Hickman. I am one of the biotech analysts here at Guggenheim, and I am joined by my colleague, Yatin Suneja, and the CEO of ProMIS Neurosciences, Neil Warma. Neil, thank you so much for being here and joining us. Maybe before we start, for anyone who is not familiar with ProMIS, just give us a short background on the company and some news from the year and some upcoming catalysts that you are looking forward to.
Yeah, of course, Eddie. Thanks again for the invitation to the conference, Yatin, you as well. Excited to be here with Larry Altstiel, our Chief Medical Officer, is in the audience with us as well. Yeah, been a fascinating year for ProMIS. Our focus has been very much on executing and enrolling and dosing patients in our phase I-B clinical study in Alzheimer's disease. ProMIS Neurosciences is a company that is technology platform is based around misfolded proteins, so the ability to design antibodies that are highly selective to a specific form, a misfolded form of a protein for a specific disease.
So we are developing a next-generation anti-amyloid monoclonal antibody for the treatment of Alzheimer's disease. Again, our trial is fully enrolled. We are now completing dosing and finishing off patients in this study. We have enrolled 144 subjects, and we are expecting top-line data coming soon in the next few months. We have guided towards top-line data Q1 of 2027.
Great. No, thanks for that. Before we dig into the data you have shown already and sort of what we should expect-
Sure
-in 1Q, maybe can we step back and talk a little bit about your hypothesis, which is different from what some of the approved therapies in this space have done, and how you think targeting the toxic oligomers is sort of different from a plaque-targeting antibody?
Yeah, sure. I mean, just to be clear, it's consistent with a few players out there that have tried to design antibodies to go after the toxic oligomer species. We're certainly not alone in recognizing that the oligomer species of amyloid beta protein appears to be the most toxic form of amyloid beta protein. When you look at lecanemab that's on the market, their aspirations and their goal was to design an antibody that selectively bound to the upstream toxic oligomers. We are, again, we're kind of part of this field who truly believes that the oligomer hypothesis is front and center in driving cognitive decline in Alzheimer's disease. I think the differentiation from our perspective is being able to design an antibody that truly is selective to that toxic species.
While others have tried, I think almost, well, every other drug candidate that's tried to be selective to the oligomers also binds other species and other forms of amyloid beta. We see with the other drugs on the market and in development, they also bind to plaque, for example, and we now know that plaque is not really associated with cognitive decline in Alzheimer's patients. There's drugs that completely clear plaque, and patients continue to decline. We now have shifted the thinking to these toxic oligomers, but again, the challenge for other drugs, other companies, is to design a drug candidate or an antibody that can avoid the other forms of amyloid beta and just hit the toxic species.
That's where our platform, our ability to predict how proteins are going to misfold, and therefore design antibodies that are exclusively selective to a given target, and in our case, these toxic oligomers, we're able to differentiate ourself. Again, a similar mechanism to what people are thinking, trying to get to the oligomers, but we're truly differentiated, and we believe we have the kind of only antibody that's in development or on the market that does selectively target these oligomers.
Yeah. Maybe quickly just talk about the data you have shown so far pre-clinically and now maybe even early clinical data that shows that you are targeting that species specifically.
Yeah, sure. I mean, it is important to us that, I mean, we have been doing this for a number of years now, and every step of the way, and again, our hypothesis, back in the days when it was not even that popular to talk about toxic oligomers, but we stuck to that method because we truly believed that to be true. And every piece of data that we have produced since then has supported our hypothesis, and that is really important as opposed to changing our story as the data come out. For us pre-clinically, and we tested this in many different ways to show that, are we truly selective to the oligomers? We did a monomer competition assay which showed that we did not bind monomers.
We did side-by-side analyses, multiple different assays testing PMN310, the ProMIS candidate, alongside donanemab, aducanumab, lecanemab, ACU193, which of these proteins does or does not bind to plaque? And in every single case, PMN310 was the only antibody that did not bind plaque. All the others bound plaque to some degree, and they have shown that in clinical data readout as well. So we took that knowledge from the pre-clinical set of studies, and then marched ahead into the clinic, confident that we had something truly differentiated. And then we did a phase I-A clinical trial in healthy volunteers, and that showed that the antibody was safe and well-tolerated. It also importantly showed that the antibody crossed the blood-brain barrier in sufficient quantities to more than fully engage the oligomer target. So the 1A was successful, supported our hypothesis.
And then most recently, Eddie, as you know, we kind of embarked on, and we can maybe touch on this in a minute, but we embarked on a phase I-B clinical study in MCI patients, so mild cognitive impairment due to Alzheimer's, so early Alzheimer's patients. And we built an interim analysis into that study, and we announced the results of this blinded interim analysis. When patients had been treated for six months, we looked at safety and biomarker movement.
Again, maybe we come back to what those data showed in just a minute, but on the hypothesis that, are we selective to oligomers and avoiding plaque, like the original hypothesis had dictated, the interim analysis showed that kind of exquisitely, that the level of ARIA that we saw with the interim analysis were zero cases of ARIA-E and just mild background, kind of placebo-like rates of mild asymptomatic ARIA-H. So we, again, consistent in that hypothesis of avoiding plaque and eliminating much of the ARIA liability, we've been consistent all the way through our clinical and preclinical development.
Thank you, Neil. I would agree. I think the data that you have shown from just an interim analysis on a blinded basis look very different and unique than anything out there, at least on the ARIA front. But I have to ask you this. We recently saw, and I'm sure you also saw, the ALTITUDE-AD result. What was your reaction? Should there be any read-through to PMN310?
Yeah, it was an interesting result, and you feel for the patients and the caregivers first and foremost. But again, and I don't think the results were overly surprising. The reaction was surprising. The results, the data that we saw, and it was limited data, but were not that surprising. Again, if you look at that product, sabirnetug from ACU193, as it's come through development, despite claims otherwise, I mean, that's an antibody that is not selective to the oligomer species. It binds multiple different forms of amyloid beta, including plaque. So the fact that it came with double-digit rates of ARIA-E and plaque clearance was not a surprise, because again, they had showed that in the earlier clinical studies, so that was kind of consistent with previous data. I think the messaging might have been a little bit disconnected from the data.
It wasn't a surprise to see ARIA-E levels and minimal efficacy. So I think that drug probably does bind oligomers to some degree, but we're not sure exactly what it does bind, but we know it's multiple different species of amyloid beta. So not overly surprising to see that result. And certainly, we don't believe speaks to the oligomer hypothesis, because as I said, we've been touting this, as other companies and as they did as well, that the oligomer species is the driver of cognitive decline. But what they fail to have in hand is an antibody that selectively targets oligomers.
Yeah.
They bind everything, so they cannot really prove or disprove that thesis, whereas we are still out there with, again, what we believe to be the drug that does selectively bind the toxic oligomers. The oligomer hypothesis hopefully will be proven with our data coming up in a few months.
Got it. When we look at the Alzheimer's space in general, obviously you have three approved products. Two of them actually are now marketed. You compare these antibodies and also look at the development that is happening. What actually separates one from another?
What is interesting is we said at the outset, I think you look at the two drugs in the market, and interestingly, lecanemab, as we said, was designed to go upstream to target the oligomers, which they probably do more selectively than donanemab. Interestingly, Eisai, the developer of lecanemab, has said time and time again that they believe the efficacy they see from lecanemab is driven by their ability to bind the toxic oligomers. Again, the challenge for these drugs, you have donanemab, which also binds oligomers. Lilly is not as forceful in their communication about it, but we know it binds oligomers. We think that the modest efficacy we are seeing from the drugs in the market comes certainly in part from their ability to bind the toxic oligomers.
Again, the challenge is if they bind other species of amyloid beta protein, which they do, and we know they do, whether it is the monomeric species or the plaque, not much of those antibodies gets delivered to the oligomer target because they get soaked up off-target binding to the plaque and off-target binding to the monomers. The monomer concentration and the plaque concentration is multifold higher than the oligomer concentration.
Yeah.
Some of the drug is getting to the oligomers. It gives you a little bit of efficacy, but most of that drug is getting soaked up by the other forms of amyloid beta, including plaque, which again results in their 17%, 20%, 25% ARIA rate.
Got it. With regard to PMN310, I think you were trying to talk about the differentiation. I think there are other differences there. Maybe if you can talk about the backbone that you've chosen, the epitope, why those were selected. Are there pros and cons of those?
Yeah, that's a good question, yeah, and it is an important distinction. Again, right from the way we designed the antibody, as I said, because some folks have come to us and said, "Well, how can other companies try to get this-
Yeah
-selective antibody and they didn't pull it off? How can ProMIS do this when others couldn't?" Again, it comes back to our discovery platform, our EpiSelect platform, where we predict how proteins are going to misfold, and we identify this binding region on this misfolded protein, and it's a three-dimensional binding region. It's not a linear epitope that's conserved across all species of amyloid beta protein. It's a three-dimensional computational epitope, and we design an antibody that binds exclusively to that 3D epitope, and that three-dimensional conformation is only present on the misfolded form of that protein. That's number one. It's a fundamentally different way to design antibodies. Then on the other side, as you design your antibodies, you can pick and choose how you structure these antibodies, and you can look at different immunoglobulin backbones, and there's IgG1, two, three, or four.
We, actually, similar to lecanemab and donanemab, thought it was very important to have kind of an effector function or an immune response associated with the binding of the antibody to the oligomer. What is important in our minds, and I guess in Lilly's and Eisai's as well, was having an IgG1 backbone, which elicits an immune response. Once the antibody binds to the oligomer, you get microglial activation, so you not only get neutralization of the oligomer, you get clearance or degradation and clearance of the oligomer. That IgG1 backbone is really important, and when you look at others, when you look at Acumen's antibody, they had an IgG2 backbone, and they chose that on purpose. An IgG2 backbone really elicits very little effector or immune response.
That removal of the oligomer construct probably doesn't happen nearly as much with an Acumen product as it does with ours, and probably with the donanemab, lecanemab product as well. It's neutralization and clearance of that oligomer construct that's really important.
Got it. With regard to the PRECISE-AD study, I mean, again, we were touching on it a little bit. What exactly did we see at six months, like both on the safety and biomarker? Again, it's blinded basis, but if you can review that for us.
Yeah, of course. It was, again, just to step back, I mean, the phase I-B study was designed to be a very comprehensive phase I-B study. I think it's a little bit atypical for a company to come out with a fairly robust phase I-B study. Again, that's in part and parcel due to Dr. Altstiel's expertise in designing clinical studies. What we wanted to have was a study where we treated patients long enough so we could see a possible clinical signal, and we would treat enough patients to give us confidence that what we were seeing was relatively accurate. That meant 12 months of treatment and over 100 patients. For a phase I-B study, that's fairly robust and comprehensive. We've designed this study, it's a placebo-controlled, randomized, double-blind study.
It's three to one randomized, which is important, three on drug and one on placebo, so 75% of the subjects are getting active drug. Three progressive doses. We got fast-track designation by the FDA, so that gave us impetus to really move quickly through the clinical development. We completed enrollment last year, and as I said, we're now finishing off the final few patients this year to report in Q1. What we did in that study, since it was a bit of a longer study, 12 months, we built in an interim analysis, and that interim analysis was conducted when all patients had been treated for six months instead of the full 12 months. What we wanted to look at, just as a way of understanding or getting a snapshot as to, are we moving in the right direction?
Not a futility study, just a bit of a picture in how things are going. That we reported July 28th, and it was an analysis of, blinded analysis only of biomarker data and safety data. Keeping in mind for the complete trial, we're looking at biomarker safety and clinical outcome measures. At six months, we didn't touch clinical outcomes, doesn't make sense. At six months, on a blinded basis, what we saw, and again, safety was front and center because maybe we get back to this, but the safety issues that we're seeing with the drugs on the market are really preventing uptake of these drugs significantly.
I think of the patient population they serve, around 5% of those patients are getting treated with these drugs, and that's mainly because of the ARIA, the bleeding and swelling on the brain, and the side effect issues. So safety is driving so much of this consent to take the drugs or even prescription habits. Safety was important for us at the interim read. Again, you've got this rate of ARIA, this bleeding and swelling on the brain that comes with drugs that bind plaque. Since we believe we do not bind plaque, we were expecting to see a much reduced ARIA liability. I think we even surprised ourselves at the interim analysis. We saw zero cases of ARIA-E. So the more serious form of ARIA-E, edema, we saw zero cases. For ARIA-H, hemorrhage, we saw rates in line with placebo.
The ARIA rates were superb on the interim basis. Even kind of interestingly, at six months, we know that the other drugs on the market, and again, their ARIA rates at six months were 20%+ , 25%, so significant levels of ARIA-E and H. What's interesting with ARIA, when you see ARIA, it typically comes in the first six months of dosing. So that six-month time point was especially interesting on that. So zero cases of ARIA-E, very low levels, clean safety profile, no serious adverse events related to treatment, no dropouts related to treatment. On the other side of the equation, because people can say, "Okay, it looks really safe," which is a huge win, but is it doing anything with respect to efficacy?
We looked at a couple of biomarkers, blinded basis, to see is there any sense of target engagement going on here? For two really important biomarkers, p-tau217, which is well-known, MTBR-tau243, less well-known but still really important. One is kind of a, they kind of bookend the whole tau cascade, if you will. In both those cases, we know that natural history suggests that both these biomarkers should increase over time in untreated patients. What we saw in both of those biomarkers was a decrease from baseline. It is blinded. All the patients are kind of aggregated together. We are not splitting this out by dose. It was a really, really interesting signal to say from baseline, p-tau217 decreased, even with the placebo cohort included in that, in both p-tau217 and in MTBR-tau243.
The only other drug that reported or company that reported on MTBR-tau243 was lecanemab, and they showed at 18 months a modest reduction in slowing of progression. They did not decrease, it is just a slowing down of progression, whereas we saw at the interim a decrease. Again, this is blinded.
Sure
Not necessarily predictive, but the interim analysis was quite encouraging, which came out in July. Since then, we have been dosing the rest of the patients in the.
This is a patient population where those biomarkers, like on placebo, you would not expect to decrease on their own?
You would not. You would expect them, Eddie, correct, to increase over 6, 12, 18 months. That is what the databases and the natural history have shown with both of these biomarkers, exactly.
How similar is the patient population relative to the lecanemab or donanemab studies?
Very similar. We wanted to design the study. I mean, again, they have been launched with that kind of MCI patient population, early Alzheimer's population, so it was important for us to kind of enroll patients that were very similar to what they are looking at. We think we are, at the end of the day, we are a better drug than them, so we wanted to enter the market kind of right where they were positioned and then expand out from there.
Got it. You were talking about ARIA, the safety liability, why it is such a problem in the space. Obviously, your program differentiates on that. What about the MRI? What do you hear from community on the convenience or lack of convenience of these significant monitoring that ARIA brings?
Yeah, that's a very good question, Yatin. It was interesting, we had a webinar when we presented the interim data, and we had a couple of key opinion leaders on the call. One, Dr. Will Mantyh, who's a practicing neurologist treating Alzheimer's patients, spoke very well to the implications of such a clean safety profile, especially with respect to ARIA. When you listen to the practicing neurologists and the areas of practicing neurologists treating Alzheimer's patients, the issues surrounding MRIs, I mean, five or six MRIs are required for these patients in the early treatment and monitoring.
You can imagine these patients are, they're Alzheimer's patients, so they require a caregiver to go with them, and they're frightened by MRIs and to get them dressed, let alone into a hospital with the infrastructure of substantial MRI equipment, and then getting them through that process on a regular monthly basis and to monitor this is part of the reason for the lack of uptake. Our thinking is if we can demonstrate clean safety and minimal or background rates, placebo rates of ARIA, does that position us for kind of a registration study and certainly commercial launch where MRIs will be, I won't say eliminated, but vastly reduced based on this. That would be a huge, again, a huge win for patients, for caregivers, and for physicians as well.
Again, it's the infrastructure alone required to treat these patients and monitor these patients, let alone getting them there and the suffering that the individual has to go through is enormous.
Got it. Let's just focus now on the upcoming data readout, right? I think the guidance is for first quarter of 2027.
Correct.
Like, what investors should be focusing on? What are you focusing on? What would enable you to move into the next stage of development?
Yeah, and that's how we're looking at it as well. What will we need to be able to advance into that next clinical study? Again, designing such a robust I-B study, we figure if we're able to show that we have clean safety and we're feeling good about that, and if we can show target engagement through the biomarker results, and we can identify a dose, and if we can show a clinical signal, then we should be in a position to advance to that next stage of clinical development. If we show all that with this study, we anticipate going into a registration stage study. Again, this will be subject to feedback from the FDA, but if again, checking those boxes, being able to step into a phase III, a registration study as a next step is important to us.
What we expect to read out in Q1 are a number of different endpoints. Certainly, safety will be critical. Biomarker movements and clinical efficacy will be very important. We've also got an oligomer assay, which we can point directly to the mechanism of action of our drug actually removing oligomers from circulation. I think for us, when you look at kind of expectations of what we're thinking to set ourselves up for that next study, and we've kind of said that if we, for us, it's all about risk-benefit, and that's how the FDA looks at it, that's how physicians and patients look at it.
What is the risk-benefit of the intervention? The risk-benefit of the drugs on the market is frankly, is pretty poor. Again, you've got this side effect issue with ARIA, and you've got kind of modest efficacy. Our goal here at the completion of the readout of the study is to show safety, ARIA rates specifically, that are in line with placebo.
Yeah.
If we can get close to placebo rates of ARIA, that would be a huge win on the safety side of the equation. If we can show efficacy at least as good as what's on the market, that will shift tremendously the risk-benefit profile, I think, very favorably. That will materially change or set us up, I think, material for a differentiated product for the treatment of Alzheimer's disease.
Got it. I think Wall Street generally focus a lot on these nitty-gritty of, you always have said you need to show efficacy that is in line with the sort of standard of care, which is donanemab and lecanemab. I think they have shown somewhere around 25%-ish number at 18 month. What is the range that you are looking for that would be a win for you to move into the next stage?
Yeah, it's a good question. Again, we think whether we put a range in. As I said, this is 140-patient trial over 12 months, not a 1,500-patient trial over 18 months.
Yeah.
It's careful how we compare and contrast. But I think, as I said, superior safety, at least as good as efficacy. If you look at those numbers at 22%, 25% efficacy benefit over 18 months from those large studies, could we envision something if you kind of back it up to the 12-month time perspective? Could we think of something in that maybe 15%-20%? I think that would be a good result for us with clean safety. So that's kind of how we're going into this, looking at similar efficacy, better safety, which again, I think will position us very favorably with FDA and kind of as we approach kind of that next clinical study.
Yeah. I mean, I would assume that in that range, 15%-20%, couple percentage up and down is sort of is a reasonable number. But, I mean, if you can get to, let's say, even above 20%, that would be like an upside.
That's a total upside, yeah. If we get kind of above 20%, I think that's a huge win for us there. And yeah, it's kind of, again, we're careful how we say this. It's 140 patients, and so a few percent here and there. And again, looking at, I think efficacy is also contingent on biomarker movements. We've got panels of biomarkers. So I think if we see trends in biomarkers that are reflective or supportive of our mechanism of action of selective oligomer targeting, combined with efficacy like that, combined with safety, that, as I said, it's a very comprehensive phase I-B study, and I think people appreciate how much effort went into being able to pull out a rich set of data.
But obviously, looking at shifting that risk-benefit profile, again, with what we believe is the only drug that selectively targets oligomers, I think we'll be in an interesting position in a few months.
Yeah. No, I agree. I mean, at least on the risk-benefit side, like you said, risk obviously much lower with the safety profile that you have. So the benefit, even with the same level of efficacy, sort of changes that equation. And then if you can support that with biomarker in a similar direction, I think it should be a pretty good outcome. Very good. How's the cash position?
Yeah, cash is good. We're in a strong cash position. We're coming, we run our earnings on Thursday, so we'll come out with fresh numbers. I think as of Q2, the last filed quarter, we had just over $53 million. So we've got cash through the end of next year, so well beyond the data release, which is a good place to be. Yeah, cash is fine for now. As I said, for us, it's just heads down, executing on the study and also preparing for what comes next.
We're looking forward to releasing the data, and then stepping into that next study ideally by the end of next year. We're working on a subQ formulation as well, so that's exciting to be thinking about bringing this product to market, as a subQ formulation in the not-too-distant future. There's lots going on at ProMIS, and we're excited.
Very good. Neil, thank you so much.
Yeah, of course. Thank you, Yatin, Eddie. Very much appreciate it.
Thank you.