ProMIS Neurosciences Inc. Common Shares (ON) 0 Earnings Call

Good morning, and welcome to the ProMIS Neurosciences webinar on the PRECISE-AD phase I-B trial of PMN310 in Alzheimer's disease. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentation and fireside chat. As a reminder, this call is being recorded and a replay will be made available on the ProMIS Neurosciences website following the conclusion of the event. I'd now like to turn the call over to Neil Warma, President and Chief Executive Officer of ProMIS Neurosciences. Please go ahead, Neil. Thank you very much, Tara.

Thank you everybody for joining today for this update. My name is Neil Warma, CEO of ProMIS Neurosciences. Today we will give an overview of our blinded six-month interim analysis from our PRECISE-AD phase I-B clinical trial in Alzheimer's disease. I would like to remind everybody to please review our forward-looking statements. We are a publicly listed company. Please also review our SEC filings. We did file an 8-K and press release this morning speaking to the data. We've also attached this presentation as an 8-K, and this presentation and the archived webcast will be available on our website as well. The structure of the morning webinar will run through the slides. I'll give just a very brief overview and introduce our KOLs.

The results themselves will be positioned with a few patient demographics from the PRECISE-AD trial. Then Dr. Altstiel, our Chief Medical Officer, will walk us through the blinded safety assessment, followed by the biomarker assessment with a few conclusions. Then we'll have a fireside chat with our two distinguished KOLs, facilitated by Dr. Altstiel. Just to introduce our two esteemed colleagues who are really leaders in the Alzheimer's field, and we thank them very much for joining and providing their perspective today. Dr. Will Mantyh, who's a behavioral neurologist at the University of Minnesota. Will, thank you so much for joining. And Dr. Michael Weiner, who's a professor emeritus at UCSF. Mike, thank you as well for joining and providing your expertise and overview of the data. As I said, I'm also joined here by Dr. Larry Altstiel, our Chief Medical Officer.

I think most of you know on the call who we are. ProMIS Neurosciences, as I mentioned, is a publicly traded company, ticker PMN on the Nasdaq Capital Market. We'll speak today to the clinical program with respect to the Alzheimer's trial. But just to remind people that ProMIS really focuses on our technology platform of protein misfolding, ProMIS. We do have a pipeline of candidates targeting selected proteins for neurodegenerative disease. Today, we'll be speaking specifically to the Alzheimer's program. We will be speaking to the interim analysis from the phase I-B clinical trial. As most of you know, we initiated this trial early last year, and we completed enrollment in the study end of last year. In December 2025, we completed enrollment. We were oversubscribed. We had targeted 128 Alzheimer's patients. We ended up with 144 subjects. We were very pleased with that.

This is 12 months of dosing, which we'll go through in a minute. Enrollment completed in December of last year. Dosing should be completed around December of this year. We're expecting top-line results from this study early Q1 2027. As we have discussed and presented over the course of the months, we would have an interim analysis. When all patients have been treated or dosed for at least six months, we will present an interim analysis, and that's where we are today. This will be a qualitative look at blinded data, specifically with respect to biomarkers and with respect to safety. We are not going to view or look at any, and we have not looked at any clinical outcome measures.

Those will all be done in early Q1 when the data becomes unblinded, and we will look at clinical outcome measures in addition to further safety and biomarker movement at that time. Today is a qualitative look at biomarker and safety information. I'd like now to turn it over to Dr. Altstiel. Larry, if you would mind please taking the group through the next few slides with demographic safety and the biomarker analysis and presentation for us, please, Larry.

Okay. Thanks, Neil. The next slide is just a snapshot of our patient demographics and our trial design. Again, just to remind everybody that this is a study in patients with mild cognitive impairment due to Alzheimer's disease and early Alzheimer's disease. The study agent is PMN310, which is a humanized IgG1 monoclonal antibody that is highly specific for toxic Aβ oligomers. As Neil pointed out, we have 144 patients totally enrolled, and our safety evaluation group consists of 136 patients. Now, the top-line demographics are that the mean age of the patients is about 73 years, 58% women, 42% men. Again, that reflects the preponderance of Alzheimer's disease in women. The race and ethnic distribution is shown below. The APOE4 carriers, we have about 50% heterozygotes and 11% homozygotes. Just a word about the trial design.

Again, it is a multiple ascending dose study, where patients are randomized to either 12 monthly IV infusions of 350 milligrams, 700 milligrams, or 1,400 milligrams, and each dose is randomized 3 to 1, and that is drug to placebo. Each dose and cohort contains its own placebo arm. Dosing escalation was adjudicated by a data safety monitoring board that looked at unblinded safety data. In the next slide, again, we took great care to make sure that the patients we were enrolling in the study actually had the fundamental pathology of Alzheimer's disease. At first, they were ascertained by clinical signs and symptoms according to the NIA-AA criteria. 100% of the patients were amyloid positive, as confirmed by PET imaging. Again, the cognitive staging is consistent with the diagnosis, and all of the patients had positive tau-based or p-tau217-based biomarkers consistent with AD pathology.

We're confident that all of the patients in the study have underlying Alzheimer's pathology. In the next slide, again, we looked at the APOE allele frequencies in our patient population. There were 11% APOE4 homozygotes, 50% heterozygotes, and 61% of the population had carried at least one or more APOE4 alleles. We compared this distribution to a meta-analysis of over 100,000 patients with AD and found that we were statistically indistinguishable from the generalized patient population. Also too, we did an analysis making sure that we were in Hardy-Weinberg equilibrium. This ensures that we are not dealing with a genetic isolate that's incompatible with the general population. We're looking at data at six months, but we do know that 78% of our patients are past nine months of dosing, and 49% of patients have completed the full 12-month trial.

The study is moving on a pace, and we think that we are well-poised to conclude the dosing in December and be consistent with our guidance. The safety data is reported currently as of July 22nd. Again, this is very current safety data. The biomarker data is presented at the six-month time point. In the next slide, this is the blinded safety analysis. Again, we're looking at the patient population as a group, not breaking it out with respect to either placebo or treatment assignment, or assignment to dosing arms. What we've found to date is that we have no patients with ARIA-E. We have no treatment-related serious adverse events. There have been no treatment-related discontinuations. We do have a 4.4% rate of total ARIA. This is all ARIA-H. These were mild, asymptomatic cases of ARIA-H radiographically detected, but they were asymptomatic and did not result in an alteration in dosing or dose continuation.

We also noted a relative lack of infusion reactions that are again inherent with some of the marketed products like lecanemab and donanemab. We had one non-serious, probably injection reaction that was non-systemic. Dosing continued, and again, did not alter this patient's course in the study. This compares with what we've seen with donanemab and lecanemab. While we did not break things out according to APOE genotype, I think we can confidently say with no ARIA that there doesn't seem to be an ARIA liability with respect to genotype. We do know that from published studies that ARIA tends to occur within the first six months of dosing. Really better than 90% of ARIA does occur early in dosing.

Our study is powered with better than 95% chance to detect one ARIA case should it exist in this population. We also front-loaded the study with MRI scans to look for ARIA, again, at screening baseline, month two, month four, and month six. We took a very hard look to make sure that we understood where we were with respect to ARIA. Here you can see at six months that donanemab had a better than 23% ARIA-E incidence. Lecanemab, the imputed prevalence here is about 12%. Again, a historic placebo, again, derived from the literature, would suggest a minimal liability of about 0.6% and here is PRECISE-AD where we have not seen any ARIA-E to date. Again, I think that's encouraging with the ARIA-E. We've also looked at the total ARIA rate over time.

Our ARIA rate consists only of asymptomatic ARIA-H cases. Here again, looking at the total rate, we can see that donanemab and lecanemab have substantial rates of ARIA really over 6 months, then it levels off at 18 months. Our ARIA-H rates, again, are tracking with what one would expect in the placebo population, that is untreated patients. We do know that AD patients do have a degree of cerebral amyloid angiopathy that can lead to sporadic microhemorrhage. Again, we seem to be tracking along the placebo rate of untreated patients at 6 months. The ARIA rates that we see in published studies are, in fact, highly influenced by APOE4 genotype. Non-carriers have a relatively modest liability, but this increases with APOE4 gene dosage.

Heterozygotes have a higher % of ARIA-E, and APOE4 homozygotes also have the highest risk for ARIA-E. This has some real-world treatment implications because, again, APOE4 homozygotes cannot receive these drugs in the European Union. Also APOE4 carriers are subject to a high degree of scrutiny and they have to be managed very carefully with respect to ARIA. Again, we think that this apparent lack of relationship to APOE4 genotype would make a drug like this more accessible to a wider swath of patients. Again, we'll turn to biomarkers. In the next slide, we looked at two biomarkers. We looked at plasma p-tau217 and the CSF biomarker, the microtubule binding region, MTBR-tau243. P-tau217 I think is familiar probably to most of the people in the audience. It is by far the best validated biomarker of Alzheimer's disease progression.

It has great utility not only in the diagnosis of Alzheimer's disease, changes occur in p-tau217 really well before the onset of clinical signs and symptoms. It is a very sensitive biomarker of target engagement. We looked at, again, the biomarker, the MTBR243. This is in CSF, this is a biomarker that's very tightly correlated to the elaboration of neurofibrillary tangles. Neurofibrillary tangles tend to begin as patients develop overt symptoms. Whereas we know that clinical symptoms are not tightly correlated to amyloid plaque density, we do know that they track very carefully and closely with the elaboration of tau pathology. Again, we're looking at an upstream biomarker of p-tau217 that really moves early before symptomatic disease. Then we look at the MTBR243, which really then looks at tau pathology. The next slide. This is just another recitation of what we know about the natural history of p-tau217.

In the graph on the right, this is from a placebo arm of donanemab phase II study, and it shows roughly about a 6% increase in p-tau217 from baseline. There are many studies, both in published or in drug trials, and also natural history studies that really do confirm that p-tau217 does have a natural increase in placebo patients. We think, again, with a rise in p-tau217 in untreated patients that we'd be interested in seeing, do we actually have a decline in our patient population? Also we know that the change in p-tau217 at 6 months does have some predictive value of clinical outcomes at 12 and 18 months.

We published a paper in conjunction with our colleagues at Pentara, again, doing a statistical analysis of published data, which would suggest that early movement in p-tau217 does have some correlation with clinical outcomes. That paper is on our website if you wish to look at it. The next slide, this is what we found. Again, in the total patient population, this is all aggregated patients, all dosing arms plus placebo treated as one individual group. We saw at day 169 about a 15% decrease in plasma p-tau217. Again, we were seeing declining values as early as 29 days after the dosing, then it continued down to about a 15% decline in p-tau217. The panel on the right shows that 68.5% of patients had a decline from baseline in their p-tau217 levels. Whereas 31.5% of patients had an increased level of p-tau217.

This roughly coincides with our three-to-one randomization schedule. Again, this may be a leading indicator here of target engagement with PMN310. The next slide describes our work with MTBR p-tau243. This is a measure of tauopathy, again, as reflecting the onset of symptomatology. The longitudinal data that we have for this biomarker is more limited than what we have seen for p-tau217, but it closely follows tau PET. Again, it increases over the AD continuum, and it is related to the onset of severe or of clinical pathology. Again, this biomarker is expected to increase over time. We would expect that a downward trend could indicate possible target engagement. Next slide indicates what we found. We had did a CSF collection at screening, then another CSF collection at day 169 at six months.

We saw about a 13.3% decrease in MTBR243. Again, looking at the patient population, we saw 62.5% of patients declining. That is, having a lower value from baseline. We saw about 37.5% of people who saw their MTBR levels increase, again, roughly consistent with our randomization schedule. We think that this is obviously interesting, and it is a meaningful result in regard to we would expect an increase in MTBR tau in the absence of any treatment effect. The next slide kind of summarizes what we've seen to date. We've seen a plasma p-tau217 decline versus baseline about 15%. This may be an indication of target engagement. We do know that the toxic Aβ oligomers, which are the targets of PMN310, do promote abnormal phosphorylation of tau. This may well be a signal that we are having target engagement.

The MTBR243 decline further underscores that. Again, we have a biomarker that reflects the abnormal phosphorylation of tau that leads to misfolding of tau and subsequent formation of neurofibrillary tangles. Again, we think that this may indicate target engagement with our toxic oligomer target with PMN310. In summary, both of the biomarkers, 217 and 243, moved in what we consider to be a favorable direction at six months and against a natural history of rising levels. The data remain blinded, and this is by no means a declaration of victory that this is absolutely dispositive in terms of a positive result. It does suggest an early and biological coherent signal that shows that we have target engagement, and it's suggesting that we could have potential disease modification.

all the data that we have will be unblinded shortly in 6 months, and we can look at the final result then. I'll turn it back over to Neil for the summary.

Thanks very much, Larry. I appreciate the summary. Just the overview. Just a couple of conclusions and we'll open it up for discussion with our KOLs. The expectations going into this interim analysis, we set fairly high expectations, but we also realize this is a blinded kind of a qualitative look. The more important analysis comes in early Q1 when we unblind all the data and look at the clinical signal as well. Again, when we summarize the expectations against our differentiated mechanism, we've been very vocal about the fact that we believe we're the only company now to have a truly selective antibody targeting only the toxic oligomers. We've designed this antibody to avoid plaque, certainly to avoid the monomer species of amyloid beta, and selectively targeting just the toxic oligomers.

We're pleased with how that mechanism is shaping up with respect to the data we've released today. Expectations around safety, again, were very high from our kind of internal perspective, and I think we've achieved and probably overachieved on safety. As Dr. Al Steel pointed out, the data show at this stage that we have a very clean safety profile, certainly with respect to ARIA. We heard a lot about ARIA at the AAIC a couple of weeks ago in London. Still a major concern. Maybe we'll touch on that with our KOLs. Having zero ARIA-E events, overall ARIA-H kind of tracking with placebo is comforting. Looking beyond just the area, the safety profile, no serious adverse events related to treatment, no patient dropouts or discontinuations related to treatments, and just a minor inclusion reaction that we saw. Safety profile is superb. Looking at the other side of the equation, is there anything going on with respect to a potential drug effect or target engagement?

As Larry just walked us through, two key biomarkers, p-tau217 and MTBR243 lined up favorably, we saw a directional movement, a downward trend in both of these markers. Again, interestingly, somewhat tracking with our 3-to-1 randomization. When you look at those who decreased or improved versus those who increased or worsened, we're optimistic about that signal as well. Target engagement appears to be working to our benefit as well. Expectations there, we're certainly pleased with. When we look at the overall Alzheimer's patients, there's a couple of categories. Certainly the APOE4 carriers, more specifically the homozygotes.

That's the patient population that remains challenged with the products on the market, and they don't have accessibility in Europe to these products, and very challenged in the U.S. That's a patient population, again, if we continue with a clean safety profile that we're very interested in addressing. Beyond that, there's a lot of focus on the preclinical AD population, the earlier stage Alzheimer's patients who are basically asymptomatic. If we can come with a drug that's more efficacious with a better safety profile, that's a whole population of patients that opens up for us as well. We're excited very much with how the drug has performed to date. As Larry mentioned as well, it's certainly not a definitive signal.

We will see that definitive signal in a number of months when we unblind the data and we connect it to the clinical outcome as well. Just to remind you all that from now on, I think we're pleased with the signal. There's still a lot of work to be done to complete the dosing of the patients, so it's really heads down for us as we execute on the remainder of the study through to the end of December when we complete our dosing. Then expect to put out the top-line data, which will look at a series of biomarkers, a whole panel of biomarkers, together with the safety profile, and importantly, with the clinical efficacy measures as well. We look forward to presenting that to you in a matter of months.

That really summarizes where we are with the data, with our assessment that the teams worked hard to pull together for you all today. I'd like now to bring our KOLs into discussion, Dr. Weiner, Dr. Monti. Larry, if I could ask you to maybe facilitate with our colleagues in a bit of a Q&A session, that would be helpful. Then if there's time, we can take a few questions from the audience as well. Larry, I'll turn it back to you and Mike and Will and ask you to facilitate, please.

Thanks, Neil. I have a question for both of you, and I'll start with Dr. Weiner. Mike, what is your impression of the data that you've seen today?

I don't think you could have asked for anything better. First of all, most importantly, there's a great safety profile. You're seeing no ARIA-E at all, and a very small amount of microbleeds being detected, which is consistent. We see this in the general population with time. These microbleeds are picked up on these very sensitive types of MRI scans. Your safety profile is great, but equally or more important, you have really, to me, impressive biomarker results, both p-tau217. p-tau217 is considered to be a marker of amyloid pathology, we don't expect that plaques are being removed. The fact that you're seeing no ARIA is consistent with the idea that you're not actually removing plaques. The antibody is specific for oligomers in the lab. It doesn't stain plaques on pathology. It doesn't bind to the fibrillar amyloid.

The fact that you're seeing a signal in p-tau217 indicates that you're getting some kind of target engagement, and it's affecting the amyloid tau cascade. To me, the most important biomarker result is the MTBR result. These are early results. It's only six months, there's just not that much data right now showing that treatments lower MTBR tau. To me, this is very exciting because we know that MTBR tau correlates with the tau PET. The people who have a lot of tau in their brain have higher MTBR tau levels. We think of MTBR tau as a real predictor of progression. If somebody has a high MTBR tau level, we expect that they are going to progress more rapidly.

There's considerable data from Randy Bateman's lab, from the C2N, now we have immunoassays for the MTBR tau, which are starting to show that as well. The fact that you're showing a decrease in MTBR tau in the CSF after six months of treatment, it's very impressive. You're getting a lack of adverse events, you're showing biomarker evidence of target engagement, the data is consistent with a beneficial treatment effect. Of course, we need to have clinical data. We're in phase I, we're not going to get too much of that's why you go on to phase II.

Okay. Thanks, Mike. I'll ask the same question to Will. What is your impression of the data you've seen today?

Yeah. That was a great presentation, Dr. Alski. I'm piggybacking off of what Dr. Weiner mentioned, that we're seeing great ARIA rates that are on par with the natural history of Alzheimer's disease. We're seeing biological activity at two pathophysiologically distinct fluid biomarkers for Alzheimer's, this is really exciting data in my mind. Of course, the mechanism of action with anti-oligomer therapy, we didn't really know how this would work. This is, as Dr. Weiner mentioned, very specific for oligomers. Our current conceptualization of ARIA is that when you have fibrillar amyloid in the blood vessels of the brain, you have an anti-amyloid antibody like donanemab or lecanemab, that binds to the fibrillar vascular amyloid, creating a local immune reaction that can break down those blood vessels and lead to ARIA.

That we're not seeing that with anti-oligomeric specific antibodies like PMN310 is a fascinating scientific experiment in of itself. I think it's very exciting to see this actually being possible with the data presented so far.

Will, I'm going to ask you another question. Let's assume that the attributes of PMN310 are consistent through subsequent development and then launch. That is, the safety profile that you've seen, the evidence of target engagement, and that we see a robust clinical signal. How would a therapy like that fit into clinical practice? How would that affect clinical practice?

Yeah. I think one of the biggest challenges in my clinical practice is ARIA. Only 40% of my patients who I discuss anti-amyloid therapy with, these are patients who are totally eligible, patients who have a positive amyloid PET scan, who have a clinical syndrome compatible with Alzheimer's, who aren't on anticoagulation. Only 40% of that group ultimately decide to go through with anti-amyloid therapy. The number one reason for deciding against anti-amyloid therapy is ARIA. When you tell someone that you have a one in five chance of developing brain bleeding or brain swelling, even if the majority of that is asymptomatic, that is understandably very scary for patients. I think a drug like this, where we're dealing with ARIA rates that are on line with the natural history of Alzheimer's, that is something that I think is going to be very exciting to patients.

Another issue with the launch of anti-amyloid therapies is developing the safety teams to properly monitor for ARIA. As we know, ARIA rarely can cause fatalities, we want to make sure that we have a multidisciplinary team of experts who can handle these emergencies. That makes it very hard to scale anti-amyloid therapy, especially if you think about, as you mentioned in your talk, preclinical Alzheimer's therapy. At that point, we're dealing with tens of millions of people that are eligible for these therapies. There's no way we can scale a therapy where we need intensive ARIA monitoring with frequent MRI scans and potential emergency room care. I think this is a very exciting data point. As you mentioned, clinical practice is a little bit variable in the U.S. in regards to APOE4 homozygotes and if they qualify for anti-amyloid therapy.

In my practice, I generally try to dissuade those patients from starting, given the rates of ARIA are very high and the subgroup analyses for the phase III trials for donanemab and lecanemab indicate that their clinical efficacy is probably lower. A drug that has very low ARIA rates would effectively be able to include the 15%-20% of the Alzheimer's population that are APOE4 homozygotes. It definitely would be a major paradigm shift in our ability to scale these therapies and to treat a larger population. Yeah, I'm very excited about this product.

Just to expand on what Will just said, there's another group of patients, about 15% of the older population are on anticoagulants because they have atrial fibrillation. Those people should either not be on the current donanemab or lecanemab, or they've got to be super careful. Especially if you're a carrier, God forbid, you're a homozygote carrier and then you're on anticoagulant, it's probably essentially just a no-no to get the current treatment. Having a treatment which is effective against oligomers and prevents the spread of tau and slows the symptom development in the absence of ARIA is a game changer in two ways. First of all, it opens the population that can be treated that currently is closed. Secondly, it reduces the fear and the need for all the surveillance and all the MRIs.

$ millions are being spent, many $ millions are being spent on all the MRIs that have to be done prior to various dosing, especially at the beginning of lecanemab and donanemab, because of the concern that people are going to be developing ARIA. You don't want to keep dosing people if they have asymptomatic ARIA because it may lead to more serious symptoms. I think that the great safety profile here, together with the positive biomarker results is just, you can't ask for more in a phase I study.

Well, Mike, you kind of answered the question I was going to ask you. I would say, you've got certainly a long view of Alzheimer's therapy really from early days until now. A product with these sort of attributes, where does this fit in into what we have seen in the past, where we are presently, and what does it portend for the future?

Well, I think it fits in two big places. First of all, there's the current treatment of people who are symptomatic. Everybody in the field somewhat concerned that the rate at which donanemab and lecanemab have been adapted in the clinical population is below what we expected. There's a lot of reasons for that, but right high on the list are the safety concerns, which just slows everything down and adds to cost. As I said earlier, that's the first place, assuming that there's a clinical benefit, but that's critical. That's got to be shown in phase II and phase III. Then there's the prevention area, which there's a lot of interest in trying to prevent the development of symptoms.

Now that we have blood tests for p-tau217 and other blood tests, we have the ability, without using PET scans, to identify older people who have amyloid in their brain and tau in their brain who have yet to develop symptoms, but who are at much greater risk to develop symptoms in the next few years. There are two large prevention trials ahead and TRAILBLAZER-ALZ 3 being done by Eisai and Lilly, who are being treated with monoclonal antibody infusions to prevent the development of symptoms. Of course, the concerns about ARIA are the same. Having a treatment which would affect the amyloid tau cascade, but which would allow a lot of safety dosing without a lot of monitoring for ARIA would, again, really make a really important impact into the future market.

Okay. Thank you. Neil I was going to say, Tara, if there's a question out there, we can see if there's any questions from the group, if you want to bring one in.

Yes, that sounds great. To our analysts joining us live, if you have a question, please use the raise hand feature. Please hold for a brief moment while we pull the first analyst in. Our first question comes from Pete Stavropoulos at Cantor Fitzgerald. Please go ahead, Pete. Hi, Neil and Larry.

Congratulations for the update, and thank you for taking our questions. I have several. To start off with, I know this is a pooled analysis, likely dilutive in terms of signal. How do changes in p-tau217 and MTBR-tau243 compare to changes observed for donanemab and lecanemab, even on a qualitative basis? Any details that you can provide in terms of upper bracket of percent change for those biomarkers? Larry, you did touch on it on the call, but can you go into a little more detail and help us understand how the six-month p-tau217 change could be an early leading indicator of benefit and a predictor of clinical outcomes at 12 months? Any details that we should be paying attention to in the article that you published?

Well, I'll take that one. Again, what we did is did a retrospective analysis of p-tau217 data from published studies and took a look at what the results were at six months, and then compared them to the clinical outcomes at 12 and in 18 months. Again, what we found with this retrospective analysis is that really the p-tau217 was much more sensitive than the clinical outcomes at six months, for sure, and did have some predictive value. Now, going into the depth of the statistics and to do this would take us pretty far afield here. Again, I could refer you to the paper that's on our website.

I think as far as speaking to maybe our colleagues can as well, Pete, thanks for the questions and for joining. With respect to comparison at six months- Yeah versus lecanemab, donanemab, it's tough for us to do that.

Again, those data points were published data at 18 months, looking back as well. We'll certainly do that comparison at the 12 months when we unbind the data. I think what we can say, and I'm sure there's people that are doing the back of the envelope calculations a little bit. It's a three-to-one randomization. We've got the dilutive effect, if you will, from the placebo arm in our downward trend here. We assume that the downward moving curve is even more pronounced once you remove the placebo group. I think at this stage, and we're not really looking to really do the compare contrast with the other agents on the market, but I think at this stage, we're certainly encouraged by what we see at six months.

If we were to hypothesize and take out that placebo group, I think we'd be at least in line with what we've seen from the other drugs. Again, we're careful not to get into a direct comparison because it's not really consistent. At this stage, I think for those who do the back of the envelope, I think it's encouraging looking at these data points. I think the three-to-one randomization, that tracking is particularly interesting when you look at those who declined or potentially improved, really close to that three-to-one randomization. That's an interesting signal as well. We're careful not to really do that compare and contrast with the others, with their published data.

Will, Mike, do you have any additional comments?

No. Just remember that when you're looking at this data, there's some people that have completed, but there's some people that have only just had 6 months of results. The fact that it's going down to this extent, to me is, I have to say I was very delightfully surprised to see this. It's a great result. If you don't mind, I just have a question for the KOLs.

We see the blinded biomarker data presented today. It suggests that there is target engagement. See that there's no cases of ARIA-E at 6 months for some patients and beyond for others. Can you just sort of discuss the importance, though you did touch on it in the call, of a reduction in these biomarkers in the context of no ARIA-E? Sort of what does that suggest to you? Thinking forward to the 12-month data point, what would you like to see at a minimum in terms of slowing of disease progression, to consider it a win, taking into account the safety benefit versus the first approved gen, first gen amyloid betas?

Yeah, maybe I'll start. As you probably remember, some of the first-generation anti-amyloid drugs like solanezumab, no ARIA. On the flip side, no disease activity. I think it's really encouraging that we're seeing no ARIA, and we're seeing biological effect onto pathophysiologically distinct Alzheimer's fluid biomarkers. As Dr. Weiner mentioned, we don't have a ton of data on MTBR-tau243 at this point. That being said, there was a published abstract from the Alzheimer's Association group on 18-month data with lecanemab showing that it reduced the progression of MTBR-tau243. It didn't reduce the absolute levels, it just slowed the increase. I think that we're seeing an actual reduction, as Dr. Weiner mentioned, is very encouraging here. Your, I think, second question about clinical effect size.

Right now, of course, we think about the trade-off between the modest clinical benefit of anti-amyloid therapies, the 25%-35% slowing. That's the average ballpark range for lecanemab and donanemab, depending on the clinical outcome measure you're looking at, versus the ARIA rate. I think if we're able to see equivalent rates of clinical slowing and we're able to basically eliminate drug-related ARIA, I think that would be a major success.

If you saw a clinical benefit in a phase I-B study, it would be, to say the least, a major success, because the study is not designed or really powered with a primary effect to detect the clinical benefits. You'd need a larger and a longer study for that to really nail that down. That would be great, I would not be disappointed in a small study like this if the actual clinical effects were difficult to detect. The fact that you're getting strong biomarker effects in the absence of side effects is, if these results are sustained in the full study and then you see the specific data in the treatment arm versus placebo, this is all confirmed. This is what we want to see.

All right. Congratulations once again, thank you for taking my questions.

Thanks, Pete. Appreciate it. Thanks, Pete.

Tara? Yes. Thanks, Pete. Our next question comes from Eddie Hickman at Guggenheim.

Please go ahead, Eddie. Thank you.

Good morning, everyone, and congrats on the data. Really nice to see and nice presentation. A question for Dr. Manty. You noticed that 40% of your eligible patients, despite being eligible and sort of fitting the criteria, opt not to go on these amyloid therapies due to safety concerns. I'm wondering if you had an approved therapy like this, beyond just the other 60%, how much wider does that discussion get in terms of earlier stage patients or earlier MCI patients in terms of just being confident with that safety profile beyond just the current eligible patients that you have?

Yeah. I think if I understood your question right, are you asking whether or not the safety profile is better for patients who are less advanced in their Alzheimer's disease and whether that affects their decision to start therapy? Is that correct? Yeah. Does having a clean therapy like this change the sort of population that you're even having those discussions with?

Oh, yeah. Absolutely. I think I'm a little bit maybe more conservative in terms of outlining the full risks of ARIA with patients. I think depending on the neurologist you talk to, some neurologists might have 80% of their eligible patients ultimately decide to go on anti-amyloid therapy. I think it is how you phrase things and how you contextualize the risks. As Dr. Weiner mentioned, though, there's a whole lot of patients that get filtered out before we're even talking to them. He mentioned patients on anticoagulation therapy. There's also patients with significant cardiovascular disease, patients that have, let's say, heart failure, or patients that have kidney disease or liver disease or other organ system issues. Those patients we generally view as not healthy enough to tolerate the side effects of anti-amyloid therapy.

If we have a drug that essentially is very well tolerated, that has very low rates of ARIA that are on par with the natural history of Alzheimer's, that has very low rates of infusion reactions, then we get to really expand the eligible population itself. The patients who are eligible, I think, are going to be much less scared away than the current population, who, again, I think when you mentioned that they have a 20% chance of brain bleeding and brain swelling, even if that's majority asymptomatic, that's of course scary for most people. I do think that this is a drug that has an amazing ARIA profile so far and that we really could capture a wide amount of the Alzheimer's patients out there.

I think that we didn't talk that much about the infusion reaction result. I don't know if it's easy to go back to that slide, but I think that's something worth really looking at more carefully. I think especially when you compare your results with lecanemab, the fact that the whole infusion reaction story just creates another obstacle. Okay? It creates the need for more monitoring, it creates more fear, and it creates more dropout. If you see in lecanemab, 20% of the patients are having infusion reactions, where so far very few have been seen. I think it's likely that this is just a very well humanized antibody. That's just more evidence of a very good safety profile.

Can you speak, Dr. Weiner? There's a question as well that came in with respect to pre-treatment with steroids. Sticking to the safety profile, there's a lot of discussion around donanemab using the shuttle. Again, the safety issues with a shuttle, pre-treatment with steroids. I know Larry speaks to this as well, maybe you could comment on that because that's a question we get a fair amount.

Well, my understanding from talking to the Roche people is the reason why they're pre-treating with steroids is for the infusion reactions. Gantenerumab, which now has a brain shuttle, they're concerned about infusion reactions, so they're adding steroids. If you don't have infusion reactions, you don't need steroids.

Will, if I could ask you what the clinical implications are of giving steroids to people with early onset AD or early AD.

Well, certainly steroids themselves have their own side effects with causing patients to be anxious, to have insomnia. Of course, it's not good for your osteoporosis risk. It can be hard on your stomach if you have stomach ulcers. It does add in an additional layer of medical complexity that makes it more difficult to scale a medication. That we're not needing steroids to see this low rate of ARIA and to not have infusion reactions is, again, I think very exciting data.

Eddie, sorry to cut you off. I don't know, you had another question.

No, that's all very helpful. Larry, I was hoping you could sort of help us walk through. I know you had a panel that you were looking at, but sort of help us understand how we should think about Aβ oligomer reduction leading to sort of plasma p-tau217, what is the sort of cascade of the disease progression, and how does that lead to potential cognitive changes that we might see at 12 months?

Eddie, we didn't include some recent data that we showed at AAIC.

Yeah. Really for the first time, we were able to detect a direct lowering of Aβ oligomers in CSF.

In conjunction with our colleagues at Adelaide in Germany, what we found was that when we looked at CSF from our phase I study, and these are healthy volunteers. Also people do tend to make low levels of oligomers even if they're healthy. We were able to detect a dose-dependent decrease in Aβ oligomers, even in this population. The assay is still a work in progress. I think at least from my understanding, this is probably the first time anybody's been able to measure these oligomers directly and then show a drug-related dose-dependent decrease in their concentrations.

While this is, like I said, it's still a work in progress and the assay's being refined, we think we'll be able to use this again in the final analysis of our data for when we unblind the study.

Nice. Very nice. Thanks, Eddie.

Appreciate it. Tara, are there any other- Congrats again.

Thank you. Any other questions?

Yes. We have another question from Keith Nikay at Chardan. Please go ahead, Keith. You might be on mute.

Can you hear me now?

Yeah. Yes. We've got you, Keith.

Go ahead. Great. Yeah. Thank you.

Question for the KOLs. The 0% ARIA at six months, very impressive. I know in your presentation you've kind of calculated what you think the placebo level is at six months from the other trials. Is that number too good to be true? What else could explain this other than maybe just the small sample size for that 0% versus maybe, and again, I know it's a rejected number, but 0.6% at six months?

Well, I think what explains it is the mechanism of action. We basically know that amyloids is caused by amyloids that pull amyloid plaque out. They pull large amounts of amyloid out of the brain. As Will said earlier, there's amyloid in plaques, and there's amyloid in the blood vessels. Those antibodies are pulling amyloid out of the blood vessels as well, makes the blood vessels leaky, and that's what causes both the edema and the bleeding. Here we have a mechanism of action, where they've done extensive work looking at pathology and animal models and everything. This antibody is highly selective for the Aβ oligomers, so it doesn't pull out the fibrillar amyloid, it doesn't pull out the plaque. The fact that we're not seeing ARIA is consistent with their mechanism of action. Is highly specific for Aβ oligomers. Does that answer your question?

I'm talking about the placebo group, because even in those placebo patients in the other trials where we end up with a very low ARIA-E, we have some, not zero.

ARIA-E is really rare in the placebo patients. There is a detectable progression of small microbleeds, which are detected on susceptibility weighted imaging longitudinally. ARIA-E, that is edema, is just very rarely seen in the general untreated population. Will is seeing patients all the time. You can expand on that.

Yeah, I think, the ARIA-E rate in the phase III clinical trials for lecanemab and donanemab at 18 months was less than 2%. That we're seeing no detection yet, I don't think is necessarily too good to be true. Another thing that I would mention that Dr. Weiner brought up is that the ProMIS team is using a very sensitive measure for ARIA-H at the bottom of the screen there. The susceptibility weighted imaging, SWI, is sort of the best MRI sequence that we have available for detecting ARIA-H. It's better than GRE, which is sometimes more commonly used. I think we're using the best in class MRI sequences to detect ARIA-H here, and that we're seeing very low rates of ARIA-E are still compatible in my mind with the natural history of Alzheimer's disease.

Right. Great. This is a really encouraging set of data, so thank you.

Thanks, Kay. Appreciate it. I think there's a couple more.

We're kind of getting to the top of the hour. Maybe, Tara, if there's another question, we can take that and probably need to wrap up shortly.

Yep, sounds good. Our next question comes from Fozia Ahmed at Brookline. Please go ahead, Fozia. Good morning, team.

Congrats on the data, and thank you for taking my question. My question is mostly on the biomarkers. I wanted to know KL's views, what additional biomarker would be most informative in assessing PMN310's biological activity and potential for disease modification beyond p-tau217 and MTBR? I have a follow-up. Yeah, I guess you want to go first, Dr. Weiner?

No, go ahead, Will. Yeah, I think it's a really interesting question because, again, I view this almost not only as a success story for patients but also a scientific experiment.

We don't really know how intervening with the oligomeric species in Alzheimer's disease is going to affect canonical Alzheimer's disease fluid or PET measurements. As we discussed earlier in the call, I think it's still a question about how amyloid PET is going to be affected. I think we could hypothesize that there's not going to be an effect on amyloid PET, given that we're not attacking the plaque species. You could maybe argue that there's a certain degree of dynamic equilibrium between different amyloid species. The oligomeric species are a minority in the brain, but you could conceive that perhaps there's a dynamic equilibrium where some amyloid PET reduction is witnessed, but we just don't know.

The same thing for fluid levels of amyloid beta. I think this is kind of terra incognita, and at the end of the day, I think we're seeing movement on at least the most tried and proven Alzheimer's blood-based biomarkers, p-tau217 being the one here that I think we can have the best handle on. In my mind, I think the next step is not so much what other biomarkers are we going to see, because they're going to be hard to interpret in the setting of oligomeric specific therapies, but the clinical outcome measures and the safety profile.

My follow-up for you, Dr. Will, would be on the APOE4 homozygotes patients. Currently, what is your first treatment choice for those patients?

For APOE4 homozygotes? Again, I tried to show them that first of all, if they decide to proceed with therapy, that's within their ability if they decide that despite the high risk of ARIA and the expected clinical benefit attenuation with current FDA-approved anti-amyloid therapies.

Again, a very small minority of my APOE4 homozygotes actually decide to proceed with therapy. At that point, we're kind of stuck with the acetylcholinesterase inhibitors with memantine. Yeah, we're kind of back to 20 years ago, basically. Yeah. Appreciate it. Thank you so much.

Congrats again to the team.

Thanks, Fozia. Maybe one last question, Tara. I think there's one teed up. We can take that. Then we can wrap up in a minute or two.

Great. Yes. Our last question comes from Boobalan Pachaiyappan at Roth. Please go ahead, Boobalan. Thanks everybody for the presentation and taking our questions.

I'll be very direct. This is for the KOLs as well as for the ProMIS team. Let's just say in your 12 months data package, you are seeing a placebo-adjusted ADAS-Cog 13 of four points improvement or greater, also a CDR-SB score of 0.5 points improvement or greater. Let's just say if this is met, do you think these results will make you believe PMN310 moved away from a promising low ARIA antibody to a meaningful Alzheimer's drug? That's my first question. Maybe, yeah, Dr. Weiner.

Yeah. Mike, Will, any comments?

If this continues and we have clinical outcome, as I said, as Dr. Weiner mentioned, it's a smallish study. We'll have 130 plus patients at the end. We are looking at clinical endpoints, we hope to show trends. I guess if the question is, if we continue and we do show a trend in efficacy, according to the CDR, some of the boxes and such, is it a promising sign?

Yes. You've got a small study. If you saw beneficial clinical results supporting all of this biomarker data, but the size of the study, it's only a year. That's a lot to expect. I would not raise expectations that you're going to see a very strong clinical benefit in this, because it's designed for safety, it's designed for biomarker, and a clinical outcome that's really a very strong clinical outcome, it would be great, but it's not what I was expecting. I don't know, Will, what your thoughts are on that.

I agree with that 100%. I had originally mentioned relative reduction in clinical trial decline of 25% or 35% compared to placebo. That was sort of what I meant to say about that is in a future trial that is powered and designed for detecting clinical benefits. I agree with Dr. Weiner that if we see signs of clinical benefit this early on, then great, that is fantastic. I will reiterate his point that this is not a trial that is yet powered or designed for detecting clinical efficacy.

Thanks, Will, and I think we will wrap it up. Having said that, though, I certainly appreciate that feedback. I think we designed the phase I-B study to be robust enough to give us certainly the biomarker read, the safety read. We would like to see clinical trends at that 12-month point, at least to be able to connect the dots with safety, with target engagement. We have found our dose. We are seeing a clinical signal ideally. If that oligomer assay shows us that our mechanism of action is what we believe, that the binding and the removing of those toxic oligomers, if all that lines up, then we feel we will be in a very good place with respect to the potential of this candidate to treat Alzheimer's patients.

On that, I would like to just wrap up and thank most certainly Dr. Monti, Dr. Weiner, so much for your valuable input and oversight as you treat patients, and you have been around patient treatment for a number of years now. We respect your judgment and really appreciate your interpretation of the data. Thank you very much for that. As we said, from our perspective, we set our expectations fairly high for this product going into the interim and certainly going into the final results in a few months. I think we met those expectations, and I think we over exceeded or exceeded or overachieved a little bit on those expectations as well. Not to get too carried away, we have got some work ahead of us in the next 6 months to complete the study. We will report out as expected in early Q1 2027.

Hopefully, we continue to see this trend with a remarkably clean safety profile. As we expand the biomarker pool and even continue with looking at p-tau217 and 243, that those line up even more encouragingly. On that note, I would like to thank everybody for participating in the webinar this morning. Thank you for the questions. Thank you for your attention. A special thanks again to Dr. Weiner and Dr. Monti for your insights into this. We look forward to continuing, and we look forward to bringing this promising drug to patients in due course who more than deserve novel treatments for their disease. Thank you again. We will update again shortly.