Of hosting Neil Warma, CEO of ProMIS Neurosciences. Neil, welcome. Thank you so much for making the trek down here to sunny Miami to be with us. But before we delve into Q&A, I would love to hear the state of the business, key data points to look out for the next 12 months or so. Sure. Well, thanks, Michael. And thanks to the organizers for inviting me again. This is always a terrific conference for us to meet some really good people and good friends. Yeah, the state of the industry, the state of affairs. And for us, we've had a really interesting, very successful, if I do say so myself, kind of year this year focused on our clinical study. I think there's a couple of kind of bigger picture items kind of looking at over the past year. I think one is on certainly the state of the industry, specifically the Alzheimer's space. That's our lead compounds and currently in a phase I-B study for Alzheimer's patients. And if we look on the landscape of Alzheimer's over the past several years, and certainly kind of over this past year with the two products in the market, good to have products in the market, most certainly for patients. I think what we're seeing, though, is these products still have a bit of a risk-benefit profile that isn't that favorable. So physicians are struggling to prescribe and how best to prescribe these products. So from a patient perspective, there's still challenges. And I think it's wide open for products and companies that come with novel drugs for the treatment of Alzheimer's. And then when you kind of look at it from our perspective, so maybe not great news for patients, but if you come up from our perspective looking at novel drugs to market, certainly that's where we feel we fit in quite nicely. We've been really pursuing our phase I-B trial with Alzheimer's patients pretty aggressively over the year. So as far as milestones and upcoming kind of events and data points, we're really pleased. And again, I'm really pleased as the CEO not to have to change guidance. And we've been pretty consistent with our guidance since the beginning of this trial. We really initiated the 1b study in kind of the beginning of this year, end of last year. And consistently, we've said we're going to target complete enrollment by the end of the year. And we're on track to do just that. And I'll maybe kind of back up to the design of the study in a minute. But complete enrollment by the end of this year. And then importantly, from data release perspective, we're expecting an interim analysis in Q2 of next year. And we're expecting final top-line results in Q4 next year. So it's been a really pivotal year for us executing on this trial, which the team has done extremely well. And data is just around the corner now, Michael. So we're excited about that for next year. Got it. Just to back up a little bit for folks who are not as familiar with the story as I am, PMN310, lead asset. It's an amyloid beta monoclonal antibody. Correct. Tell us why your target is perhaps the most optimal to target as opposed to a competitor of yours who are kind of targeting the same or similar species of amyloid beta plaque, but maybe higher molecular weight? It's interesting. I think the field has shifted. It wasn't that long ago that plaque was the amyloid beta target of choice. And there's a number of different and the challenge to designing these antibodies or these drugs are how to selectively target only the harmful species of amyloid beta. And there's multiple different species of the same protein, the monomeric form, the oligomeric form, the plaque form. So the challenge has been which is the most damaging that drives disease progress. And then how do you target that and not target the others? And the industry has shifted off the plaque form of amyloid beta. I think there are drugs that completely eliminate plaque, but the patient continues to progress with Alzheimer's disease. So there's modest benefit to the patient by clearing plaque. And now we know there's also this significant side effect issue, ARIA. So, drugs that focus on clearing plaque are really not, and those are the kind of all the drugs kind of in development and on the market are not the drugs of choice. But then, as you say, Michael, the challenge is, well, how do we avoid plaque and how do we avoid monomers. Because we know that's not the right target, but go after these toxic oligomers. And the industry has now shifted away from plaque onto these oligomers. And these are low molecular weight, highly soluble, highly toxic forms of amyloid beta. And the toxicity really comes from their kind of attacking, if you will, of the neurons, specifically the synapses. So these oligomers really go after the post and presynaptic terminals to drive disease progression. So for us, and we've stuck with this premise since day one, probably beaten up a little bit back in the days when it's like, how can you design something that avoids plaque on purpose? And it's like, well, we believe it's the toxic oligomers that are driving progression. And now that the industry swung back, it's like, wow, we think it is as well. And others have tried. And lecanemab was designed to selectively target oligomers. But at the end of the day, they cross-react with different forms of the, so they bind plaque and they cause ARIA, and the efficacy is not very good. So it's interesting that now people are focusing on ProMIS to say, it looks like you guys really have this antibody that does selectively target only the oligomers. The low molecular weight. The low molecular weight oligomers. Exactly. And that really seems to be the species. And there's tons of publications on this that's really driving the toxicity and the progression of Alzheimer's. OK. And not to drill down on this, but there's a competitor that's also targeting oligomers. But I think they're targeting a higher molecular weight species. Why is the low molecular weight optimal here? I think the low molecular weight is the ones that appear to be most toxic. And we kind of do bind some of the high molecular weight as well. But we're more selective on these low molecular weights, which I think has been shown to be the real driver of toxicity here. I see. OK, now onto the phase I that's ongoing. You guys have a clean safety profile so far in cohorts one or two. Very encouraging. But presumably the real test comes as patients spend more time in the third cohort at the 20 microgram dose. So how should we think about the safety picture evolving as patients are exposed to higher dosage here? Yeah, really good question, and just for the audience, we are, again, we're expecting complete enrollment, and this study is enrolling, targeted enrollment is 128 patients, so we are targeting enrollment of 128 to end up with 100 completers, so we've got that buffer for typical rate of dropouts in Alzheimer's study, and on that note, our dropout rate is significantly lower than what we've seen in other trials, so we're probably going to end up with quite a few more than 100 patients, so 100 patients over three doses, 5 mg, 10 mg, and 20 mg per kilogram, and again, we got DSMB approval months ago to dose escalate from dose one to dose two, and then months ago again from the DSMB to dose escalate from dose two to dose three, so we are well into cohort three as far as the highest dose in enrolling patients. The safety profile, as you correctly say, has been kind of superb to date. I mean, one of our positions here in differentiating factors is that we believe we will eliminate much of the ARIA liability that we've seen with drugs. And we're not saying there will be no ARIA because even in placebo patients, there's an underlying rate of ARIA kind of in that 1% - 5%. So we're expecting that PMN310 will be equivalent to placebo levels in ARIA incidents. So we've seen, as you rightfully say, a really superb, touch wood, side effect profile to date as far as SAEs, as far as ARIA incidents. I mean, we are treating patients now in that higher dose. So we are kind of at the higher dose that you mentioned, Michael. So we are kind of maximizing the dose there. We're still seeing very above expectations levels, certainly of clean safety and such. It's also important to keep in mind that for other similar programs, lecanemab, donanemab, the majority, kind of 90% of all cases of ARIA were seen in the first six months of dosing. So we've front-loaded our MRIs to really be able to pick up any ARIA if there is any because it's important for our differentiation, and to date, we're really kind of pleased with the safety and side effect level that we're seeing. OK, so in the current phase I PRECISE- AD trial, six-month interim is expected middle next year, correct? Correct. And that's not an efficacy look. It's just safety and biomarkers. Am I correct by saying that? It is. I mean, there'll be an inference that we can get on kind of efficacy, if you will, from the biomarkers are a measure of target engagement that are somewhat predictive of clinical outcome. But you're absolutely right. The interim analysis, middle of next year, and there's really three sets of endpoints we're looking at: the biomarkers, safety, ARIA, and clinical endpoints. It was really important for us in the design of this study, which is pretty atypical for a I-B study to have 100+ patients, 12 months of treatment, and this is monthly dosing with a clinical endpoint read. But important for us, the interim analysis, the biomarker panel that we are looking at is very well understood in Alzheimer's disease that the biomarkers are very well understood. We've got pTau217, which measures disease progression, pTau243, which measures downstream tau phosphorylation, neurogranin, a sign of neuroinflammation. And importantly, on the synaptic markers, GFAP and SNAP-25 postsynaptic, presynaptic biomarkers are going to be really important for us to look at. So the markers themselves that we'll look at in a blinded fashion in the interim analysis should paint a pretty interesting picture as far as potential clinical benefit. We're not going to look at clinical after because this interim analysis, for those in the audience, as I said, 100 patients treatment over 12 months. The interim analysis comes when all 100 patients have been treated for six months. So we're not going to look at efficacy. Again, that's more a 12-month kind of signal. But the biomarkers, and we just published a paper. We put out a press release yesterday, this week, really fascinating paper that was done with our colleagues at Pentara, one of the top biostats groups in the world. And it was interesting. And it's somewhat surprising. It was only done now with Pentara and ProMIS looking at the correlation or the predictive value of pTau217 as a biomarker in clinical outcome, kind of CDR Sum of Boxes. And the correlation is remarkable, statistically significant. And we've all known and spoken about pTau217 and pTau181 as well, the pTaus being predictive of clinical outcome. And now this paper kind of really shows its statistical predictability, which is important. So again, to your point, there will be no kind of CDR Sum of Boxes clinical endpoints in an interim analysis. But I think if we see separation of the two groups on a biomarker perspective, that will be really, really interesting in addition to potentially clean safety. So it will give a kind of infer a signal of efficacy as well, if you will. Got it. So a key question I get when talking to clients about just the Alzheimer's space is that when PMN310 comes up, you guys don't clear plaque. But in light of this paper that just came out on pTau and the predictability and potential utility of it, where do you think, or how long do you think it'll take the FDA to kind of accept pTau as a valid biomarker just as they do plaque reduction? That's interesting. I mean, I think because again, keep in mind when aducanumab, Biogen's forerunner, if you will, was approved, it was approved on the basis because of plaque reduction. Plaque reduction. But reduction. But the FDA approved it, obviously. But the FDA has backed away from that pretty, I guess, dramatically, if that's the word, since then to say they're not doing that anymore. Because again, what they found was even though it cleared plaque, there was no clinical benefit. So the FDA kind of a little bit got its wrist slapped and said, OK, well, that leaning on biomarkers for predictability is not kind of a great way to do. So they backed up. And now FDA is all about clinically validated endpoints, CDR Sum of Boxes, ADAS-Cog. So to your question, to be able to say for the FDA to come back and say, well, we did it once for plaque, maybe now we're going to look at pTau217 as a biomarker for approval, I'm not so sure the FDA will get there. And I'm not so sure they should. I think for us designing studies, and the one thing it showed in that paper that was really interesting is that pTau217, pTau181, the pTaus can be highly predictive in that the ability to run smaller studies in the 100 patients. And this is done after we already designed our study. So it's kind of an interesting conclusion. But the ability of a smaller study to predict clinical outcome is certainly on the table now. But I don't know that the FDA is going to go as far as saying pTau217 is an approval endpoint. I think they're still going to stick, which I think, rightfully so, they should stick to that clinical endpoint. I see. I see. So you had the interim readout after patients complete six months. The 12-month readout, I think, is still set or expected to complete at the end of next year. Correct. Correct? So that's when we're going to get a first glimpse of, I guess, clinical efficacy. So how do you define what's meaningful, what's a meaningful clinical outcome when that data comes out? I think it's a good question. Again, the design of the study, and it was one of our better decisions last year in how to design a study that's going to give us a definitive answer. Because the one thing we didn't want to do is end up, and some companies before us have done a three-month, 30-patient biomarker-driven study. They kind of do it. Biomarkers are interesting. Then it's kind of like, now what? They go and do a larger study. For us, it was like, let's define a study or design a study that's going to give us a definitive endpoint, hence the 100-patient 12-month study. Again, 100 patients or 120, whatever it ends up being, is a very large I-B study. Certainly not. It's not designed as a pivotal study. So, I think with respect to clinical outcome, and if you look at the complete picture that we'll have at the end of next year with biomarker safety and clinical outcome, what I'm expecting is that statistical significance around some of these key biomarkers, again, the 100+ patients should certainly lead us there. So, statistical significance on the biomarkers, which shows that the drug we're engaging target, the market's all about, are you engaging target? Yes, we are at a dose that we've defined our dose. We've defined target engagement. We've got safety. And I think we'll have statistical significance around safety endpoints. Have we reduced significantly the ARIA liability? That should be on the table as well. And then finally, with the FDA kind of approved clinical endpoints, are we seeing a healthy trend? I mean, 100+ patients is not a huge number to show a 0.05 p-value on a clinical endpoint. But I think if we show efficacy or a strong trend in efficacy clinically, kind of the clinical trend, efficacy trend is important. Can we deliver it safely, which we'll show? Can we deliver at a dose that we're engaging target? We should show that as well. And if we have that, and then in discussions with FDA, will that be enough then to go straight into a pivotal phase III study? And I think from our perspective, it will be. And what we're hearing from the strategics as well, that if you get to that result, biomarkers, safety, and a strong clinical signal, then the ability to step into a pivotal phase III and avoid this whole middle several hundred million two, three-year trial would be huge. It's a faster time to market and gets us there that much more quickly. Got it. Granted, it's a phase I, but it's kind of a relatively large phase I. It is. And have you disclosed the powering or what effect size you're assuming? In In the past, can you talk about that or no? We have not. We haven't kind of put out there kind of, and again, as far as the clinical signal, it would be superb to get to some statistical, but we're not kind of really expecting that with 100+ patients. It's really a nice solid trend, as I said, supported by, because some have said if you deliver a product that kind of just removes significantly the safety issue, the ARIA liability, but even delivers similar efficacy, it's a huge win, which I think it is given the challenges out there in the market today. But for us, even with a product that selectively targets these oligomers, so all the drug is delivered to the target, I think our efficacy will be superior. Not that the efficacy threshold's that high, unfortunately, for patients, but being able to kind of amplify the efficacy signal in addition to having clean safety, I think certainly is in the cards. Got it. As we think about the ARIA profile, again, very stellar safety profile to date. But in terms of APOE4 carriers, that's a really big deal in terms of just people who have that genotype. And your own materials kind of frame that APOE4 carrier as a major white space opportunity. So can you walk us through how you're thinking about APOE4s in the phase I PRECISE- AD trial? Who's getting in? What you're hoping to learn from this group? And if things break the right way, how could that ultimately shape PMN310's positioning? Yeah. Again, from a mechanism perspective, Michael, I don't think we're kind of treating the APOE4 any different. We're not stratifying the trial to kind of include/exclude. There'll certainly be, I think, what is 50% of subjects have that. So I think they'll certainly be part of the trial. So we'll do an analysis of the APOE4 patients, kind of post-hoc analysis. But I don't think we're treating them any differently. I think the ability of PMN310 targeting the oligomers, the effect it'll have on whatever the genetic makeup, the APOE4 or not, I think will be similar. So for us, if we can benefit that population equally, I think it'll be a huge opportunity for us. So that's something we'll look at certainly post-hoc. But we don't want to kind of limit our label, for one thing. And we don't want to kind of stratify at this stage. If there's something we can do on top of that, looking at a future study, specifically in this patient population, we certainly could. But again, for us, there's no reason to stratify right now because mechanistically, it's probably going to affect them, would anybody else, quite favorably. Makes sense. In the final time we have, I want to touch upon the possibility of going subcu. Seems like everyone's exploring subcu as a long-term modality. So at what point will you make the go/no-go decision to pursue that formulation? That's a really good question. I think that decision will probably be made at an interim analysis. So in a few months when we see the interim data come out. The interesting thing is right now we're looking at, and the half-life of the antibody is around 27 days, which we learned from the phase I-A study. So monthly dosing for sure. Knowing that, again, all of our drug that crosses into the CNS hits the target. And we've got about 100 molar excess of drug to target. So even at the low dose, the 5 mg and certainly the 10 mg, we believe we have enough drug in the CNS to bind all of the oligomer targets, which again kind of obviates the need for any brain shuttle mechanism. We don't have ARIA liability. We have enough drug in the CNS anyway, so that the need to have a shuttle doesn't really make sense for us, so from that perspective, if we can deliver maximum efficacy at the 5 mg or 10 mg dose, that certainly bodes well for subcu. Because you don't want to have, I know there's companies out there looking at subcu at a fairly high dose, which is a lot of protein to give under the skin, so if we can hit that 5 mg or 10 mg sweet spot, and we'll see, we'll get a hint of that certainly at the interim analysis, that would be a point to kind of trigger the subcu and kind of go all in for the subcu and develop that in parallel next year. As we finish the study, we get the subcu formulation going, do the bridging study into the pivotal design. That's all been planned and thought of as well, as has the pivotal design. A lot of work's been done behind the scenes to prepare for success, which we expect really in the coming months to be able to take this forward pretty aggressively once the data are there. Got it. Well, unfortunately, that's all we have time for. But fascinating story, Neil. Thank you so much for spending time with me. And we wish you the best of luck in the months ahead. Thanks very much. It's a product we all probably need at some point, unfortunately. I appreciate the attention from the audience. Thanks for the questions, Michael. Great. Very much.