For joining this afternoon. My name, Neil Warma, CEO of ProMIS Neurosciences. Thanks to the Bloom Burton & Co. folks for the invitation again this year. Great to see the enthusiasm in the crowd, and it's been an interesting year for us. I'll take you through a little bit of the storyline. We're excited. It's been an especially productive few months. ProMIS Neurosciences, I'll go through a bit of an operational update here. Just as a bit of a way to remember us, ProMIS is based on our platform technology, which is based on protein misfolding. A little bit of a play on words, ProMIS. Our founder, Dr. Neil Cashman, is one of the leaders in protein misfolded diseases. We are a publicly listed company, so I'll just remind you to all please look at our SEC filings, just to get a true understanding of our operations. ProMIS is a publicly listed company. We're traded on the Nasdaq Capital Market, ticker is PMN. We are based primarily in Boston and Cambridge, but we do have a Canadian history. As I mentioned, Dr. Neil Cashman, our founder, our CSO, developed this technology, protein misfolding technology, out of the University of British Columbia. Our discovery lab is still in Vancouver, whereas most of us, we're pretty scattered, but when we meet, we meet in Cambridge. We have a strong historical root in Canada. I'm Canadian. I studied up the road at University of Toronto. I have a neuroscience degree, so it's nice to come full circle with the neuroscience platform. I'll touch on a few of the highlights here. The company is a clinical stage company, and I'll spend a few minutes talking through our clinical trial and our clinical candidates. Our platform, I'll come to this in a minute, is really based on our ability to design and create novel, selective antibodies targeting misfolded proteins, and that's really kind of our claim and our differentiating factor as far as the design of our antibodies. Our lead asset is in the clinic. As I said, it's been a big year for us. It will be a huge year moving forward for us in 2026. We have data that reads out in a matter of months in Alzheimer's disease, so we are running a fairly robust Phase I-B clinical study in Alzheimer's patients. As I said, there's an interim analysis coming up in a few months, and then final top-line results will come towards early next year. Significant milestones moving forward this year. I won't really touch on the market expectations around an Alzheimer's product. We know there's a huge unmet medical need. Even though we have a couple of products on the market in Alzheimer's disease, the risk-benefit of those products are pretty poor. We have an outstanding team, in addition to Dr. Neil Cashman, our founder, CSO in Vancouver. Our Chief Medical Officer is a practicing neurologist, Dr. Larry Altstiel. He's treated Alzheimer's patients all of his life, and he ran CNS at Pfizer. Our Chief Development Officer ran CNS at Genzyme. A really quality group of management here. Interestingly, we are just coming off the back of a really important financing. The one box we had not checked was, are we fully funded to data? Now we are. We closed the financing a couple of months ago, up to $175 million, the syndicate that came together was superb. It was led by Ally Bridge and Janus. Wellington participated, Deep Track. Now we're funded through to the end of next year. Cash position is quite favorable. Just touching on the platform a little bit, a lot of the discussion we get around, well, how are we able to design these antibodies that are truly selective to a particular species of protein? It really comes down to the differentiation between our platform and the conventional approach to designing antibodies. Just focusing on ours, it's really the beauty of having the ability to predict how proteins are going to misfold. We know that proteins are manufactured by the cell, and as they come out of the cellular machinery, you remember from your biology days, they're folded upon themselves in the three-dimensional form, this very elegant shape. As they are folded properly, they go on to perform their function. Constantly or continually, these proteins are coming out of the other side of the cell, and they're misfolded or misshapen. Typically, your immune system grabs hold of these misfolded proteins and discards them. As you get older, immune-compromised, sometimes your immune system can't keep up with getting rid of these misfolded proteins. If they're allowed to build up and aggregate, that's when you get many different diseases that are established because of these misfolded proteins. We have the ability to predict how certain proteins are going to misfold, and I won't get into the details. It's a computational approach. We have a chief physics officer in our company, this is an algorithm that we apply, kind of like we were doing AI before AI was cool, to be able to understand how proteins misfold. It's a linear epitope, but it's also a conformational epitope, a three-dimensional epitope to which we design an antibody, and that antibody selectively targets only this conformational epitope, which exists only on the misfolded form of the protein. I'll come back to that in a minute because it's really important in differentiating us from the conventional way of designing antibodies. Because of that, we've built up a pipeline of candidates. Different diseases are driven by different proteins, misfolded proteins. Our target for Alzheimer's is amyloid beta and a well-recognized Alzheimer's target. A-beta protein for Alzheimer's. The candidates coming behind that are misfolded forms of TDP-43 for ALS and misfolded alpha-synuclein for Parkinson's and Lewy body dementia. We've got a really healthy pipeline of highly selective antibodies. I'll touch on the Alzheimer's space since that's where we are in the clinic and that's what the focus is certainly going to be on over the next number of months. Just kind of briefly in the scientific cascade of Alzheimer's disease, there's, as you can imagine, a whole pathway that leads to different pathologies, if you will, all building towards Alzheimer's disease. For us, I'm not sure if there's a laser on this or not. Doesn't really matter. For us, you can see the PMN310 target. Our target, because there's multiple different species of amyloid beta protein, and we're specifically going after kind of this upstream in the cascade, these low molecular weight oligomers. That's our target upstream of plaque, upstream of tau. Our thinking is, and knowing that these oligomers are highly toxic to neurons, that's where our selective antibody is targeted towards only these toxic oligomers that occur upstream in the pathogenesis of Alzheimer's disease. You can see as you move down, as I mentioned, plaques will form through the aggregation of oligomers, which go to form protofibrils, which go to form plaque, and then they trigger the phosphorylation of tau. We believe, given the toxicity of the oligomers and given the upstreamness, if that's a word, that's a relevant target for us, and others certainly believe that as well. Part of the challenge in Alzheimer's, as I mentioned, there's multiple different species of amyloid beta. We, the field, used to think that plaque was driving kind of disease progression in Alzheimer's. You all are familiar, I'm sure, with the buildup of plaque depositions, plaque formation in the brain. That was supposed to be the target. You could image plaque. You could see it. It doesn't look nice. It's got to be harmful. It's got to be driving disease progression. We now know that's not true. There are drugs that completely eliminate plaque, and the patient continues to decline. Plaque is not the target, and I'll come back to plaque in a minute. We know there's the monomers, another form of amyloid beta, but that's a beneficial form of A-beta protein, so you don't want to target that. You've got these toxic oligomers, which now the field is pointing at these upstream toxic oligomers that drive cognitive decline. They're very low concentration versus the plaque and the monomers. The challenge is how do you design an antibody that only hits the top of the pyramid and doesn't cross-react with all forms of amyloid beta? That's the beauty of our platform. As I mentioned, the binding three-dimensional epitope only exists on oligomers. We believe we don't bind plaque, and we certainly don't bind monomers. We've done a ton of studies to pressure test whether or not we're binding plaque. That's one of our claims is we won't bind plaque. The other interesting thing with drugs that bind plaque, which is all of them out there, the two in the market and many in development, because they can't selectively target the oligomers. All drugs that bind and clear plaque are associated with a very serious side effect known as ARIA, A-R-I-A. ARIA essentially is swelling and bleeding on the brain. You can kind of imagine a little bit of an analogy. You've got these kind of plaque deposits in the cerebrovascular structure, and if you bind and kind of pull them away, you're going to get bleeding and disruption of the vasculature. That's what we see with the drugs that bind plaque. 20%, 25%, 30% of patients have bleeding and swelling on the brain. Not only is it not really responsible for driving cognitive decline, it's also associated with a pretty severe side effect issue. Our claim now is that we've got a drug candidate that targets only the oligomers. All of our drug is directed towards the actual target. We're not binding plaque, so therefore, we believe we will significantly reduce the incidence of ARIA, which is a big deal currently with the drugs on the market. If you look at kind of the generation of antibodies really over the years and how they've been designed and developed, you have kind of solanezumab, which was designed kind of interestingly, they targeted these monomers. This is back years ago when they thought that monomers was the actual target. As I said before, we now know that monomers are actually useful form of amyloid beta. Totally the wrong target, they saw no clinical benefit. You come with the other antibodies, gantenerumab, which is now being repositioned and refashioned into trontinemab by Roche. Gantenerumab binds everything. It got soaked up by the monomers, it got soaked up by plaque, very little of the drug actually got to the toxic target. Showed no clinical efficacy. We'll see what trontinemab does, probably similar. You get to the donanemab, which is Eli Lilly's drug. It's on the market. Lecanemab, which is Eisai's drug, Biogen-Eisai, on the market. They're more selective. I mean, lecanemab was actually designed to exclusively bind the oligomers. Again, it's more selective, but it still cross-reacts with monomers and plaque. It's still associated with ARIA. As you work through the generations, if you will, of antibodies, you get more and more selective. We come to the clinic, and hopefully to the market, with what we believe is an antibody that's highly selective, again, but only for the toxic oligomers. You can see on the side there the% of ARIA that's associated with the drugs that have been developed in those other areas. This is one kind of one study we did in-house, because as I said, we really wanted to pressure test whether or not we bound plaque, whether or not we had a differentiated asset, because it's really important. Well, it should be important for anybody. It's certainly important for me as a CEO to have a differentiated product that has a chance to be best in class. Because others have said they exclusively bind oligomers, and in the end, they cross-react and have ARIA. We tried and tested. The top row, these are brain sections from Alzheimer's patients. They light up green showing that there's plaque in these sections. The purple shows which antibodies actually bind to that plaque in the brain. If you can see, the ones certainly on the right-hand side here, all fluorescing purple, all bind plaque. That's lecanemab, donanemab, ACU193 from Acumen. The only one that does not bind plaque is PMN310, kind of third from the left. This is something we did. We did a quantified analysis to say, what's the level of fluorescent for these antibodies? Again, PMN310 on the left there, the only one that showed, that demonstrated no binding of plaque. Again, we were confident going into our clinic that we had something that was truly differentiated. It was important to talk about it with the investors. It was important to talk about it with the investigators in the trial as well. If you look at the two drugs in the market that I mentioned, again, the ARIA in the middle, this bleeding and swelling on the brain, is a huge challenge for them. The FDA has put a black box warning on each of those drugs, you know the black box means extra careful attention because they've got a serious side effect issue. The efficacy on the right side, on the left side, you might not be able to see it, but essentially it's kind of modest efficacy. These drugs have shown to be moderately efficacious in kind of 27% range of efficacy. Pretty modest efficacy, pretty serious side effects. The risk-benefit, pretty poor. Again, everything's a step in the right direction for sure. I don't want to beat them up too much because these are all advances which are helpful for patients. At the end of the day, they're still predicting $3 billion-$4 billion peak sales. Even with moderately effective, somewhat safety issues, they've got a $3 billion a year drug. Which also points out that there is commercial validation, there's regulatory validation. If we come or when we come with our drug that has a better risk-benefit profile, we'll be in good shape. The phase I-A study that we completed a year and a half ago, again, it was in healthy volunteers. It showed that the drug is safe and well-tolerated. It also importantly showed that the amount of drug we had across, the amount of antibody we had across the blood-brain barrier was sufficient to fully engage our target. That's important in the day of brain shuttles and such, that we've got enough drug across the blood-brain barrier. We don't believe we'll have an ARIA liability. The phase I-A was positioned us well for the phase I-B that we're running now. Probably the best decision we made as a company was in the design of the phase I-B study. Where others have kind of done quick and dirty studies and a few number of patients looking at biomarkers, we took a step back and said, I told the team, I want to have a study design, even though it's a phase I-B, first in patients, I want to have a study that gives us a fairly definitive answer as to whether this antibody truly works. It's got to include enough patients and it's got to have a clinical signal. The team came back and we designed this study. It's a placebo-controlled, double-blind, randomized study, 3 cohorts, 3 ascending doses. We wanted to target 100 completers. We initially thought about enrolling 128 patients to end up with 100 completers, given the dropout rates of other Alzheimer's studies. The endpoints we're measuring are kind of a series of biomarkers. There's a number of them we can touch on that are quite relevant. We're looking at safety. Obviously, the incidence of ARIA, the swelling and bleeding in the brain is going to be definitive for us. Then we've also got the FDA clinical endpoints here, the CDR Sum of Boxes, ADAS-Cog. It's a very robust study for a phase I-B study. We have completed enrollment. Enrollment's complete as of last December. Interestingly, as we were winding up the study, kind of getting close to our 128 target, the sites were very encouraged. I think they've been very encouraged with the study, given the potential for lack of ARIA for the first time. They kind of rushed to get patients into the study, we were oversubscribed, and we ended up with 144 instead of 128 patients. The dropout rate is much lower than anticipated. I think the physicians like the study, like the drug, and the patients certainly want to stay involved in the study. This is running now. Because it was 12 months, we built in an interim analysis. That's coming up soon. The interim analysis occurs when all patients have been treated for six months instead of 12. And that time point occurs kind of mid-year. We said publicly that we expect to communicate blinded interim data in early Q3 of this year. Again, it's blinded data. I'll touch on this in the next slide in a minute, but it's a blinded analysis at interim, only looking at safety and biomarkers. Then the final results, all patients are expected to be fully dosed by the end of the year, and we'll communicate top-line results, as we said publicly, early Q1 next year. It's a very robust study. We did get fast track designation from the FDA last year, said fully enrolled. Now it's heads down, execute, and get the data, the interim analysis done, and then the final. The interim analysis here really is kind of a qualitative look, a blinded analysis, as I mentioned, just to give an indication of safety, which is going to be important, ARIA incidence, side effect profile, and to give an indication of target engagement. We want to show that not only ideally is it safe, but that it's actually engaging the target with potential then for beneficial effect or efficacy. It'll be a qualitative sneak peek, hopefully saying everything's going in the right direction, comes up in early Q3 in a matter of months. There is no clinical analysis at interim. We're not breaking the blind on any of this. It's important to know that it's a blinded qualitative analysis as we move forward. The biomarker data, as I said, there's a number of biomarkers that are very well understood in Alzheimer's disease. p-tau217 as a measure of disease progression. GFAP is a measure of neuroinflammation. As I mentioned, the oligomers are highly toxic to synapses. We've got a presynaptic marker, SNAP25. We have a postsynaptic marker, neurogranin. Aβ42/Aβ40 is a true indicator of disease progression as well. In the blinded analysis, we'll have a few of these data, ideally showing a downward trend in some of these key biomarkers, because if there is a beneficial clinical effect with the drug, we expect to see a downward movement in most of these biomarkers. Importantly for us over the course of this year, we're certainly not just going to sit on our hands and wait for the outcome. And if the data's there, yippee, now what do we do? We're plotting and planning really the whole life cycle management for PMN310. That not only involves executing on the trial, but what's important is we expect to be more efficacious, so better efficacy, better safety, but we also want to maximize compliance. Right now, the drug is in the phase I-B trial we're conducting. The drug is administered monthly IV. Our goal is to have a SubQ formulation to be delivered when we get to commercial launch. The acceleration, if you will, of the SubQ formulation, will likely kick in later this year. The interim analysis might give us an indication. To ramp up SubQ is going to be important to us. The one thing we thought about significantly in the design of the phase I-B study, that if it's successful, if we can show that it's safe and well-tolerated, which we think we can, that enough drug crosses the blood-brain barrier to engage target, that we're actually engaging the target, which will be measured by biomarker movement, and if we've nailed the dose and we have a clinical signal, that's enough to step into what we believe is a phase III registration study. In a way, we're kind of bypassing or leapfrogging the phase II component and going straight to a phase III registration trial on the back of positive data and FDA feedback. That's kind of the plan as well. This year, we're in the middle of designing that phase III clinical program as well. The whole regulatory path, the end of phase II meeting, which we'll have early next year once we complete the study. In addition, the pipeline that I pointed to at the beginning of the study, the next candidates that are kind of coming behind in ALS, targeting misfolded TDP-43, and PMN442, which is looking at misfolded forms of alpha-synuclein for Parkinson's disease and dementia with Lewy body dementia. Those pipeline candidates, we want to also march closer to clinic, because ideally what we'd like to say when the Alzheimer's study reads out is that not only have we demonstrated proof of concept in Alzheimer's disease, which will be transformational for the company and ideally for the patients, most importantly, but we'll also show proof of concept of the platform itself. We want to have those next candidates kind of jockeying for position towards the clinic. Advancing these two candidates, and again, this is pretty cost minimal. We've done a lot of work already on these candidates to move them through pre-clinical development. Again, marching them closer to the clinic so that when all this reads out in a matter of months, that people will see that we've got a really robust company focused on neurodegenerative assets with certainly meaningful clinical data. Last slide, just as we kind of sum it up. The differentiation, I keep hammering on that. I think it's absolutely important for us. We do believe we have the chance to be best in class for the treatment of Alzheimer's disease. I think there's a lot of focus on Alzheimer's. I think it is going to be a watershed year for Alzheimer's patients and families and caregivers and companies that are successful. Again, if we've got a real chance to lower the side effect issue and come with better efficacy, we'll be off to the races. We do have near-term catalysts, which the investors and The Street always likes to see. We've got the interim analysis in a matter of months, and the final readout six months beyond that. I think the interim analysis will give, as we say here, kind of an early signal on safety and potential in target engagement and efficacy. That's an important jumping-off spot early Q3. The clinical profile, as I said, the team's done a superb job executing the study and designing it in the first place. We've got our fast track. We're going to get in front of the FDA as quickly as we can to start plotting and planning for that phase III registration study. We've been in front of all the strategics. Obviously, there's a lot of interest. There's been a lot of deals done in Alzheimer's disease. I think we've interacted with all of them who are interested to date, they're all kind of waiting, some at the edge of their seats for the data to come out. We'll see how that plays out. I'd certainly like to think we'd be in a position ourself, and again, this speaks to the financial strength. As I said, we just closed on a $175 million pipe with the likes of Wellington and Janus and Ally Bridge and these guys, deep pockets. I've gone to them and said, "If this trial does read out, I want to be in a position to at least think about funding that phase III study ourself." For me as a CEO, you always want to have options on the table. Coming with a potential pharma deal, which if it goes well, that certainly could be there, but also with the ability to control our own destiny and have a couple of options and weigh them against each other. These guys that are at the table have the pockets and have the intelligence to be able to fund that next study. These are things we're all kind of preparing and plotting over the course of the next number of months, such that when the data read out towards the end of the year, early next year, that we'll be in a position to kind of react pretty favorably that supports, well, not only the shareholders, obviously, but more importantly, or most importantly are the patients and the families. Obviously, Alzheimer's is a tough one for all of us. If we can do something impactful, that'll be pretty inspirational for us and the team. As I said, it's been an interesting few months and interesting year since I stood on this very stage about a year ago. Thanks for your attention. I don't know if you have time for questions then? Yeah. Thank you. Brilliant presentation. Congratulations. Yeah. Brilliant presentation. Congratulations. It's okay. You have to speak up a little bit. Hold it closer to your mouth. Can you hear it? I can, but yeah, it's okay. Yeah, can you hear that? Brilliant presentation. Oh, he did say brilliant presentation. I'll repeat the stuff that's important to him. Congratulations doing this. One of the questions I have, you did mention in the phase I-A, you were able to show or see the drug going into the brain. I'm just curious, how did you measure that? The same question, same time I'm asking, I know you want to go to phase III. What's the number? How many you are anticipating- Patient number? in phase III. Yeah, two questions. One around the drug across the blood-brain barrier. How did we measure that? How do we know how much drug's across the blood-brain barrier? Again, we did lumbar punctures at day 1 and day 29 of that. These were multiple ascending doses. Lumbar puncture to measure CSF levels of antibody in the CSF, the drug that crossed the blood-brain barrier. Again, it's no different than any other antibody. It was still the 0.1%-0.3% that naturally traverse the blood-brain barrier. I think the interesting thing in this patient population is that the target itself, the oligomers, are in very low concentration, in picomolar concentration. The amount of drug that we get across, while no different than most antibodies-