Good morning everyone, and welcome to the H.C. Wainwright 28th Annual Global Investment Conference. We are pleased to welcome Neil Warma, CEO of ProMIS. Mr. Warma, thank you for being here. Take it away.
Thanks, Katie. Appreciate it very much. That is loud. Thanks everybody for joining this morning and thanks for those attending on the webcast as well. Appreciate it, and appreciate the Wainwright folks for inviting us yet again to a superb conference. My name Neil Warma, President Chief Executive Officer of ProMIS Neurosciences.
Just like to remind everybody first, please, we are a publicly traded company. Please review our SEC filings for a complete and accurate picture of our operations. Just to walk through our company a little bit, for those of you who might be introduced to us for a first time.
Just as a bit of an important fact, I guess, the name ProMIS, in addition to the promise of novel therapies to help patients, it is also based on our technology which is focused on protein misfolding. So ProMIS.
It might give you a way to remember us a little bit in the future. We are a publicly traded company, as I mentioned. The ticker is PMN, traded on the Nasdaq Capital Market Exchange. We are based in Cambridge, Massachusetts. We had our foundings, if you will, out of Canada. Our chief scientific officer, one of the leaders in the field of protein misfolding, was and is a professor at University of British Columbia.
So our discovery platform came out of University of British Columbia, and we have built on that over the past number of years. But now based in Cambridge and Boston, Massachusetts. Our lead candidate is currently in the clinic, and I will touch on that over the next few minutes. That is probably our most important milestone over the past number of months. We have top-line data coming in a matter of months, actually.
In Q1 2027 top-line results. I will touch on the interim results that we just put out there publicly with our Alzheimer's study. We are well-financed. We are coming off a few months ago now in February, we closed a significant financing up to $175 million. Importantly, with an absolutely superb syndicate of investors, co-led by Janus, Ally Bridge, participation by Wellington, Deep Track, Great Point Partners.
We are funded, as we said publicly, through the end of 2027. So nicely funded. Superb leadership. Dr. Larry Altstiel is joining us today in the audience, and he is our chief medical officer.
But beyond Larry, the team is superb in its ability to develop neurodegenerative drugs that we are developing. I am going to touch on. Actually, maybe I will back up a little bit. The protein misfolding aspect of our company is very important.
We are truly a differentiated company in that we are able to design highly selective antibodies that specifically target a specific misfolded protein responsible for the disease we're focused on. As many of you know, proteins are manufactured by cells, and as they come out of the cellular machinery, they're folded upon each other in an elegant three-dimensional shape, and they go on to carry out their function.
But very often proteins come out of that cellular machinery and they are misfolded or folded improperly, and typically your immune system will grab hold of those misfolded proteins and remove them.
But as you become older, immune-compromised, your immune system can't keep up with these misfolded proteins that are being generated. If they're allowed to aggregate and build up, that's when you get serious diseases that are forming.
Our technology allows us to design antibodies, and all our therapies are monoclonal antibodies designed to selectively target misfolded proteins and remove them from circulation, preventing them from aggregating and building up over time. I'm going to touch on the interim data, and I'm going to come back to this because this was a significant milestone for the company that we reported on July 28.
It was an interim analysis based on six months of dosing with our PMN310 lead candidate in Alzheimer's patients. I'll come back to the design of that study. But just to put out a bit of a teaser now, the interim blinded six months analysis came back very positive. We were very pleased with the interim analysis on a blinded basis. It showed a clean safety profile, which is important to us. I'll come back to that in a minute.
Importantly, it showed target engagement, we believe, by the antibody on some key biomarkers. So some directional movement on biomarkers, and a clean safety profile on the interim result. I'll come back to that in a few minutes. The ability of our platform to allow us to design antibodies that target multiple different diseases.
As I mentioned, different proteins are important for different diseases. Our target for Alzheimer's is beta-amyloid protein, specifically the oligomer species. But then beyond Alzheimer's, we have antibodies targeting misfolded TDP-43 for ALS and misfolded alpha-synuclein for Parkinson's disease and dementia with Lewy bodies. So a relatively healthy pipeline, again, with a strong patent position all around focused on neurodegenerative diseases.
One of the interesting aspects around the selectivity of these antibodies is to be able to design a drug candidate that identifies and selects and targets only the harmful species of the protein you're going after. If you look in this diagram here, this represents kind of multiple species of A-beta protein. Our target is A-beta as it is for donanemab, lecanemab currently on the market for Alzheimer's.
The challenge becomes that there are multiple different species of A-beta protein. There's the monomers, there's the plaque, which we all know about, and there's the oligomers. It was previously thought that plaque was the driver of cognitive decline in Alzheimer's patients.
So drugs were then designed to target plaque, remove plaque. We now know that removing plaque in individuals, has little impact on cognitive benefit or in preventing further cognitive decline.
This, we've learned over the decades, that plaque is not really a driver of cognitive decline. Not only that, drugs, and the two on the market are examples of that, drugs that bind and remove plaque are also associated with a very serious side effect, and this is swelling and bleeding on the brain, known as ARIA, A-R-I-A.
Not only is targeting and removing plaque not that beneficial at preventing cognition, it also results in 20%, 30% of the patients getting swelling and bleeding on the brain. The challenge becomes, and now the field has really shifted to, well, if it's not plaque, because there are drugs that can totally clear plaque and the patient continues to decline. If it's not plaque that's driving the cognitive decline, what is it? That's where the field has come back to. It's upstream of plaque.
There's these low molecular weight, soluble oligomer species of amyloid beta protein. Now we know that these oligomers are highly toxic, especially to the neurons, more specifically to the synapses. These oligomers are destroying the synapses, destroying the neurons, and that is responsible for most of the cognitive decline in Alzheimer's patients.
The challenge becomes, well, how do you design a drug, since this is all the same protein, that can avoid monomers, avoid plaque, and only get to the oligomers? That's been the challenge to the industry, which is where ProMIS comes with its very differentiated technology.
Our ability to design antibodies comes from our ability to predict how proteins are going to misfold. It's not just the linear epitope we're targeting, but it's this three-dimensional conformational epitope. It's only ProMIS that has the ability.
We have a chief physics officer and very computationally driven approach to designing antibodies that says it's the linear epitope plus this three-dimensional confirmation. From that, we design an antibody that binds that three-dimensional epitope, which only exists on that misfolded protein, and that gives us our differentiation. We can design antibodies that avoid the monomers.
That's a good species of beta-amyloid. You certainly do not want to target that. It avoids plaque. We know that it's not really that beneficial, and it has a side effect. We seem to be the only company that can selectively target only these toxic oligomers.
I won't go into this, but we've pressure tested our antibody against multiple other antibodies to say, can we bind plaque? Do we bind plaque? Let's make sure our key differentiating factor is true.
Side by side with all the antibodies, it was clear PMN310 is the only antibody that we can see that does not bind plaque. Then we headed into the clinic with our. Just touching on the two drugs on the market, by Eli Lilly and Eisai. These drugs have modest efficacy. Every step is positive for the patient.
They have modest efficacy, but they come with a black box warning because of this ARIA side effect. The risk-benefit profile of the drugs on the market is pretty poor. Yet they're still generating significant revenue.
The opportunity exists, which we believe, for a company to come with a much safer and much more effective antibody and capture much of this market. The commercial validation is certainly there, but the risk-benefit for the drugs on the market is quite poor.
That gives us a whole opportunity to step into this market. Probably the best decision we made a couple of years ago, and certainly with the help and guidance of Dr. Altstiel, our Chief Medical Officer, was the design of the study we are running now, this phase I-B study. We wanted to run a study that would provide us with a fairly definitive answer as to whether the antibody worked.
That meant having enough patients over enough period of time to be able to detect a clinical signal. Again, it is a phase I-B study, so it does not mean hundreds of patients. We have to keep that in moderation. Our study design, and it is a placebo-controlled, double-blind, randomized study in MCI, so mild cognitive impairments, early Alzheimer's patients.
It is a three-dose study, so low, medium, high, if you will, randomized 3 to 1, so 3 patients on active, 1 patient on placebo. Importantly, it is being conducted over 12 months. That 12 months will allow us to see a clinical signal, which we feel is really important to allow us to then step into the next phase of development.
We wanted over 100 patients. We ended up with 144. So we over-subscribed. There is a lot of enthusiasm for this study, given the potential for significantly reduced side effects and potential improved efficacy.
The site is being run in the U.S. at 22 sites. A lot of enthusiasm, 144 patients over 12 months of treatment. It was fully enrolled last December. It should be fully dosed by this December. We are expecting top-line results in Q1 of next year, of 2027.
We received Fast Track designation from the FDA last year, so we have got that ability to get in front of the agency a lot more efficiently and rapidly. Importantly, we built in an interim time point, an interim analysis time point.
When all patients have been treated for six months instead of the full 12, we planned on doing a blinded six-month analysis of biomarkers and safety signals only. Not touching the clinical, because that we save to 12 months.
We presented this, as I mentioned at the beginning. We presented interim analysis July 28th, and we are quite pleased with the results, and I will flash up a few things here for you today. The top part of the slide just points to the design of the slide I referenced. In the bottom bits, we can see some of the background demographics.
The average age was about 73 years, split 58/42 female and male across multiple different ethnicities. So a fairly well-balanced study. When we look at the safety, and again, safety is absolutely critical because as I mentioned, the drugs on the market have safety issues. We all know that.
The physicians, the patients, the caregivers, the agencies, FDA, all understand that there are significant side effect issues with the drugs on the market, with all those drugs that target plaque, which everybody cannot help but PMN310 ProMIS.
When we looked at the safety profile at the six-month time point, really importantly, this ARIA signal, this swelling and bleeding on the brain, and the E represents edema for swelling, which is the more serious of the ARIA events. In the first six months, zero cases of ARIA-E.
We also noticed that there's not one treatment-related serious adverse event and not one treatment-related dropout in the trial. The safety profile of the drug was superb. Infusion reactions, which we see with lecanemab, that's 26%. Outside of ARIA, the safety profile of the drugs in the market is not great. For PMN310, just superb.
We couldn't be more pleased with the signal on the ARIA. Trying to present it a little bit more graphically, we can see in the previous trials with lecanemab, donanemab, their phase III studies read out, and they had roughly a 12% or 23% level of ARIA-E. These are the serious edema events of ARIA in their trials. When you plot ours, PMN310, we had zero cases.
Importantly, you can see by this graph that the majority of ARIA events, if they're going to occur, will occur in the first 6 months. That was demonstrated in the previous trials. The first 6 months of treatment, that's when you get most of your ARIA.
That 6-month interim signal has that extra importance to it, if you will, because 6 months you expect to see most of your ARIA. We saw zero cases of ARIA-E. When you look at the overall ARIA, so there's the E plus the H. Again, you can see our PRECISE-AD, our trial readout was right in line with placebo.
We know that in Alzheimer's patients, there's an underlying rate of spontaneous ARIA. We saw that in the placebo groups from the other large trials, and that placebo ARIA rate was anywhere from 9%-14% over 18 months.
We're tracking with the ARIA-H, and this is mild, asymptomatic, right in line with placebo or spontaneous. All that to say that the ARIA, the safety profile is absolutely superb in this interim phase of the trial.
When you look at, and there's a genetically predisposed population with the APOE4 allele, and these are patients that are highly susceptible to Alzheimer's and highly susceptible to ARIA.
So much so that the two drugs in the market in Europe, they're not approved for this patient population. In the U.S., they're rarely given, just given the severity of what ARIA can do to these individuals.
These individuals, whether they're a single carrier or double carrier, represent about 60% of Alzheimer's patients. A significant portion, and I believe around 10 to 15 have the homozygote, which are even more serious.
You can see with the lecanemab data, 30% of ARIA at 6 months. For us, we're at zero. This patient population is an interesting one for us to further develop. On the biomarker side, it's interesting because people say, "Well, if you show such great safety, is there anything going on on the other side? Can you show us some sort of hint of efficacy on a blinded interim basis?"
That's important to say, maybe it's just not doing what we think it's doing, that's why it's safe. We looked at a couple of biomarkers, and this was important to us to say, what are relevant biomarkers?
Which ones can we show on an interim blinded basis that show potential target engagement? One that's very well understood in kind of Alzheimer's biology is p-tau217. It's a biomarker which measures disease progression, essentially.
Kind of upstream disease progression. Typically, in untreated patients, you will see this biomarker increase over time, which is what this slope shows you over in those different databases.
Over 18 months, 5%, 6%, 7%, 10% increase over time. For us, and this is what we showed in our study, at six months blinded, and again, this is a 3-to-1 randomization, so it includes the placebo group.
We actually took this upward slope and shifted it downward. Our results in the first six months show that a decline of p-tau217 by roughly 15% over the first six months. Again, very interesting to us.
And keep in mind, this 15% includes the placebo group and includes the low-dose patients. And we have not backed it out to say, well, if we backed that out, what would we show here? How much further would this drop down?
For us, it was important to show, is there a trend in a biomarker that suggests target engagement or a potential drug effect? And interestingly, it seemed to track 3-to-1 with our randomization code.
That was a really interesting signal. We also looked at another downstream tau marker, MTBR-tau243. Similarly, you expect that marker to go up over time. And what we showed, very similar to the p-tau217, was a downward. So we took that upward slope and we were able to pull it downward over six months of treatment in a blinded fashion.
Again, tracking somewhat with the 3-to-1 randomization. So really important for us, really interesting to show. We summarized it here. The overall summary of the study was, is this speaking to our differentiated mechanism of action?
Is what we are seeing in this interim analysis reflective of the mechanism where we do not target plaque, we are not expecting ARIA, but we are targeting these upstream oligomers, so we are expecting to see some oligomer-mediated biomarker reaction. And that is certainly the case from the interim analysis. We showed superb safety across and beyond ARIA.
We showed our target engagement profile that we believe is indicative potentially of what is to come downstream. Although keep in mind, it is blinded, it is interim. Nothing is predictive of what comes in 12 months, but it is an interesting signal for sure.
The APOE4 carrier population is one that certainly can be explored further. Interestingly, the preclinical Alzheimer's patients, and this is an area that a lot of the large pharma companies are moving into, and it is the asymptomatic Alzheimer's patients.
Earlier in the treatment paradigm, the thinking being If we can go early in patient or individuals' lifetimes when they have the underpinnings of pathology and Alzheimer's disease, but no symptoms, should we treat then and hold them at that level? And the obvious answer is yes.
But if the consequence is you have 20%, 30% chance of bleeding and swelling on the brain, no one is going to take those drugs. So we are pleased that the pharma industry is building out that whole significantly large patient population for us to slide into that with a much safer and more effective, we believe, product.
Just the last couple of slides here. For us as a company, it is important not just to wait for the data to come out in Q1, but it is like what comes beyond that? What is the next step? What is the life cycle management of this product?
Our thinking was, if we can conduct this study such that we can show safety, we can show target engagement, we can identify our dose, and we can show a strong clinical signal, that should allow us to step into a phase III registration study. Skip over the phase II, straight to a phase III registration study, subject to FDA feedback, and that is what we are doing now.
We are in the planning stages of what does that next study look like? Cost, how big, how global. That step is being looked at. Also important to us is the development of the subcutaneous formulation.
We are currently dosing with an IV, monthly IV dose. The goal is to get a sub-Q formulation to market at launch. That development plan, formulation plan is now ongoing within the company, and it is advancing well.
We also have, as we mentioned at the outset, a really interesting pipeline. Advancing those next pipeline candidates in ALS and Parkinson's towards the clinic is important for us as well. At the end of the day, my last thing, the differentiation, which is absolutely critical for any company in any industry as far as I am concerned, is to have a differentiated product that has the potential to be best in class.
I think we are certainly currently going down that path. Near-term catalysts are coming off the back of the interim data. We have final, so we have improved or increased the likelihood of a successful result since the interim is pointing in the right direction. We have that potential successful result coming in Q1 with the final top-line data.
The clinical signal that we saw in a relatively large 140-plus patient trial has been quite important in showing us a lot of enthusiasm for that result. Then importantly, the financial strength.
We are nicely financed, and we have capital through the end of next year, well beyond the top-line results. We are interested, and we are kind of heads down as we execute the rest of the study and look forward to presenting top-line results in a matter of months. Thank you for your attention.