With the thesis team here at Stifel, I am really excited to introduce Neil Warma, CEO and President of ProMIS Neurosciences. Do you want to maybe start with just a kind of overview of
Yeah, of course.
what is going on?
Yeah, no, thanks. There is a lot going on. Thanks, Emily. Terrific conference as always. We are pleased to be invited, so thanks very much. Thanks for you attending in the audience as well. I will excuse my voice at the outset in case I need to break for a sip of tea or water. Thanks very much. Appreciate it. I am happy to. I am being represented here with Dr. Larry Altstiel, our Chief Medical Officer as well, who is responsible for a lot of the design and development of this program. My name, Neil Warma, President, CEO of ProMIS Neurosciences. I will walk through a few slides with you today, and I will give a kind of a summary, Emily, if that is okay, just to
Yeah
just to walk through the slides, and I can-
Yeah
interrupt, and you can interrupt me with questions as we go through. Just to remind everybody, we are a publicly listed company. PMN is the ticker, so please review all of our SEC documents that we file online. As Emily said, there is a lot going on in ProMIS currently. We are a company that is focused on neurodegenerative diseases, and we are right now in the throes of a really exciting clinical trial in Alzheimer's disease, which reads out in a matter of months. We have said publicly that the Alzheimer's study reads out in Q1 of next year, so we are on the verge of finishing up patient dosing and final visits to get our data out in Q1. So early catalysts coming up for sure. We are well-funded.
We did a significant financing a number of months ago with some of the top investors coming into the financing with Ally Bridge, Janus, Wellington, Deep Track. So we are funded well beyond data through to beyond the end of next year. The company, ProMIS, is really based on our platform technology, protein misfolding. A little bit of a play on words, promise of novel drugs, but also the technology around misfolded proteins and their impact on a number of different diseases. And our ability, as we say here, EpiSelect is the platform, but our ability to selectively target misfolded forms of protein. So very selective approach to design of, very exquisite approach at designing antibodies, which differentiates us from, I believe, certainly in Alzheimer's, all other kind of drugs currently on the market or in development, even those that claim to be selective to oligomers.
Really, all of the others bind multiple different species of amyloid-beta. We believe we are the only drug that selectively binds the toxic oligomers. Should I Do you want me to continue through, or do you want to ask the questions back and forth? I am happy just to run through the slides, and if that is easiest for you, Emily.
Yeah. Maybe just since we've kind of paused right here.
Sure.
Obviously, we recently got the data from Acumen that was a bit disappointing. Maybe if you could just talk to us a little bit more about, more in detail, what you think, why you're different, and maybe point to any data that you can kind of show about why you think you are really selective for these oligomer species.
Of course. That's a good question. Yeah, the data that came out a week or so ago from our colleagues at Acumen, disappointing certainly for, first and foremost, for the patients. But again, just to be front and center, we put out a bit of a communique last week as well. There are clear differentiations between our PMN310 antibody and their antibody, and frankly, every other antibody, as I mentioned, out there. For one thing, ACU193, Acumen's antibody, is not purely selective to oligomers, although that's been the thesis all along, and they're big believers in it's the toxic oligomers that are driving cognitive decline, as we believe, as the folks at Eisai believe with lecanemab. It was designed to selectively target the oligomers, but at the end of the day, all the other antibodies, including ACU193, bind a multiple assortment of amyloid-beta species.
Not one is selective to the oligomers. The data that came out from Acumen doesn't really inform on the oligomer hypothesis because they bind multiple different species. The other thing, which is an important differentiator, if you look at the oligomer, because these are the toxic species of amyloid-beta protein, it's important in our minds, and I think most people's, not only to go in there and bind the oligomers to prevent them from further destruction, but also clear them and remove them from circulation from within the CSF. Because of that, we designed our antibody, which is actually similar to what lecanemab and donanemab did. We designed our antibody with an IgG1 background, not to get too immunological on you, but an IgG1 background provides for an immune response.
When the antibody binds to the oligomer, there is an immune response, there is a recruitment of microglia. The microglia come in, they bind the antibody-oligomer complex and remove oligomers from the CSF. It is not only neutralization, it is clearance of those antibodies. Acumen chose an IgG2 backbone, and an IgG2 does not elicit an immune response. So they do not have that clearance aspect. They go in and bind the oligomer, and they bind much weaker than we do, which is another differentiating factor. But they bind the oligomer, but they do not clear it. I think the two key differentiation points between us and all others, including Acumen, because I think Acumen is more like the other group, the two out there and other folks, rather than similar to us.
Their differences are the drug does not bind selectively the oligomers, and it has a different kind of mechanism of action, if you will, in not being able to clear the oligomers. The data really is important, Emily. When we look at the premise or the hypothesis supported by the data that we have communicated really for years now, that we believe it is the toxic oligomers, not plaque, and that is a whole other story, not plaque that is driving cognitive decline. As a result, we have got this elegant platform, because people say, "Well, if all the other people tried to design a selective antibody, and they end up binding all forms of amyloid-beta, how is it that you at ProMIS can actually do this?" Again, it comes to our EpiSelect platform.
I can probably advance some of these slides just to kind of show people what I mean here. But the EpiSelect platform really is an elegant way of us being able to predict how proteins are going to misfold. It is a conformational epitope, a three-dimensional epitope, to which we design an antibody against. So that epitope is only present on the misfolded form, the toxic oligomers. It is not present on monomers, and it is not present on plaque. Therefore, the design of the antibodies from the get-go, very different from the way other people design these antibodies. The data we have produced pre-clinically, we have tested, we have looked at multiple antibodies, including the Acumen antibody and donanemab, lecanemab, side by side to say, "What are the binding profiles of each of these? Are we differentiated with PMN310?
Are we true to our belief that we are not binding plaque?" I will come back to why that is really important, or not. We did side-by-side testing, and this slide here shows that the green shows the presence of plaque in brain sections of Alzheimer's patients, and the purple shows which antibodies are actually binding to the plaque. Every antibody here, except for PMN310, shows binding to plaque. With that, and we will come back to this in a minute, with that binding of plaque, not only is it not that relevant for preventing further cognitive decline, but clearing plaque is also associated with very serious side effects known as ARIA. ARIA essentially stands for bleeding and swelling on the brain.
You have kind of this double whammy that targeting plaque, you are not really getting a clinical benefit, but you are also getting the side effect issue with swelling and bleeding on the brain. The challenge becomes, how do you design something? Because if you look at this picture, which is kind of a bit of a representation of there are multiple different species of amyloid-beta protein. As I have just said, the field has really shifted away from plaque, because there are drugs that can clear plaque totally, and the patient continues to decline. Therefore, we have this belief now, we understand it is the upstream, these oligomers, that as they travel downstream, trigger tau phosphorylation, they form into plaques. Our goal is to go upstream of all of this and hit the oligomers.
As I mentioned, the challenge is, how do you just hit the oligomers and avoid plaque and avoid monomers? The other drugs cannot, and Acumen showed that they were not able to. But every step of the way, we have shown that we can bind oligomers, avoid plaque, avoid monomers, and I will maybe touch on that in a minute, kind of the clinical data and how that is supported. All the way along, all the data has supported our story, and we have not changed our story at all. Again, not to pick on Acumen, but if you look at them, they were wanting to be that selective oligomer binding agent, but their data just told a different story for the past few years. They obviously bind plaque in the phase I-B, they came with ARIA incidents. Now we see in the phase II, double-digit ARIA incidents.
It is clearly a non-specific binding agent versus ours, which we believe is very specific to the toxic species.
It is our understanding that there are not necessarily great assays in humans for oligomers. Could you maybe talk a little bit more about the data you guys have shown thus far, and why, again, you think in patients you are binding to oligomers?
Yeah, it's a really good question. To that point, I'll come back to this, but up until now, there's never been an assay to enable us or people in the industry to look at and measure levels of oligomers. These are low molecular weight, very low concentration, soluble species, very challenging to actually measure with an assay, which is why no one's been able to show that until now. At ProMIS, we've been designing an assay to allow us to really, I guess, prove or elucidate our mechanism of action. To do that, you have to show that here's these circulating oligomers, very low concentration, and here's what happens in the presence of the PMN310, our antibody, pre and post-treatment. So that's an assay we've designed. We presented kind of validating data on that back in July at the Alzheimer's Conference in London.
So we're excited that for the first time, we're going to be able to take that assay and plug it into this clinical study. The study, I think the most important decision we made as the company, and this is very much in part thanks to Dr. Altstiel, our CMO, and Larry was our Chief Medical Officer, but he ran CNS at Pfizer for years.
When I joined the company as CEO, I said to Larry and the team, "We need to design a study that's going to give us a fairly definitive answer as to whether this works or not." Kind of coming on the back of our colleagues at Acumen, who had done a shorter three-month, 30-patient study, look at a few biomarkers, we said, "Well, that doesn't really tell us much." So Dr. Altstiel planned a study that's going to give us an answer. So Larry said, "We need to show some sign of clinical benefit here, because biomarkers only don't really tell a story.
We have to do it in enough patients that kind of give it some meaning." Again, it's a phase I-B first-in-human study, but we designed this, so we needed to treat at least 100 patients for 12 months, because 12 months could give us a signal of efficacy. So we designed this placebo-controlled, double-blind, randomized study, 12 months of IV administration. We look at three ascending doses. We were targeting 128 patients. We ended up over-subscribing. There's a lot of enthusiasm for the trial. We ended up with 144 subjects. This is being run across the U.S., and a lot of the physicians were, "This is an interesting study.
If this truly does not bind plaque and does not come with ARIA liability, I want my patients in that study. We set the study up, and it was fully enrolled last year, again, ahead of target, more patients than we were thinking we would get, that we were targeting, which is a good thing. We are now looking at winding up final patient visits over the next month and reporting on data in Q1. Again, it is a very comprehensively designed study. We are looking at multiple kind of baskets of endpoints. Certainly, safety is key, and I will come back to this in a minute, because safety is imperative in the two drugs on the market, and maybe I will back up in a second.
The ARIA incidence, the 20%-30% bleeding and swelling on the brain is, as you can imagine, significantly preventing uptake of the two drugs in the market. It is a significant market. The two drugs on the market do not even have or have approximately 5% of the addressable patient population in Alzheimer's because of the challenges around safety. The efficacy is moderate, so we really come back to and we really emphasize this risk-benefit profile. That is what the FDA looks at, that is what the physicians look at, that is what the patients look at. What is the risk versus benefit? Currently, with the two drugs on the market, it is pretty poor. The risks are really heavy on the ARIA, and not only is it swelling and bleeding on the brain, which is as serious as it sounds, but these patients require multiple MRIs.
I think it is six, Larry, six MRIs in the first year of treatment. These are cognitively impaired elderly patients, and you have got to get them to the institution, got to get them inside an MRI, so that is a challenge unto itself. That risk-benefit is really poor. Our thinking was, if we can solve or rebalance or materially change the risk-benefit, that would be a huge achievement for an Alzheimer's drug. This study is running well now, and as I said, we are presenting data across multiple endpoints, safety, biomarkers, efficacy, because we are looking at clinical efficacy. Again, it is a 12-month, 140-plus patient study, so we keep it in perspective. We are also looking at the oligomer mechanism of action measures as well. What we did in this study was we built an interim analysis.
Since it was a longer study than, I think, than anybody has run in a phase I-B study, certainly as an emerging company, we knew it was going to be a little bit longer to enroll for news flow for public companies. That is kind of critical. We built an interim analysis to say after six months, so when all patients have been treated for six months instead of 12, let us have a blinded look at what is going on with safety and what is going on with one or two of the biomarkers, just to give us a little bit of a sense as to, are we on the right track? This is a bit of the background of the trial. The trial is very representative of early Alzheimer's patients. These are mild cognitive impairment due to Alzheimer's, so early AD patients.
Very representative, very similar profile of lecanemab, donanemab, big phase III studies, including the APOE4 hetero/homozygotes, which is absolutely critical, as they are at most risk for developing Alzheimer's and developing ARIA on top of it. What we saw in the interim analysis, and this was reported on July 28th, I think, end of July, halfway through our study, was really encouraging. We had high expectations on the safety side, and again, everybody had been claiming selectivity and lower ARIA. No one had achieved that. We were kind of saying the same, selectivity and reducing ARIA liability. What we saw at interim was, yeah, super safety. We were really, really impressed, if that's the right word, with our own drug. But as you can see, the two forms of ARIA, the edema, which is the more serious ARIA-E, and H for hemorrhage.
Those are the two forms of ARIA. We saw zero cases of ARIA-E in the first six months of therapy, which again, and I will show you the slide in a second, which is really, really encouraging. We saw no cases of, zero serious adverse events related to treatment, zero discontinuations related to treatment. The overall kind of one infusion reaction. The safety profile of PMN310 was absolutely superb. Again, a little bit better than our very high expectations. Safety, we are thinking this. It is interesting, you can see the next slide, I think, has our. We kind of map this against the other drugs that had come before us, donanemab, lecanemab, how did they look with their ARIA cases at six months? We know what it was at 18 months, the length of their trial, and we looked at six months.
You can see by the curve, this is just ARIA-E serious cases. It is interesting because we know that if when ARIA occurs, it typically comes in the first six months. 95% of the ARIA cases in donanemab, lecanemab came in the first six months. That six-month time point is extra special for that reason. We hit zero while they were hitting double digits. That was a really encouraging sign for us. On the other side of it is like, some of the people can say, "Well, that's great, Neil. It looks like it's safe, but is it actually doing anything?" Again, this is a blinded analysis. We want to be careful that we are not unblinding because we are halfway through and things are going well.
Let's look at a couple of the biomarkers that might give us a signal as to whether this is working. We looked at two biomarkers, and these are measures of, excuse me, of tau phosphorylation and disease progression. There is really two. There is p-tau217, which is a little bit upstream in the tau cascade, and there is MTBR. We kind of bookmarked the two biomarkers. Excuse me, thanks. Normally, for both these biomarkers, we typically see, excuse me, we typically see an increase in. I am getting choked up over the data.
It's just so It's okay. It's all right. Just drink some water. Maybe also a quick question. Will you guys be measuring Are you guys measuring PET in this phase I-B study?
Will that kind of be available by the time you guys release your top line data?
Sorry for those listening in the back, that microphone's like blowing their eardrums. Yes, we are measuring PET. We have a PET
Okay.
image at the beginning for inclusion, and we have a PET scan at the end. We're not expecting much because we're not impacting plaque.
Yeah.
We are not expecting much, but we are certainly looking at PET to see if there are any changes. With the biomarkers, again, to see if there was some sort of target engagement. Really impressive to see that both p-tau217 and MTBR showed a decrease in biomarkers from baseline to six months. The typical progression is an increase in these biomarkers in untreated patients. To be able to take these patients and bring them in a downward slope at six months with two key biomarkers. Interestingly, the graph on the right here is our randomization was three to one, three on active and one on placebo. The tracking, if you will, of the patients that were less than 0 versus greater than 0 was pretty close to our three to one randomization. Sorry, I am kind of choking up here.
That is really the data that we have presented to date that kind of is supportive very much of our mechanism that gives us kind of enthusiasm going into the final top-line data coming in, coming in Q1, coming in a few months. The data has been supportive all the way along and quite encouraging. I will let you ask while I take a break.
Okay, perfect. I guess, kind of my next question here is just, what do you expect as this data matures? As you come up to this 12-month readout-
May I interrupt? I have a lozenge. Is that going to help you? Oh, hi. Nice to see you.
Yeah, Maya, that is awesome. I have not seen you for years, and all of a sudden you are my Thanks, my dear. Appreciate it.
Yeah. With the 12-month data, what is maybe your base case
scenario, and what do you maybe think you need to see to kind of move this product forward?
Really good question. We've thought about that a lot. I think it comes back to risk-benefit. We want to materially change the risk-benefit versus the drugs on the market. That's risk is safety, benefit is efficacy. When we look at our base case, ARIA is certainly going to drive safety. Can we materially lower this rate of ARIA that's really crippling the patients and the drugs on the market? If we can decrease that side of the balance significantly, even if we hit similar efficacy, that would be a significant win because that materially changes the risk-benefit ratio of the drug. Our thinking going into this, and we're careful how we do this, because it's 12 months, 140 patients, and I know the tendency is to compare to 18 months, 1,500 patients from the other drugs in the market.
We have to put this in perspective and context. Our thinking is, a win for us base case, if you will, is taking the ARIA rate close to the placebo level, as close as we can. I won't say hitting placebo, but that's where we want to go, dramatically reducing ARIA, certainly ARIA-E, down to placebo-ish or background rates. We know there's a level of ARIA that exists in Alzheimer's patients without treatment. Dropping down to that level would be outstanding, would be really impressive for a drug to get there. So that's kind of our, I say base case, but that's pretty an aggressive case. The other side of the equation from efficacy, if we want to be at least as good as the drugs in the market from efficacy.
That tips the scales, whichever way it goes, that tips the scales significantly in a much improved risk-benefit profile. If you look at, what does the efficacy signal look like in the base case? If you look at the efficacy currently with the drugs on the market, we saw after 18 months, again, longer study, 18 months in the range of 22%-27% benefit. We are trying to be careful with this, but if we say, if we kind of back that up to 12 months a little bit, if we see something in the range of 15%-20%, this is slowing of cognition versus placebo. If we see in that kind of range, coupled with some relevant and important trends in biomarker movement on the efficacy side, I think that would be a significant win for us.
If it kind of goes above 20% separation versus placebo, that is all upside. I think we are trying to balance this and put it in context with what we want to see, and I think if we get that separation on the efficacy side versus placebo, that is kind of the signal, and then the biomarkers at the end kind of tell us why we are seeing that. That is the biological mechanism as to why we are seeing efficacy separation where we are. If we just hammer the ARIA down to manageable levels, if we take the MRIs, for example, that is the goal here, the goal is to get to that next study. If we come with a safety profile like this, and we reduce the MRIs from six per year down to one or two, that is a huge win as well.
This is kind of our base case, and I think if we deliver this with the data, again, 140-patient trial, so we put it in perspective, we look holistically at what we are seeing here, the trends and the separations, but I think that will be a huge win, Emily, and given the market potential and given the unmet medical need, pretty fantastic for us.
Could you remind me, I know this is a smaller study, could you remind me what you are powered for in this study, or are you just looking for a clinical trial?
Yeah, we're looking for, again, trends most certainly.
Yes. Okay.
We're powered, interestingly, and Larry likes to tell this story as well, we're powered kind of 97%, give or take, to detect a single case of ARIA, because it's important to us. I mean, this ARIA, which I keep hammering on, obviously, is important. We didn't want to be accused of, "Well, there was ARIA, you just didn't look hard enough. That's why you're not seeing any." The trial's power is 95% plus to detect any case, a single case of ARIA. Then for biomarkers, we want to see some key trends and key biomarkers, and same with efficacy. At 140 patients, we're not expecting a p-value of 0.05 on the efficacy side at all. It's just too small-
Yeah.
a population. So favorable trends, clean safety is what we're shooting for.
Okay, that makes sense. I know we only have a couple minutes left, but I was wondering, if this study is successful, what does next steps look like? I know you guys are developing a subQ
formulation, and could you maybe also talk about whether or not a next study could incorporate that subQ dosing? Is that a separate development plan, and kind of just like your plan on the path forward?
Yeah, exactly. It's important because we're not just sitting here waiting for the data to read out and then, "Oh, it's really good. Now what do we do?" by any means. We've been thinking and planning, and part of the rationale for developing a study as comprehensive as this for phase I-B is to ideally, if we show we're safe, if we show we're engaging target with the biomarkers, if we show we've selected a dose and we've got clinical benefit, then those are the boxes that Larry likes to say, "Give us the preconditions and give us the support to go into a registration study," subject to feedback from the FDA. We'll sit down with the FDA next year with all the data. So designing that phase III registration study is what we've been doing now.
We announced last month, we've just hired a Chief Commercial Officer, Dr. Rubino, and Dr. Rubino was responsible for the global launch of lecanemab at Biogen. She was 11 years at Biogen. Prior to that, she did all the Alzheimer's research and CNS lead at Roche Basel. She came in, outstanding individual, tons of expertise to lead the whole charge through phase III reimbursement pricing and trial design with our team. So planning the phase III trial design is ongoing. SubQ is, you're exactly right, is very important to us. We initiated the subQ development when we saw the interim results, and we're pushing forward on that. The goal is to launch the product with a subQ formulation. So that's really important. We're full steam ahead on that.
Interestingly as well, the idea in a lot of the bigger trials, as you know, are going after this preclinical or asymptomatic patient population. These are patients that appear very healthy, but they have the underpinnings of Alzheimer's disease. They've got the formations of plaques and oligomer levels are elevated. It's kind of going in and saying, "Oh, we're detecting these, and we can detect them earlier and earlier now." Then the thinking is, "Why don't we treat you earlier and really kind of hold you at that level forever kind of thing, and prevent you from ever developing signs of Alzheimer's disease?" That premise is superb. But again, the challenge for the companies going after that now, Lilly, Eisai, and now Roche has gotten into it, they've got drugs that give you 20% chance of potential bleeding on your brain.
It's really a challenge, I think, for those patients or those individuals, I mean patients, those individuals, to think about taking a drug with serious side effects. But for us, if we come with a clean safety profile like that, we'll kind of launch with the market with the MCI early AD patient population, but then kind of expanding into that preclinical or asymptomatic patient population is really attractive. But right now, it's first things first, get the data out the door in Q1, but also develop the subQ regulatory path, registration path to be able to kind of step right into that next study as soon as the data, hopefully are positive. In a few months, initiate that next clinical study as a phase III and get to market. Speed to market is what it's all about for the patients and for the company, for the shareholders.
We're really focused on what comes next after hopefully a solid set of data in Q1.
Well, it looks like we're out of time.
There goes it.
But thank you so much. This has been a really great discussion.
Well, thanks so much. I apologize for the lozenge. Thanks, Monica, for the lots. But thanks for your attention. You too.