Welcome back to the Guggenheim 2025 SMID Cap Biotech Conference. My name is Eddie Hickman, and I'm one of the biotech analysts here. I'm joined today by ProMIS CEO Neil Warma. Neil, thank you for joining us again. Exciting year for ProMIS. Can you maybe spend a few minutes giving us some highlights from last year and some key milestones that you're looking forward to this year? Yeah, sure. Thanks for the invitation, Eddie. Always good to catch up. Thanks for attending and listening in. Yeah, we had a very successful year last year. I think there were three key milestones, objectives that we were trying to achieve in 2024. That was the completion of our phase 1a clinical study. This was in healthy volunteers. Execute that and execute on time. Finance the company was our second objective. Design and initiate our phase 1b clinical study in Alzheimer's patients. Three big objectives, and we achieved all of those quite well. Our team is superb, and we executed really well on the phase 1a data. Again, it was a healthy volunteer study, but we saw positive results, safe and well tolerated. Our PMN 310, our lead candidate in Alzheimer's disease, so safe and well tolerated. Also importantly, we saw levels of PMN 310 in the CSF, crossing the blood-brain barrier in concentrations that were highly encouraging for us to believe that we're going to engage target in the patient population. Phase 1, positive 1a results. On the financing, we did an interesting financing, which we completed on July 27 last year. It was a PIPE financing. We did a kind of a tranche financing to raise up to $122 million, almost $123 million, so very successful financing. Importantly, the design of the 1b study. This was really spearheaded by our Chief Medical Officer, Dr. Larry Altstiel, in coming up with a design of a 1b study that was comprehensive and thoughtful enough such that when we completed the study, when we flipped that card, so to speak, we would have a result that really indicated that PMN 310 is safe and effective in Alzheimer's disease. The design of the 1b study, a 12-month, 100-patient study, again, very thoughtful design. We wanted to initiate that by the end of last year, and we did. Again, a successful 2024. Kicking off this year with the initiation of the 1b, we are focused again on a few objectives. One, execution of the 1b study. We're expecting interim results. We can come back to this in a minute. Interim results in the first half of 2026, final results at the end of 2026. Execution of the 1b study is front and center. Engaging with investors, getting out there and telling our story, how we are differentiated in the field of Alzheimer's. We are also augmenting our discussions with strategics. We've started our discussions with pharma partners. We expect them to be a big part of where we go after this study. The whole business development strategic discussions are a big part of what we're doing this year as well. Exciting for us. Yeah, great. I want to get into the phase 1b trial a little bit. First, can you sort of maybe, for those who aren't as familiar with the program, just maybe summarize what the approach of using 310 to specifically target these toxic oligomers versus the plaques is? Can you just remind us what preclinical data is out there that sort of suggests that this might be the optimal approach for Alzheimer's disease? Yeah, sure. I think over the past couple of decades, the field has really moved away from plaque clearance as the be-all to end-all. I think now people realize that it's these toxic oligomers that are driving disease progression. We know that there's modest efficacy with these drugs that are on the market that kind of target plaque. We also know there's a significant side effect issue or this ARIA liability. We've shifted away from plaque, trying to focus on how to get at these toxic oligomers. We, as ProMIS, have come and said, look, we believe we're the only company that has designed an antibody that selectively targets only these toxic oligomers. This is resonating well. We know that the risk-benefit with products on the market is such that these products are just not getting picked up. I mean, there's challenges with the risk and it's ARIA. For us, we've designed an antibody. We can tell you how. It's our whole premise of being able to identify misfolded forms of these oligomers, identify an epitope that is present only on this misfolded form of oligomer, manufacture, create an antibody that binds the epitope and clears these toxic oligomers. This epitope, this binding site, is not present on monomers, and it's not accessible in plaque. We can target our antibody to the toxic oligomers only, and we can avoid plaque, which isn't clinically relevant, and we can avoid that ARIA liability, which is huge. That's how we're differentiated. The preclinical studies we've done were very extensive, looking at, do we bind plaque? Are we seeing any of this ARIA- H or ARIA- E? We applied our PMN 310 in multiple brain segments, Alzheimer's brains, to see if there's any binding of the plaque in these Alzheimer's brains, and there was none. As part of our formal toxicology program, we treated mice in a placebo and an active study. We looked at whether, at very high doses, we dosed these mice, these transgenic mice who had significant depositions of plaque. We dosed them for 26 weeks, so half a year, up to 800 mg per kg of PMN 310. We did sections, and we looked at every brain, and there was not a trace of hemorrhage in any of these brains. We've done essays. Now it's a pretty high dose, right? Yeah, 800 milligrams for half a year and squeaky clean brain sections. We have done side-by-side comparisons with all the antibodies in development around the market with PMN 310 to see if there is any plaque binding. We know there is plaque binding in these other antibodies, and we saw that, and we saw none with PMN 310. We have done extensive preclinical testing to test the hypothesis where we have designed an antibody uniquely binding to these oligomers, which gives us a lot of confidence going into the clinical study now. Without having plaque removal or plaque reduction as sort of a biomarker, what are the key biomarkers you expect to change when you are inhibiting this toxic form? And how does it may differ from sort of targeting the plaque? Yeah, the biomarkers are interesting. In Alzheimer's, biomarkers can be very predictive of clinical outcome. I mean, for us, it was not enough to design a biomarker-only study because we wanted to have that clinical signal. We have a 12-month study with a clinical endpoint. In Alzheimer's, it's interesting that a number of these biomarkers are very predictive of clinical outcome. In our biomarker panel, I mean, the ones that really are most important, if you will, p-Tau217, which measures levels of disease progression, is probably the best-known biomarker out there for clinical predictivity. We've actually got a publication that we're coming out with, with one of the top kind of biostatistics groups, which shows the impact of p-Tau217 on its predictability and clinical outcome. That's an important one for us. p-Tau243, which again is a well-known, validated biomarker, if you will, shows kind of downstream hyperphosphorylated form of tau. That's another key endpoint for us. We also know that these toxic oligomers really beat up and destroy synapses in the brain. It's either presynaptic, postsynaptic. The function of the synapse is a very important signal for us. There are two biomarkers specifically that look at presynaptic function, and that's SNAP-25. We're looking at that closely. Postsynaptic function is neurogranin. We're looking at both those biomarkers and a number of others. It's interesting. We've got a broad panel of biomarkers that we're investigating in the trial. Importantly, we've also got the clinical endpoints that we'll be measuring kind of at the end of the study. Yeah. Are there any comps in the space? I know Leqembi may bind oligomers as well as plaques, and there are other antibodies in development. I am just wondering if there are clues to what the level of these biomarker changes you could see is and how early you might be able to see them based on sort of other programs or in your proof of concept work to show how soon might we see some of these changes. There is. I think looking at some of the benchmark studies that have kind of gone before us with some of these other drugs that are on the market, it's interesting because we've seen biomarker movements kind of as early as three months. We are expecting, and I'm not sure if I mentioned, but part of the design of the 1b study, again, it's a 12-month study with clinical endpoints, but we've also built in an interim analysis, which occurs when all 100 patients have crossed the six-month treatment timeline. Back to your question then, we've seen there's precedents out there from other companies that even at three months, there's been interesting separation of biomarkers. We expect that at six months, we will be able to see a separation in some of these key biomarkers. The interim analysis will look at the biomarker separation and will importantly also look at ARIA incidents. Safety and biomarkers at that interim analysis will be absolutely critical. We know that ARIA typically occurs early on in treatment. Those first six months of treatment should be particularly interesting. If we see in an interim analysis basis, if we see even on a blinded basis where we've got the two groups are at similar low levels of ARIA, that will be very encouraging. If we see that the two groups are starting to show separation in biomarker movement, so again, in theory, we could say that safety is very encouraging. We've removed the ARIA liability. We're seeing separation. We know that there's a potential efficacy coming from the interim analysis. That would be sometime in the first part of 2026? Correct. Yeah, we've given guidance. First First half of 2026, we'll look at the interim analysis. Importantly, the top-line analysis comes just a number of months later towards the end of the year. It's not like people have to see interim and then wait months and months and months. That final result should be forthcoming fairly quickly thereafter. Gotcha. This is still a MAD study. Can you maybe just talk about when you expect to finish every cohort, and then you'll have sort of the IDMC tell you you can move forward? Is there any sort of disclosure you can make at that point to sort of clue us into the safety or just give us some confidence that you're seeing clean safety before you move to the next one? Yeah, that's a really important question. Certainly, I mean, we have our independent data safety and monitoring board, the DSMB, that looks on an unblinded basis at the safety data coming through the study. We will most likely communicate when the DSMB has given us the green light or the thumbs up to dose escalate. There are three doses in this study, 5 milligrams, 10 milligrams, 20 milligrams per kilogram. When after the first cohort we see a thumbs up from the DSMB to advance to the next cohort, that will be a, I mean, it's always an important signal that shows safe and well tolerated. Especially for us, when safety has this definition of ARIA, I think that signal will be especially interesting as we go from dose one to two to three. We expect to get that signal over the course of the year, over the next number of months from dose one to dose two and then dose two to dose three. I think that'll be an important message coming out from us to say that safety is looking good. Again, that implies that safety and ARIA are looking encouraging. Yeah. So you've started the study and you're enrolling now. Can you maybe just clue us into how many sites you have up and going, what your target number of sites is, and then sort of what the enrollment cadence is looking like so far? Sure. Yeah, no, it's been really encouraging. I think, yeah, just to, I mean, back up for a minute. When you look at the products that are on the market, and there's a real challenge to get these products to patients given this risk-benefit that we talked about, I mean, physicians are just not prescribing the product because of this ARIA risk and modest efficacy. We're seeing the sales numbers from donanemab or Leqembi, they've been downgraded a couple of times now. We're seeing signals from EMA around the past approval of Leqembi. donanemab was not approved. You've got this huge issue with the drugs on the market that's challenging to physicians who are not prescribing. The idea of managing this risk is not worth it. You've got the regulatory bodies that are just not approving. At the same time, it's a huge unmet medical need. It's not like there's a no desire to treat Alzheimer's patients. To the contrary, there's an even bigger desire now to do this. I think it's been a commercially validated space. Drugs have been approved, and doctors are prescribing them in small amounts. There's that urgency. They're looking for that differentiated asset that has a much different risk-benefit profile. That's where we come in with a very differentiated asset. We're seeing that with our clinical trial sites. We're looking at activating, and pretty much all of them are activated now, 22 sites in the US. We want to have 100 complete well-enrolled, 128 to get to 100 completers. It's really encouraging. We got a message from our clinical person just this morning who's kind of out there doing the site initiations. Enrollment's kind of picked up really nicely. Encouragingly from us, I mean, the investigators, the physicians who are running these sites are really enthusiastic about getting into the study. IRB approvals are moving faster than they have before. Getting these site activations is moving quickly. I think that's really driven by the fact that they believe they will not have this ARIA liability. Knowing if there was that, and every other drug has some sort of ARIA liability associated with it. I think the docs are thinking, do I want to get involved in another study? If there's a patient that I have to monitor, as Dr. Altstiel said, if somebody presents with a headache, is that, oh my goodness, what do I do with that? Do I have to get them into the neuro ICU? How do I manage that? Physicians have, I think, had enough of that. When we come with an asset that potentially does not have that liability, that's really motivating for the physicians. They're signing up and getting patients enrolled and screening really rapidly. We'll be able to update as we go along. Any exclusions in terms of the types of Alzheimer's patients or any genetically defined that you would avoid, or is this a broad population? No, this is broad population, but it's early onset. These are mild cognitive impairment patients that are due to Alzheimer's. We are careful how we select these early patients that are defined by imaging and biomarker analysis that are true Alzheimer's patients. We are looking at early-stage patients. For us, the goal would be to catch them early and certainly halt progression of disease. I think even as we've talked with some physicians and internally, if we catch these patients early enough, and if there's damage to the neurons or damage to the synapses that has just started, and if we cut off that destructive potential, do the neurons then have the ability to recover? We think that's definitely possible. That's why getting early in the process in the Alzheimer's diagnosis is important to us. If we can halt disease and keep these patients at a stable level for years and years and years, essentially we've cured Alzheimer's. And if there's a potential for reversal, that would be outstanding. Right. So you don't expect to reduce plaque, but you might hope to prevent the progression towards plaque? Exactly. Because I mean, it's the oligomers. It's the upstream process, these oligomers, which feed all the downstream plaque building and tau phosphorylation, neuroinflammation. If we can work upstream and sequester and remove these toxic oligomers before this downstream damage has happened, then ideally, you prevent the buildup of plaque. We're not expecting to clear existing plaque. There might be some indirect mechanism we see, but essentially we do not bind that, so we're not expecting much. We're preventing that whole upstream process of creating these new plaques and really preventing the destruction of the neurons. When we think about then the bar for these clinical endpoints sort of at the 12-month mark, is the bar the same for the sort of plaque-clearing antibodies, or do you expect to sort of maybe improve more or maybe change the magnitude of improvement or the direction because of this differential approach? As opposed to clearing plaques, you're preventing progression of neurogenic? Yeah, I mean, again, the endpoints and how they're evaluated by the agency are consistent. I mean, we've got our clinical endpoints. The CDR-SB, the ADAS- Cog measurements, which are defined clinical endpoints. Obviously, that's how we build our study, and those are the endpoints we look at clinically. Again, there's kind of two aspects. We've had these discussions with strategics, with KOLs. Are you looking to just remove the ARIA liability? That's certainly a big part of what we're going after. Many have said, well, if you get similar levels of efficacy, which are not great, but you remove the ARIA piece, that's a huge win. I would agree with that. These are experts saying that, not me, but I would agree with that. I think our thinking is we expect to see improvements in efficacy. Again, because if you can imagine, our drug, if there's multiple forms of this amyloid beta, monomers, plaque, and oligomers. Regardless of side effect, if you're administering the drug, but some of it's going to bind the monomers, which are at much higher concentrations. They're being distracted here. They're off target on plaque. Very little of the drug is going to the oligomers. I think that's why Leqembi was designed to bind oligomers. That's what they have, the company has said. They know that their product binds oligomers. Maybe that's where the efficacy is coming from. They also get absorbed by monomers and plaque. That's why efficacy is maybe muted, but at least they're getting the right target to some degree. If we're saying all of our drug, none of it gets distracted because it can't, it's all going to the oligomers. We do expect, obviously, no safety issue, but we also expect higher efficacy. All of our drug is going to the target. That could be two outcomes. One is higher efficacy, but also if we are saturating the target with lower volumes, lower concentrations of drug, that is not a bad thing unto itself. It is even more relevant because if we can maximize target engagement at these 5 or 10 milligrams per kilogram, we know right now it is monthly IV dosing. If we could anticipate that if we are at these low levels, could it be a subcutaneous dosing? Other companies are talking subQ. There are levels where multiple grams of protein have to get injected, and that is not going to work. If we're at these 5 or 10 milligrams per kilogram levels, maximizing efficacy, and we can convert that to subQ once a month, that would be superb. I want to go back just to the endpoints a little bit. Do you have a sense of what magnitude on some of these endpoints you'd want to see that gives you confidence in 12 months that you'd see clinical benefit? If there's sort of mixed results at six months, are there changes you can make, or are there sort of adjustments you can make to improve the chances of success? I'm just wondering, at six months, will we have a good clue into what the 12-month efficacy data could look like? I think we'll have a good clue as to what the 12-month clinical data can look like, in part because these biomarkers are very, I won't say validated, it's not the right word, but are predictive of clinical outcomes. We said p-Tau217 is highly predictive of clinical outcome. We haven't gone as far, certainly externally, to say, here's the range we want to see at six months. We expect across this threshold with p-Tau217, this threshold at 243 in neurogranin. We haven't communicated that externally. We certainly look at it internally, Eddie. As far as disclosing that at a six-month analysis. No, I was just curious if you had a bar at six months. We do. I mean, internally, we know kind of how these have moved in the past and what would be meaningful or a very positive signal at six months. We have a good understanding based on precedence and based on our knowledge. It is certainly reinforced by the fact that these are very well-understood biomarkers. We are probably not going to look, we are not going to unblind these biomarker data. I think for us, we want to be really careful we do not compromise the data. I know a lot of people would be like, what are we seeing and what is out there, what are we getting at? We want to be careful not to piecemeal the communication of this. I think at six months, if it's blinded and we see, as I said, if we see the two groups at low levels and we see this separation, that will be an interesting signal. For us to go in and tear it apart and look then, we probably won't unblind ourselves. Because again, it's so quick thereafter that the final endpoint comes. As I said, we don't want to jeopardize the data at all. We do internally have some ideas of how these things should shape up. Yeah. Last thing I want to talk about is you mentioned sort of some conversations with strategics. I know there have been some deals in the space recently. I'm wondering, when you talk to these guys, what they want to see. Are they convinced by the oligomer hypothesis because of Leqembi, or does the FDA's use of sort of an amyloid reduction accelerated endpoint make them? I'm sort of wondering, do pharma, do they understand this differential approach, or do they need to see the full 12-month sort of efficacy data to convince them that this is the way to go, or will some interim safety or biomarker data? It's a really interesting question. I think, yes, the interim might drive some pretty interesting conversations. We've had a number of discussions. We're also kind of ramping up our business development strategic discussions kind of now once our trial's running and going. It's a really good opportunity to get in front of the strategics. They've been very, like I said before, we sat with a number of them in the design of this study to say that once this is completed, we want to come to you to do that registration study with us, that 1,000-patient study. We will certainly, as our interim analysis comes, have a good understanding of how that next study looks. We would like to partner that ideally with large pharma. We've had those discussions. They've helped in the design of the study. There are a lot of them that are leaning forward and kind of really interested. I think many of them, most of them now kind of understand the relevance of these oligomers. Again, 10, 20 years ago, kind of plaque was ruling. Now they understand, as we've talked about, that we're shifting away from plaque onto these oligomers. They understand that ARIA is a huge signal. They see the sales numbers coming, and it's just, that's not doing it. We've got to get at these oligomers. It is important to kind of have these discussions with strategics now, build those relationships. When the interim analysis comes out, it'll be interesting to see their reaction. I'm anticipating that when the final results come out, that's when we'll see something really robust from the strategics. Again, I mean, we saw the takeout by AbbVie of Aliada a couple of months ago, very early-stage Alzheimer's drug. This was a company that was where we were a year ago, so pre-phase 1a readout. AbbVie acquired them for $1.4 billion. The drug is a donanemab, me-too. This is a similar epitope. It is a known entity, modest efficacy, high side effect issues. They have got the brain shuttle mechanism there from the company too. It is interesting from our perspective, if AbbVie's or pharma's willing to go in that early to pay $1.4 billion for a modestly efficacious and highly risky drug, probably bodes well for us. Yep. Anything else we missed? No, I think that's it. Eddie, really stay tuned. As I said, we're excited. The enthusiasm from the physician community is, I mean, I haven't really seen that before in my years, and I don't think Dr. Altstiel has either. We're really buoyed by that and the enthusiasm. We want to get this trial ramped up and enrolling, and we'll kind of come back and communicate. As I said, for us, it's execution on the study and get out there in front of the investors and retell our story and how we're truly differentiated in the field of Alzheimer's, an area that has a huge unmet medical need, and then really pushing with the strategics to get them more familiar with the story and show them what we can do with our novel antibody. Great. We'll look for some updates on the enrollment throughout the year. Thanks for being here. No, thanks very much. Appreciate it. Thanks, everyone.