Welcome to the Cantor Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have ProMIS Neurosciences. With that, I'd like to welcome ProMIS's CEO, Neil Warma, and CMO, Larry Altstiel.
Altstiel.
Altstiel, sorry. I always get that one wrong. Thank you for joining us and for your time. Let's start off with introduction of yourselves, followed by an overview of the company, including lead candidate, its status on near-term catalyst, financing, and runway.
Sure, happy to. Thanks Pete for the invitation. Thanks also to the Cantor group for inviting us to the conference. Appreciate it. My name Neil Warma, President and CEO of ProMIS Neurosciences. I've been on the board for a number of years. Been CEO for about two and a half years now. Happy to be leading the charge at ProMIS. Larry, I'll let you introduce.
I'm Larry Altstiel. I'm the Chief Medical Officer for ProMIS, and I've been with the company about three and a half years. I'm a neurologist, neuroscientist by trade.
So as far as the update overview of the company, where we stand now, actually quite interesting time for the company. We're excited to be here. A couple of elements to touch on. From a financing perspective, which is always important for emerging companies, we are well-financed. We did a relatively large financing a number of months ago, so we're financed through to the end of next year, 2027. So financially, fairly strong.
Superb syndicate of investors who came in in that round a few months ago as well. Importantly, we're coming up on some very important milestones for us. Our clinical candidate, PMN310, is currently in the clinic in a relatively comprehensive, relatively large phase 1-B study for the treatment of Alzheimer's patients. We've recently had an interim data result, about a month and a half ago, a couple of months ago, which was quite positive.
We were pleased with that blinded interim analysis. But more importantly, we have a top line, kind of final top-line results coming in Q1. So in a matter of six months, give or take, we will unblind the data from the Alzheimer's study and look at top-line results in what could be a transformational treatment for Alzheimer's patients. We have a very unique differentiated monoclonal antibody which selectively targets the oligomer species of amyloid- beta protein. So well-financed. Some very near-term milestones coming up that we're very excited about.
All right. When most hear about amyloid- beta antibody therapies for Alzheimer's, they think about plaque reducers, like the approved drugs lecanemab and donanemab. However, the therapeutic hypothesis for our PMN310 is differentiated from the approved amyloid- beta antibodies. Can you just give us a synopsis of the different Abeta species? How that it binds to, sort of how you design your antibody and a bit more about the MOA?
Well, yeah. I'll start-
No, go ahead.
You can jump in. That's kind of an important point because we certainly believe in differentiation of the asset for any company, and that's where we stand. Really from the very beginning of ProMIS, our idea to design antibodies are selected for specific species of a protein based on the misfolding of that protein. Our whole premise is on being able to identify and predict how proteins are going to misfold. In fact, our name ProMIS-
ProMIS
is protein misfolding.
Yeah.
But it's really the ability to design antibodies that selectively target a misfolded form of protein. For us, that has been from day one the oligomer species of amyloid- beta protein. There's multiple species of amyloid- beta protein. There's the monomeric species, there's the oligomers, there's the plaque species.
Important for us, years ago, we decided as the industry and the field was moving towards the oligomer species of amyloid- beta being the most toxic and the one that really drives progression cognitive decline. We've seen over the years, there's been this shift away from plaque. Over the past few decades, clearing plaque, removing plaque was thought to be the be all to end all. That was where the cognitive decline emanated from. But now we know, and we have drugs that completely eliminate plaque and patients continue to decline.
Now the field has come back to, well, if it is not plaque, and also with plaque, as we know, removing plaque is not really sufficient to prevent or affect cognitive decline. We also know that drugs that clear plaque are also associated with this very serious side effect known as ARIA, so swelling and bleeding on the brain. Again, not much clinical benefit, but some safety issues with clearing plaque.
The field has shifted more towards this upstream, these toxic oligomers, low molecular weight toxic oligomers, which are highly destructive to neurons, and that we now understand is driving cognitive decline in Alzheimer's patients. For us, the ability to design an antibody that can avoid certain amyloid- beta protein, the monomers and the plaque, and selectively target only these toxic oligomers sets us apart from everybody else.
We firmly believe that we are the only company out there that has an antibody that can avoid the plaque species, the monomer species, and really go after these toxic oligomers. That seems to be a key point of differentiation to have a much improved safety profile and a solid efficacy profile as well.
Awesome. Larry, can you just expand a little bit on the oligomer hypothesis, what evidence actually points you towards oligomers being the disease-driving species?
Well, I think the oligomer hypothesis really starts decades ago, when people noted that toxic low molecular weight oligomers of Abeta peptide actually do cause synaptic damage, neuroinflammation, and actual direct death of neurons. We have also known for a long time now that plaque density is not really related to cognitive decline in the sense that people have looked in autopsy studies at plaque density and cognitive status when people died.
There was really no relationship. Same way with more modern neuroimaging techniques. Right now, we do know that there is a very strong relationship between synaptic loss and cognitive status, and we know that these toxic oligomers are very synaptotoxic. There have also been reports of a couple of mutations in the amyloid precursor protein. These mutations cause a very malignant form of Alzheimer's disease, but there is very little plaque.
In the case of the Osaka mutation, there is no plaque, but multiple oligomer species that really drive a very malignant and aggressive form of Alzheimer's disease. The Arctic mutation, again, which actually formed the basis of lecanemab, forms toxic protofibrils, toxic oligomers with very little plaque indeed. We do know from early in vitro experiments, in vivo experiments, and also now with confirmed clinical data, that toxic oligomers are really very important in driving pathology in Alzheimer's disease.
All right. Just to hone in on the specificity of PMN310 Abeta binding, there are multiple species.
Right
As we just spoke about. Just what exact Abeta species does it bind to and that could translate to a differentiated efficacy and safety profile?
Yeah. I think what we found with toxic oligomers is that they arise from a misfolding of the Abeta peptide. The Abeta peptide is cleaved off of precursor, the amyloid precursor protein. In its native state, it has a lot of important biologic functions. But it can misfold, and that misfolding then leads to aggregation forming these toxic oligomers.
What we've been able to do, using some sort of sophisticated techniques with statistical thermodynamics and modeling, is to identify the area of this peptide where it misfolds. Not only can we measure the amino acid sequence of that, but we can also look at the three-dimensional structure, and we can make antibodies against this three-dimensional structure that then really hones in on toxic oligomeric species. What we have is a very highly specific antibody that only recognizes low molecular weight, oligomeric structure of Abeta.
And that is important. What it does, it is highly specific for that, but it is equally important what it does not bind to. It does not bind to the monomeric Abeta, and it does not bind to plaque. The not binding to plaque means that it confers safety, that it does not have an ARIA liability or reduced ARIA liability. Not binding to the monomer means that it is not expending all of its energy on a target that is really a millionfold more prevalent than what we are trying to bind to.
No sink effect?
No sink effect. Exactly.
It really is a fundamentally different way of designing antibodies because, again, other companies have come before us and said, we have an antibody that is selective to the oligomer species. As Larry said, lecanemab was designed to bind these upstream low molecular weights. But because there is a conserved linear epitope across all species of amyloid- beta protein, they cannot help but bind everything.
Again, people have said, well, if they could not do it, how can ProMIS do it?. That is what Larry explained. It is just, again, a fundamentally different way of looking at that conformational three-dimensional epitope, which we are allowed to identify based on, this is all computationally algorithmically driven. We have a chief physics officer in our company that helps us design how to identify these computational three-dimensional kind of binding domains, which others are not able to do because that is proprietary to us.
Yeah. The epitope identified, you had a very particular antigen. It was a cyclic peptide, and you were able to-
Exactly. Yeah.
Okay. Switching gears to the phase I-B study, PRECISE-AD. Blinded interim data were recently disclosed, I believe it was back in July. Full 12-month data locked in for the first quarter of 2027. Can you just walk us through the thinking as you designed the study?
Well, yeah. The interim analysis was disclosed. We presented actually a webinar with a couple of KOLs. I think it's still housed on our website if people want to listen, on July 28th of this year. As I've said many times, Pete, and I think I've told you as well, the design of this phase I-B study was probably the most important decision we made as a company.
We took a lot of thinking around how to design a study because there were companies, again, that had gone before us, that had done a smaller, three-month, 30 patients, quicker study, a little bit more typical for biotech. But we thought we didn't want to go down that road and get to a three-month study with a few biomarker movements and it doesn't really tell you much.
We took a step back and said, "Okay, let's design a study that's really going to give us a fairly definitive answer as to whether this antibody works." Again, Larry Altstiel, who's had years of work, ran CNS at Pfizer, so certainly has the capacity and the capability, the experience to design these studies. But it was important that it had a few elements.
We wanted to have enough patients to give us a meaningful signal. We wanted to treat patients over enough period of time to allow us to get to a clinical read. So that was minimum of 100 patients, 12 months of treatment to get to that clinical signal. Because we want to design an experiment that really gave us a fairly conclusive result.
Phase I-B, PRECISE-AD, as we call it, was designed a couple of years ago, and the team has executed extremely well on it. We anticipated getting 128 patients enrolled in the study. We were oversubscribed, as we say, over-enrolled. There's a lot of enthusiasm for the drug, given its potential to reduce ARIA.
There was a lot of enthusiasm from sites, and this is run across the U.S., 22 sites across the U.S., multiple ascending doses. So three doses, and it's placebo-controlled, double-blind randomized study, randomized 3:1 , which is important, drug to placebo. So we're looking at kind of three buckets, if you will, of endpoints. So we've got the biomarker panel, and we've got a significant panel of many, many biomarkers. We're looking at safety.
Again, one of our big claims here is on improving the safety profile with respect to the drugs on the market, lowering ARIA rates, lowering infusion reaction rates, so coming with a much better safety profile. We're also looking at the clinical endpoints as well. So the FDA approvable CDR Sum of Boxes and a number of clinical measures.
So the thinking going into this study was a well-designed study that would give us a fairly definitive answer at the end, and also that if successful, if we can demonstrate target engagement, safety, identify our dose, show a clinical signal, then our expectation is to step into a single registration study.
If we can take this phase I-B design, a comprehensive phase I-B design, and kind of leapfrog, if you will, the phase II step and go straight to a phase III registration, that will save enormous time and cost and, most importantly, get the drugs to patients who need it that much more quickly. So an awful lot of thought went into the design of the phase I-B study, and its execution has been superb.
The interim results were added because the 12 months evaluation was a little bit lengthy, so we wanted to have a little bit of a signal just in the interim. So when all patients have been treated for six months instead of the 12 months, we had a blinded look at biomarkers and safety, not at the clinical endpoint, to see if we're on the right track.
Is the safety signal that we are expecting, is it showing signs of encouragement? Are we seeing any target engagement or biomarker movement in one or two biomarkers that would be suggestive of target engagement or drug effect in addition to clean safety, which is exactly what we saw. We were really pleased with the interim analysis, and again, on route to the final results coming in Q1 from a very comprehensive phase I-B study.
All right. What are some of the key takeaways from the interim?
Yeah, the interim, again, not simply put, because it is not simple, and this is the brain, this is neurophysiology. From a simple perspective, we were looking at safety and biomarker movement, as I said. Safety was superb. Again, this is blinded data, so we got to be careful that it is not unblinded, so it is not necessarily predictive of what is going to come at the end of the study.
From a safety aspect, again, ARIA is a big concern of patients and caregivers and prescribers, the swelling and bleeding on the brain. ARIA incidence was important to us. We saw zero cases of ARIA-E, the edema form of ARIA, which is the more severe.
Zero cases of ARIA-E, and we have seen with drugs on the market that after six months, the ARIA-E cases are in the 20%-30%, so we significantly improved on ARIA incidents. The infusion reactions were almost negligible. We had one. Importantly, we had no treatment-related serious adverse events, no treatment-related dropouts or discontinuations.
The safety profile was, I think, above our expectations, which were pretty high going into the interim analysis. Safety was superb. Then on the other side, looking at potential for target engagement. Is there one or two biomarkers that show that, yes, you have clean safety, but what is going on with potential drug effect? One of the better understood biomarkers, p-tau217, which is a strong measure of disease progression.
We showed a downward trend against the historical up where you expect these biomarkers to increase over time as the patient worsens. Ideally, you want to see the biomarkers decline over time. In the first six months on a blinded basis, we saw p-tau217 decline, which was highly encouraging to us. We saw with another tau biomarker, MTBR-tau243, also decline and matching the randomization rate closely 3: 1.
The signal from the biomarker target engagement potential was also very encouraging. Coming out of the interim analysis, clean safety, the potential for target engagement, supporting our differentiated mechanism of avoiding plaque and hitting these toxic oligomers. Everything played out quite nicely from the interim analysis, and now it's heads down to get this enrolled and completed in the next few months.
All right. Focusing on safety. Given that ARIA, driven by the approved Abetas, often emerge early in treatment. How much confidence can we take from getting the first six-month window without an ARIA signal? What might this mean for the, I think it was what, 60%, 61% of the population that were APOE4 carriers?
I think so far so good. I think that, again, we saw an absence of ARIA-E, and we do know from published trial results with lecanemab and donanemab and aducanumab that ARIA-E tends to peak within the first six months of treatment. The fact that we've avoided that seems to be an encouraging signal. The ARIA-H, which is microvascular hemorrhage, that's part and parcel of Alzheimer's disease.
The reason everybody we worry about ARIA is that Alzheimer's disease patients have deposits of amyloid- beta in their blood vessels, in the microvasculature of their brain. All Alzheimer's patients have this. If an antibody binds to that, it can weaken the blood vessel and cause either leakage of fluid, edema, ARIA-E, or it can cause frank rupture of the blood vessel, ARIA-H.
We also know because of this is that people do have a spontaneous rate of microvascular hemorrhage, in Alzheimer's disease. It's common. It can be exacerbated by amyloid binding drugs. When we saw this 4.4% rate of ARIA-H, that is pretty much what one would expect in a population of Alzheimer's patients who are not being treated with anti-amyloid drugs. It tracks the placebo rate of ARIA-H that we saw with lecanemab and donanemab. I think that what we're looking at here is the background rate of ARIA-H that would be expected in this patient population.
Mm-hmm. It is important, too. You commented on the APOE4 carriers, and these are patients with either single or double alleles, so they are heterozygous, homozygous. The APOE4 population are far more, what is the word? Far more
Well, the prevalence is if you are an APOE4. The most common APOE genotype is an E3. An E3/E3 homozygote we take as sort of baseline risk for Alzheimer's. If you are an E4/E3 or carry one E4, you have about a 5 x relative risk of developing Alzheimer's disease, age-specific relative risk, compared to an E3/E3.
If you have a E4/E4, it ranges somewhere between 12 to 18 times the risk. This also translates into a risk of ARIA. A E4/E4 homozygote cannot receive lecanemab in Europe. It is considered to be too dangerous. Here, some practitioners in the U.S. will make some exceptions for E4/E4 homozygotes, but they have to be really followed very carefully.
The fact that we did not see any ARIA-E, and we do know what our APOE4 genotype distribution is, which looks like every other Alzheimer's population that has ever been studied, argues the fact that we do not really see an APOE4 effect. I think that if this carries out into clinical practice, that will be a major benefit for these patients.
Yeah, because this patient population, 60% of them carry at least one allele, so there is 15% with both alleles. Again, as Larry said, the drug is not available, it is not approved in Europe for these patients. Even in the U.S., given the risk for these patients, they are almost always excluded from treatment with the two drugs. This opens up that potential for these serious APOE4 carriers.
All right. One aspect of the biomarker data that I personally found particularly interesting is the consistency across the two different parts of tau biology. p-tau217 is an upstream marker associated with amyloid-driven tau dysregulation, whereas MTBR-tau243 is more closely associated with tau tangles and tau burden. To see in both biomarkers move in the same direction suggests that this is just what's happening upstream at the amyloid oligomer levels starting to propagate downstream.
Yeah, that's what we think. We were gratified by the convergence of how these biomarkers were moving. As you point out, p-tau217 is a biomarker that is quite well understood in terms of not only its ability to help diagnose Alzheimer's disease, even in preclinical stages, but also following the progression of Alzheimer's, and especially the early oligomer-mediated pathologies with regard to abnormal phosphorylation of tau.
The MTBR really measures the onset of tau pathology, which is really quite carefully correlated right now with the emergence of cognitive decline. So we're really kind of looking at early-stage disease as people are at their beginning stages of cognitive decline, and then also catching that later stage when they really do start to decline.
We think that, again, this sort of convergence of both ends of the Abeta oligomer-mediated tau pathology was very interesting for us to see. Also the fact that we could do it safely, which is important.
All right. Moving ahead. You have the 12-month readout for the phase I-B with about 144 patients, rather than it being an extremely large phase III, so likely not powered to see clinical efficacy. How do you have the unblinded phase I-B coming out in 1Q of 2027? Just what can we expect to see related to the next, and also related to the next steps of development?
Yeah, from that perspective, and again, we're certainly looking beyond the data readout. We're expecting great things from the data. Also, not resting on waiting to see what happens and then reacting. For us, it's all about the lifecycle management of the product. Expectations going into the data read are high and positive at this stage.
What comes next, as you say, Pete Stavropoulos, is, and part of the rationale for the phase I-B design, as I alluded to at the beginning, was if this reads out well, if we can show our target engagement, clean safety, got our dose, clinical signal, then we do expect to step into a single registration study. This is subject to FDA discussions. We expect to have our end-of-phase II meeting with the agency first half of next year. We have fast track designation already.
That allows us to interact with the agency a lot more meaningfully, if you will. Going into the next study, we would envision doing a single registration study. Again, we haven't really given guidance as to the size or the cost of that. We're looking at that now. Importantly, looking at the commercial potential here is something that we're busy planning and preparing for.
Another important aspect that we're working on that we've talked about a little bit before is on the subq formulation. As you know, the current dosing for this trial are monthly IV dosing. Very important to us is to deliver this product to market, as a subq formulation. Again, we expect to have improved safety. We expect to have improved efficacy. We want to also match improved patient compliance with the subq development program.
That's moving forward to thinking being that, as we demonstrate, look at the viscosity and the appropriateness of subq, how to roll that into that next study as well, such that we can deliver PMN310 as a subq formulation. There's a lot of thinking towards next steps. Obviously, this area that there's a lot of discussion now, when you look at the large pharma companies moving to this preclinical Alzheimer's population, and these are patients that are even earlier in the treatment paradigm, if you will.
They're asymptomatic patients, that really show no signs or external symptoms of Alzheimer's disease, but yet they have the underlying kind of pathology of disease. A lot of us are thinking about how to capture these patients, because if you can treat them early and hold their progression at an even earlier time point, that would be superb.
I think there's going to be challenges for the drugs in the market to get people who are relatively healthy to take a drug with serious ARIA issues. I think for us, coming with a much safer product, that's an area that we're excited to think about and move into as well. There's lots of life cycle, the preclinical, the subq, the phase III registration programs that are all in discussions internally.
All right. You are funded through 2027, beyond the readout. Strategically speaking, what are you thinking in terms of next round of funding or possibility of a partnership to help move it into later stage?
Yeah, the discussions with the strategics have been going on for the better part of a year. I'm a big fan of building those relationships and showing them how you're progressing. The pharma companies are certainly very aware of what we're doing. They're certainly very aware of the interim analysis that came out a month or two ago.
The potential to license or partner with a pharma company is certainly an option we are pursuing. I think similarly another option we're pursuing, because I'm a big believer in multiple options, not limiting yourself to one outcome or one option. The other option we're thinking about is, do we fund that next study ourself? Do we have the capability, if the data are supportive, to go out there and do a round of financing to carry that program forward ourself? Maybe it's U.S. only, partnering Europe.
There's a few different combinations that we're thinking of, but I think from my perspective, having the option to certainly do an attractive pharma deal or a co-development deal, but also funding the program ourselves are two options that I want to maintain on the table. We're talking about that with pharma now. It's a good leveraging, sorry, negotiating position as well.
Looking at funding, if the data's there, we also have the trigger for the warrants that can bring in another CAD 100 million based on our previous funding. That's on the table as well, and that'll come into play Q1 next year. Again, different options on funding the company. We are well-funded through the end of next year, so no pressure on funding or financing now, which is a great position to be in.
Right. In the last couple of minutes, let's touch on your pipeline. You have a number of earlier-stage candidates. I'm curious to hear how you're thinking about these assets and which may enter the clinic next, and what will be the driving factor behind that decision?
Yeah, that's a good question. Again, we can't forget that we have this really dynamic kind of EpiSelect™ platform that has allowed us to design antibodies for multiple different neurodegenerative diseases. Certainly Alzheimer's front and center, and that's where the focus of the company is, obviously executing on the study. But beyond that, we have a really healthy pipeline targeting different misfolded proteins, different diseases, or different misfolded proteins are associated with different diseases.
For example, misfolded TDP-43, which is well-known driver pathology in ALS and FTD, that's a pipeline candidate of ours that we're moving forward. Misfolded alpha-synuclein, again, another driver of Parkinson's and dementia with Lewy bodies, which we're interested in. So those two preclinical candidates are moving forward. Again, we're careful to allocate resources to the lead to the Alzheimer's program.
But we're also interested in advancing one or two pipeline candidates because ideally when the Alzheimer's trial reads out in a few months, we want to be in a position when people say, that's awesome. You've got proof of concept with a transformative Alzheimer's drug, but you've also got proof of concept for this remarkable platform of yours. What else is next? What else does ProMIS have?
When they look over our shoulder, so to speak, they can see an ALS candidate coming down. So we want to get that kind of jockeying for position, ready to enter the clinic. Same with potentially a Parkinson's candidate as well. So the idea being to obviously create shareholder value, but more importantly to get novel drugs and safe drugs to patients.
If we can demonstrate that we've got this valuable platform, later stage preclinical candidates with a now clinical candidate ready for phase III registration study in a huge area of medical need, that will unlock significant value for the company, we believe.
Right. We've come to the end of our chat. Thank you very much for attending the Cantor Healthcare Conference, and again, looking forward to watching the progress over the next couple of months.
Yeah. Thanks very much, Pete.
Okay, thanks Pete.
Really, really appreciate it. Thank you.