All right, I think we're live. Good morning, everyone, and welcome back to the second annual Healthcare Innovation Conference here at Guggenheim. My name is Eddie Hickman. I'm one of the biotech analysts. This morning, I'm welcomed by ProMIS Neurosciences CEO, Neil Warma. Neil, thank you for joining us this morning. Maybe if you want to take two or three minutes just to give everyone here who's not familiar a quick overview of ProMIS, and then we'll jump into the Q&A. Yeah, sure, happy to. Thanks for the invitation to the conference, Eddie. Thanks for those in the audience and for those listening on the webcast as well. I'm joined today with our Chief Medical Officer, Dr. Larry Altstein. As Eddie said, Neil Warma, CEO of ProMIS Neurosciences. We are a publicly listed company, ticker PMN, on the NASDAQ Capital Markets. Excited to be here today. We are kind of in the middle of a really kind of a landmark study in Alzheimer's disease. We're running a 100-patient study in Alzheimer's with our lead monoclonal antibody. We'll get into a little bit the story and the design of the study and the design of the molecule itself. We're excited at this stage. We've got data coming just around the corner in our relatively robust phase 1b study in Alzheimer's patients. This is a 100-patient study. The drug's administered over 12 months of therapy. We are roughly over 90% enrolled in this study. As I said, data's just around the corner. We've got an interim analysis coming up towards the middle of next year, and then final top-line results coming towards the end of next year. The data to date from a safety and our expectations perspective looks really, really encouraging. Very excited to be here. Again, we've got a differentiated molecule in the clinic. We've got a really exciting pipeline of candidates. We're focused on neurodegenerative diseases and a little bit more specifically around multiple dementias. Lead program in Alzheimer's. We've got preclinical candidates coming along for ALS and for Parkinson's disease. We're excited right now, as I said, with our first clinical data set coming up in the next number of months, Eddie. Great. No, I appreciate that overview. Let's start with PMN 310. You said this is your lead candidate. You're targeting Alzheimer's disease. This selectively targets the amyloid beta oligomer. Can you just sort of talk about what is known right now about the amyloid, the role of amyloid in Alzheimer's disease, and sort of where others have tried to target this epitope? Can you sort of talk about your sort of secret sauce for how you've targeted this specifically and why it's so important in your mind to target this particular species of amyloid versus the others? Yeah, very good question, kind of a complex question. We have an ability in the design of our antibodies to create antibodies that selectively target a misfolded form of a specific protein. Our name, ProMIS Neurosciences, is based on protein misfolding. Our founding scientist, Dr. Neil Cashman, our CSO, is really a pioneer in designing drugs that selectively target misfolded forms of a protein. For Alzheimer's, we've known, the industry, the field has known for a long time that amyloid beta protein is really a driver of disease progression in Alzheimer's. The complexity comes because there are multiple different forms or multiple different species of the same amyloid beta protein. The question becomes, or the challenge becomes to the scientists, how to selectively target only the toxic or the harmful forms of this protein and avoid targeting the non-harmful forms of the amyloid beta protein. For us, our differentiation is really around our ability to design these antibodies. It's important because there have been a number of companies, if you back up a little bit, I think some of the initial thinking decades ago was that this plaque form of amyloid beta was the culprit. This was the bad form of the amyloid beta species that you had to go after. That thinking has shifted quite dramatically over the past 10 or 20 years. Plaque is no longer really the necessary target, because there are drugs that totally clear plaque from the brain, and the individual patient continues to progress. Not only that, and we'll get into this in a minute, but drugs that bind and clear plaque also are now associated with this very serious side effect known as ARIA, and this is bleeding and swelling in the brain. The thinking that plaque was the culprit has now shifted. The efficacy, the drugs that are on the market that target plaque and remove plaque are not that efficacious, and they are saddled with this side effect issue. The question becomes, how do you design something that avoids plaque and potentially goes after a different species? The field has come to think that these oligomer forms, these upstream forms of the same protein, are the toxic form of A beta. The challenge has been to design an antibody that selectively goes after the toxic form and leaves the other forms, including plaque, alone. That's really where ProMIS has come over the past years to design an antibody that selectively targets only these toxic oligomers. We believe we're the only company that actually has an antibody that's selective. If you just give me a second, I'll explain, because it's important. People have said, well, lecanemab was designed to selectively target oligomers. Other companies have tried to design antibodies that only go out, and they've claimed they have these antibodies that only target oligomers. At the end, they all cross-react. They bind with plaque. They're associated with ARIA. What makes ProMIS special? How can you do something that Biogen couldn't even do? This is when it comes back to our founding scientist, Dr. Cashman, who is one of the leaders in protein misfolding diseases. The way we design our antibodies is fundamentally different from the way everybody else does. We are able to, and we've been using AI back when it was not even cool to be talking about AI. We've been using AI for years to really come at it from a computational or a statistical physics perspective. We can predict and identify areas on a protein that are prone or vulnerable to misfolding. Once we identify, and again, this is algorithmically driven, these specific epitopes that occur only on the misfolded forms of protein. It's a linear epitope, but it's also, importantly, kind of a three-dimensional conformation. We get this 3D conformational epitope that exists only on these misfolded forms of proteins. It's only on this misfolded toxic oligomer. Once we have this 3D shape, we can create a cyclical peptide. From that, we design our antibodies that only bind this cyclical peptide. This binding site, this epitope, is only expressed on these toxic oligomers. They're not expressed on monomers, the monomeric form of A beta, and they're buried in plaque. Our antibodies can only, we believe, selectively target these toxic oligomers. This is very different from the way others have designed their antibodies, typically looking at a synthetic oligomer to design an antibody. Almost by definition for those companies, and that's what we've seen, those antibodies that are generated using synthetic oligomers will cross-react to monomers, plaque, and oligomers, but they bind across different species of amyloid beta. That's a little bit how our secret sauce works. That's really helpful. Now that we have this antibody designed against the sort of synthetic peptide that mimics what this three-dimensional shape would translate look like, sort of in vivo, what work have you done prior to starting this clinical program in humans? Have you done to really verify that you did what you said you were going to do and got a specific antibody? I mean, excellent question, because we wanted to prove to ourselves, if not to the investigators and to the investors, that what we had conceptually designed actually mechanistically did what we wanted it to. We went through a rash of preclinical studies. We looked at multiple different ways of testing whether our antibody and side by side by side by all the other antibodies, we looked at donanemab, lecanemab, aducanumab, and side by side assays, immunohistochemistry assays, fluorescence assays to see which of these antibodies actually bound plaque. We used brain sections from Alzheimer's patients that were laden with plaque, and we laid them side by side to say, OK, who's binding plaque? The only antibody that, in all these different assay forms, that did not bind plaque was PMN 310, was our antibody. All the other ones, fairly robustly, all bound plaque. That is what we have seen in development. That is what we have seen on the market. All these antibodies bind plaque, will certainly clear plaque with very little efficacy, but with significant safety because they all yield an ARIA liability. We tested that in multiple assays. We also did a very robust toxicology study preclinically, where we looked at transgenic mice who were predisposed to have plaque. They were laden with plaque. We dosed these mice with placebo and with PMN 310 for 26 weeks, so half a year and up to 800 mg per kg. We dosed these mice substantially over half a year. We sectioned all the brains, and we looked at whether or not we were causing any of this ARIA, any of the bleeding in the brain. There was absolutely none. All the sections of the mice up to the highest doses, we saw kind of squeaky clean brains, no evidence of REH. To your question, Eddie, we did multiple studies preclinically to give us the confidence prior to going into the clinic and raising money for that, that we had an antibody that was clearly differentiated, that did not bind plaque, and that selectively really targeted these oligomers, which, again, the field has now come to understand is these toxic oligomers, these low molecular weight oligomers that are driving disease progression. They're highly toxic to neurons, to synapses in particular. That is the species that we, as an industry in the field, need to target. It looks like ProMIS was the one that's got that antibody that's selective. Yeah, no, that's really interesting. Now, from an efficacy perspective, how do you sort of counter the argument that you might need plaque binding or plaque reduction to show efficacy in an Alzheimer's clinical trial where you're saying that your antibody doesn't clear plaques, doesn't bind to plaques? Can you sort of just talk about what your rationale is for thinking that just these toxic oligomers are driving disease progression and you can still get sort of separation without reducing plaques? Sure. I think, I mean, almost to look at the inverse of the question is, what confidence do we have or what evidence do we have that clearing plaque actually benefits the patient? There's really little evidence of that. We've seen the drugs on the market that now donanemab and lecanemab with modest efficacy. There, and as I said, there's drugs that clear plaque where you see the patient continue to decline. This whole idea that you've got to have plaque clearance, I think we've shifted away from that. When we measure and we look at these oligomer species and say, are these the ones, and again, these are upstream, and are these the ones that are toxic to the neuron, these are the ones that are driving disease progression? I think the field has kind of come, I won't say full circle, but it's certainly come to the realization that you need to target these upstream oligomers. These are the ones that are kind of driving kind of downstream tau phosphorylation, neuroinflammation. I think it's understood now that it's the targeting of these oligomers that are really driving disease progression. One of the complications is if you've got a drug like the ones on the market, and if you're administering these drugs to patients and they are cross-reacting to different species, from an efficacy perspective, if we know that we've got to get at these toxic oligomers, and we also know that the concentration level of these oligomers is much, much less than plaque and monomers. If you can imagine, if you're administering your drug across the blood-brain barrier into the CSF, and if X% of your drug is getting soaked up, so to speak, by the monomers and the plaque, and some of it eventually gets to the oligomers, then you might see modest efficacy because some of your drug is getting to the target. I think that's probably why we're seeing a little bit of efficacy with lecanemab, because it does make it to the target. Most of this is kind of net sync effect, if you will, the off-target effect to the other forms of the species, which are, again, regardless of the side effect issue, you've just got kind of wasting of drug and not hitting the oligomer target. Right. So, what is the evidence then, or maybe not evidence, but what is your sort of hypothesis or view of what these plaques are doing at the synapse to cause this sort of maybe what you think, what you're calling an upstream process that's initiating the disease? Do we know a lot about how these oligomers are binding to synapses and causing sort of an early stage of atrophy? I think, I mean, that's kind of it exactly. Dr. Altstein can talk to this in more detail. Yeah, I think it's really the toxic effects, specifically binding and interacting at the synaptic level, that's kind of driving this disease progression. Exactly. OK. I want to move now into, you have a phase 1b ongoing. What data did you have prior to that? Sort of talk about the design and what you're truly trying to determine in this pretty robust phase 1b study. Yeah, just on that last point. Again, it was probably one of the most important decisions we made last year prior to initiating this study, was the design of the 1b. We wanted, because other companies before us had taken a little bit of a different route to do a shorter kind of a three-month, 30-patient study, a little bit of a quick and dirty to see if there's any biomarker effect. We made a decision not to do that. Again, keeping in mind that the individuals designing this study for us, Larry Altstein, used to run CNS Advisor and is a practicing neurologist treating Alzheimer's patients all his life. We had the benefit of this expertise to say, OK, let's design a study that's going to yield an answer that's going to give us a definitive answer whether this drug works or not. That really implied having enough patients to get to a statistical outcome, defining the right endpoints, and treating the patients over a long enough period of time such that we can see clinical benefit. We wanted to see our endpoints in this study are certainly biomarkers, certainly safety and ARIA. Again, that's one of our key differentiators. We're not expecting to show ARIA liability above and beyond placebo rates. The third endpoint that was really important to us was a clinical signal. We wanted to show that, yes, the biomarkers were tracking nicely. We've got no ARIA liability, and we've got this clinical signal at the end of this study. It is a very robust phase 1b study. The number of patients, we're looking at treating over 100 patients. We're enrolling 128 patients to end up with 100 completers. The design of the study is very robust, again, to give us a really definitive answer as to whether this works as to our expectations. Another factor we considered, Eddie, when we were thinking about this is, if the data result in kind of what we expect with increased efficacy and better safety profile in a 100-plus patient population with all the measurements we're taking, MRI, imaging, PET, biomarkers, we expect, and this is subject to FDA discussion, but we would expect then we could just step right into a phase III registration trial. That was part of our thinking. If we can avoid this middling roll, the phase II clinical development program, which is a three-year program and a couple hundred million dollars, if we could avoid that and go from this 1b design into a pivotal phase III study, that would speed time to market and dramatically reduce costs. That is kind of how this was designed and set up. That is why we are excited now, because it is enrolling so well and it is. It's dose escalation. Can you sort of tell us what you can about what you know so far about, I mean, you've obviously had two dose escalations so far. Clearly, the DSMB is giving you some go-ahead. Talk about what you know about the trial so far, and then we'll get into expectations. Sure. You're correct. It's three dose levels at five, 10, and 20 milligrams per kilogram over 12 months of treatment in 100-plus patients. It's a placebo-controlled, double-blind, randomized study. It's randomized three to one, so three on drug, one on placebo. As you correctly say, Eddie, we've had two DSMB, Data Safety Monitoring Board. This is our independent safety board that looks at all the data and makes a decision whether we can escalate from dose one to dose two and dose two to dose three. We've cleared those milestones. We got DSMB approval months ago now to go from dose one to dose two, and then a couple of months ago from dose two to dose three. We've completely enrolled cohort one, completely enrolled cohort two. We're almost finished cohort three. We've got the DSMB in the middle of this. We announced earlier this year we were granted fast track designation by the FDA. That was a good milestone for us. Again, keeping in mind that our, you know, we get a signal, if you will, from the DSMB on the safety perspective. One of our key differentiations, in addition to improved efficacy, but a critical differentiation is in what we believe to be a lack of ARIA liability. To date, from a safety profile, we've been really, really encouraged by what we've seen. The safety profile kind of is well above our expectations. Dropout rates are kind of almost zero. We're really excited about where we are as far as information we can gather. We're not unblinding anything now, but information we can gather as we're going through dose one, two, and three. As I said, we're about 90% of the way enrolled with data just around the corner. We've got that interim analysis in Q2 and final results in Q4 next year. Yeah. I want to talk about that interim analysis. We're not going to have the cognitive endpoints at six months, but we will have sort of a nice basket of biomarkers. Talk about what those biomarkers are and sort of how you expect them to move relative to what we've seen previously. Maybe sort of how does that support the hypothesis that these toxic oligomers are driving the disease. The important kind of learning we'll get from the biomarker analysis is whether we're engaging our target. PMN310 is engaging its target as we expect. That should be reflected in the movement of the biomarkers. Again, great care was taken in the design of the biomarker panel. In Alzheimer's disease, there's a number of biomarkers. Many of these are kind of very well understood and understood how they kind of potentially correlate to clinical outcome. The key ones we're looking at, pTAU217, which is a well-known measure of disease progression. pTAU243, a measure of downstream tau phosphorylation. We've got neurogranin, a measure of neuroinflammation. As we keep referring to the synaptic, the synaptic toxicity of these oligomers is absolutely critical. We've got a presynaptic, postsynaptic biomarker we're looking at, GFAP, SNAP25, we're reviewing. We've got NFL we're looking at as well. We've got a relatively comprehensive, and in addition to that, we've got a whole collection of additional kind of tertiary biomarkers we're looking at. That initial basket will tell us an awful lot, Eddie. We would expect, knowing how these biomarkers move, that if a patient continues to decline, we would expect to see elevated levels of all of these biomarkers. At six months and certainly at 12 months, we would expect to see a drop in these biomarkers if PMN 310 is having an effect as we expect. The biomarker data will give us a really good understanding of target engagement if we're kind of, if we're hitting our toxic oligomers as expected. That clinical outcome will kind of confirm that, ideally, at the end of that 12-month treatment. Given you mentioned plans to try to, given the robustness of this trial, to try to accelerate into a, or move right to a phase III pivotal based on these data, do you have a sense of sort of what those clinical biomarker level of change would need to be at 12 months to sort of give you confidence that this signal is real and that you feel confident going into a large phase III study? Do you sort of have internal benchmarks for where you'd like to be? Do you have a prediction of what the biomarkers would need to show six months prior to that to sort of get you within those expectations? Yeah, I mean, it's a very good question. We do have kind of internal kind of guidelines, if you will, of where we expect those biomarkers to be. We've seen other companies, other trials have run similar biomarker analyses. We know that at three months and six months, we've seen a change, a separation, if you will, in biomarker levels. We have not kind of gone out publicly and said, this is where we need to be. Certainly, looking at benchmark data, we have a really good understanding. It's interesting, we published a paper with Dr. Altstein and Dr. Kaplan, our Chief Development Officer, with probably one of the top neurostatistics groups out there, Pantera, looking at the correlation between pTAU217 and clinical outcome. I think it was the first time this analysis had been done to show a direct correlation between pTAU217 and clinical outcome. This will be a really interesting and important signal for us at the interim analysis. This will be a blinded analysis at the interim. Correctly, we're not going to look at clinical outcome in a blinded way. That does not make sense. Keep in mind that when we get to that interim analysis, it is only a matter of a few months that we're going to flip the card on the final top-line results. Yeah. No, and I know that there's been some recent deals in this space from a business development standpoint, looking at early-stage Alzheimer's assets. What do you get a sense from looking at those deals? What these large strategics are looking for in terms of early data, how differentiated they need to be? Is ARIA a significant piece that comes up in these conversations with your experts? That is a huge piece of the pie that needs to be filled from a next-generation therapy in this space. Yeah, most certainly. ARIA is a critical factor in making the decision. Again, us believing that we will reduce significantly the ARIA liability is driving a lot of these discussions. We know that the risk-benefit profile of these drugs on the market is pretty poor. ARIA drives a lot of that risk, obviously. If we can lower that dramatically, then the impact this will have on prescribing habits, on patient confidence in taking the drug, in revenue, I think will be augmented tremendously. ARIA is certainly a driving factor. I think it's interesting. We had a strategic pharma company come to us a couple of months ago and said, it's kind of exciting in the field because for the first time, because of ProMIS and where we are, this is a huge pharma company that's actually very active in the space. They said, for the first time, we're going to be able to understand whether this oligomer hypothesis is true because you guys seem to have the only antibody that's going to answer this question at ProMIS. Not only that, this is kind of nice to hear as well, that they felt that ProMIS had so great an antibody, but had a very well-designed clinical study. We're going to get an answer on the oligomer hypothesis, and we're going to find out whether PMN 310 really is the answer we've been looking for because you've run a really nicely designed trial. We've had a, yeah, I mean, and the early acquisitions and the early partnerships we've seen from pharma for some of these Alzheimer's companies, frankly, is quite encouraging. We like to see, well, we like to see these pharma M&As or pharma transactions, period, because it's good for the industry, but it certainly reflects well on companies like ProMIS that are coming with a truly differentiated antibody. I think there's a lot of encouragement and enthusiasm. We're seeing that in our business development discussions as we've been kind of going over the past six months as data is becoming closer and closer. As our kind of safety signal looks superb to date, and that's what we've been touting for a long time, yeah, there's a lot of pharma companies that are leaning forward to say, as these folks said the other month, this could be something that's truly differentiating in an area where even weak-ish, and I don't want to take anything away from our colleagues at Lilly or Biogen, but even products with poor risk-benefit are generating $1 billion in sales. The commercial validation, if you will, has been proven. The regulatory validation has been proven because these drugs are on the market. I think it's still, there's a huge area of unmet need, medical need for companies that can come with drugs that improve on the safety profile, which is pretty significant. We also expect, given our selective targeting of our antibody to these oligomers, we expect that we would show improved efficacy as well. If we can dramatically shift that risk-benefit ratio, I think that'll be huge, number one, for the patients, but I think it'd be pretty significant for our shareholders. Yeah, no, from a scientific perspective, I think it's great. We've always been hearing about these sort of non-amyloid therapies that are sort of bubbling under the surface. It's really nice to have sort of a nice robust trial that'll give us that scientific answer, hopefully, next year. It is. And it's exciting because we're not, yeah. Sorry, just general comments. Yeah, just to finish, because we're not kind of out there, as Larry likes to say, we're not out there on an island by ourselves. I mean, the whole idea of misfolded proteins driving disease progression is very well understood. That mechanism we've got covered. The idea that toxic oligomers, this amyloid beta species, is driving disease progression is well understood. We have the potential to be that best in class on two very well-known mechanisms of action. That's where we get a lot of support and enthusiasm from the industry. Great. We'll look forward to data next year. Good luck on all the progress. Thanks, Eddie. Appreciate it very much. Thanks for coming. Thanks for coming.