together. So the regulatory path is important to us. We're also developing or looking at developing a sub-Q, subcutaneous formulation. That program is ongoing right now. It's monthly IV dosing. Getting to market with a sub-Q formulation is very important to us. So that's also in the works as well. And then we're also looking, you know, this, as Larry said, this patient population we're addressing now is that MCI, early Alzheimer's patients. There's a lot of interest in the asymptomatic preclinical AD patient population. So we're also looking at that expansion or label expansion, if you will, as to how we address that market, because we think having a product like PMN 310 that ideally delivers better efficacy, but importantly, much better safety profile, That preclinical AD population is one that we could address, you know, quite well with a very safe and effective product. So there's multiple prongs here that are being internally assessed and evaluated and prepared really is that lifecycle management for PMN 310. In addition, obviously, we're having discussions with strategics. There's a lot of interest in the pharma companies in what we're doing. So, looking at, you know, how to work with them potentially in the future or potentially looking how to fund the next study ourselves. So, those strategic options are also part of the discussions internally.

Very good. That was excellent, Neil. Then perhaps the two follow-up questions. So, one is on the biomarker and then the one is on the safety. So, with regard to the biomarker or the blinded biomarker, I understand I think you and Larry have emphasized that we should not be overeating it at this stage. But to us, the target engagement is pretty clear, at least pretty evident, and because we don't think there is any reason for PTAO-217 to decline in an untreated AD population. So the question is, how should we think about target engagement for 310? And then on the safety side, yes, I think it's very clean safety and tolerability. So the question is, you know, with regard to ARIA-E, does it reflect the front-loaded fast pattern or does it hold beyond six months? Love your answer on both of those.

Maybe I'll turn that over to Larry. Larry, if you want to speak on the, you know, kind of what do we kind of feel about the target? I think we're pleased with the target engagement signal. Maybe you can speak a little to that and then to the safety as well, please.

Yeah, I think we're pleased with the target engagement signal. Again, we were happy to see a robust decline in PTA217, really, you know, beginning at the first month and then continuing on and increasing up to six months. And as Neil pointed out, the natural history of PTA217, if it's unopposed by any sort of therapy, is to increase over that period of time. So we were happy with that result. And we were also happy with the PTAU, the MTBR243 result, because that really represents a form, you know, the onset of tauopathy. And when tauopathy begins, that's really the onset of, you know, frank clinical decline. So we were happy with both of them. And because they bracket kind of two ends of pathology, of oligomer-based pathology, that is one increasing, you know, tauopathy with P-tau-217, and then the increase in abnormal phosphorylation of tau going on to neurofibrillary tangles, we think that that's an interesting sign of potential target engagement. And now with the safety, the safety data were not really cut off at six months, but actually reflected the total safety data, which we review every day, by the way, up to, you know, the time of the interim analysis, which was July 22nd. And so a substantial number of patients had crossed the six-month threshold. Almost half of the patients had finished the study. So we think that, again, the absence of ARIA-E is certainly due to the fact that we engineered PTAO or PMN310 to avoid amyloid plaque. It does not bind to amyloid plaque in the brain and also in the vasculature. So we think that that's principally the reason why we're not seeing any ARIA-E. and the ARIA-H data probably represents the baseline increase that you see in Alzheimer's patients due to cerebral amyloid angiopathy. And this is what is commonly seen in patients who are not being treated with drug. You'll see a small amount of ARIA-H that increases over time. So, again, I think that with the ARIA that we were, you know, quite gratified to see that signal. And then also, too, safety and tolerability don't really end with ARIA. We didn't see any serious adverse events related to drug therapy. We didn't see any dropouts related to treatment. and also the infusion reaction rate was actually quite low with just simply one case of a mild infusion reaction that did not require a change in dosing. So all in all, I think that our impression is that the safety is really quite remarkable and that we do have evidence of target engagement.

And to your point also, Yatin, that the importance of six months, I think, is also kind of emphasized when we know that the majority of ARIA cases, ARIA-E and ARIA-H, but certainly when you look at our graphs on our presentation, the majority, 90 plus percent of ARIA-E cases occur in the first six months of dosing. So to see zero cases in, as Larry said, six-plus months, half the patients have actually completed 12 months of dosing. So it kind of goes beyond six months. So again, that six-month threshold, when we know typically from the dadanumab and lakanumab studies, 90% of the cases occur, we're that much more pleased with our zero cases over the first six-plus months.

Excellent. Thank you.

No, thanks, John, for the questions. Operator, I think we can take a couple more.

Next question, Pete Stavra-Poulis with Cancer Fitzgerald. Please go ahead.

Yeah, hi, Neil and Larry. Congratulations on the updates and progress for the quarter, and thank you for taking our questions. One question is whether you have targeted engagement when dosing humans in PMN 310. We did present some data at AAIC about a month ago. Can you just talk about this assay and outcomes, and when can we expect to see a similar analysis for the Phase I-B? And, you know, will we get any additional biomarker data from the blind and interim look before 1-2-27 readout?

Yeah, Pete, I think I'll start with your kind of work backwards through your question. We'll have a, you know, a much more fulsome presentation of all the biomarkers in the clinical trial, along with the clinical outcomes when we unblind the data. you know, after the study is concluded. With respect to the assay that you were speaking about that we disclosed at AAIC, this is an assay to detect A-beta oligomers in cerebral spinal fluid. Now, the A-beta oligomers, although they are extraordinarily toxic, are present in very low concentrations, in picomolar concentrations, 10 to the minus 12. So they're very hard to detect. Other companies have used an antibody saturation level to look at antibody saturation of them, but no one has really to date measured the exact thing itself, that is the A-beta oligomers. And I think what we showed here for the first time in conjunction with our colleagues in Germany was to show that we actually measured the concentrations of A-beta oligomers. And we did this in a phase 1A study. These are patients who were, you know, otherwise healthy, but nonetheless had low amounts of A-beta oligomers. And we were able to detect the dose response with that, even after a single dose of PMN310. This assay is still being refined, but we expect that it will be used and we'll present the data again when the study is completed.

Yeah, I think the importance, and thanks for the question, Pete, and your comments, the importance of that assay, as Larry said, is really to kind of elucidate the mechanism of action that we've been predicting, if you will, over the number of years since we've been developing PMN310, that being the binding to the oligomers and the removal of those oligomers And as Larry said, that has not been possible because there's never been an assay sensitive enough to measure these oligomers. So now that we've shown kind of early data that we can indeed develop an assay that is sensitive enough to not only measure these oligomers, we also show that in the presence of PMN310, the actual reduction of these oligomers from circulation. And again, this was done in our 1A samples, but it really is kind of connecting the dots around the mechanism of action. So this assay will be implemented into the Phase 1B study so that we can look at pre-treatment and post-treatment results to see whether or not, indeed, we actually are able to reduce the level of these circulating oligomers. And then ideally, that lines up with the clinical evidence we see at the end of the study and ideally with the biomarker evidence. so having that mechanism of action piece is significant for our own use but certainly when it comes to um you know regulatory authority approval as well and there yeah and there will be no um kind of unblinding or blinded data presentations um prior to the final results coming out okay a couple of follow-ups um so current formulation in the phase 1b is iv uh administered.

How are you thinking about the potential sub-Q formulation? You know, is it feasible? Are you working on it? And what formulation, you know, would you actually like to bring it forth, assuming the phase 1B is positive?

Yeah, that's a good question. We touched on it a minute ago a little bit, but it's important to us to deliver the product to market in a sub-Q formulation. I think we're expecting to have improved efficacy versus products in the market certainly improves safety. So what we want to ensure is that we'll have kind of improved patient compliance, if you will. So entering the market with a sub-Q formulation of PMN 310 is certainly in our sights, and we've actually started the formulation development of that program. We've actually hired somebody on board to really lead the effort on the sub-Q formulation. We haven't kind of, you know, presented any data results on that. We will, you know, we'll kind of give some clarity as we get going with this program. We think it's quite possible. Again, others have gone before us and formulated antibodies as a sub-Q formulation, so I don't think it's overly complicated. But understanding what's required, viscosity, volume, you know, we need to understand the PKPD and dose from the clinical study. But all of that seems very, very possible. Again, without giving too much away until we kind of do the actual data in the work, it does seem like it is possible that we need to understand how to roll it into that next study such that we can get it to become commercially available as soon as possible. But it is very much a priority for us developing this over the next couple of years.

All right, great. And last question, you did touch on it. You do have early stage candidates. Just curious to hear how you're thinking about these assets and which may answer the clinic next and what's going to be the driving factor for those decisions.

Yeah, I mean, the driving factor is certainly going to be, and thanks for the question, we really are excited about the pipeline as well, although we obviously remained, as they say, laser-focused on the execution of this study to deliver the results on time and safely as well. But beyond that, there's some very exciting products coming along. I think our EpiSelect platform is unique and differentiated in that we can, I think we've proven, we can, you know, develop very selective antibodies to these misfolded proteins. So, as we said, coming, you know, close behind is the antibody targeting misfolded forms of TDP-43, you know, which is implicated in most of the ALS patients. So ALS is another candidate indication we're going after. And then the misfolded forms of alpha-synuclein, whether it be dementia with Lewy body or Parkinson's disease, is also very interesting to us. So we are actually advancing both those candidates preclinically. We would like to get additional preclinical proof of concept for those candidates as well. It would be, you know, it'll be important if we can generate data, obviously, with the Alzheimer's program, clinical data, but then also have some preclinical proof of concept data in the follow on assets that all kind of read out in the same time. We want to demonstrate that we have, you know, a robust kind of discovery engine, if you will, and a viable pipeline beyond Alzheimer's. So the goal is to kind of advance these towards the clinic, the two pipeline candidates towards the clinic over the next, you know, six to nine months, such that they'll be ready for IND enabling studies and can enter the clinic, you know, within the next year or so. So that's very much a goal of ours is to, you know, advance these. Again, we're selective. Again, you know, what's the driving factor will be data, obviously, as it always is, and resources. You know, again, the bulk of our resources is focused on the Alzheimer's program, so we're careful how we allocate resources beyond that. So we're modestly kind of allocating certain resources to advance a couple of the pipeline candidates as well in order to generate, you know, in order to generate value and get those to the clinic for the patients as soon as we can.

All right, great. Thank you, Neil and Larry, for taking our questions and have a good evening.

No, thanks so much, Pete. Really appreciate it. No, thanks. Thanks, Pete.

Next question, Fazia Ahmed with Brookline Capital Markets. Please proceed.

Hi, team. Thank you for taking my question. My first question is, hi. My first question is, I see on the press release you'll be presenting at the upcoming CTAD meeting. If you could share what would you be presenting at that meeting, that would be great. Then I have a follow-up.

I mean, CTAD, for those who don't know, you know, Clinical Trials for Alzheimer's Disease is a medical conference focused on Alzheimer's, and that takes place in mid-November. And it's really kind of the next one. As you all know, we attended the AAIC in July, and this is the next one following kind of the AAIC coming up in November. We're kind of submitting abstracts similar to what we presented already, Fazay. So we don't have, you know, we don't have any kind of acceptance yet of abstracts. So we're careful what we're saying we're going to do at CTAD. I mean, we are at CTAD. We're going as a team. It's in Boston this year where we're located. But we plan on being at CTAD certainly to engage with KOLs, to engage with, you know, pharma companies and with, you know, interested parties. Ideally, we'd like to, you know, present similar data that we presented a couple of weeks ago around the interim analysis. Again, we're not looking to present additional data, but if we're given the platform by the organizing committee at CTAD, it would be nice to stand on the podium and present again. Again, we haven't been given that yet. They haven't decided on all the speakers, but we'll be there in force to kind of talk to folks and ideally to re-present, if you will, the interim analysis that we presented a couple of weeks ago.

Thank you. And my next follow-up question is on the sub-Q formulation. So I just wanted to see if you could shed a little more color on assuming that phase 1B study is positive. How do you incorporate sub-Q? Would it be part of the potentially registration study, or would you expect to establish efficacy with the IV formulation first and then bridge to sub-Q separately?

Yeah, we haven't. I mean, those are things we're kind of asking ourselves internally. As I said, we're kind of building out that plan now. You know, the important thing is we get it to patients as quickly and safely as we can. You know, a lot depends on, you know, assuming the data is positive, a lot depends on clinical trial design. You know, that in part depends on FDA feedback. So there's a lot of moving parts, Fazia, on, you know, is it a separate arm of a registration study? Does it follow? Does it come before? So we really haven't given any guidance yet on that. Again, a lot of these questions we're asking ourselves internally and with our experts. So since we have some clarity around, you know, how the sub-Q, you know, folds into the next clinical development piece, we'll certainly update the folks. But right now, as I said, there's a lot of questions that we need to answer first around dosing and viscosity. And some of the stuff we're advancing now just to understand a little bit more, again, viscosity is an easy one to mention because that's something that needs to be done early. So these are the studies we're doing in order to understand. And, you know, we're also looking at, you know, kind of devices. And is this an auto-inject pen, for example? Does that make sense? So, again, a lot of questions to answer first before we know exactly, you know, how it plays out in the clinical development picture. But it is our intention to, you know, have a subcutaneous form of the product to patients, you know, as quickly as we can.

Thank you.

I appreciate it. Sorry I can't be more specific. Again, there's a lot here, but we'll clarify, and it's not trying to avoid the question. It's just, you know, as I said, we're determining a lot of this ourselves with our experts.

No, I understand. Thank you so much.

Thanks, Fauzia.

Next question, Kay Nakay with Chardin. Please go ahead.

Hi. Hey, Neil, thinking forward to 2027 and assuming the Phase 1B data reads out positively. As you're thinking about the design for the registrational study, what can you learn that can inform the design of that study from the phase three studies of the Canamab or Denonimab, whether it's, you know, patient inclusion exclusion criteria or your choice of the primary endpoint, you know, whether that's CDRSB or IADRS, you know, what are you thinking there and how might those studies be helpful in your design?

And maybe Larry, I mean, I'll follow, but Larry, you might have some thoughts around Yeah, I think the outcomes will be pretty clear. The FDA really recommends the CDR sum of boxes as the primary clinical outcome measure because it includes both functional and cognitive assessments. and then with the ADAS-COG and ADAS-COG composite scores like the IADRS, you know, as secondary outcomes. So I think that we're pretty well fixed on what the outcomes will look like. In terms of what the trial design will look like, you know, we think that obviously the trial will have to be, you know, of a large enough size in terms of patients and a long enough duration to, you know, make some credible statements about, you know, affecting disease progression. And it has to be large enough that we can power it to see a credible change in the CDR sum of boxes, which will be the primary outcome. And it's important to note that, again, the primary things that are involved in getting and approval are one, safety, and then two, a clinical, a positive clinical outcome. So I think that we can learn something from their studies and something from their recruitment strategies and something about, you know, the time that it takes to enroll such a study. So I think that, again, what we'll learn probably most of all is, you know, what's our effective dose from our Phase I-B study, what kind of clinical signal do we see in our Phase I-B, which will help us power that larger Phase III study?

Yeah, we'll kind of give a little bit more color around that, too, as we decide. Again, those trials are certainly, you know, formative and give us some colors to, you know, a little bit of precedence. They were done a number of years ago. And also keep in mind that, you know, we certainly expect to go to the agency, the FDA, with a much differentiated product, certainly with respect to safety profile. So when you look at the numbers of patients that the Nanomabs and the Lacanomabs, Lilly and Asai, had to build for their safety database, we're expecting, you know, ours does not have to be that large if all continues well as we've seen. So, you know, patient numbers might be less, again, powered for efficacy, not because we need a large safety database. Again, we're not expecting a black box warning. You know, ideally our RE and safety profile, you know, would prevent that from happening. So there's certain things we can certainly learn. But I think, you know, I think our product is going to be differentiated in a very positive way, such that there'll be, you know, there'll be elements of our clinical trial that make it, you know, more streamlined and such. You know, we do expect to run a global clinical study. We want to make this product available to patients around the world. That's our kind of one of our, you know, philosophy here at the company. But also, you know, market size globally is interesting for us as well. So we'll give more clarity around, you know, the trial design as we interact with the agency. And again, we have fast track, so we can do that in a pretty expedited way. But I think it's going to be a, you know, differentiated enough product that we might be a little bit more streamlined in our approach.

Well, great to hear. We'll look forward to hearing more about that.

Thanks so much, Kay. I really appreciate it. Operator, do we have one more?

Next question, Rajaram Salvaraju with HC Wainwright. Please go ahead.

This is Yanzi sitting in for Ram. I have two questions. The first is, so at top line, what magnitude of PTAO-217 or MTBR-TAO-243 change could you consider beyond assay and within patient variability? And how will that placebo separation and dose exposure response factor into your interpretation?

Yeah, I mean, thank you.

Go ahead, Neil.

Well, I'll just start quickly, and then you can probably speak to this better than me, I mean, again, as far as kind of expectations and what do we expect, we're kind of really being careful not to go into, you know, into the next six months and top line, you know, predicting what might happen. Again, we're, you know, we're expecting and we're hoping to kind of continue along the same framework here with clean safety, you know, and a strong clinical signal. So predicting what, you know, what expectation is tough at this stage. We want to be careful not to kind of give any guidance on these are the numbers or this is the level of separation. I think we want to be at least as good as, from an efficacy perspective, what's on the market. When you look at, you know, expectations and biomarker movements and percent biomarker movements, again, we don't want to give any expectations here. I know, Larry, maybe you can speak to the, you know, holistic approach of the biomarkers. And I think we're very expansive with the panel of biomarkers that we're looking at. So that's kind of more important for us to think through mechanistically how the drug might affect some of these biomarkers rather than kind of leading with, you know, know, we expect to see this percent change. But Larry, you can maybe speak to that a little bit.

Yeah, I think, Neil, that's correct. We look at the biomarkers in their totality. We chose them, you know, really to reflect a lot of the biology that is affected by A-beta oligomers. We expect them, you know, to move at different times and at different magnitudes. But we think that they will tell the total story of what PMN 310 is doing. And I think it probably doesn't make a lot of sense is to tie, you know, success or failure to a particular percentage of PTAO-217, especially at this stage in the study. So, again, we look at the biomarkers in their totality, and, again, that will give us a more fulsome notion of the biology of PMN310 and also really help guide us in, you know, in our subsequent studies as well.

Got it. And my next question is actually, you know, speaking of biomarkers. So with SVETA, what controls, I'm curious, have you run the rule out PMN310 interference with assay capture or detection, you know, just for example, so that a lower signal reflects lower?

The answer to that is yes. Again, with our new assay that we have, that's being optimized right now. So I think we're in pretty good shape with that assay.

Thank you.

Thank you. Thanks, Alfred. Over to Neil for closing remarks.

Yeah, again, I'd like to thank everybody for, you know, your attention this afternoon. It's been, again, an interesting call. thank you also to the folks for their um you know very interesting questions appreciate that um and thanks for your attention your interest in promise and our programs you know we look forward to uh presenting more updates over the remainder of this you know really an exciting and pivotal year for us at promise so thanks again for your attention and and um you know we'll continue to update you as we progress thank you this concludes today's teleconference you may disconnect your at this time and we thank you for your participation.