Today, and thank you for standing by. Welcome to the NewAmsterdam Pharma conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I'd now like to hand the conference over to Mr. Matthew Philippe, Executive Vice President and Head of Investor Relations. Please go ahead, sir. Good morning, and thank you all for joining the call today. We're excited to present our data from our Broadway's Alzheimer's analysis, which was presented this morning at AAIC. We are also excited to welcome three experts in Alzheimer's disease who will provide their interpretation of the data and be available for Q&A after the call - Dr. Phil Scheltens, Kellyann Niotis, and Dr. Nathan Chin. Before we begin, we'd like to direct everyone to slide two and remind everyone that the statements made on today's conference call will include forward-looking statements. Certain statements included in this presentation that are not historical facts are forward-looking statements for the purpose of the Safe Harbor provisions under the U.S. Private Securities Litigation Reform Act of 1995. These statements are based on various assumptions whether or not identified during this presentation and on the current expectation of the company's management and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and not intended to serve as and must not be relied on as a guarantee and assurance of prediction or a definitive statement of fact or probability. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are subject to a number of risks, which are described in more detail in our annual report on Form 10-K and subsequent quarterly reports on Form 10-Q. Forward-looking statements reflect NewAmsterdam's expectations, plans, and forecasts of future events and views as of the date of this presentation and are qualified in their entirety by reference to the cautionary statements herein. NewAmsterdam anticipates that subsequent events and developments will cause the company's assessment to change. Accordingly, undue reliance should not be placed upon the forward-looking statements. Neither NewAmsterdam nor any of its affiliates undertakes any obligation to update these forward-looking statements except as required by law. Additionally, the remarks of our invited panelists, Dr. Shelton, Naiotis, and Chen, represent their personal views and opinions, which may differ from those at NewAmsterdam. With that, I'd like to turn the call over to Dr. Michael Davidson, CEO of NewAmsterdam. Michael? Thank you, Matt, and good morning, everyone. This is Dr. Michael Davidson, CEO of NewAmsterdam Pharma. I appreciate you joining us today for what marks another significant milestone in our company's journey. Just moments ago, Professor Philip Scheltens presented a pre-specified analysis from our Broadway trial at the Alzheimer’s Association International Conference. This late-breaking new science presentation showed that obicetrapib resulted in significantly lower increases in PTL217, a well-established biomarker of Alzheimer’s disease progression. This data is incredibly exciting and further differentiates obicetrapib from other LDL-lowering therapies by suggesting the potential to slow or even prevent Alzheimer’s disease progression, particularly in APOE4 carriers. This milestone follows the founding of NewAmsterdam five years ago. From the beginning, we hypothesized that obicetrapib, by significantly lowering LDL-C and robustly raising HDL-C, could have disease-modifying potential in Alzheimer’s disease pathology. As shown in slide three, LDL-C reduction is a well-established strategy for reducing ischemic stroke and vascular dementia. However, no LDL-lowering therapies have previously demonstrated an ability to impact Alzheimer’s biomarkers. In slide four, elevated cholesterol levels in the brain are known to precede the formation of amyloid beta plaques. We hypothesize that obicetrapib could counteract the impaired clearance of 24/7 hydroxycholesterol, the brain’s main cholesterol metabolite, particularly in APOE4 carriers. Moving to slide five, APOE4 is a well-documented risk factor for both cardiovascular disease and Alzheimer’s. Carriers experience a 22%- 45% increased cardiovascular risk with elevated LDL-C and LP(a) and reduced HDL-C. APOE4 carriers also exhibit impaired cholesterol transport and clearance, leading to amyloid accumulation and aggregation. Heterozygous E3/E4 carriers have a three times higher risk of Alzheimer’s. E4/E4 homozygotes are 10 times higher risk. Two-thirds of all Alzheimer’s patients fall into these genotypes. Following a proof-of-concept trial in 13 E4 carriers with mild cognitive impairment, where we observed reductions in CSF and plasma 24 and 27 hydroxycholesterol, as well as stabilization in AD biomarkers and cognition, we convened a panel of Alzheimer’s experts to help guide further clinical development of obicetrapib for Alzheimer’s disease. Our advisors recommended that we evaluate AD biomarkers, especially the new one at the time, PTL217, in our ongoing Broadway trial shown on slide seven, in which 2,500 patients with high CV risk were treated with obicetrapib compared to placebo in a two-to-one randomization with a mean age of 65. This population represents a high-risk cohort for Alzheimer's. As seen on slide eight, we collected plasma samples at baseline and at day 365 for 1,515 patients, including 367 APOE4 carriers. Our primary biomarker of interest was PTL217, with other assessments including the Aβ42/40 ratio, PTL181, GFAP, and neurofilament light (NFL). Slide nine shows the baseline demographics of the APOE4 carrier status, the average age being 65- 70. Two-thirds of the patients were males, and they were at high cardiovascular risk, with a large percent having diabetes and hypertension and atherosclerotic cardiovascular disease. Now for the primary results in slide 11. We are thrilled to report a statistically significant reduction in PTL217 progression over 12 months. In the full analysis population, N equals 1,515, PTL increased by only 1.99% with obicetrapib compared to nearly 5% with placebo, P equals 0.019. In APOE4 carriers, obicetrapib led to a 1.45% increase versus 7.19% with placebo, P equals 0.022. In E4/E4 homozygotes, we observed the most striking effect, a 20.5% absolute difference in PTL217 progression, P equals 0.01, with some showing actual reductions. Turning to slide 12, we present the changes observed in select higher-risk populations. As anticipated, PTL217 levels increased progressively with age, rising in individuals over 60 and even more markedly in those over 70. Importantly, among APOE4 homozygotes, E4/E4, the group at the highest genetic risk, we observed the greatest increase in PTL217 over the 12-month period in the placebo group. In contrast, patients treated with obicetrapib exhibited either a substantial attenuation in progression or even a decline in PTL217 levels, underscoring the potential of our compound in this vulnerable population. Moving to slide 13, we evaluated a broader panel of validated Alzheimer's biomarkers. Across the board, we saw favorable directional trends in response to obicetrapib in this analysis. Notably, we assessed the PTL217 Aβ42/40 ratio, a composite marker reflecting amyloid burden and Tau pathology. This ratio offers an integrated view of disease state, and the results were striking, showing a statistically significant difference, P equals 0.0042, in favor of obicetrapib compared to placebo. On slide 14, we focused on the E4/E4 homozygotes, which we believe represent one of the most consequential findings in the entire trial. In this genetically high-risk group, we observed a robust benefit across all Alzheimer's disease biomarkers. These results reinforce the biological prevalence of targeting this population and suggest the potential of obicetrapib to alter disease pathology. To put this in perspective, when taken together, these biomarkers, Aβ42/40 for amyloid, GFAP for glial activation, and neurofilament light NFL for neurodegeneration provide a comprehensive molecular profile of Alzheimer's disease. When measured in concert, they have been reported to deliver diagnostic accuracy with an area under the curve exceeding 0.9 across the full disease continuum from preclinical stages to overt dementia and correlate strongly with cognitive outcomes and imaging biomarkers. The magnitude of the benefit of PTL217 we observed with obicetrapib in E4/E4 carriers in this analysis is comparable to that seen with anti-amyloid monoclonal antibodies in interventional trials, yet achieved with an oral therapy. On slide 15, we share least square regression curves that plot the absolute change in PTL217 across age. In the placebo arm, as expected, PTL217 levels increase with advancing age. However, in the obicetrapib group, this age-related rise was blunted and in many cases reversed. This blunting effect was especially pronounced among APOE4 carriers, and the difference between the treatment and placebo groups was highly statistically significant. Finally, turning to slide 16, we examined outcomes based on baseline PTL217 levels, a highly validated biomarker for amyloid accumulation in the brain. Here again, we saw that patients with higher baseline PTL217 experienced a greater magnitude of benefit from obicetrapib across the full population and even more so among APOE4 carriers. These findings reinforce the biological consistency of our data. Obicetrapib showed a clear signal of benefit in attenuating PTL217 levels, particularly in genetically at-risk individuals. Let me now walk you through why PTL217 is such a valuable biomarker and how it ties into APOE4, starting with slide 18. APOE4 is the strongest known genetic risk factor for late-onset Alzheimer's disease. Approximately two-thirds of all Alzheimer's patients carry at least one copy of the APOE4 allele, either as E3/E4 heterozygotes or as E4/E4 homozygotes. Risk increases substantially with age and APOE4 status. In fact, E4 homozygotes face up to a tenfold higher risk of developing Alzheimer's disease compared to non-carriers. Crucially, PTL217 tracks closely with this risk. Our concern going into this pre-specified analysis was that changes in PTL217 are modest before age 70, making early prevention difficult to detect. In APOE4 carriers, especially those over 70, we observed a sharp exponential rise in PTL217, a strong proxy for early Alzheimer's pathology. We're pleased to report that over a 12-month treatment period, obicetrapib blunted or reversed this trend, most notably in E4 homozygotes in patients over 70. These findings align perfectly with the underlying biology of Alzheimer's and may suggest obicetrapib's potential as a disease-modifying agent. Slide 19 highlights the predictive strength of PTL217, with a reported AUC of 0.96 for detecting Alzheimer's pathology. This makes it an excellent early-stage diagnostic tool. We also observed benefits in PTL181, another validated marker that typically increases in later stages of the disease. Seeing favorable movement in both PTL217 and PTL181 over just 12 months further suggests the potential for obicetrapib to intervene early in the disease cascade before irreversible neurodegeneration sets in. We believe these results suggest that obicetrapib could have a place in prime prevention of Alzheimer's disease. That means intervening before patients develop symptoms by preventing amyloid accumulation in the brain, which PTL217 directly correlates with. For context, prime prevention targeting individuals before amyloid deposition and cognitive impairment. Secondary prevention slowing progression in patients with known amyloid buildup but no symptoms. Tertiary treatment managing late-stage disease with established neurodegeneration. An LDL-lowering therapy with the ability to delay increases in PTL217 and even reduce levels in E4/E4 homozygotes could be uniquely positioned in the primary prevention space, something no oral LDL-lowering therapy has demonstrated to date. What are our conclusions? I and the rest of our NewAmsterdam Pharma team are very excited about what this could mean for the differentiation of obicetrapib from any other LDL-lowering therapy. Obicetrapib is just not about LDL-C reduction. It could represent a new paradigm in cardiometabolic and neurodegenerative prevention. Slide 21, which some of you may recall from prior presentations, highlights our multifaceted profile on HDL raising, LDL particle reduction, especially small LDL particle reduction, lowering small dense LDL cholesterol, ApoB, and non-HDL as well, and has this very differentiated benefit as an oral therapy on lowering LP(a) in the 50% range in patients that have LP levels between 50 and 150 nmol/L. As we also observed in Broadway, a reduction in the incidence of new-onset diabetes mellitus endpoints. Now, importantly, we add a potential novel benefit in brain health, particularly in APOE4 carriers who represent 25% of the general population and carry elevated risk for both atherosclerotic cardiovascular disease and Alzheimer's disease. This strengthens the case for obicetrapib as a first-in-class oral therapy with the potential to address both vascular and neurodegenerative risk in a convenient once-daily oral therapy. To summarize, on slide 22, we believe the future of lipid management lies in a personalized approach, and obicetrapib is designed to meet the future head-on. Despite statin therapy, many patients still carry residual risk by elevated LDL particles, particularly small particles which obicetrapib reduced by up to 90% in clinical trials, high LP levels which statins do not lower, and in some cases may even increase. In our pooled phase three analysis, obicetrapib significantly lowered LP(a) in patients in the 50-1 50 nmol/L range. Diabetes risk, where obicetrapib was observed to reduce new-onset diabetes in Broadway, is an enormous unmet need given that nearly 30 million Americans currently live with diabetes or pre-diabetes. Now, with our Alzheimer's biomarker data, we add a potential fourth layer of impact, especially in APOE4 carriers, a population that lacks any effective oral preventive options. The data supports further evaluation of obicetrapib's potential in the prime prevention of Alzheimer's disease by reducing PTL217, a key biomarker of amyloid accumulation and disease progression. In doing so, we believe obicetrapib could interrupt the pathological cascade that leads to cognitive decline and neurodegeneration. Given the limited treatment options for the APOE4 homozygotes, we view this as not only a major clinical opportunity but a critical public health imperative. Thank you very much for your attention. Before we open the floor to Q&A, we're honored to have assembled a top-tier panel of key opinion leaders to offer their initial impressions of the data and discuss potential clinical applications. To start, I'd like to invite Dr. Philip Scheltens to share this perspective. Philip? Thank you, Michael. It's been a real pleasure to be able to have presented the data this morning for a wide audience at the Alzheimer’s International Conference. I think for many of the participants, this was really new. Many of the participants coming to these conferences over the last 20 years are used to sort of amyloid-lowering therapy as the primary goal. Now we have achieved that with two monoclonals on the market, but they're actually sort of only reaching a very, very small subset of patients. There are many, many reasons for that. I think the most important one is that some of those patients who carry the APOE4 allele, as Michael just alluded to, are actually at a higher risk of side effects and actually do not benefit from these therapies. That's already an angle where you think, there's a room for another sort of form of therapy. Second, I think the whole sort of CETP inhibition, if you look at the animal models, if you look at the Mendelian randomization studies, the evidence that CETP knockout mice or even humans, there are a few, do not develop Alzheimer's disease, is very, very powerful towards hinting at another mechanism where Alzheimer's disease and the cholesterol metabolism are so closely linked. The linking pin, again, is here APOE4. I think the rationale behind testing CETP inhibition in an Alzheimer's disease population is really very, very strong. We saw the phase 2A results where we showed actually that obicetrapib is able to, act on the brain, I would say. We do not exactly know how it enters the brain, but it has an effect on neuronal metabolism, on cholesterol metabolism, I must say, looking at these cholesterol sort of hydroxycholesterol 24, 27 in CSF. That gave us a lot of confidence to look in the Broadway data. Now you have seen Michael presenting those data, and I think there are a few things to comment on. We have now agreed in the field that plasma biomarkers are equivalent to Alzheimer's disease. The recent update of the AA 2024 criteria simply states having a biomarker abnormality in PTL217 is Alzheimer's disease. That's one. That's an important thing to know and to take into account. PTL217 in plasma correlates really dramatically well with amyloid PET. It's actually a very cheap way of predicting who will be positive on amyloid PET and is now being used in trials. What has not been shown yet is a direct effect of any intervention on PTL217 in plasma. The only thing that we have seen in lecanemab and donanemab studies is that downstream in a subset PTL217 is actually going down, but that's only in a subset of patients and as a result of massive amyloid lowering. A direct effect of plasma PTL217 that we have now shown with obicetrapib, and especially in APOE4 carriers, has never been shown before. To be really honest, when we started this, I and my colleagues also, I don't think we expected such a huge effect that we are now observing. That combined with the fact that this is an absolutely safe drug, has been tested in so many patients already and has no significant side effects, really opens the door to thinking about the application of obicetrapib at a very early stage in people who carry the APOE4 gene, who have the highest risk for progression and developing AD at a very early stage to take obicetrapib, delay the onset of AD pathology, delay the onset of dementia symptoms and dependence on others. I think that's where I think the sort of the position of obicetrapib in the future will be. To just remind you, there is no other statin therapy ever sort of has any effect on Alzheimer's disease pathology. It's just not sort of just the LDL lowering. There is another mechanism that we are hitting here with CETP inhibition, which is really quite promising. I'm very excited to have seen the data and excited also to work with NewAmsterdam on the next steps. How do we develop this compound to the next stage to really sort of get another indication, as Michael also said, for this particular drug in the Alzheimer's field? Yeah. Thank you, Philip. Kellyann Niotis, we appreciate your comments. Thank you, Michael. Just brief background about me. Maybe I have a little bit of an atypical background. I am one of the few preventive neurologists in the world. I just rejoined the faculty at Weill Cornell to establish a formal preventive neurology fellowship for emerging neurologists. I've dedicated my entire life to the field of preventive neurology. I'm a brain health researcher at the Institute for Neurodegenerative Disease, and we are specifically looking at blood-based biomarkers in terms of their potential for monitoring efficacy of various interventions, not just in affected individuals but in those that are at risk. I genuinely believe that a precision medicine approach to Alzheimer's is needed. There is no one size fits all for this disease, and it's going to take multiple drugs with multiple different targets to really address this looming health crisis that we know is all coming for us. In my practice, which is a little bit atypical but I believe is the future, we are using plasma biomarkers to help us personalize care, analogous to how people are using ApoB and LDL-C to measure risk for cardiovascular disease. I really believe that plasma biomarkers, especially PTL217 but also PTL181, Aβ42/40 ratio, GFAP, and NFL, have utility in monitoring responses to various therapies, and that's what I'm seeing in our own research at the Institute for Neurodegenerative Disease. We're looking at them not just in those that have clinically apparent symptoms but, like I said, in those that are at risk, whether that's due to an APOE4 gene or family history. I am really excited about this data that Michael just presented because I do believe that the magnitude of changes that we're seeing in PTL217 are clinically relevant. It's been my personal experience with using these biomarkers for the last several years, especially in very, very early-stage disease, that when PTL217 improves, clinical symptoms also improve in patients. Of course, I have to acknowledge that the big limitation that we have here is that we don't have cognitive outcomes. I am excited to work with NewAmsterdam Pharma in the future to hopefully monitor these cognitive outcomes in these at-risk individuals. As Michael mentioned, the prevalence of APOE4 is high. About one-fourth of people in the general population carry the APOE4 gene, and more than 60% of people who are affected with Alzheimer's disease carry this gene. I can speak from experience that this is a highly activated population. They're willing to go to extremes to delay and hopefully prevent this disease. That is why we need a field of preventive neurology. When they present for care and inevitably have elevated LDL-C or elevated ApoB, the go-to for many would be to put them on a statin. In my world, I would argue that we need to think more about that decision. APOE4 carriers, we know, have altered cholesterol transport both peripherally and centrally. How I really envision using obicetrapib in my clinical practice is, of course, in APOE4 carriers but also in those with baseline low ApoA1 levels or HDL levels because we do believe that one potential mechanism by which obicetrapib may improve markers and progression of Alzheimer's disease is through increasing ApoA1, which has the potential to cross through the blood-brain barrier and potentially substitute for dysfunctional APOE4 in the central nervous system. Again, the overall safety profile really stands out to me. I have no hesitancies using this in my own clinical practice. Worst-case scenario, my patients would improve their cardiovascular disease risk. Best-case scenario is they'll decrease their dementia risk, and I would monitor these biomarkers alongside traditional lipid measures in this population. I'm really, really excited about this data. It has so much potential. We need precision medicine-based approaches to this disease, and I'm really, really looking forward to the future here. Thank you, Kellyann. We look forward to working with you as well. Now, I'd like to hear Dr. Nate Chin's comments. Thank you, Michael. I'm Nate Chin. I'm a geriatrician and the Associate Program Director of our memory clinic at the University of Wisconsin. I'm the Medical Director of our Wisconsin Alzheimer's Disease Research Center and the WRAP study. Being the third person here, it's hard for me to add something new to what I, and I agree with everything that Philip and Kellyann have said. I find the results of this study to be quite remarkable. Just to echo some of the key points, to have disease-modifying therapy that is not anti-amyloid, that is not infusion-based, that's an oral medication is pretty incredible. We are using PTL217 in our memory clinic and certainly in our research, and we find this to be the equivalent of CSF studies and amyloid PET, which has been the gold standard. To see this sort of impact in something as powerful as a PTL217 really does speak volumes. It isn't just in a few people. This was a pretty impressive study, more than 1,500 participants, more than 300 people with APOE4. These numbers are quite incredible. To see a decrease in PTL217 in APOE4 homozygotes is not something I have seen in any other medication outside of direct anti-amyloid therapy. I think it is really important to note that the side effect profile is incredible. This is not something that patients are going to be fearful of. In fact, they're very accustomed to having small% of muscle aches or dizziness. This is not the same thing as ARIA. I certainly see both clinicians and patients being excited at the opportunity of being on something like this. Kellyanne just said it wonderfully. What is the downside? Potentially, you're going to have an improved cholesterol profile, and everyone wants that, and there's other benefits to that. I think it is important to know, especially in people over the age of 65, co-pathology is very common. Having Alzheimer's and vascular disease, we see this in our research over a third of people. We are addressing, or this would be addressing, multiple different venues of cognitive change. The other thing I think is important to know is that people are learning their APOE4 more and more than they ever have before, whether that's through research, through clinic, or through direct-to-consumer testing. These are the individuals coming into clinic asking, "How can I reduce my risk?" What can I do to delay, to prevent the development of Alzheimer's disease and symptoms? They are the motivated individuals. This is going to be a huge population of people looking for opportunities outside of what they know, which is healthy lifestyle, and the point of study has shown that, but looking at other ways that they can do this. I do think this idea of primary prevention and secondary prevention is a huge opportunity and frankly not a very common space right now. There is great potential in being able to do this. I do think of this medication as complementary as well as, in its own right, the first of its kind. I would like to thank our panelists. We're going to open it up for Q&A now. I would just like to remind everyone, we have Michael and John here to answer questions as well as our panelists are available. Please keep it to one question, and if you have more, jump back in the queue because I know there's a lot of you and we don't have a lot of time to get through them. With that, I'll hand it over to the operator to open up the questions. Thank you. We will now begin the question and answer session. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We will now take our first question from the line of Dennis Ding from Jefferies. Please go ahead, Dennis. Hi. Good morning, and thanks for taking our questions. One for the team here. Can you just talk more broadly about how pharma is thinking about this sort of opportunity? Obviously, without getting to the details on any potential individual discussions you've had, do they understand the biology around cholesterol metabolism in the brain and the role of CETP inhibition? If you can comment around that being an area that they're closely following, have a good understanding of, and are excited about. Thank you. Yeah. Thanks, Dennis, for the question. Yeah, obviously, this is novel, exciting data, and we're just beginning to educate our pharma potential partners, and our KOLs are helping with that. The KOLs that you just heard from are involved in educating the people that have been involved in the Alzheimer's field for a long time. I have to be honest, anti-amyloid approaches are dominant right now. That's what people are focusing on. We see modest benefit there. As Philip mentioned, the APOE4 homozygotes don't respond or even have more adverse effects. There's clearly a gap there even in the treatment of Alzheimer's disease with anti-amyloid therapies. APOE4 homozygotes and even the heterozygotes don't respond as well. We see this as a great opportunity. We're just starting the discussion today with our first release of the data. It will take time and effort on our part to educate the community, all stakeholders. We are starting that process, and we're seeing a really good response. We hope that we can continue to build on that with more work by NewAmsterdam. As we have described, we have the ongoing PREVAIL trial with 9,500 patients. We are looking into going forward with other studies after we talk with the FDA about how that prevention-type indication could potentially be realized with obicetrapib. As we've heard about, we do feel this is a very strong differentiator of obicetrapib compared to any other lipid therapy. That's our focus right now. We'll have more data to come from this trial, actually. We have been doing more work on the analyses. We have a large trial, as mentioned. We hope to continue to develop the data and further present it in the appropriate timing. Again, we're very excited about today. This is just the starting point of education to the various stakeholders out there. Great. Thank you. Thank you. Our next question comes from Tyler Van Buren from TD Cowen. Please go ahead, Tyler. Hey there. Thanks very much for the intriguing presentation. I was going to ask if there are plans to launch clinical development specifically in Alzheimer's and head towards registration, but you just mentioned the potential for other studies beyond PREVAIL. Could you just elaborate on that a bit more, what the strategy would be, what the prevention studies might look like, and what the timeline to market could potentially be? It's really too early, Tyler. Thanks for the question. I think we're very excited about the data. We want to continue to develop it, but we know we have a great drug for LDL lowering, HDL raising, all the other benefits. That's our focus. Again, filing in Europe very soon and then looking forward to the PREVAIL completing and regulatory interactions. We'll have a lot of data from PREVAIL. What I can say is we do want to develop this area more fully, but we don't know yet until we talk to the FDA and hear their thoughts on potential studies. That'll take some time. In the meantime, you know we will have PREVAIL reading out at the end of 2026. Again, it's a much larger trial. We'll have, you know, well over 1,000 E4 carriers and, you know, a few hundred E4 homozygotes. It'll be a very powerful, another powerful way of looking at primary prevention using PTL217 as well as other biomarkers that are evolving that even provide potentially even greater accuracy. This is the great time for the Alzheimer's field because now we have these very good biomarkers that can correlate with the disease pathogenesis. I think we feel it's almost a renaissance time to figuring out how to utilize these therapies much more effectively in the broader trials. Great, thanks so much. Thank you. Our next question comes from Yasmeen Rahimi from Piper Sandler. Please go ahead, Yasmin. Good morning, team. Congrats on really a great presentation. I thought the KOLs' insights were really helpful and put really in perspective this data set. The question is PTL217 is a key biomarker. For our KOLs, is there an opportunity that over the next, say, 12- 18 months, we could move forward to specifically use of this biomarker as a registrational endpoint? Is that, or is that difficult to do given that there is no cognitive outcome data that is linked? I appreciate if you could share some color around it, and I'll jump back in the queue. You want to take that, Philip? Yeah. Yeah, I think my colleague can also respond. I think it's a very, very good question. As of now, I think the FDA would not be sort of willing to accept PTL217 as a single surrogate endpoint, but that may change. I think evidence builds up how important this biomarker is to reflect AD pathology in general. I think we already have accepted that amyloid PET is a surrogate biomarker. You have seen accelerated approval based on that in the very early days with aducanumab already. I think it's a question of time, but it would be helpful. I think that will not sort of eliminate the fact that you would ultimately have to prove that that effect on this biomarker correlates with something clinically, functionally, and cognitively. There is the burden of proof there, but there could be a path forward to say, based on these results in the next trial, sort of prospective trial, and you see sort of this sort of, I would say, effect on PTL217, give you accelerated approval, and then the burden is to show also a functional change. Mind you, if you go to prevention, that may take a lot of years. I think FDA may be swayed to give you a sort of a readout of two years accelerated approval and then wait another two years to see a functional change. That's just my thought at the moment. We'll have to have these discussions with the regulators, I think. Nate, [audio distortion] Thank you so much. Yeah. I guess I would add to Philip that we do need to think of these things in two separate spaces, you know, in those with impairment phase and then in the prevention phase. For those with impairment, I mean, PTL217, there's a lot of power in this test, not only in identifying or representing amyloid but also at higher levels representing Tau pathology that would be evident on a Tau PET scan, its predictive ability in future decline over a certain number of years. I do see this test as being very used and very viable when it comes to even the earliest stages of thinking change. Now, in prevention, though, as Philip said, we can't wait for someone to develop cognitive symptoms. If it's true primary prevention, it really is the prevention of amyloid buildup. Secondary prevention would be the prevention of symptoms or even arguably Tau. This test, as of now, seems to be the one that we can use in many different scenarios. I certainly think in the primary prevention space, we are going to need a biomarker as an outcome. Philip knows this better than I do as far as what the regulators would say. When it comes to the science of it, the PTL217 does carry a lot of power to it. In the primary prevention space, I certainly see this as one that I hope would be acceptable for those in studies. Kellyann, as a preventive neurologist. Yeah. Just Just to weigh in, I think originally, going back to your question, I think the FDA was a little burned by using surrogate markers with aducanumab, using amyloid clearance as the marker for approving aducanumab in the past, even though that did correlate with some clinical improvement or cognitive improvements. I think it's probably going to be hard to get the FDA to approve this for Alzheimer's disease without having cognitive outcomes. That said, it's really, as my colleague said, so important to differentiate between prevention and risk and disease progression in people who are clinically affected. My world, again, is in prevention, and it is so difficult to set up trials that'll extend over 20 or 30 years to prove that prevention works. One of the key reasons, I think, having cognitive data in this trial is actually because we can see different biomarker changes earlier on in prevention cohorts or at-risk cohorts that may be useful to monitor longitudinally. I think our group and lots of other groups across the country are doing more work in biomarkers earlier on in people who do not have cognitive outcomes or cognitive symptoms but have risk factors. That data that we're getting from cohorts like ours and others is showing us what the normal ranges of these biomarkers are in at-risk populations and how we can potentially use those to monitor efficacy of treatment. Kellyann, let me just follow up. I think one of the things that was, at least for me, very exciting was in the APOE4 homozygotes. We saw the PTL181, of course, go down, a 20% difference from placebo. Neurofilament light, GFAP, PTL181, Aβ42/40 all got better. I've heard people say they've never seen that before. They've never seen all the biomarkers go in the right direction. I hope again, we need to talk to the FDA, but it's not just about, it's not a single biomarker here. We're seeing many biomarkers that are all really good biomarkers all improving in this very high-risk subset. I wonder if you can comment on the composite of all those biomarkers improving and what that means as a clinician. Right. Looking at biomarkers for neuroinflammation, which would be GFAP, is a great one to look for that. Looking for biomarkers for actual neurodegeneration, how quickly are the brain cells deteriorating? That's NFL. Putting that into perspective with not just these pathological proteins really does give us a lot of power to say that we aren't just changing the pathological proteins, but we're modifying the inflammatory process that leads to the actual degeneration of the neurons themselves. That in itself is very powerful. Right. Thank you. Our next question comes from the line of Steve Seedhouse from Cantor. Please go ahead, Steven. Yes. Hi. Thanks for hosting the call and taking the question. I wanted to ask if the company has done any preliminary work assessing what a preventive study would look like in terms of, let's say, you enriched it for APOE4 homozygotes, maybe by age. Just how large and how long of a study might you need to show a prevention benefit? As you think about that type of preventive study, are you open to getting that underway now and adjusting sample size or some of the assumptions when the PREVAIL data come in? Because the level of conviction that the company and the KOLs here seem to have, I guess, why wait for PREVAIL? Can you pursue this right now? Thank you. Yeah. It's a good question. I think it's too early for us to comment yet, Steve, on that. We need more work to do. Like I said, I think meeting with the agency, understanding what that would look like, is our important next step. We'll get back to the community, all stakeholders again, the medical community, the investors, and our potential partners to talk about that. Right now, it's just like I said, today is the first day presenting the data, and we want a chance to get the feedback and move forward from there. We feel so excited about the data. We do want to move forward, but how we do that is yet to be determined. Thank you. Thank you. Our next question comes from the line of Matthew Phipps from William Blair. Please go ahead, Matthew. Thanks for taking my questions and the presentation and also the KOL perspectives. Did you all look at PTL217 in the previous phase two trial? I'm just wondering if you have ever looked and been able to compare plasma PTL217 versus any CSF changes. It seems like from other publications, companies either look at one or the other. I haven't seen one that looks at both and see how those might correlate with each other. We didn't have it available two years ago when we did the first study. We didn't have PTL217 then, which is why we don't have that data. There are other studies. Maybe others can comment. There is quite a bit of data correlating CSF and blood PTL. A lot of studies are doing that. Nate's shaking his head. Philip, we have a lot of data on that mass already, and it correlates, of course, very highly with PET, you know, amyloid as well. It's how it got validated. I mean, the PTL sort of assays are all validated against amyloid PET and CSF as being the gold standard, and towards pathology in the end as well. Those studies are abundant. Yes. As far as changes while on some kind of treatment, because some of the amyloid and like the tau isoforms from like Biogen, it looked like they were just looking at CSF. I didn't know if they've also published. Oh, that's true. With the Biogen, I mean, that's a good example. That's an ISO against Tau, MAPT actually, intrathecally. The effect is measured by looking at CSF PTL and CSF total Tau as a direct measure of knocking down Tau on the RNA level. That's totally different. Just a comment. For example, the donanomab study did look at plasma levels of PTL217, even though it was an anti-amyloid drug, and measured improvements in PTL217 as well. It's been used as secondary outcome measures in other drug trials before. Based on some of that data, do you have any expectations for what a magnitude of reduction would be that would be meaningful based on any of that data? We did comment on the 20% difference. That's the same difference we saw in the homozygotes. Yeah, we think it's, we said, make the point. It's not just the PTL. It's every biomarker - NFL, GFAP. Apparently, no one's ever seen this before. All the biomarkers are getting better in this population. Yeah. Remember, it's only 12 months. Yeah. Those studies are much longer, much more disease state population. To see the consistency of all the biomarkers improving over 12 months is unprecedented. I know it's going to take time for everyone to kind of understand that, but this is an unprecedented finding in this population. Just one other comment. PTL217, despite the name, is actually an amyloid marker more than a Tau marker. If you look at the donanomab studies, they showed a downstream effect on PTL plasma 217, but they didn't show it on Tau PET. That signifies the fact that what they see in the PTL217 is actually the amyloid. It's driven by amyloid removal. We think also what we are seeing in our trial is that the changes in PTL217 and PTL181 are changes in amyloid that are the result of direct CETP inhibition. Towards this, GFAP is the inflammatory component. The NFL is really astonishing. I mean, that I have never seen before. It's only in the E4 carriers that you see this huge difference. That has to do with neuronal changes already in the year. We have to figure out how that sort of comes about. That may be ultimately to correlate also to cognitive changes that we didn't measure now, but are going to measure in the future, of course. One thing I would add too, the anti-amyloid therapies, those are used in individuals anywhere ranging from mild cognitive impairment to mild stage dementia. The amount of amyloid in those individuals is actually quite high with centiloid values, which is a standard scale for amyloid PET, being close to 100. The magnitude of reduction can be seen as large, but that's because there was a large amount of amyloid burden. Whereas what we're seeing here, at least in this data, this is early. There's not as much amyloid, so you wouldn't be able to compare apples to apples in this just simply because it's a different population of individuals with a different level of amyloid. I'd be careful to compare just the amount of amyloid reduction as I think the trend is actually what's significant. The fact that other biomarkers, even at this early stage, are already starting to show change is also reflective of true disease modification and not just one particular endpoint. Can I make one remark? Yes, sir. Sure. This is John. Thank you. Yeah, John Kastelein, CSO, [Co-founder]. Thanks. Yeah. I'm not pretending to make remarks about Alzheimer's disease, but I think what's important for the scientific community, especially for the neurology community, is that most of the data that actually came before Broadway were not really noticed. What's interesting is that in modern drug development, what you want is that the genetics are on your side, the genomics are on your side, and preclinical work is on your side before you basically embark on clinical studies. That has all been happening. Of course, the wider Alzheimer's neurology KOL community did not take notice of these findings because they occurred in part of science where they don't look that often. There is actually very good genetic data that people that have mutations in CETP are protected against Alzheimer's. There's very good Mendelian randomization evidence that it's also true for Lewy body dementia and the dementia in Parkinson's disease, especially if you're E4. Last, as was noted today also at AAIC, there's very robust preclinical data in mice that if you give them the human CETP gene, their cholesterol metabolism in their brain grows all wrong. If you then give a CETP inhibitor, you can actually restore cognition. We have basically met all the prerequisites to bring this into humans. Because we had a trial, we did bring it into humans. It's not like this is in isolation or something. I think it's important to realize that basically everything was done that you would normally also do for any other drug, but it wasn't simply noticed in this community. Right. Thank you. We will now take our next question from the line of Nick Jennings from Goldman Sachs. Please go ahead, Nick. Hi, all. Thanks for the presentation and taking the question. I'm wondering, do you anticipate this being an Alzheimer's-related label expansion for obicetrapib or a distinct product? As far as funding for the opportunity, do you feel that you have the adequate resources currently, or would you be seeking new sources of financing? Again, we're not looking at new sources of financing. It's too early to talk about the next steps until we meet with the FDA. I guess, you know, I think we want to be clear on that. Yes. We really are focused on the LDL benefits, well-established, but we see this as an important differentiator. We do want to advance the science. We haven't really made any decisions about spending. As I mentioned already, we don't expect any additional cost until PREVAIL is or very little additional cost until PREVAIL is completed. Thank you. We will now take our next question from the line of Dejit Choudhury from Guggenheim Securities. Please go ahead, Dejit. Hey. Good morning, and thanks for taking the question. Just out of curiosity, assuming PREVAIL reads out positively back end of 2026, do you think the PTL data could be added to the label? Number two, I know you have not discussed this with the FDA. I know this is evolving, but this is more for the esteemed panel here. If the panel has an opinion on how they would like to see obicetrapib develop in Alzheimer's, whether it's preventative or in the treatment landscape, what would the panel like to see from the development plan? Thank you. Yeah. That's an extensive question. I think we like to see a lot, but I think it's early days now. We have just seen these data, and we have to make up our minds what is the best next step to develop this compound. Prevention has been mentioned many, many times. That also takes a long time. How do we go in the middle way to see where this drug is best placed in the Alzheimer's spectrum? I do remind you that if you look at the baseline PTL value, actually, the effect of the obicetrapib was actually even higher in those who started with a higher level of PTL. Meaning that it's not only in the very early preventive stage but also in the more advanced stages. The jury is still out there. We have to make up our minds together what will be the next step. Given all the other properties of obicetrapib, this clearly needs and clearly deserves a place in the treatment armamentarium for Alzheimer's disease. As was mentioned by my colleague also, we will never be able to treat Alzheimer's disease with one single drug. There needs to be many, many approaches, and this fits really perfectly in there. Kellyann or Nate, do you want to have a comment about the type of study? I would add that, you know, to what Philip had said, yes, prevention, I think, is a very exciting venue. Even in individuals who have early cognitive change, it's going to be a multimodal approach to helping people, whether that is delaying or preventing future declines and symptoms. Having just one that removes amyloid directly is not going to be enough. We know this as a field. Having medications that can complement an approach that really can affect other disease processes besides Alzheimer's, such as cardiovascular disease and Lewy body changes, I think is going to be needed. I think medication like this is certainly going to be welcomed by, I would say, clinicians who are fearful of potential side effects or wanting more options, as well as patients who are looking for a holistic approach and not just one particular target. Yeah. We studied a multimodal approach to Alzheimer's prevention. I didn't mention that. I managed the first Alzheimer's prevention clinic in the country at Weill Cornell. We are in the business of studying this and understand just how difficult it is to design trials in this space, but not impossible. It's doable. You need, again, it's challenging in that this population is highly activated. They're going to be addressing lifestyle factors, which make it difficult to get a perfect, you know, randomized control, placebo control trial. As I mentioned when I was giving my couple-minute overview, this fits into the personalized approach to the disease. Not everyone is going to need to treat their elevated LDL-C, but a large majority of people are going to need to. Not everyone's going to have insulin resistance and metabolic derangements, but some people are going to need to. We really do have to look at multiple risk factors when we think about prevention. The answer isn't going to be one drug or one treatment. This disease is so, so complicated, and it's also very different from person to person. I think what I really want to emphasize here is that the APOE4 population is a unique one in that we understand a little bit more about how the disease progresses and presents and develops in this population, which makes them really prime candidates for a medication that can alter cholesterol metabolism and transport, hopefully, in the central nervous system. Great. I think we're already over time, but we have time for one more question. Unfortunately, we'll have to end the call. Feel free to reach out with any additional questions. Thank you. We will now take our last question from the line of Leonid Tymoshchenko from RBC. Please go ahead, Leonid. Hey. Yeah. Thanks for squeezing me in. I wanted to go back to just trying to compare and understand the magnitude of effect here. I appreciate that it's difficult to compare to the anti-amyloid therapies. Maybe two parts to the question. I guess the first is you showed about an 8% decrease in the HETs versus maybe more of a 20% decrease in the homozygotes. Are both of those figures meaningful, or should we really be seeing this as more of a therapy that would be tailored to the homozygous population? The second part of the question, I think the anti-amyloid antibodies showed maybe 30%- 40% decreases in PTL217. Most of that was driven by decrease rather than increases in the placebo arm. I guess for obicetrapib, it looks like placebo also worsens fairly meaningfully. How confident are you that the effect sizes you're seeing aren't just driven by the 10 placebo patients maybe accumulating PTL217 faster than expected? That's it. Thanks. Do you want to comment? Yeah. Those are excellent questions. I would start by saying this is its first study, and the numbers are what they are, and it's a smaller subset. It's hard to compare a medication that directly removes amyloid to something that has a different pathway. When you directly remove amyloid, you will have a larger effect on PTL just inherently versus a mechanism that is really approaching it from a different perspective. There was a slowing or attenuation even in those without APOE4. I do think that speaks to the importance of cholesterol and lipid metabolism when it comes to the pathogenesis of Alzheimer's disease. I don't think it's going to be one to one when it comes to anti-amyloid versus a different pathway that affects lipid metabolism. think that the fact that we don't see even larger effects of anti-amyloid medication speaks to the fact that we need to approach this from other venues as well. I do see this as one of those potential venues. Kellyann, I'll give you the last word. You can wrap up on that because that's that question. Yeah. I'll comment on your question as it relates to how we could be so confident that this change wasn't due to the placebo accumulating more PTL217 or progressing their Alzheimer's pathology a little more quickly. I think two things. One, here's where cognitive outcomes really do matter and how we can stratify who's truly prevention. Of course, it seems that most patients that were enrolled did not have clinical symptoms. Of course, they were enrolled in the study, so we're going on that idea that they were not cognitively impaired. That said, could there be subtle cognitive changes that maybe weren't so obvious or the patient didn't recognize? Sure, we do see that, which is why having that cognitive data is really, really helpful and an important next step in all of this. That said, from my experience, the changes in the placebo group in the APOE4 homozygotes do mirror what we see in that population. They tend to progress more quickly and earlier on. Okay. Thanks, everyone, for the questions and the interest. Like I said, we're very excited about what this data means. I I really appreciate our KOL colleagues providing the clinical context here. This is our first day to launch the data, and we look forward to continuing to dialogue with all of you about what the data means and what our next steps are for NewAmsterdam Pharma. Thank you very much for listening, and look forward to more interactions in the coming months. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Thank you.