expect to have efficacy and proof of mechanism data could be established already in phase I for our gamma-secretase modulator, which is expected to be a strong value driver for the company. You will be able to download the presentations you have seen today and re-see it if you go in on our homepage. And also, to stay tuned with the development of our programs, please scan the QR code or go to our website and sign up. And then again, a big thank you to Professor Zetterberg, Henrik, and also to Johan, one of the our co-founders, for today's presentation. And thank you as well to taking the time and listening to today's presentation, and have a great day. All the best. Cheers. Bye. Bye.