But good afternoon. My name is Matt Sykes. I'm the Life Science Tools and Diagnostics Analyst at Goldman Sachs, and I have the pleasure of welcoming Masoud Toloue, President and CEO of Quanterix, to my right, and Joel Braunstein, Co-Founder and CEO of C2N, on, further to my right. These are two companies which are at the forefront of developing or commercializing blood-based biomarker testing for Alzheimer's disease. Masoud and Joel, welcome. Hey, Matt. Hey. This is a discussion that I've been selfishly looking forward to for some time. Last week, my team published a deep dive on blood biomarker testing for Alzheimer's, where we developed a market model for Alzheimer's testing, outlining a potential $60 billion market size over the long term, and highlighted what we think is a very compelling value proposition for blood-based testing versus PET and CSF in the diagnostic framework of this large indication. Hopefully, we can shed some more light on this exciting topic in the next 45 minutes or so, and I think you've already heard in a number of the panels this morning discussion of blood-based biomarker testing in the diagnosis and also the monitoring and therapy selection of Alzheimer's treatment. Thanks for joining us. Maybe we'll start with you, Masoud. For those people in the audience who are not familiar with Quanterix, maybe just give us a high-level overview of the company, where Quanterix fits into the Alzheimer's diagnostics landscape. Yeah, absolutely, Matt. Thanks for having us. So Quanterix was founded in 2007 by David Walt. So David Walt also was a founder of Illumina, and the technology at the company is basically an immunoassay system that gives you, you know, three orders of magnitude greater sensitivity in detecting blood-based biomarkers versus traditional methods of detection, including ELISA or chemiluminescence-based methods. And so the company, you know, is now, you know, at commercial scale, just over $100 million in revenue. 75% of what we do is really towards platforms, platforms and assays that we put into labs around the world, both in research and the clinic. And then, you know, 25% are services, both research and through our CLIA lab. We're offering blood-based diagnostics specific for Alzheimer's disease. Great. And Joel, thanks for being here as well. Maybe you can give us a brief overview of C2N, sort of the genesis of the company, and, and maybe some background on your PrecivityAD and, and your new offering, PrecivityAD2. Great. Thanks, Matt. Real pleasure to be here and honored to have the opportunity to talk a little bit about C2N. We are a private company. We, too, started in 2007. I joined forces with another colleague, who's a longtime colleague, formerly from the FDA, Ilana Fogelman, and then David Holtzman and Randall Bateman, who are two research professors and clinicians out of Washington University School of Medicine. When we started in 2007, you could imagine there wasn't a great deal of discussion about blood biomarkers, but we had this vision. We were going to try to take a really unique platform tool that was developed out of the Holtzman- Bateman lab, back in 2006, and try to ultimately get to point-of-care testing. We were about 10 years too early, and... But in the early days, we actually pioneered the work, and I give a lot of tribute to Randall Bateman and David Holtzman, who really characterized the metabolism of brain-derived proteins. So the implications of that are actually profound because when we start talking, we've talked already this morning about targeted therapies that are approaching the amyloid plaque accumulation and tau tangles in different ways. But the way we think about it as a blood biomarker company, we think about multiple different compartments to which these pathological proteins are moving. And when you think about metabolism and dysregulated metabolism of proteins, that is really characteristic of Alzheimer's disease. So that dysregulation of a biochemical process starts with abnormal processing of amyloid beta 42/ 40. From what we can tell in all of our over, well over 15 years of focus, it's that dysregulation that you can ultimately pick up in blood testing and then ultimately start thinking about when you pick up these soluble biomarkers, because that's really what we're measuring. We're not actually measuring the direct plaques, which are aggregates. We're measuring a dynamic process and characterizing the quantitation of those proteins in the role that they might play in disease or being able to predict disease. And so, over 15 years, C2N has exclusively focused on neurodegeneration. We have about 70 employees. We're based out of St. Louis. We have a CAP CLIA lab of about 20,000 sq ft with R&D, intensive R&D. And as Matt indicated, we've introduced two tests to commercial testing, which we'll talk more about, PrecivityAD and PrecivityAD2, and it's using that domain knowledge to quantitate these different analytes that are implicated in disease, phosphorylated tau forms and amyloid beta 42/ 40, to be able to infer disease and help in treatment selection and management. Great. Thank you. And maybe I'll start with some general questions for both of you, so feel free to chime in. But just for simplicity, Masoud, why don't you start out? Just give us a brief overview of the landscape for the use of blood-based biomarker testing to the diagnosis of Alzheimer's, and importantly, how that differs versus some of the traditional methods of diagnosis, like PET and CSF, that we heard a little bit about today, and what sort of the value proposition for blood is versus those traditional methods. Yeah, Matt, thanks. I think, you know, what you heard in some of the earlier conversations is that PET and CSF today are a lot of the gold standards for diagnosis of the disease. And what you're hearing more and more is that, you know, are there non-invasive ways to be able to detect, you know, whether it's tau or amyloid in blood prior to sort of a more invasive way or invasive method of detection? So I think, you know, the advantages of some of the gold standard methods is that there are a lot of access to, unfortunately, autopsy patients and brains. And so that comparison to PET began, and that began as part of a gold standard. And when we today compare things to PET or blood to PET, we're doing a sort of not a direct comparison. And so, but there's been, you know, a lot of research over the last several decades in blood that's shown very high correlation to both CSF and PET, and it's becoming more and more promising. So I think if you take a look at the literature today or you take a look at some of the, you know, earlier speakers begin to see that blood can be a very effective screen for, you know, Alzheimer's disease and, you know, can be used as a rule-out. I think, today, the LucentAD test that we offer, the PrecivityAD test, that's offered by C2N, is being used as, an aid, to a physician, in the diagnosis, for Alzheimer's disease. So, I think, very clearly, the blood's role in the ability to, be an aid or an additional tool, for a clinician in making a diagnosis, is here today. And one of the goals, that we have is progressing that to from, you know, a rule-out test to being more and more a rule-in test. So, you know, you're using it as a tool, but it becoming eventually, the replacement, for imaging, or for screening in the future. I think in the midterm, there's a big, you know, case where you'll need both, and as you can see, there's a lot of decision-making that has to happen, with, with a lot of parties, including the family, including, you know, monitoring a patient, for symptoms of, you know, ARIA and, other additional reasons you need PET. But in the long term, in the future, you know, I could see a scenario where blood does become a replacement and, really provides access to, those that are seeking therapy. Maybe, Joel, for you, Masoud, feel free to chime in as well. But, you know, we've talked a lot about in our note about the some of the limitations of PET and CSF, and some of them have to do with cost, with PET particularly, and also availability, access to PET. And earlier panels talked about sort of the FDA sort of revisiting that decision about multiple PETs and reimbursing them. But how do you see blood-based biomarkers improving cost, invasiveness, ease of use, and what kind of feedback have you gotten from some of your early customers as in that regard? Great. Thank you. Yeah, so the way we think about blood testing is similar to Masoud, is that today, yes, there's a lot to still be learned about these blood tests, but actually, the blood tests have gotten extremely good. In our circumstance, where we use high-resolution mass spectrometry to measure some of these analytes that we know are highly implicated in disease progression, we can achieve performance characteristics that are comparable to PET and in some ways are potentially even superior to PET. Now, we're not going to make a superiority claim today, but there is data that has been shared at prior meetings that shows you can actually start to pick up the biochemical abnormalities earlier than you can pick up some of the changes in PET and even possibly in CSF. So Suzanne Schindler from WashU presented some really incredible data at this past AAIC, where she looked at over 1,000 individuals using a phosphorylated tau 217 over non-p-tau 217 assay, which is effectively the methodology that we run, and that was work done out of WashU. So what she showed was actually you get the same level of performance for identifying amyloid pathology as FDA-cleared CSF tests. In addition, she found that those markers in plasma were more sensitive at picking up early cognitive decline than what you could see in CSF. And so we're seeing this rapid evolution towards a time where, in fact, you can see an alternative. So we actually like to... I think that, that the way in which you become a standard is obviously through evidence accumulation, and that will probably require some correlations with neuropathology because the CSF and PET are imperfect values. We know that the visual inspection of the amyloid PET, which is the FDA-approved methodology for looking at PET in the real-world community, is only about 85%-90% accurate. So we're dealing with an imperfect reference standard when we do our correlation studies. When you see very high AUC, kind of correlation concordance with these other methods that are being used, we tend to think of, "Oh, there's this gold standard," if you will, that is a perfect analyte or perfect measurement, when in fact, you can see very high correlations. And then the question is: What's more accurate, is the blood test or the CSF or PET? A lot more to be learned and developed there, but we're seeing clear evidence. So now getting to the value proposition, it becomes very clear. Because CSF is contraindicated in 15% of people due to anticoagulation or bleeding concerns, many of the patients, given the preference, would not want to undergo a lumbar puncture. Amyloid PET is inherently limited. There is a non-insignificant exposure to radiation, which the FDA views as a safety hazard for repeat imaging. I think really a bigger issue is the access capabilities for PET. Most of the PET facilities throughout the U.S. are consumed by oncology applications, and so there's. When we look at the data, and I saw you mention this in your report, too, there's about 60 million Americans who have no access whatsoever to specialized PET facilities. So the question is, in an era where we have new therapies and we're looking for, access and inclusion, you need to think about other modalities that will be useful. And, Dr. Mark Monane, who's in the audience with me today, he's one of our, medical officers, will be actually presenting the first, economic analysis of blood biomarkers at CTAD in an oral presentation. So we're very much looking forward to share the, what we think is a clear value proposition for using blood biomarkers. Masoud, maybe I'd take it and just keep it high level, but just a slightly different direction, one where you've talked about that a lot, which is, you know, we heard a lot of talk about what is the right biomarker and different biomarkers. It seems like p-tau 217 is having a moment right now. But I think that the ability to offer a multiplex test over time seems to be sort of the direction of travel. And maybe talk about what you think in terms of the future environment will look like. Will we need to have a multiplex? And what is the competitive advantage of a technology like yours that can do multiplex? Yep, absolutely. So I, you know, I think, Matt, you're absolutely right. I think, p-tau 217 is appearing, as probably one of, the most, advanced and some of the best data, in terms of correlation to a PET. And we're able to, you know, with the p-tau 217 marker in blood, look and identify patients much earlier in the disease cascade than some of the other markers. And so, it's coming to be a very promising, technology, and antibody based system for this detection. So we're very, you know, we're very happy and pleased with some of the 217 data, and we've been working with, a few partners, around, those 217 tests. And we mentioned we'll be adding it to the, Lucent platform, shortly. Right now we offer a p-tau 181 test with our LucentAD, and then we'll be, you know, offering by the end of this year, a 217 assay. So very, very, very positive about that. And then going to kind of, hey, multi-markers, and hey, you add additional biomarkers, and what do you get? I think the addition of additional biomarkers will tell you more things. I think one of the things that more biomarkers will do is that they'll provide this potential for a differential diagnosis. And I think, you know, you heard from some of the speakers in that, hey, a patient comes in, and they may not have amyloid pathology, but what do they have if they're exhibiting signs of dementia or other disease? And I think that answer is gonna be important. It's a, it's sort of a much more complicated sort of disease pathology than yes and no, and the addition of more markers will help a physician in making a diagnosis. And those markers could be, you know, NfL, they could be GFAP, they could be, you know, Aβ 40/42 in combination. With our immunoassay platform, we're able to look at, you know, let's say, all of those in a single run in a multiplex fashion. Right now we're in advanced clinical trials to be able to look at, you know, the power of 217, you know, alone versus, you know, four or five of these markers together in patients both at memory centers, also at primary care offices. Got it. And maybe, staying with you for a second, Sud, I just wanna dive into the dynamic of potentially improving costs throughout clinical trials. I mean, this has been sort of the main market so far, where post-memory, you know, cognitive assessment, you can insert a blood-based test and then rule in, rule out a larger population, which requires less PET scans and saves money. But what is sort of the message to pharma from that you get from, you know, from them in terms of the power of inserting a blood test? And as we kind of continue to work on Alzheimer's and more trials are going on, do you expect that sort of replacement of PET, that you talked about ultimately, to appear first in the clinical trial setting before we get to sort of the other types of markets that will be going on with therapies in the market? I do. Yeah, Matt, I do see that, and it's something that at Quanterix we've experienced. So we're involved in, you know, many of all of the sort of Alzheimer's-based tests and trials, both at biotech companies and pharma companies, and this begins, you know, in the clinical trials. And so a pharma company begins the invitation or the beginning of a clinical trial by looking at different types of patients, and right, every patient is different and has their own background and their own characteristics. Baselining and looking at the stage of each of those patients with blood biomarkers is not only, you know, as Joel mentioned, very effective because you can potentially look at patients earlier than you might with CSF or PET, but also a lot more cost-effective than doing, you know, CSF and PET on screen prior to a clinical trial. So that's one mode where some pharma companies are using blood-based biomarkers for screening patients prior to a trial. But it's also, you know, you know, prognosis, it's also monitoring. You know, as Joel mentioned, measuring patients with PET, there's radiation that's involved, there's access, not just cost. and monitoring these patients over a period of time to see, you know, the efficacy of the therapy and using biomarker as a proxy for that, is incredibly important. And then I think as you see with the current Leqembi label, it's, well, the involvement of blood biomarkers in the clinical trials is important for then the adoption of these blood biomarkers as a testing mechanism, but also in the future, as you know, regulatory approved tests. Got it. And Joel, one for you, just what are some of the challenges that you see in gaining widespread adoption of blood-based biomarkers? I mean, you know, in the context of eventual FDA approval, coverage from private insurance payers. I mean, to put it into context, we're not talking about massively expensive tests, certainly relative to the standard of care in diagnostics for Alzheimer's. But what do you see as sort of the hurdles that blood-based biomarkers need to get over in order for wider adoption? My question is: how long do we have for this conference? Yeah. I think we've been in the field now for three years with CAP CLIA assay, the first generation test PrecivityAD, which measures Aβ 42/ 40 plus APOE plus age into an algorithm that provides an output of amyloid presence or absence. Then we just launched our second test, which is PrecivityAD2, which includes the p-tau 217 ratio, which looks at phospho to non-phospho, which we find to be an important metric for reporting that measure, and then combine it with 42/40. So what you're doing is you're now combining these markers, and I think that generally speaking, it starts with probably education. So while a lot of the clinical community understands the behavior of these markers, they really haven't spent a lot of time thinking about implementation and clinical practice. So there's a lot of education is one, mass education requirements, and that's gonna come from not only the efforts of Quanterix, C2N, and other companies that are developing these markers, but also the pharmaceutical companies that are developing the innovative therapies, because they are developing disease modifiers that are based on rational targets, and it's gonna be essential for clinical community to understand. So education's one. Then two is really being able to have the real-world evidence that implementing these tests makes a difference in clinical care. So Medicare is particularly focused on the clinical utility of these tests, and it's one thing to say that your test can do a great job of identifying amyloid pathology or tau pathology. But then, if you're a payer, you know, one of the first questions you might ask is, "Well, what's the difference? What impact does it have on patient care outcomes or processes?" And so it's really important to get that real-world evidence. And then the third is obviously having the analytical robustness, if you will, to be able to get through, in the case of, let's say, FDA or even some of the CLIA requirements, as a qualified laboratory-developed test, that you need to have that robustness to the assay. And that includes a lot of analytical validation and clinical validation. So you bring all these together: education, real-world effectiveness, analytical and clinical validation. It's actually a pretty heavy lift. And then there's also infrastructure, which we'll talk a little bit later. But while one might assume, well, it's so easy to just collect blood, and that is true. But the reality is that these assays are, for the most part, today being done in central labs, so there's distribution, logistics, and all the other elements that go into having a test that can be easily processed and reported out. I don't know if you have any comments on that? Yeah, no, I think, Joel covered many of the, you know, things, and I think chief among that, we, and absolutely agree, is education. And I think, was super pleased at the last, CTAD conference when, sort of there was a roll call, "Everybody raise your hand, and if you think that blood-based biomarkers are here as a mode for, you know, testing in Alzheimer's disease." And I, I don't know if it was unanimous, Joel, or almost unanimous. It was over 50%- Right. Who said it's, you know, blood biomarkers are here. So, I think, you know, that's a good first step, and then it's taking that and educating the medical centers and then, the clinicians and the primary physicians with, data, with strong, you know, clinical trial information, and really bringing that as, quite frankly, a quite, you know, important and needed tool. You know, when we're having, conversations with physicians that are, beginning to offer these, therapies, their number one kind of, sort of question is: "Yes, I need more tools. This is a complicated thing. It's not just a yes or a no. I need a, I need blood screening and blood testing. Not everyone is gonna qualify for PET. I have to have that sort of onboarding, you know, solution. So education is critical, but we definitely see the opportunity and the desire for that tool. Okay, last question for both of you. There was some discussion about, I think it was Dr. Lah talked about sort of the five-year vision of screening patients or just people over the age of 65. There's been a lot of debate, and we did a number of KOL calls for this report that we did. The one thing that did come up was the potential, if this does move to a primary care setting from a screening you know, from a screening capacity, could that result in an overdiagnosis of Alzheimer's? Not necessarily weighing on that, but just sort of your view is, do you think there are gonna be some a level of triaging of Alzheimer's in the primary care level? What role do you think blood-based biomarker testing could play in that? Yeah, I can. Absolutely. So I think, you know what? We have also the same view that in the future, for the therapy to be, you know, to get broad adoption, it's going to be absolutely needed for there to be broad access. And broad access is gonna be not just, you know, access to a, you know, major city where you have a medical center and you can get infusions. One, the therapy has to be able to be, you know, easily administered. And if we get to that stage, the need for broad-based testing, triaging, and diagnostics is gonna have to go to where you're doing the blood testing or where you're doing the blood, the sampling. That's you know, 90% of the population today is close to where you can do a blood draw, but that's nowhere near where you have to be for a CSF or a PET, a PET scan location. I think that this does become broad-based. I think blood screening does become the first mode in addition with you know, clinicians' workup of a patient for screening, and I think it does get there. I think it's reasonable to say that that happens you know, in under you know, five years. Thoughts on this, Joel? Yeah. So, I'm pleased that my finance officer and myself just completed our 10-year planning, number of different business scenarios. But when we think about, like, how this market is gonna be shaping up, we think about where we are today, which is diagnosis. There is a major unmet need in just properly diagnosing people with MCI and early dementia. And as we heard in earlier panels, the earlier one intervenes, the more effective these therapies are gonna be. That, that's indication number one. Then, what's gonna have to follow is, understanding how to use these markers in treatment monitoring and disease progression assessments. And so there's still some work to be done there. There's some incredibly early compelling data, and, it is very, both... You know, some of Quanterix's tests and C2N's tests have been used in some of the pivotal studies that for both Leqembi and Lilly, where you know, some of our markers were able to show very nice correlations with amyloid PET resolution. But there's still more work to be done there. And then we think about the third indication, which is kind of that asymptomatic high-risk screening. The moment you start moving to the broader population and the involvement of primary care, I think that I come from the field of cardiology, and it's. I personally think it's a bit paternalistic to think that this will remain a very memory care-focused effort. It just isn't possible. There aren't enough neurologists and memory care specialists in the U.S. to be able to accommodate the bottlenecks. Primary care will be absolutely fundamental to involvement in the patient care. I think that as we've seen from many other new modalities that are being incorporated into new standards of care, that the primary care clinician plays an absolutely pivotal role in identifying that patient who needs to then go see a specialist or maybe go get some additional care that requires more sophisticated treatment techniques or other assessment methods. I think what you're gonna see is us moving towards much better understanding of how these markers fit into each of these three indications: diagnosis, monitoring, disease progression, and then also identifying high-risk individuals. I think that to just simply use the one key message, which we're adamant about, is that these tests should not be looked at in isolation. They are not pure diagnostic tools. A diagnosis of Alzheimer's disease is made the same way that one would evaluate a patient who appears to have ongoing ischemia. You have to look at all the data, and it will involve that cognitive evaluation. It will involve MRI, it will involve PET tracers to some degree, and it will involve blood testing. So I think that when you start looking at this in the context of a broader clinical care picture, it becomes transformative, and we do think that it will be a standard practice at some point with the primary care community. All right. Maybe if we drill down into each of your companies and offerings, and maybe, Masoud, just talk about the importance of your Simoa platform, sort of the basis of your technology, and how you think Simoa and the advantages that it brings you can sort of unlock the opportunity in Alzheimer's diagnostics and neurology more broadly. Yeah. You know, so Simoa technology is really single-molecule array, and it uses basically a pair of antibodies to, in a very sensitive way, detect proteins that are very low in concentration. Yeah. Yeah. And so if you were going to do a measurement, a very common protein in blood, you wouldn't use necessarily the Simoa platform. But if you're going to look at something that was rare or, hard to measure in blood, that's where the Simoa platform offers, you know, broad range of sensitivity. You know, as I said, two to three orders of magnitude, better detection than, you know, anything that's, you know, sort of immunoassay-based, in the, in the market. So the technology is not, you know, only, been used in neuro, but that's been a key focus, of the, of Quanterix. And then, you know, the application in neuro, is so compelling. At the end of the day, a lot of these proteins are misfolded or, you know, they're going to your CSF, and they're going to your blood, and you'll need something that is able to differentiate, with all the other proteins that are out there. And that's why Simoa has been, I know, a key differentiator for us. And it's a lot of the hard-to-measure proteins. It's the, you know, the tau proteins, but it's the phosphorylated tau at these unique positions that are important. It's the, you know, neurofilament lights. It's the, you know, looking at the axons, neuronal axons, looking at the astrocytes. So, exquisite measurement of these proteins in blood requires just a much higher degree of sensitivity than what you could do with a typical immunoassay. And so, we offer basically a sample-to-answer platform. It's called our HDX platform, where you can put sample in and you get results out. And then we have two benchtop platforms where there's some more, you know, manual intervention, but they both offer that sort of sensitivity. Got it. Joel, one thing that I found was interesting was your proprietary algorithm that creates an amyloid probability score, you know, ranging from low, intermediate, to high. Can we talk through the specifics about how each patient is bucketed in the respective categories and why this approach? Great. No, great question. So, the way we think about, blood biomarkers is that, as, kind of Masoud indicated, is that there's probably no single analyte that is going to be able to provide the complete picture that you need, right? So we already know what kind of the contribution and the importance of amyloid beta 42/40 is, as an analyte that you can measure in plasma, and it's extremely good at picking up early disease presence. But, it has its own analytical liabilities, like virtually any analyte that you're measuring. And so when you look at that as a standalone, we say, "Well, there's probably something we can do to make it even more robust." And that's where you start looking at different combination markers. What we do is with these algorithms, so we use high-resolution mass spectrometry. Mass spectrometry is a powerhouse for discovery and development applications. It is a very rapidly growing area of clinical diagnostics, and you see all the major instrument manufacturers that are developing mass spectrometry, working on moving some of their instruments into regulated clinical, routine clinical use. But it is really the ideal standard for being able to use characterization, quantitation, and looking at different analytes, i.e., the multiplexing capability of a mass spec. And a mass spec pretty much looks at a bunch of different analytes, and it separates them by mass and charge. So if you have two molecules at different, in subatomic weight difference, take p-tau 231 and p-tau 217. They have different ion charges, and they also have different subatomic weights. That's what the mass spec is designed to do. It can pick out those different species, and in fact, it can report out all these different species at one time. So what we do is we combine different markers that we think are important to the disease process. We combine them, we develop models based on a lot of data, and then we develop a parsimonious model that identifies whatever the outcome of interest is. So our first products, PrecivityAD and AD2, use what we call this amyloid probability score, and that is basically taking the 42/40 value plus ApoE proteotype plus age into an algorithm that we've extensively validated clinically, that we know based on a scale of zero to 100, where that individual falls, the certainty that they have amyloid pathology or not. Most of our correlation studies have been either with PET, which would be considered the reference standard, in most cases, certainly according to the FDA and CSF. So, the PrecivityAD2 test represents yet another algorithm that incorporates Aβ42/40, plus this, well, p-tau/non-p-tau 217 ratio. And when you combine those two, you get a very powerful score that will tell you whether or not amyloid is present or not. We could theoretically do the exact same thing for looking at tau pathology. We could do something similar for looking at really the outcome of interest. And you've seen this applied in many different fields of medicine, like oncology. Oncotype DX is a good example to predict certain risk of recurrence. So we think about the power of more than just the single analyte combined to really tell a more complete and robust picture. Got it. And, Masoud, you've talked already about the utility of p-tau 217, particularly in the early diagnosis. You also have a LucentAD test, which includes p-tau 181. Maybe talk about sort of the context of how important it is to have that early diagnosis, given what the therapies actually are treating. And in that context, p-tau 217 versus 181, and sort of where you are in terms of emphasizing one or the other. It sounds like you're gonna be combining them, but maybe just talk a little bit about that dynamic. Because I think there's a lot of confusion. Everyone hears all these biomarkers and wonders, you know, which one is gonna win. But, like, I do think that there's a sort of a broad range of outcomes here, so maybe your expertise in that area would be helpful. Yeah, absolutely. So I, you know, I think that begins with some of the, you know, collaboration and work we're doing in these, you know, early clinical trials. And, you know, part of this is a lot of learning and seeing, you know, sort of results versus you know in actual, real in patient settings. So you do a clinical trial, you have a cohort of patients who come in for that clinical trial, and you're able to measure sort of results from that clinical trial with various biomarkers. So a lot of times when we begin a trial, it's not, you know, in the early, you know, pretrial days, it's not, "Hey, this is the biomarker that we're going to go with," and that's it. It's looking at a panel of blood biomarkers and looking to see, hey, with this age, with this sort of contextual setting, with this patient setting, these are the biomarkers that are gonna be most informative. Some are better adapted towards just general neurodegeneration and sort of large, you know, proxies for brain health, and some are a lot more specific to specific pathologies, and some are better for, you know, patient monitoring, and then the combination of that. So this is part of a learning of where the biomarker is going to be important in the pathology and then selection of that biomarker. In the case of, you know, amyloid pathology, tau has shown, you know, incredible correlation, as we mentioned earlier, on the CSF and PET scans. And so, detection of a patient early in the stage of Alzheimer's disease appears, to be, you know, best indicated by the, p-tau, series of, phosphorylated, proteins and, you know, specifically p-tau 217. And as we look at these different markers, when can you detect, the pathology earliest, in a patient? It appears, through these clinical trials and a lot of publications that p-tau 217 is able to catch that patient, at a much earlier stage. And as we start to kinda look at the clinical trial data that are coming from, Leqembi and donanemab and some other, trials, you start to see that the efficacy of the therapy, is, is, better when you can identify a patient that's early in the cascade. We start to put those two together, 217, becomes a very important candidate for that identification. We have a p-tau 181 test. When you look at the p-tau 181 test and the 217 test, 217 appears to be able to perform and identify patients earlier in the cascade. And so, you know, we think it's gonna become a very important marker on the LucentAD platform through our CAP/CLIA laboratory for patients. Got it. And, Joel, a similar question for you. I mean, a very common question I get early on when people are just looking at this is, well, if the therapies are addressing amyloid beta plaque buildup, why aren't you just testing for amyloid beta? And your PrecivityAD was just that on the 42/40. But you've since added the p-tau 217 ratio that you talked about earlier. So, why did you make that switch, and what caused you to kind of add that in order to increase the sensitivity, specificity, and the metrics rule around that test? Yeah, so similar to what Masoud was saying regarding each of these different analytes, every one of them kind of tell a different story. In fact, the phosphorylated forms of tau, and there's many, many different forms, all tell a slightly different story. p-tau 217 has some very unique properties as an analyte that make it quite interesting to be able to track, in this case, let's say, amyloid pathology. p-tau 217 is not the most... not likely to be the most robust marker for looking at tau pathology, which sounds a little bit like a oxymoron because, well, tau is in the nomenclature of p-tau 217. But what we find is that this concept of integrating Aβ42/40 with our phospho to non-phospho 217 value, we find that, again, each of them are slightly telling a different story. So we know that Aβ42/40 with a really good assay that can measure 42/40, and 42/40 is very difficult to measure precisely and with high accuracy in plasma. And mass spectrometry has proven to be a pretty robust method for being able to look at that analyte. We know that that analyte plays an important role in the earliest stages of disease. But as disease progresses and one gets closer to clinical onset of symptoms, that's where you start to see the p-tau 217 signal intensify. p-tau 181 does follow some of that similar behavior. In our experience, using mass spectrometry, 217 is a far more robust analyte than 181. It relates a little bit to dynamic range and variability. When you start thinking about across the entire spectrum of, let's say, amyloid pathology, burden, if you will, the 217 does a nice job of tracking earlier stages of amyloid pathology plus later stages. But then the question is, like: Okay, so you've, you've kind of collectively, the field, has made great progress to identifying amyloid pathology, and you could make an argument for combining a few of these markers to get the best tools to properly identify amyloid pathology. But then there's the question, like: Well, what do you do about tau pathology? There's tau tracers that are being used today in clinical care, but not as much being said about what kind of blood testing can be used, and so there's a lot of great innovation occurring there. C2N is involved with some very interesting programs, and there will be some very exciting data presented at CTAD this year that talks more about the tau angle to the story. But I think, again, this concept of looking at different analytes, knowing that each of them tell you something slightly differently about the disease, will be important if you want to provide a more complete picture of the patient. Got it. And, Masoud, just... We talked a little bit about screening. I wanted to reference one study that came out that I thought was really interesting and probably longer term in nature, but it kind of gives people an idea of where this can go. There was a study from researchers at Gothenburg and Lund University that used finger prick samples, where they collected dried blood spot samples and ran measurements on your Simoa platform. And they found that for 217, NfL, and GFAP all corresponded really well to measurements of just a standard blood sample. So just in the context of sort of the future market, the potential for finger prick versus traditional blood draw, I mean, we're already getting huge advantages of blood draw versus a spinal tap. But if you can move to finger prick, like, how realistic do you think this is, and maybe just talk about the potential for that? Yeah, you know, it was a great, super interesting study, and I think it goes to... One of the reasons why the study was even performed was the simple need that, look, there's a lot of folks that are suffering from dementia and Alzheimer's disease, and infrastructure and access are probably, you know, two of the most important things for therapy. Once there are a few therapies in the market that are pretty widely adopted, what about that access and infrastructure? And I think that, you know, blood is a big step forward, and then can you start to look at things in a dried blood spot, a physician-ordered dried blood spot test to be able to measure, you know, very small quantities of blood? And maybe that answers the question of, "Hey, maybe you should come to the clinic, and maybe you should speak to your physician because of this test." And so I think that's the sort of next level of decentralization that we're paying a lot of attention to. It's still very early stages, still small sample numbers, but goes to speak as to the need for incredibly sensitive technology, whether it's mass spec or whether it's, you know, a Simoa assay, where you're able to get that sensitivity, very limited amount of material, to be able to begin to just, you know, improve access to patients. Got it. Why don't I pause here and see if there are any questions from the audience? Thanks for the panelists. It's been great. I'm curious, as you think about the future of testing, how you think when the primary care physician is the kind of touch point, how is the testing gonna be integrated with conversation? Because I feel like this could be obviously a difficult conversation, especially if it becomes more widespread. Two, you know, do people wanna be tested? Do they wanna know? And three, if they do, the combination of drug, potentially drug, drug intervention, as well as the lifestyle conversation. And, you know, I'm thinking in that part of the question, what's going on with the weight loss drugs, where we're seeing now that there's a plateau in terms of how much we can lose. People, you know, if you wanna keep it off, you gotta kinda hit the gym, for lack of a better phrase. So this combination of drug, medical intervention with lifestyle choices. So a lot there, but yeah, you've brought up some really interesting concepts, so thank you. Maybe I can give a little bit of feedback of what we're hearing today. So when we're talking to physicians, one of the first things that they come to us is that I'm getting patient population or folks coming in through my door that I would ordinarily not refer to a neurologist. And they're worried because of either a family history or you know memory or forgetfulness, and this is a concern, and that's part of the desire of what I mentioned earlier is a tool, additional differential you know testing that you know in addition with a cognitive test, would be able to determine whether the patient you know would be qualified for a therapy. And I think that's where a blood test becomes you know important. And so, you know, that serves as, you know, a stage of, "Hey, who do I rule out today, and what sort of, you know, discussion can I have along with the patient and, and their neurologist to begin to say, 'Hey, you know, does this make sense today at your age? Okay, you have a family history.' Maybe you should be coming back, you know, on, on this, you know, sort of interval for additional testing, until something, you know, might come up, either through a blood test, or then eventually, a PET test.'" So I think that, that, that demand is there, and that's, that's at least what we're hearing, that there's, there's too few tools, to talk to this, broad, patient base, and, and blood testing is gonna be, you know, a very important one in the arsenal. And then, and then sort of on the, your, your other question on sort of the long-term, you know, sort of view, I think, monitoring is important. Right now, very little is talked about monitoring. You get onto the therapy, then what? You know, what happens over a period of time? Do you have to go back on the therapy? A lot of these questions are unknown, and I think the blood plays a, you know, heavy, I think, leading role, from a monitoring perspective. Yeah, I guess one other thing I would add. I agree with all those points, but one other point I think that is actually going to be quite disruptive to the field is, as some of you may be aware, the National Institute on Aging, along with the Alzheimer's Association, came out with a revised context for diagnosing Alzheimer's disease. And they're almost completely flipping the narrative for how you arrive at an Alzheimer's diagnosis, and they, they're turning it into a biological staging process. So that biological staging, to me, sounds a lot like kind of the playbook in oncology, where you it will turn out that if these turn into practice, right now, these are draft guidance, but that document basically said a person with MCI, which is mild cognitive impairment, theoretically, the earliest stages of cognitive impairment when they present to the clinician, actually has stage three Alzheimer's disease. So if I'm a patient, the moment some of this stuff starts getting discussed and becomes part of a much more common vocabulary and discussion, with the advent of new therapies and new approaches, blood testing being more accessible, as a patient, I'm thinking: How can I get to stage one? Because we all know that treating heart failure in stage one is much easier than treating heart failure in stage three. In the same—I think the same thing as... or cancer, same application applies. So by turning it away from a little bit, there's clearly emotion attached to the clinical diagnosis, but the ability to provide it more in a biological construct... and getting patients to understand that this is just, this is a biological marker that we now have approaches, whether it's lifestyle or treatments, and there are a number of really innovative preventive strategies that are being tested in large randomized clinical studies. You're going to see, I think, a major movement towards earlier stage assessment. And I think that that starts at the top with the KOLs and some of the advocacy saying that it's really not enough to simply say that one has cognitive impairment and dementia, if you will. No, the pathological description and classification of where that patient is in the disease spectrum becomes a much more kind of intellectual approach to thinking about the disease, and I think will lead to better outcomes longer term. We're almost out of time, but I would love to keep this going for a while longer. I do have one last question that we discussed, which is the monitoring market. We can talk about therapy selection market. I think a lot of it depends on the amount of mAb label and things like that. But in the monitoring market, it was interesting. In an earlier panel, they talked about you're gonna be doing multiple PETs every six months or something like that, and that just struck me as one, a very big burden on the system, high cost, not enough capacity. Maybe talk about what you think the potential is for the monitoring market, and do we need a forcing mechanism to get blood into that protocol after going through maybe a period of time of there being just a flood of PETs needed if this therapies, if these therapies prove to be pretty popular? Yeah, Matt, I think, you know, I think that's absolutely really important, and it's really beginning. So if you look at the Leqembi label, there are quite a few blood biomarkers that were used in monitoring patients over, you know, the 79-week period, and I think that's gonna extend. There's a lot that's unknown, and as you say, PET, you know, may be a good... Let's take a look at, you know, results in the beginning, and maybe you do, you know, PET towards the end, but that regular PET scan is just completely non-feasible. And I think blood there, everything we've been talking about today has been sort of that screen or the test or the aid to diagnostic, but that period of time where you're doing that monitoring is gonna require multiple blood testing. And then after you're done with the therapy, you continue to do PET. It just doesn't make sense. I think that's where blood plays a, you know, big and probably leading role. Yeah, I guess I would just add that clearly important application. I would say that to be able to start talking about blood biomarkers in the context of treatment monitoring, that requires very careful attention to the data and understanding. I mean, earlier discussions talking about the need to have evidence-driving decision-making for the best patient safety and outcomes. That's clearly gonna be the need for the adoption of blood biomarkers into clinical care for treatment monitoring. Because just one simple analysis of how we think about PET and how we should think about plasma and CSF biomarkers. PET represents a cumulative exposure of pathology that you're visualizing at a single point in time. When you're looking at blood or CSF, you're actually talking about soluble markers that are part of a dynamic exchange process. And so you can imagine that, while we were involved in the Clarity AD study and the phase II Leqembi study, as well as, the Trailblazer 2 study, and they used some of our markers, and at a group level, you get some beautiful correlations. As PET, amyloid PET resolves, you see changes in biomarkers. That's great, but I think there's a lot more that we want to do as a field and need to do as a field to really be able to think about how we're gonna incorporate those tools into routine clinical care because the patient's life depends on it, right? We wanna make sure that these patients have... There's good evidence supporting our, decisions for how we're going to start titrating and changing therapies. Great. With that, why don't we conclude? I think, you guys have been great and shed a lot of light on what I think is one of the clearest value propositions in diagnostics and where it's such an early stage. I think it's a really exciting time to talk about it. Masoud, Joel, thank you very much. Thank you, Matt. Thank you.