Hello, everyone, and welcome to this latest in a series of fireside chats here at the Perspectives on Neurology mini conference hosted by H.C. Wainwright. My name is Ram Selvaraju, and I'm a managing director and senior healthcare equity research analyst here within Wainwright's Equity Research Department. I'm joined here today by Neil Warma, Chief Executive Officer of ProMIS Neurosciences, a publicly traded biotechnology company focusing on next-generation therapeutics development in a wide array of neurodegenerative disorders, including but not limited to Alzheimer's disease. Neil, it's a pleasure to have you with us today. Ram, it's always a pleasure to talk with you and talk about our science. Thanks for having me. I think it'd probably be helpful, given the fact that Alzheimer's is basically considered one of the most serious, if not the most serious, worldwide epidemics, particularly as we face the relentless aging of the global population, and in particular in developed countries, to maybe reflect an opening on the size of the overall Alzheimer's disease opportunity, why it is such a serious problem, and to what extent there exists an opportunity for innovative drug developers like ProMIS to access this market and potentially offer something differentiated versus what we currently have available to treat the disease, which is a very, very long way from even being able to reduce or slow down or arrest deterioration, let alone effect a cure. Yeah, that's a big question. Obviously, there's been a lot of research being done towards Alzheimer's disease over the number of decades. As you know, ProMIS is focused specifically on neurodegenerative diseases. We have a vast pipeline, but our lead candidate, as you say, is certainly targeted towards Alzheimer's disease. As the population ages around the world, this becomes a bigger and bigger unmet medical need. There's a lot of research. Our focus over the years has been on trying to develop a differentiated asset. I think that's what we're looking for in the world of Alzheimer's treatment, a drug, or maybe there's a combination of drugs, but a drug that is differentiated and really addresses the underlying pathology of the disease. Progress has been made over the past 5, 10, 15 years. We've seen a couple of products come to market. I feel, and I think others feel as well, that there's still a significant unmet need in the Alzheimer's population. I mean, there are millions of patients around the world suffering from Alzheimer's disease. The market opportunity is significant. We see the revenue being generated by the two products on the market, really donanemab and lecanemab. Although they are less than expected, they're still generating sales. That kind of commercial validation of novel products in Alzheimer's is being recognized. I still think, and I think we as an industry in Alzheimer's feel that progress has certainly been made. Trying to identify the specific target, and once identified, trying to selectively go after that disease-causing target has been a challenge for many. What we're seeing on the market today are products that deliver modest efficacy, and the side effect profile is fairly significant as well. The risk-benefit that's being delivered by the drugs on the market is really not sufficient to make kind of a large impact on the Alzheimer's population. I think what we as an industry need to focus on, and certainly what we at ProMIS are focusing on, is developing a product that is differentiated, that tips the balance of this risk-benefit profile more towards a benefit, trying to come with improved efficacy and a much-reduced side effect issue that we're seeing on the market. I mean, ARIA, this brain bleeding and swelling, as we've spoken about, is really limiting the impact of drugs and the prescribing of these drugs on the market. Coming up with drugs that are differentiated to reduce the level of ARIA, improve efficacy, is certainly something that the field needs to come up with. I think we at ProMIS feel that we're really leading the charge in developing an antibody that will come with a much better risk-benefit profile. For those of us in the audience who don't already know this, ARIA stands for amyloid-related imaging abnormalities. It is effectively considered a hallmark, a characteristic of treatment with some of these novel anti-amyloid monoclonal antibody therapeutics, which, of course, target amyloid, one of the pathological hallmarks of Alzheimer's disease, a misfolded protein that accumulates in the brains of Alzheimer's patients. Now, ARIA is indicative that there might be a more serious problem, like, as you said, brain bleeding, brain swelling, right? Maybe just quantify for us for a second. How often does ARIA typically crop up if you've got a patient with Alzheimer's disease who's being treated with one of these anti-amyloid drugs? Does it occur 50% of the time, 30% of the time, 5% of the time? How often does it typically lead to more serious problems? It's a really great question, Ram. I'm just going to flash up a couple of slides here, and we can talk about ARIA, because it really is impacting the treatment of patients. Let me just pull this up. Treatment of patients. ARIA, as you say, it's really related to this swelling or bleeding of the brain that's caused by these antibodies that specifically target plaque. Plaque is kind of embedded within the blood vessels of the brain. As these antibodies bind to and clear plaque, what we'll see often is kind of leakage of the cerebral vasculature or rupture of that vasculature. There's either edema, swelling, or bleeding in the brain related to drugs that target plaque. We're seeing this issue kind of depending on the drug and on the antibody and the treatment. Anywhere from kind of 15%-30% of patients will exhibit swelling and/or bleeding of the brain due to ARIA. It is a significant concern. What we show here is the impact that we are seeing is numerous. We see the impact on patients, again, patient uptake, so consent from the patients. The burden that impacts the patients on having to manage ARIA and potential ARIA is significant. Therefore, the prescribing habits of the physician are impacted as well. We see physicians, again, with this benefit-risk when the benefit is modest, but the risk is significant. The physicians are really very careful in prescribing these plaque-binding antibodies to their patients. Obviously, there is an impact on revenue. I think the bigger picture we see with ARIA is in the managing. As I said, if it's in the range, and you can see some of the numbers here, overall ARIA at kind of 20%-30%, which is significant. I think part of the issue is managing ARIA itself. There's a number of components, which we say here from the surveillance, monitoring of patients. How does a physician know if it's a headache or if it's something more serious? They have to monitor the patient. There's the clinical intervention. There's the imaging and the managing of that patient. In addition, it's the entire infrastructure that's required to manage these patients. Obviously, there's a significant amount of MRI and looking and managing the patients from a screening perspective and MRI and imaging. The infrastructure that's required is significant within a hospital setting. Not many or not all hospitals certainly have that required infrastructure. Even if you can get by the physician willing to prescribe the drugs to their patient, they still need that infrastructure within their hospital system to be able to manage and monitor those patients. Many of those hospitals do not have it. It is a significant impact. Again, to emphasize that the efficacy that is coming with these drugs that bind plaque is relatively modest in that 27%-30%. It modestly slows down disease progression, but comes with a significant cost around ARIA. We tend to see ARIA early on in patients being administered these drugs that bind to plaque. The ARIA comes relatively quickly in the treatment with these drugs. I think that kind of gives an impact as we see some of the sales or revenue that is impacted as well by this risk-benefit. The ARIA is impacting the two drugs on the market. The expectations are certainly below what was given at the onset. We are seeing kind of impact of ARIA kind of across the board. I think what the focus is on is trying to come up with drugs that reduce the level of ARIA, that avoid this ARIA liability. That is a complicated issue. I think we at ProMIS have addressed that quite well. We are excited to be in the clinic now to test that hypothesis. I think that's a really great segue into an explanation of ProMIS's kind of secret sauce, as it were, and the core technology platform. Maybe you could enumerate for us kind of firstly what the EpiSelect platform is, which is really the core of ProMIS's science, and what powers it, because as I understand, this is a computational approach. Where it originated from in the lab of Dr. Neil Cashman, who is basically one of the key brains behind ProMIS. Maybe also give us a sense of how this enables the development of more promising amyloid-targeting drugs. I want to preface this by saying that where does amyloid come from? It doesn't appear simply as plaque de novo. There's a whole pathological cascade. Maybe targeting plaque is not the answer that we want in Alzheimer's disease, because it's very clear that targeting plaque in the brain disrupts microstructures in the brain, causes these ARIA-related side effect issues. There's a whole host of other amyloid species floating around in the brain that you can target before targeting plaque, which I think is one of the core elements of the uniqueness of the ProMIS approach, right? That's it exactly, Ram. It is how to selectively target the harmful or pathogenic species of a protein in the case of Alzheimer's, the amyloid-beta protein. How can you selectively target only the damaging one and leave the other ones? That really has been at the crux of development of all sorts of drugs over the years. That really is, as you say, our secret sauce, because we have the ability, we believe, to selectively target only the harmful, only the misfolded form of that protein that's causing the disease pathology. Really, as you mentioned, kind of at the outset of this is Dr. Neil Cashman. Dr. Cashman is our Chief Scientific Officer. He's our founder. He's really one of the world leaders in understanding protein misfolding. As we know, proteins are manufactured by the cells. As they come out of the cellular machinery, they form these elegant three-dimensional shapes, and they go on to carry out their function. Very often, proteins exit the cellular machinery, and they are misshapen or misfolded. It's these misfolded forms that go on to cause harm and cause disease. Typically, the immune system will grab hold of these misfolded proteins and eliminate them. As patients age, or if there's mutations, weaker immune system, they're not able to remove these misfolded proteins, which allows them to build up and aggregate and cause multiple diseases. We've really come at it from our EpiSelect platform to be able to identify and predict how proteins are going to misfold. It's a whole kind of algorithmic, maybe an AI perspective or a computational approach to being able to understand how and predict how proteins are going to misfold. It is interesting because it is not only the epitope that is exposed that we want to bind to, but it is the shape of that epitope. That is really important, kind of the conformational shape of that epitope. That is what we are able to identify and design. With that understanding of the conformational epitope, we then create a conformational kind of construct with our EpiSelect platform. With that, we then immunize and identify antibodies that can bind to that specific epitope. Predicting the misfolding of the protein, identifying conformational epitopes that only exist on that misfolded protein, creating an antibody that binds specifically to that epitope. Since that epitope only exists on the misfolded form, it does not bind to other non-misfolded forms, if you understand what I am saying. We have the ability then to generate these antibodies that selectively bind to epitopes that are only exposed on a specific misfolded form of that protein. That is really key to kind of how our technology differentiates us significantly from others that are trying to identify epitopes that are selective. If I can just—so I'll jump ahead in a second. Specifically, what it allows us to do is develop these targeted antibodies for specific proteins for a range of disorders and a range of diseases. We at ProMIS are focused only on neurodegenerative disease. These misfolded proteins are produced across a range of diseases, even outside of neuro. In autoimmune, in oncology, our focus really at ProMIS is on neurodegenerative disease. For Alzheimer's disease, the misfolded protein we're going after is A beta. For other diseases, such as ALS, our kind of next candidate in the pipeline, misfolded TDP-43 is our target. When we're looking at multiple system atrophy, Parkinson's, misfolded alpha-synuclein, we've got a range of different proteins that we can create selectively targeted antibodies towards. That really uniquely sets us apart from probably everybody else that's out there developing candidates for Alzheimer's. I'll just use this one slide to show the audience that the complications in Alzheimer's are really driven by the fact that there are multiple species of the same protein. As you say, there's kind of a cascade of events. These toxic low molecular weight oligomers are kind of upstream. As the process, as the patient progresses, these toxic oligomers then go on to form plaque. There's a whole series of events created over the life of the kind of Alzheimer's patients. The challenge becomes, well, how do we target only those toxic oligomers? We want to avoid plaque because, as we've shown, plaque clearance is not sufficient to really halt or slow down significantly Alzheimer's disease. There are drugs that will totally clear plaque, and the disease continues to progress. We also know that clearing of plaque results in ARIA, the serious side effect. We are trying to avoid plaque. Then there's the A beta monomers. These are very plentiful, high concentrations of monomers. This is another form of A beta protein, but it's a beneficial form. It has a biological role. Therefore, you do not want to target monomers. Again, the challenge is how to avoid monomers, how to avoid plaque, and how to only go after these toxic oligomers. That's where ProMIS is unique and differentiated in. We have designed an antibody that enables us to selectively target only those toxic oligomers, avoiding plaque, and certainly avoiding monomers. That is really been the feature as we have moved through preclinical and into clinical development now. I want to emphasize, based on what you just said, Neil, first of all, that there is a very unique approach to targeting amyloid here, which could conceivably allow you to avoid ARIA or significantly reduce the risk of ARIA while maintaining efficacy and potentially even outperforming the efficacy seen with existing anti-amyloid antibodies, because they're much more inefficient in terms of addressing the truly toxic elements of the amyloid cascade in the brain. This is also a technology platform, which, of course, ProMIS is using specifically to address misfolded proteins in neurodegeneration, but which could also conceivably be used to address misfolded proteins and the toxicity and pathology that occurs downstream of that in areas outside of neurodegeneration. Now, I wanted to see if you could maybe briefly comment on the preclinical work that's actually been done, benchmarking PMN-310 against some of these existing anti-amyloid drugs, so that we can kind of see just how specific your approach is relative to what's out there. Yeah, that's very flashed up the thing story to the audience to kind of keep flashing back and forth. That's a good question. I think it was imperative to us to really prove our hypothesis preclinically. If we're out there claiming that we believe we're the only company that can develop an antibody that selectively targets these toxic oligomers, thereby potentially delivering a more efficacious and a safer product, we wanted to make sure preclinically that that was indeed the case. We did a number of kind of preclinical studies just to show whether we were really delivering an antibody that was differentiated, how we anticipated. This is an assay that we did looking at kind of binding of a variety of these antibodies in an Alzheimer's model. These are brain samples of Alzheimer's patients. We looked at the various antibodies that are in development or on the market to say, do they demonstrate binding to plaque? What do we see with PMN-310 specifically? Does it bind plaque or does it not? As you can see on this slide, kind of the brown markings demonstrate the antibody binding to plaque. You can see on the left column, the aducanumab, donanemab, lecanemab, all have these large brown spots. We know them to bind to plaque. They certainly, in our hands, as we did the side-by-side kind of analysis, those antibodies bound plaque, as we knew. We look at the middle column with additional antibodies, ACU193 from Acumen, PRX from Prothena. All these antibodies in our hand demonstrated binding of plaque. When we look at PMN-310 or the right column, we see no binding to plaque. Again, this was our hypothesis. This is how we designed our antibody. Again, this is giving us confidence that, yes, it appears in our hands preclinically that we are not binding plaque. Solanezumab, which is an interesting kind of control, if you will, does not bind plaque, does not show any incidence of ARIA, because solanezumab only binds monomers. You remember monomers are those plentiful A beta proteins that are beneficial. Solanezumab only binds monomers, which is the wrong target, so no efficacy, but also no ARIA. In our hands, PMN-310 seems to be the antibody that does not bind plaque. We also did another binding assay, a fluorescence assay, where we looked in the top row, which shows the presence of plaque. We did, again, Alzheimer's brain samples. We stained for plaque. The green fluorescence shows that there was plaque in the samples. The next row, the middle row, shows whether the antibody is actually bound to that plaque. As you can see, PMN-310 in the middle, no binding to plaque. When you look at the other antibodies, you can see the right fluorescence, the purple fluorescence demonstrates they are binding to plaque. Interestingly, we took this one step further, and we looked kind of quantitatively at the kind of intensity of the fluorescence with the antibodies. We can see, again, PMN-310, similar to our IgG1 control, no binding to plaque. We see quantitatively kind of fluorescence incident binding to plaque with all the other antibodies. This was another assay that we did in our hands to really give us confidence as we went to the clinic that we were not binding plaque. Finally, I'll just speak to our very robust tox study that we did. We, in transgenic mouse models of plaque, dosed kind of placebo and PMN-310 at very high levels, 800 milligrams per kilogram over 26 weeks. For half a year, we dosed at very high concentrations, PMN-310. We sampled and sliced every mouse brain to see if we could demonstrate any signs of ARIA, ARIA H. In our hands, doing this tox program, there's not one incidence of bleeding of these mouse brains. Again, this gave us a lot of confidence that our hypothesis to design the antibody, but then looking specifically at very robust preclinical studies, we believe that we had an antibody probably for the first time that did not bind plaque, that was selective to the oligomers, and it would not have this ARIA liability moving into the clinic. I think there are three important key takeaways that I want our audience to focus on. Firstly, PMN-310 appears to have a unique profile, and you've demonstrated that head-to-head, albeit preclinically, against existing anti-amyloid antibodies. Secondly, you can target elements of the amyloid cascade that are clearly not associated with causing ARIA. The concept of being able to create an antibody, as it were, for which effectively no ARIA risk exists, is possible. Lastly, and maybe you can opine on this as well. If prior to the advent of the existing first-generation anti-amyloid antibodies, everyone was talking about all of them potentially being mega blockbusters. Then, of course, this ARIA side effect cropped up. Clearly, an anti-amyloid antibody, even if it doesn't cure the disease, even if it doesn't reverse the disease, without ARIA, could still have that mega blockbuster potential. Mega blockbuster, for those who don't know, is annual peak sales in excess of $10 billion a year. Isn't that correct? That's very true. I think if we can deliver, and some have said, if you can deliver an antibody that removes this ARIA liability, even with similar efficacy, it's a blockbuster. I think that's true. I think what we believe we can deliver, in addition to the lack of ARIA, is we can deliver an antibody that has improved efficacy. I think we're going to really demonstrate more significant efficacy, much better side effect profile, and potentially even better patient compliance as well. That potentially can transform the treatment of Alzheimer's disease, which would be wonderful for patients. Obviously, PMN-310 is currently in the clinic. You did phase 1A development. You are currently in phase 1B. This is a study called the PRECISE-AD trial that is currently ongoing. You are looking for interim results from this trial at, if I remember correctly, the six-month time point to be released imminently. Maybe just walk us very quickly through the salient features of the data that you are planning to collect and release at the interim time point, what the future time points are for assessment in this study, what you are looking for, what you are hoping to see from the interim data, and why it would be so significant. Yeah, most certainly. This is the design of our study that we've got up on the screen. We took great care in designing this study. I think it's a little bit atypical for a phase 1B study to have such a comprehensive design. We wanted to make sure that at the end of the study, we would have a clear signal as to whether PMN-310 worked as expected. This study is a 12-month study in 100 patients with early Alzheimer's disease, so mild cognitive impairment due to Alzheimer's disease. It's in three doses, three increasing doses, 5, 10, and 20 milligrams per kilogram. We are measuring three buckets of endpoints, if you will. We're looking at a biomarker panel very carefully, and the biomarkers are listed here. Some are very indicative of clinical outcome. Biomarker assessment will be critical. We're obviously looking at safety and ARIA incidence. We're also looking at clinical signal as well. It was important to us to design a study that had a clinical read in it as well, rather than just a biomarker read. This study is enrolling extremely well. I think what we're seeing, Ram, is the enthusiasm from the physicians treating the patients in our study is very high, given the fact that they believe or potentially there will be no ARIA liability. They're excited to enroll patients into the study. We've completed enrollment in cohort one. We're now moving forward. We're excited about that. We've built in, as you rightfully say, an interim analysis into the study. The interim analysis will look at biomarkers and safety. This will be at a point when all 100 patients have been treated for six months. We'll do that interim analysis. That interim analysis will occur in the first half of next year. About a year from now, we'll have that interim analysis. It will look at biomarker signal, and it will look at safety, so ARIA incidence. Interim analysis, first half of next year. The final results will come towards the end of next year. Relatively near term, we're going to see whether we have a treatment for Alzheimer's that, as we expect, has improved safety profile and improved efficacy. That interim analysis, I think, will be really, really important to give us a signal as to, are we seeing what we expect? A few months later, we'll have the flip of that card on the final results to hopefully demonstrate that we have something really special in our hands. Just for clarification, usually when ARIA occurs, it occurs within less than six months of being originally exposed to the anti-amyloid drug in question. If you do not see ARIA at this interim time point at all, that potentially is a very significant finding and clearly clinically meaningful. Is that correct? I think that is correct. You're exactly right. ARIA tends to occur early on. You can see in this slide, that's why we front-end loaded our MRI or imaging just to make sure we pick up on that ARIA. We say here we're powered to provide 95% confidence that if one case of ARIA exists, we will see it. That interim signal around ARIA incidence could be quite interesting. Just to clarify, we do expect, we do see ARIA, although a small percentage, 1%-2% of ARIA, even in placebo patients. There's this underlying ARIA that does occur in placebo. We expect our results with PMN-310 from an ARIA perspective to be similar to that to placebo. It will be remarkable to kind of come with a drug that removes that ARIA liability. I very much agree with your sentiment. Just turning attention to our pipeline because we have only a few minutes left. I wanted to, first of all, draw folks' attention to PMN-267, which you are using to target amyotrophic lateral sclerosis, or ALS. That's a very serious, debilitating orphan disease that historically has resisted any attempts to effect a cure or even a meaningful reduction in the progression. It is a debilitating, relentless, inevitably fatal condition. I also wanted to ask one quick question about PMN-440, which is your program addressing synucleinopathies. Now, alpha-synuclein is a protein very much like amyloid that is found in the brain normally. It is misfolded in an array of neurodegenerative conditions, probably the most well-known of which is Parkinson's disease. I was just wondering, Neil, if you at this point have a sense of how you might approach clinical development with PMN-440, and if you would specifically focus on a particular disease indication where a pathological misfolding of synuclein is well-known and observed routinely, or if you might look to focus on a more basket approach where you enroll patients who have misfolded synuclein but are not necessarily just Parkinson's sufferers, for example. Yeah, really, really good questions. It'd be nice to talk for hours about the pipeline, Rom. I agree. It's really exciting. As you say, the next candidate coming along, all based on similar technology, misfolded proteins, the ALS program. We've had lots of inbound interest around ALS, obviously a huge unmet medical need. We've seen some larger trials not go our way over the past few years. There still is this strong urge and desire to come up with an ALS treatment. Misfolded form of TDP-43 driving ALS is certainly a well-understood mechanism. It affects the majority of ALS patients. Again, the challenge in ALS and TDP-43 is selectively targeting only the pathogenic form of TDP-43. That's that misfolded. If you wipe out all of TDP-43, you're going to get a worse outcome from the patient. It is how to selectively target only that misfolded form of TDP-43. Again, that is what we have with our exquisitely designed antibody. That program is fairly well advanced. The data is superb. We prevent the transmission of disease propagation from cell to cell going in with our antibody. There is also an intrabody approach, which we are looking at as well. ALS is something that we are really excited about. We are close-ish to the clinic. We probably have IND-enabling studies before we kind of get into the clinic and launch that program. ALS is exciting. The alpha-synuclein program, very similar. Your question around disease indication is an interesting one. We are discussing internally, potentially, is there some sort of basket trial since the synucleinopathies kind of affect different disorders from multiple system atrophy, which we tend to favor. Parkinson's is there, Lewy body dementia. This is something, the alpha-synuclein program is something that's exciting to us. Again, it's approaching the clinic as well. How we develop that potentially is a basket study moving forward is something we're considering as well. That's very exciting. We have the vaccine program. Just to touch on that for 30 seconds, as you know, we've got an Alzheimer's vaccine in development that is really exciting to us. It's generated really interesting preclinical data. It's essentially the same premise as PMN-310. We would be administering this as a vaccine where the individual would manufacture their own PMN-310 as a preventative, if you will. The vaccine approach to Alzheimer's disease is exciting for us. As we see the interim analysis potentially from the therapeutic vaccine, that might be a time for us to advance forward the vaccine program as well. Kind of having this franchise around a therapeutic and a preventative vaccine in Alzheimer's disease could be a really, really exciting kind of opportunity for us and for potential partners as well. The vaccine program is one that we're excited about in addition to that really healthy and deep pipeline of candidates. Once again, a very interesting company. We really thank you for taking the time to walk us through the salient features of ProMIS Neurosciences today. Obviously, very exciting. You're on the cusp of releasing data from this phase 1B trial with PMN-310. Look forward to having you participate in more of our events in the future. Neil, thank you so much for your time. Thanks so much, Ram, for your terrific questions and allowing us to talk about this. Appreciate it. Thank you. it. Thank you.